EP2385942A1 - Dérivés de benzimidazole et pyrazolopyridine pour le traitement et/ou la prévention de maladies cardiovasculaires - Google Patents

Dérivés de benzimidazole et pyrazolopyridine pour le traitement et/ou la prévention de maladies cardiovasculaires

Info

Publication number
EP2385942A1
EP2385942A1 EP10701445A EP10701445A EP2385942A1 EP 2385942 A1 EP2385942 A1 EP 2385942A1 EP 10701445 A EP10701445 A EP 10701445A EP 10701445 A EP10701445 A EP 10701445A EP 2385942 A1 EP2385942 A1 EP 2385942A1
Authority
EP
European Patent Office
Prior art keywords
formula
group
compound
alkyl
hydrogen
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Withdrawn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
EP10701445A
Other languages
German (de)
English (en)
Inventor
Alexander Straub
Frank SÜSSMEIER
Frank Wunder
Johannes-Peter Stasch
Volkhart Min-Jian Li
Joachim Mittendorf
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 Intellectual Property GmbH
Original Assignee
Bayer Pharma AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Pharma AG filed Critical Bayer Pharma AG
Publication of EP2385942A1 publication Critical patent/EP2385942A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present application relates to novel fused, heteroatom-bridged pyrazole and imidazole derivatives, processes for their preparation, their use alone or in combinations for the treatment and / or prevention of diseases and their use for the preparation of medicaments for the treatment and / or Disease prevention, in particular for the treatment and / or prevention 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 that is part of the regulatory center. This is central to the activation mechanism. NO can bind to the iron atom of the heme and thus significantly increase the activity of the enzyme. On the other hand, heme-free preparations can not be stimulated by NO. 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.
  • soluble guanylate cyclase only compounds such as organic nitrates have been used, whose action is based on NO. This is formed by bioconversion and activates the soluble guanylate cyclase by attack on the central iron atom of the heme.
  • the development of tolerance is one of the decisive disadvantages of this type of treatment.
  • Anellated pyrazole derivatives are described inter alia in WO 98/23619, WO 00/06568, WO 00/06569, WO 02/42299, WO 02/42300, WO 02/42301, WO 02/42302, WO 02/092596, WO 03 / 004503, WO 03/095451 and WO 2008/031513 as stimulators of soluble guanylate cyclase.
  • some of these compounds are sensitive to their physicochemical properties, such as their solubility, or to their in vivo properties, such as their behavior in the liver, their pharmacokinetic behavior, their dose-response relationship and / or their properties Metabolization path, have disadvantages.
  • WO 03/076408 describes indazole derivatives for the treatment of cardiovascular diseases and disorders of the central nervous system.
  • WO 03/035005 discloses heteroindanes as cannabinoid mimetics for the treatment of pain and neurodegenerative diseases.
  • 3-Aminoindazoles are claimed in WO 2007/075847 for the treatment of metabolic diseases.
  • the present invention relates to compounds of the general formula (I)
  • R 1 is hydrogen or (C 1 -C 4 ) -alkyl
  • L is (C 5 -C 7 ) -cycloalkyl, phenyl, pyridyl, pyrimidinyl, furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl or isoxazolyl,
  • (C 5 -C 7 ) -cycloalkyl can be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine and (C 1 -C 4 ) -alkyl,
  • M is a bicyclic heteroaryl group of the formula
  • T, U, V and W are each CR 2 or N,
  • R 2 is hydrogen, halogen, cyano, (C 1 -C 4 ) -alkyl, trifluoromethyl, amino, (C 1 -C 4 ) -alkoxy and trifluoromethoxy,
  • Q is an unsaturated 5- or 6-membered heterocycle or a 5- or 6-membered heteroaryl
  • n is a number 0 or 1
  • p is a number 0, 1 or 2
  • R 3, R 4 and R 5 are each independently hydrogen, (Ci-C 6) -alkyl, (C 2 -C 6) alkenyl, (C 3 -C 8) -cycloalkyl, (C 3 -C 8) Cycloalkenyl, (C 6 -C 10) -aryl, 4- to 8-membered heterocyclyl or 5- to 10-membered heteroaryl,
  • R 3 , R 4 and R 5 in turn, having 1 to 5 substituents independently selected from the group halogen, azido, nitro, cyano, trifluoromethyl, (C, -C 6 ) alkyl, (C 1 -C 6 ) alkylcarbonyl , (C 1 -C 6 ) -alkylcarbonyloxy, hydroxycarbonyl,
  • R 3 and R 4 together with the radical to which they are both bonded, form a 4- to 8-membered heterocycle
  • R 3 and R 5 together with the radical to which they are both bonded, form a 4- to 8-membered heterocycle
  • N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of 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.
  • Compounds of the invention are also N-oxides of the compounds of the formula (I) and their salts, solvates and solvates of the salts.
  • the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the present invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
  • the present invention encompasses all tautomeric forms.
  • 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 salts of chlorinated water.
  • acid hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • Physiologically acceptable salts of the compounds according to the invention also include salts of 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 from 1 to 16 carbon atoms, for example and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, trisethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methyl-mo ⁇ holin, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • alkali metal salts for example sodium and potassium salts
  • alkaline earth salts for example calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines having from
  • 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 present invention also includes prodrugs of the compounds of the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but are converted during their residence time in the body into compounds according to 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 in the context of the invention is a monocyclic, saturated alkyl radical having 3 to 8 carbon atoms. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • 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 straight-chain or branched alkenyl radical having 2 to 4 carbon atoms and one 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.
  • Cycloalkenyl is in the context of the invention a monocyclic carbocycle having 3 to 8 carbon atoms and a double bond. Examples which may be mentioned by way of example include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
  • Alkynyl in the context of the invention represents a linear or branched alkynyl radical having 2 to 4 carbon atoms and a triple bond.
  • alkynyl in the context of the invention represents a linear or branched alkynyl radical having 2 to 4 carbon atoms and a triple bond.
  • ethynyl n-prop-1-yn-1-yl, n-prop-2-yn-1-yl, n-but-2-yn-1-yl and n-but-3-one in-l-yl.
  • Alkylcarbonyl in the context of the invention is a linear or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms in the alkyl chain and a carbonyl group attached in position 1.
  • Alkylcarbonyloxy in the context of the invention represents a linear or branched alkylcarbonyl radical which is bonded via a sueraratomide and carries 1 to 6 or 1 to 4 carbon atoms in the alkyl chain.
  • alkylcarbonyloxy in the context of the invention represents a linear or branched alkylcarbonyl radical which is bonded via a sueraratomide and carries 1 to 6 or 1 to 4 carbon atoms in the alkyl chain.
  • 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.
  • Alkylthio in the context of the invention is a linear or branched alkylthio radical having 1 to 6 or 1 to 4 carbon atoms. Examples which may be mentioned are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, n-pentylthio and n-hexylthio.
  • Alkoxycarbonyl in the context of the invention are a linear or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms and an oxygen-bonded carbonyl group.
  • Preferred is a linear or branched alkoxycarbonyl radical having 1 to 4 carbon atoms in the alkoxy group.
  • Mono-alkylamino in the context of the invention represents an amino group having a linear or branched alkyl substituent which has 1 to 6 carbon atoms. Exemplary and Preferred 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 6 carbon atoms. Examples which may be mentioned are: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N-tert-butyl-N-methylamino, N Ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.
  • Mono-alkylaminocarbonyl in the context of the invention represents an amino group which is linked via a carbonyl group and which has a linear or branched alkyl substituent having 1 to 6 or 1 to 4 carbon atoms.
  • Preferred is a mono-alkylaminocarbonyl radical having 1 to 4 carbon atoms in the alkyl group.
  • Di-alkylaminocarbonyl in the context of the invention represents an amino group which is linked via a carbonyl group and which has two identical or different linear or branched alkyl substituents each having 1 to 6 or 1 to 4 carbon atoms. Preference is given to a dialkylaminocarbonyl radical having in each case 1 to 4 carbon atoms per alkyl group.
  • N N-dimethylaminocarbonyl
  • N N-diethylaminocarbonyl
  • N-ethyl-N-methylaminocarbonyl N-methyl-NH-propylaminocarbonyl
  • Nn-butyl-N-methylaminocarbonyl N-tert-butyl -N-methylaminocarbonyl
  • Alkylcarbonylamino in the context of the invention represents an amino group having a linear or branched alkylcarbonyl substituent which has 1 to 6 or 1 to 4 carbon atoms in the alkyl chain and is linked to the ⁇ -atom via the carbonyl group.
  • alkylcarbonylamino in the context of the invention represents an amino group having a linear or branched alkylcarbonyl substituent which has 1 to 6 or 1 to 4 carbon atoms in the alkyl chain and is linked to the ⁇ -atom via the carbonyl group.
  • Alkoxycarbonylamino in the context of the invention represents an amino group having a linear or branched alkoxycarbonyl substituent which has 1 to 6 or 1 to 4 carbon atoms in the alkyl chain and is linked via the carbonyl group to the ⁇ -atom.
  • alkoxycarbonylamino in the context of the invention represents an amino group having a linear or branched alkoxycarbonyl substituent which has 1 to 6 or 1 to 4 carbon atoms in the alkyl chain and is linked via the carbonyl group to the ⁇ -atom.
  • methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, n-butoxycarbonylamino, isobutoxycarbonylamino and tert methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, n-butoxycarbonylamino, isobutoxycarbonylamino and tert.
  • Aryl in the context of the invention is an aromatic carbocycle having 6 or 10 ring carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • 5- to 10-membered heteroaryl is in the context of the invention for a mono- or optionally bicyclic aromatic heterocycle (heteroaromatic) having a total of 5 to 10 ring atoms, up to three identical or different ring heteroatoms from the series N, O and contains S and is linked via a ring carbon atom or optionally via a ring nitrogen atom.
  • aromatic heterocycle heteromatic
  • Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxa zolyl, benzothiazolyl, benzotriazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [3,4-b] pyridinyl.
  • a 4- to 8-membered heterocycle is in the context of the invention for a monocyclic, saturated heterocycle having a total of 4 to 8 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.
  • An unsaturated 5- or 6-membered heterocycle is in the context of the invention for a monocyclic heterocycle having a total of 5 or 6 ring atoms, which contains up to four ring heteroatoms from the series N, O and / or S, via a ring carbon atom or optionally a ring nitrogen atom is linked and in the case of the five-membered ring contains a double bond and in the case of the six-membered ring contains one or two double bonds.
  • Examples include: pyrrolinyl, dihydropyrazolyl, imidazolinyl, dihydrooxazolyl, dihydroisoxazolyl, dihydro-l, 2,4-triazolyl, dihydro-l, 2,4-oxadiazolyl, dihydro-l, 3,4-oxadiazolyl, dihydro-1,2, 4-thiadiazolyl, dihydropyranyl, 1,4-dihydropyridyl, tetrahydropyrimidinyl, 1,3-oxazinyl.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.
  • An oxo group in the context of the invention is an oxygen atom which is bonded via a double bond to a carbon atom.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred.
  • A is O, S or NR 1 ,
  • R 1 is hydrogen
  • L is phenyl, thienyl, pyridyl or pyrimidinyl
  • phenyl, thienyl, pyridyl and pyrimidinyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl and trifluoromethyl,
  • M is a bicyclic heteroaryl group of the formula
  • T 1 , U 1 , V 1 and W 1 are each CR 2A or N, wherein a maximum of two of the ring members T 1 , U 1 , V 1 and W 1 are simultaneously N,
  • R 2A is hydrogen or fluorine
  • T 2 , U 2 , V 2 and W 2 are each CR 2B or N,
  • R 2B is hydrogen or fluorine
  • D is CH or N
  • J is CR 8 , N or N + -O " ,
  • n is a number O or 1
  • R 3 , R 4 and R 5 are each independently hydrogen, (Ci-C 6 ) -
  • R 3 , R 4 and R 5 in which R 3 , R 4 and R 5 in turn have 1 to 3 substituents independently of one another selected from the group of fluorine, Chlorine, cyano, (C 1 -C 4 ) -alkyl, trifluoromethyl, hydroxy, (C 1 -C 4 ) -alkoxy, trifluoromethoxy, oxo, amino, mono- (C 1 -C 4 ) -alkylamino and di- (C 1 -C 4 ) alkylamino may be substituted,
  • R 3 and R 4 together with the radical to which they are both bonded, can form a 5- to 7-membered heterocycle
  • R 3 and R 5 together with the radical to which they are both bonded, can form a 5- to 7-membered heterocycle
  • R 9 represents hydrogen, (C r C6) alkyl or (C 3 -C 7) cycloalkyl,
  • N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • A is S or NR 1 ,
  • R 1 is hydrogen
  • L is phenyl, pyridyl or pyrimidinyl
  • phenyl may be substituted by 1 or 2 substituents fluorine
  • M is a bicyclic heteroaryl group of the formula
  • U 1 is CH
  • W 1 stands for CH
  • V 1 stands for CR 2A
  • R is hydrogen or fluorine
  • n the number 0 or 1
  • R 3 is hydrogen or (C 1 -C 4 ) -alkyl
  • Methoxy can be substituted
  • R 4 is hydrogen, (C 1 -C 4 ) -alkyl or (C 3 -C 7 ) -cycloalkyl,
  • (C 1 -C 4 ) -alkyl in turn may be substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl, hydroxy and methoxy,
  • R 5 is hydrogen or (C r C 4) alkyl
  • R 3 and R 4 together with the radical to which they are both bonded, can form a 5- to 7-membered heterocycle
  • R 6 is hydrogen or amino
  • R 7 is hydrogen or amino
  • N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • J is CR 8 or ⁇ , wherein
  • R 3 is hydrogen or (C r C 4) alkyl
  • R 4 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 6 is hydrogen or amino
  • R 7 is hydrogen or amino
  • L is phenyl
  • phenyl may be substituted with a substituent fluorine.
  • M is a bicyclic heteroaryl group of the formula
  • T 1 is CH or N
  • U 1 is CH
  • W 1 stands for CH
  • V 1 stands for CR 2A
  • R 2A is hydrogen or fluorine.
  • M is a bicyclic heteroaryl group of the formula
  • T 2 is CH or N
  • U 2 is CH
  • W 2 is CH
  • V 2 is CR 2B or N
  • R 2B is hydrogen or fluorine.
  • X 1 represents a suitable leaving group such as, for example, halogen, mesylate, tosylate or triflate,
  • X 2 is halogen, in particular bromine
  • R 10 is (C r C4) alkyl
  • the resulting compounds of the formulas (IA), (IB) and (IC) according to conventional literature further modified in the scope of the individual substituents and radicals given above and / or the resulting compounds of the invention optionally with the appropriate (i) solvents and / or (ii) converting acids or bases into their solvates, salts and / or solvates of the salts.
  • Inert solvents for process steps (H) + (ET) ⁇ (IA) and (VI) + (TS) ⁇ (IB) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol Ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents, such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU).
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol Et
  • Suitable bases for process steps (II) + (ST) ⁇ (IA) and (VI) + (TS) ⁇ (IB) are customary inorganic bases. These include in particular alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali hydrogen carbonates such as sodium or potassium bicarbonate, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, or alkali hydrogen phosphates such as disodium or dipotassium hydrogencarbonate. phosphate. Cesium carbonate is preferably used.
  • palladium catalyst for the process steps (II) + (IH) ⁇ (IA) and (VI) + (IH) ⁇ (IB) are, for example, palladium on activated carbon, palladium (II) acetate, tetrakis (triphenylphosphine) - palladium (O), bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) palladium (II) chloride and [1,1 'bis (diphenylphosphino) ferrocene] dichloroalladium (II) dichloromethane complex , optionally in combination with additional phosphine ligands such as (2-biphenyl) di-tert.
  • additional phosphine ligands such as (2-biphenyl) di-tert.
  • -butylphosphine dicyclohexyl [2 ', 4', 6'-tris (1-methylethyl) biphenyl-2-yl] phosphine (XPHOS), bis (2-phenylphosphinophenyl) ether (DPEphos) or 4,5-bis (diphenylphosphino) 9,9-dimethyl-xanthene (xantphos) [cf. eg Hassan J. et al., Chem. Rev. 102, 1359-1469 (2002)].
  • the reactions (H) + (IE) ⁇ (IA) and (VI) + (IE) ⁇ (IB) are generally in a temperature range from +20 0 C to +180 0 C, preferably at +50 0 C to + 120 0 C, optionally in a microwave performed.
  • the reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
  • Inert solvents for process step (VQ) + (VIII) -> (IC) are, for example, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers, such as diethyl ether, dioxane, tetrahydrofuran, Glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethyl propyleneurea (DMPU), N-methylpyrrolidone (.PHI.) , Pyridine, acetonitrile or water. It is likewise possible to use mixtures of the solvents mentioned. Preferred is dimethylformamide.
  • DMF
  • Suitable bases for this reaction are the customary inorganic or organic bases. These include preferably alkali metal hydrides such as sodium hydride, alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali metal bicarbonates such as sodium or potassium bicarbonate, alkali metal alcoholates such as sodium or potassium, sodium or Potassium ethoxide or potassium tert-butoxide, amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, organometallic compounds such as butyl lithium or phenyllithium, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1.8 - diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 5-diazabicyclo [4.3.0] non-5-ene (DBN).
  • the reaction (VII) + (VIII) -> (IC) are generally in a temperature range from +20 0 C to +180 0 C, preferably at +50 0 C to +120 0 C, optionally in a microwave, carried out.
  • the reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
  • the compounds of the formula (IH) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature.
  • compounds of the formula (I-B) or (I-C) can also be prepared analogously to 2 ⁇ 1 to the processes specified in WO 03/095451 and WO 2008/031513.
  • a compound of the formula (II) in which A is S can be prepared by reacting a compound of the formula (IX)
  • T 1 , U 1 , V 1 and W 1 each have the meanings given above
  • X 3 is halogen, in particular bromine or iodine
  • a compound of the formula (E) in which A is NH may be prepared by reacting a compound of the formula (XU)
  • T 1 , U 1 , V 1 and W 1 each have the meanings given above
  • R 12 is (C r C4) alkyl
  • R 13 is hydrogen or both radicals R 13 together form a -C (CH 3 ) 2 -C (CH 3 ) 2 - or -CH 2 -C (CHj) 2 -CH 2 -BrUcICe form,
  • [PMB p-methoxybenzyl a) NaOH, DMSO; b) NaH, DMF; c) SnCl 2 , ethanol; d) tert-butyl nitrite, HCl (aq.); e) TFA; f) Pd 2 dba 2 , XPHOS, Cs 2 CO 3 , toluene / DMF].
  • R 9 has the abovementioned meaning can be prepared analogously to the processes described in WO 2008/031513.
  • 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, EDRF (endothelium-derived relaxing factor), NO donors, protoporphyrin DC, arachidonic acid or phenylhydrazine derivatives.
  • the compounds according to the invention can therefore be used in medicaments for the treatment of cardiovascular diseases, for example for the treatment of hypertension and cardiac insufficiency, stable and unstable angina pectoris, pulmonary hypertension, peripheral and cardiovascular diseases, arrhythmias, for the treatment of thromboembolic disorders and ischaemias such as myocardial infarction, stroke, Transitory and ischemic attacks, peripheral circulatory disorders, reperfusion damage, for the prevention of restenosis such as after thrombolytic therapy, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasty (PTCA) and bypass, as well as for the treatment of arteriosclerosis, asthmatic diseases, erectile Dysfunction, female sexual dysfunction, are used by osteoporosis, glaucoma and gastroparesis.
  • cardiovascular diseases for example for the treatment of hypertension and cardiac insufficiency, stable and unstable angina pectoris, pulmonary hypertension, peripheral and cardiovascular diseases, arrhythmias, for the treatment of
  • the compounds of the invention may be used to treat 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 the like used to promote wound healing.
  • the compounds according to the invention are suitable for the treatment of urological diseases such as, for example, benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic hyperplasia (BPE), bladder emptying disorder (BOO), lower urinary tract syndromes (LUTS), diseases of the urogenital Systems including neurogenic overactive bladder (OAB) and (IC), incontinence (UI) such as mixed, urgency, stress, or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, benign and malignant organs of the male and female urogenital system, kidney diseases such as acute or chronic renal failure, immunological kidney diseases such as kidney transplant rejection, glomerulonephritis, immune complex-induced kidney disease, glomerulopathies, nephritis, toxic nephropathy and obstructive uropathies.
  • BPS benign prostatic syndrome
  • BPH benign prostatic hyperplasia
  • BPE benign prostatic hyperplasia
  • BOO bladder emptying disorder
  • the compounds according to the invention are suitable for the treatment of acute and chronic lung diseases, such as the respiratory distress syndromes (ALI, ARDS) and chronic obstructive pulmonary diseases (COPD), as well as for the treatment of acute and chronic renal insufficiency.
  • acute and chronic lung diseases such as the respiratory distress syndromes (ALI, ARDS) and chronic obstructive pulmonary diseases (COPD)
  • COPD chronic obstructive pulmonary diseases
  • 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, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, Sc hizophrenia with dementia or Korsakoff's psychosis. They are also suitable for the treatment
  • the compounds according to the invention are also suitable for the regulation of the cerebral
  • the compounds of the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • the present invention furthermore relates to the compounds according to the invention for use in a method for the treatment and / or prevention of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, thromboembolic disorders and arteriosclerosis.
  • 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 prevention of Erkran- kungen, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of 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 prevention 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, nitroglycerine, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-I, as well as inhalatives
  • cGMP cyclic guanosine monophosphate
  • PDE phosphodiesterases
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;
  • Antihypertensive agents by way of example and preferably from the group of calcium antagonists, angiotensin Aü antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid Receptor antagonists and diuretics; and or
  • Lipid metabolism-altering agents by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-Co A reductase or squalene synthesis inhibitors, the ACAT inhibitors,
  • CETP inhibitors MTP inhibitors, PPAR 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.
  • 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 GPUb / IIIa antagonist, such as by way of example and preferably Tirof ⁇ ban 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. 3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin Aü 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 by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.
  • the compounds according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, carazalol, Sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, Carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucine dolol administered.
  • a beta-receptor blocker such as by way of example and preferably propranolol, atenolol, timolol
  • the compounds according to the invention are administered in combination with an angiotensin Aü antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • an angiotensin Aü antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • the compounds according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.
  • a mineralocorticoid receptor antagonist such as by way of example and preferably spironolactone or eplerenone.
  • the compounds according to the invention are administered in combination with a diuretic, such as by way of example and preferably furosemide.
  • 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, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-I).
  • a CETP inhibitor such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-I).
  • 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, for 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.
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
  • a lipase inhibitor such as, for example and preferably, orlistat.
  • the compounds 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.
  • ASBT DBAT
  • the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, such as by way of example and preferably gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as by way of example and preferably gemcabene calcium (CI-1027) or nicotinic acid.
  • compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally.
  • they 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 inventive compounds 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 ophthalmic 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.
  • 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, polyoxysorbitol oleate), 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 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
  • UV ultraviolet spectrometry v / v volume to volume ratio (of a solution) XPHOS dicyclohexyl- (2 ', 4', 6'-triisopropylbiphenyl-2-yl) -phosphine LC / MS and HPLC methods:
  • Device type MS Micromass ZQ
  • Device type HPLC Waters Alliance 2795; Column: Phenomenex syn ergi 2.5 ⁇ MAX-RP 100A Mercury 20mm x 4mm; 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 ⁇ 3.0 min 5% A ⁇ 4.0 min 5% A ⁇ 4.01 min 90% A; Flow: 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
  • Device type MS Micromass ZQ
  • Device type HPLC HP 1100 Series
  • UV DAD Column: Phenomenex Gemini 3 ⁇ 30 mm x 3.00 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
  • Flow 0.0 min 1 ml / min - »2.5 min / 3.0 min / 4.5 min 2 ml / min
  • Oven 50 ° C .
  • UV detection 210 nm.
  • the precipitated solid was filtered off, washed with 5 ml of propanol and purified in DMF by preparative HPLC (Cromatorex C18 10 ⁇ m, 250 ⁇ 30 mm, flow 50 ml / min, run time: 38 min, acetonitrile / water gradient + 0.1% formic acid). After evaporation of the product-containing fractions, 76 mg (40% of theory) of the target compound were obtained.
  • Trifluorethyltrichlormethansulfonat and stirred at 20 0 C for 20 hours.
  • Trifluorethyltrichlormethansulfonat added and stirred at 20 0 C for 2 days. After addition of 0.1 ml of water, by preparative HPLC (Cromatorex Cl 8 lO ⁇ m, 250x30 mm, flow 50 ml / min, running time: 38 min, acetonitrile / water gradient + 0.1% formic acid). This gave 20 mg (17% of theory) of the target compound.
  • 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-fumed Krebs-Henseleit solution of the following composition (in each case mM): NaCl: 119; KCl: 4.8; CaCl 2 ⁇ 2 H 2 O: 1; MgSO 4 ⁇ 7H 2 O: 1.4; KH 2 PO 4 : 1.2; NaHCO3: 25; Glucose: 10.
  • composition in each case mM: NaCl: 119; KCl: 4.8; CaCl 2 ⁇ 2 H 2 O: 1; MgSO 4 ⁇ 7H 2 O: 1.4; KH 2 PO 4 : 1.2; NaHCO3: 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. This is used to calculate the concentration required to reduce the level of the control value by 50% (IC 50 -wt).
  • the standard application volume is 5 ⁇ l, the DMSO content in the bath solution corresponds to 0.1%.
  • the cellular activity of the compounds of the invention is measured on a recombinant guanylate cyclase reporter cell line as described in F. Wunder et al., Anal. Biochem. 339, 104-112 (2005).
  • a commercially available telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA is used for the blood pressure measurement on awake rats described below.
  • the system consists of 3 main components:
  • Implantable transmitters Physiotel® telemetry transmitters
  • Data acquisition computer are connected.
  • the telemetry system allows a continuous recording of blood pressure heart rate and body movement on awake animals in their habitual habitat.
  • the day - night rhythm in the experimental laboratory is changed by room lighting at 6:00 in the morning and at 19:00 in the evening.
  • the TAH PA - C40 telemetry transmitters are surgically implanted into the experimental animals under aseptic conditions at least 14 days before the first trial.
  • the animals so instrumented are repeatedly used after healing of the wound and ingrowth of the implant.
  • the fasting animals are anesthetized with pentobabital (Nembutal, Sanofi: 50 mg / kg i.p.) and shaved and disinfected on the ventral side.
  • pentobabital Nembutal, Sanofi: 50 mg / kg i.p.
  • 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.)
  • a solvent-treated group of animals is used as a control.
  • 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.
  • 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-I) and stored in individual data. Further technical details can be found in the extensive documentation of the manufacturer (DSI).
  • test substances will take place at 9 o'clock on the day of the experiment. Following the application, the parameters described above are measured for 24 hours.
  • the collected individual data are sorted with the analysis software (DATAQUEST TM A.RT. TM ANALYSIS).
  • the blank value is assumed here 2 hours before application, so that the selected data record covers the period from 7:00 am on the day of the experiment to 9:00 am on the following day.
  • the data is smoothed over a presettable time by averaging (15 minutes average) and transferred as a text file to a disk.
  • the presorted and compressed measured values are transferred to Excel templates and displayed in tabular form.
  • the filing of the collected data takes place per day of the experiment in a separate folder containing the Test number carries. Results and test reports are sorted in folders and sorted by paper.
  • the substance to be examined is administered to animals (eg mouse, rat, dog) intravenously as a solution, the oral administration is carried out as a solution or suspension via a gavage. After substance administration, the animals are bled at fixed times. This is heparinized and then plasma is recovered therefrom by centrifugation. The substance is analytically quantified in the plasma via LC / MS-MS.
  • the pharmacokinetic parameters such as AUC, C 013x , T 1Z2 (half-life) and CL (clearance) are calculated from the plasma concentration-time curves thus determined by means of a validated pharmacokinetic calculation program.
  • PBS buffer pH 7.4 90.00 g NaCl pa (for example from Merck, Item No. 1.06404.1000), 13.61 g KH 2 PO 4 pa (for example from Merck, Item No. 1.04873.1000) and Weigh 83.35 g of 1 N NaOH (eg Bernd Kraft GmbH, article No. 01030.4000) into a 1 liter volumetric flask, make up with water and stir for about 1 hour;
  • Acetate buffer pH 4.6 Weigh out 5.4 g of sodium acetate x 3 H 2 O pa (eg from Merck, Item No. 1.06267.0500) into a 100 ml volumetric flask, dissolve in 50 ml of water, add 2.4 g of glacial acetic acid Make up to 100 ml with water, check the pH and if necessary adjust to pH 4.6;
  • Dimethylsulfoxide e.g., Baker Co., Art No. 71572500
  • Preparation of the starting solution for calibration solutions (stock solution): Approximately 0.5 mg of the test substance is accurately weighed into a 2 ml Eppendorf Safe-Lock tube (Eppendorf, Item No. 0030 120,094), to a concentration of 600 ⁇ g / ml mixed with DMSO (eg 0.5 mg of substance + 833 ⁇ l of DMSO) and shaken to complete dissolution by means of a vortexer.
  • Calibration solution 1 (20 ⁇ g / ml): Mix 34.4 ⁇ l of the stock solution with 1000 ⁇ l of DMSO and homogenize.
  • Calibration solution 2 (2.5 ⁇ g / ml): 100 ⁇ l of the calibration solution 1 are mixed with 700 ⁇ l of DMSO and homogenized.
  • Sample solution for solubility up to 10 g / l in PBS buffer pH 7.4 Approximately 5 mg of the test substance are weighed exactly into a 2 ml Eppendorf Safe-Lock tube (Eppendorf, Item No. 0030 120,094) and added to a Concentration of 5 g / l with PBS buffer pH 7.4 added (eg, 5 mg of substance + 500 ul PBS buffer pH 7.4).
  • Sample solution for solubility up to 10 g / l in acetate buffer pH 4.6 Approximately 5 mg of the test substance are weighed exactly into a 2 ml Eppendorf-Safe-Lock tube (Eppendorf, Art No. 0030 120,094) and added to a concentration of 5 g / l with acetate buffer pH 4.6 added (eg 5 mg of substance + 500 ul acetate buffer pH 4.6).
  • Sample solution for solubility up to 10 g / l in water Approximately 5 mg of the test substance are weighed exactly into a 2 ml Eppendorf-Safe-Lock tube (Eppendorf, Art No. 0030 120,094) and added to a concentration of 5 g / l mixed with water (eg 5 mg substance + 500 ul water).
  • sample solutions thus prepared are shaken for 24 hours at 1400 rpm in a temperature shaker (for example, Fa. Eppendorf Thermomixer comfort No. 5355 000.011 with alternating block No. 5362.000.019) at 20 0 C. 180 ⁇ l of each of these solutions are taken off and transferred to Beckman Polyallomer Centrifuge Tubes (Item No. 343621). These solutions are centrifuged for 1 hour at about 223,000 xg (eg Beckman Optima L-90K Ultracentrifuge with Type 42.2 Ti rotor at 42,000 rpm).
  • a temperature shaker for example, Fa. Eppendorf Thermomixer comfort No. 5355 000.011 with alternating block No. 5362.000.01
  • 180 ⁇ l of each of these solutions are taken off and transferred to Beckman Polyallomer Centrifuge Tubes (Item No. 343621). These solutions are centrifuged for 1 hour at about 223,000 xg (eg Beckman Optima L
  • the samples are analyzed by RP-HPLC. Quantification is achieved by a two-point calibration curve of the test compound in DMSO. The solubility is expressed in mg / l. Analysis sequence: 1) Calibration solution 2.5 mg / ml; 2) Calibration solution 20 ⁇ g / ml; 3) Sample solution 1: 5; 4) Sample solution 1: 100; 5) Sample solution 1: 1000.
  • Agilent 1100 with DAD (Gl 315A), quat. Pump (G1311A), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); Column: Phenomenex Gemini C18, 50 mm x 2 mm, 5 ⁇ ; Temperature: 40 ° C .; Eluent A: water / phosphoric acid pH 2; Eluent B: acetonitrile; Flow rate: 0.7 ml / min; Gradient: 0-0.5 min 85% A, 15% B; Ramp: 0.5-3 min 10% A, 90% B; 3-3.5 min 10% A, 90% B; Ramp: 3.5-4 min 85% A, 15% B; 4-5 minutes 85% A, 15% B.
  • Agilent 1100 with DAD (G1315A), quat. Pump (G1311A), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); Column: VDSoptilab Kromasil 100 C18, 60 mm x 2.1 mm, 3.5 ⁇ ; Temperature: 30 ° C .; Eluent A: water + 5 ml perchloric acid / l; Eluent B: acetonitrile; Flow rate: 0.75 ml / min; Gradient: 0-0.5 min 98% A, 2% B; Ramp: 0.5-4.5 min 10% A, 90% B; 4.5-6 min 10% A, 90% B; Ramp: 6.5-6.7 min 98% A, 2% B; 6.7-7.5 min 98% A, 2% B.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • the mixture of the compound according to 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.
  • a single dose of 100 mg of the compound according to the invention corresponds to 20 g of oral solution.
  • 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.
  • the compound of the invention is dissolved in 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 solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

Landscapes

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

Abstract

La présente invention porte sur de nouveaux dérivés de benzimidazole et pyrazolopyridine, sur un procédé permettant de les fabriquer, sur leur utilisation individuellement ou dans des combinaisons pour le traitement et/ou la prévention de maladie ainsi que sur leur utilisation pour la fabrication de médicaments pour le traitement et/ou la prévention de maladies, en particulier pour le traitement et/ou la prévention de maladies cardiovasculaires.
EP10701445A 2009-01-09 2010-01-05 Dérivés de benzimidazole et pyrazolopyridine pour le traitement et/ou la prévention de maladies cardiovasculaires Withdrawn EP2385942A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102009004245A DE102009004245A1 (de) 2009-01-09 2009-01-09 Neue anellierte, Heteroatom-verbrückte Pyrazol- und Imidazol-Derivate und ihre Verwendung
PCT/EP2010/000011 WO2010079120A1 (fr) 2009-01-09 2010-01-05 Dérivés de benzimidazole et pyrazolopyridine pour le traitement et/ou la prévention de maladies cardiovasculaires

Publications (1)

Publication Number Publication Date
EP2385942A1 true EP2385942A1 (fr) 2011-11-16

Family

ID=41809296

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10701445A Withdrawn EP2385942A1 (fr) 2009-01-09 2010-01-05 Dérivés de benzimidazole et pyrazolopyridine pour le traitement et/ou la prévention de maladies cardiovasculaires

Country Status (5)

Country Link
US (2) US20120029002A1 (fr)
EP (1) EP2385942A1 (fr)
CA (1) CA2749048A1 (fr)
DE (1) DE102009004245A1 (fr)
WO (1) WO2010079120A1 (fr)

Families Citing this family (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2009322836B2 (en) * 2008-11-25 2013-04-04 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
DE102008063992A1 (de) 2008-12-19 2010-09-02 Lerner, Zinoviy, Dipl.-Ing. Neue aliphatisch substituierte Pyrazolopyridine und ihre Verwendung
ES2524826T3 (es) * 2009-11-27 2014-12-12 Bayer Intellectual Property Gmbh Procedimiento para la purificación de {4,6-diamino-2-[1-(2-fluorobencil)-1H-pirazolo[3,4-b]piridin-3-il]pirimidin-5-il}metilcarbamato de metilo
UY33041A (es) * 2009-11-27 2011-06-30 Bayer Schering Pharma Aktienegesellschaft Procedimiento para la preparaciòn de {4,6-diamino-2-[1-(2-fluorobencil)-1h-pirazolo[3,4-b]piridin-3-il]pirimidin-5-il}carbamato de metilo y su purificaciòn para el uso como principio activo farmacèutico
WO2011119518A1 (fr) 2010-03-25 2011-09-29 Merck Sharp & Dohme Corp. Activateurs de guanylate cyclase solubles
DE102010021637A1 (de) 2010-05-26 2011-12-01 Bayer Schering Pharma Aktiengesellschaft Substituierte 5-Fluor-1H-Pyrazolopyridine und ihre Verwendung
WO2012058132A1 (fr) 2010-10-28 2012-05-03 Merck Sharp & Dohme Corp. Activateurs de la guanylate cyclase soluble
DE102010043380A1 (de) 2010-11-04 2012-05-10 Bayer Schering Pharma Aktiengesellschaft Benzyl-substituierte Carbamate und ihre Verwendung
DE102010043379A1 (de) 2010-11-04 2012-05-10 Bayer Schering Pharma Aktiengesellschaft Substituierte 6-Fluor-1H-Pyrazolo[4,3-b]pyridine und ihre Verwendung
EP2489663A1 (fr) * 2011-02-16 2012-08-22 Almirall, S.A. Composés en tant qu'inhibiteurs de la syk kinase
DE102011075398A1 (de) * 2011-05-06 2012-11-08 Bayer Pharma Aktiengesellschaft Substituierte Imidazopyridazine und ihre Verwendung
EP2716642B1 (fr) 2011-05-30 2016-07-20 Astellas Pharma Inc. Composé imidazopyridine
DK2782914T3 (en) 2011-11-25 2018-11-26 Adverio Pharma Gmbh PROCEDURE FOR PREPARING SUBSTITUTED 5-FLUOR-1H-PYRAZOLOPYRIDINES
DE102012200349A1 (de) 2012-01-11 2013-07-11 Bayer Intellectual Property Gmbh Substituierte annellierte Pyrimidine und Triazine und ihre Verwendung
DE102012200360A1 (de) 2012-01-11 2013-07-11 Bayer Intellectual Property Gmbh Substituierte Triazine und ihre Verwendung
ES2644781T3 (es) 2012-03-06 2017-11-30 Bayer Intellectual Property Gmbh Azabiciclos sustituidos y su uso
NZ746490A (en) 2012-10-02 2018-12-21 Bayer Cropscience Ag Heterocyclic compounds as pesticides
TW201439090A (zh) 2012-11-30 2014-10-16 Astellas Pharma Inc 咪唑並吡啶化合物
AU2014220801A1 (en) 2013-02-21 2015-09-10 Adverio Pharma Gmbh Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate
EP3004094B1 (fr) * 2013-06-04 2017-03-01 Bayer Pharma Aktiengesellschaft Imidazo[1,2-a]pyridines à substitution 3-aryle et leur utilisation
PE20160201A1 (es) 2013-07-10 2016-05-06 Bayer Pharma AG Bencil-1h-pirazol[3,4-b]piridinas y su uso
WO2015106268A1 (fr) 2014-01-13 2015-07-16 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de la sgc pour le traitement de troubles neuromusculaires
JP2017507140A (ja) 2014-02-19 2017-03-16 バイエル・ファルマ・アクティエンゲゼルシャフト ３−（ピリミジン−２−イル）イミダゾ［１，２−ａ］ピリジン
WO2015171527A1 (fr) * 2014-05-05 2015-11-12 Global Blood Therapeutics, Inc. Pyrazolopyridine, pyrazolopyrimidine et composés apparentés
CA2969268A1 (fr) 2014-12-02 2016-06-09 Bayer Pharma Aktiengesellschaft Imidazo[1,2-a]pyridines a substitution heteroaryle et leur utilisation
EP3242878B1 (fr) 2015-01-08 2020-10-14 Impetis Biosciences Ltd. Composés bicycliques, compositions et applications médicinales de ceux-ci
EA201792346A1 (ru) 2015-05-06 2018-05-31 Байер Фарма Акциенгезельшафт ПРИМЕНЕНИЕ sGC СТИМУЛЯТОРОВ, sGC АКТИВАТОРОВ, ОТДЕЛЬНО И В КОМБИНАЦИЯХ С PDE5 ИНГИБИТОРАМИ, ДЛЯ ЛЕЧЕНИЯ ПАЛЬЦЕВИДНЫХ ЯЗВ (DU), СОПУТСТВУЮЩИХ СИСТЕМНОМУ СКЛЕРОЗУ (SSc)
SI3325013T2 (sl) 2015-07-23 2023-11-30 Bayer Pharma Aktiengesellschaft Stimulatorji/aktivatorji topne gvanilat ciklaze v kombinaciji z zaviralcem NEP in/ali antagonistom angiotenzina II in njihova uporaba
EA201891416A1 (ru) 2015-12-14 2018-12-28 Айронвуд Фармасьютикалз, Инк. ПРИМЕНЕНИЕ СТИМУЛЯТОРОВ sGC ДЛЯ ЛЕЧЕНИЯ ДИСФУНКЦИИ ЖЕЛУДОЧНО-КИШЕЧНОГО СФИНКТЕРА
JP7237823B2 (ja) 2016-10-11 2023-03-13 バイエル ファーマ アクチエンゲゼルシャフト Ｓｇｃアクチベーターとミネラルコルチコイド受容体アンタゴニストとを含む組合せ
US10918639B2 (en) 2016-10-11 2021-02-16 Bayer Pharma Aktiengesellschaft Combination containing SGC stimulators and mineralocorticoid receptor antagonists
US20190381039A1 (en) 2016-12-13 2019-12-19 Cyclerion Therapeutics, Inc. USE OF sGC STIMULATORS FOR THE TREATMENT OF ESOPHAGEAL MOTILITY DISORDERS
AU2018252099B2 (en) 2017-04-11 2021-08-12 Sunshine Lake Pharma Co., Ltd. Fluorine-substituted indazole compounds and uses thereof
US10474967B2 (en) * 2017-05-23 2019-11-12 International Business Machines Corporation Conversation utterance labeling
BR112020022340A2 (pt) 2018-05-15 2021-02-02 Bayer Aktiengesellschaft benzamidas substituídas por 1,3-tiazol-2-il para o tratamento de doenças associadas com sensibilização de fibras nervosas
US20210177846A1 (en) 2018-07-11 2021-06-17 Cyclerion Therapeutics, Inc. USE OF sGC STIMULATORS FOR THE TREATMENT OF MITOCHONDRIAL DISORDERS
WO2020164008A1 (fr) 2019-02-13 2020-08-20 Bayer Aktiengesellschaft Procédé de préparation de microparticules poreuses
US11057415B1 (en) * 2021-02-09 2021-07-06 Lookingglass Cyber Solutions, Inc. Systems and methods for dynamic zone protection of networks

Family Cites Families (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2458965C3 (de) 1974-12-13 1979-10-11 Bayer Ag, 5090 Leverkusen 3-Amino-indazol-N-carbonsäure-Derivate, Verfahren zu ihrer Herstellung sowie sie enthaltende Arzneimittel
DE19642255A1 (de) 1996-10-14 1998-04-16 Bayer Ag Verwendung von 1-Benzyl-3-(substituierten-hetaryl) -kondensierten Pyrazol-Derivaten
DE19649460A1 (de) 1996-11-26 1998-05-28 Bayer Ag Neue substituierte Pyrazolderivate
DE19744026A1 (de) * 1997-10-06 1999-04-08 Hoechst Marion Roussel De Gmbh Pyrazol-Derivate, ihre Herstellung und ihre Verwendung in Arzneimitteln
DE19834044A1 (de) 1998-07-29 2000-02-03 Bayer Ag Neue substituierte Pyrazolderivate
DE19834047A1 (de) 1998-07-29 2000-02-03 Bayer Ag Substituierte Pyrazolderivate
JP4295505B2 (ja) 2000-11-22 2009-07-15 バイエル アクチェンゲゼルシャフト 新規なラクタム置換ピラゾロピリジン誘導体
AR031176A1 (es) 2000-11-22 2003-09-10 Bayer Ag Nuevos derivados de pirazolpiridina sustituidos con piridina
DE10057754A1 (de) 2000-11-22 2002-05-23 Bayer Ag Neue Sulfonamid-substituierte Pyrazolopyridinderivate
DE10057751A1 (de) 2000-11-22 2002-05-23 Bayer Ag Neue Carbamat-substituierte Pyrazolopyridinderivate
DE10122894A1 (de) 2001-05-11 2002-11-14 Bayer Ag Neue Sulfonat-substituierte Pyrazolopyridinderivate
DE10132416A1 (de) 2001-07-04 2003-01-16 Bayer Ag Neue Morpholin-überbrückte Pyrazolopyridinderivate
CA2464333C (fr) 2001-10-26 2011-07-26 University Of Connecticut Heteroindanes: nouvelle classe de ligands cannabimimetiques efficaces
WO2003076408A2 (fr) 2002-03-08 2003-09-18 Abbott Laboratories Derives d'indazole qui sont des activateurs de guanylate cyclase soluble
US20040048866A1 (en) * 2002-03-08 2004-03-11 Teodozyj Kolasa Indazole derivatives that are activators of soluble guanylate cyclase
DE10220570A1 (de) 2002-05-08 2003-11-20 Bayer Ag Carbamat-substituierte Pyrazolopyridine
TW200401641A (en) * 2002-07-18 2004-02-01 Wyeth Corp 1-Heterocyclylalkyl-3-sulfonylindole or-indazole derivatives as 5-hydroxytryptamine-6 ligands
GB0303910D0 (en) 2003-02-20 2003-03-26 Merck Sharp & Dohme Therapeutic agents
GB0403819D0 (en) 2004-02-20 2004-03-24 Merck Sharp & Dohme New compounds
EP1966152A2 (fr) 2005-12-20 2008-09-10 Takeda Pharmaceutical Company Limited Activateurs de glucokinase
DE102006043443A1 (de) 2006-09-15 2008-03-27 Bayer Healthcare Ag Neue aza-bicyclische Verbindungen und ihre Verwendung
WO2008089310A2 (fr) * 2007-01-18 2008-07-24 Lexicon Pharmaceuticals, Inc. Méthodes et compositions utilisées dans le traitement de troubles corporels
AU2008323694A1 (en) * 2007-11-07 2009-05-14 Foldrx Pharmaceuticals, Inc. Modulation of protein trafficking

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2010079120A1 *

Also Published As

Publication number Publication date
CA2749048A1 (fr) 2010-07-15
WO2010079120A1 (fr) 2010-07-15
DE102009004245A1 (de) 2010-07-15
US20130303559A1 (en) 2013-11-14
US20120029002A1 (en) 2012-02-02

Similar Documents

Publication Publication Date Title
EP2385942A1 (fr) Dérivés de benzimidazole et pyrazolopyridine pour le traitement et/ou la prévention de maladies cardiovasculaires
EP2379071B1 (fr) Nouvelles pyrazolopyridines à substitution aliphatique et leur utilisation
EP2576547B1 (fr) 5-fluoro-1h-pyrazolopyridines substituées et leur utilisation
EP2729476B1 (fr) Pyrazolopyridines hétéroaryl substituées et leur utilisation en tant que stimulateurs de la guanylate cyclase soluble
EP2590987B1 (fr) Dérivés de 4-aminopyrimidine condensées et leur utilisation en tant que stimulateurs de la guanylate cyclase soluble
EP2802580B1 (fr) Dérivés de la triazine substituée et leur utilisation en tant que stimulateurs de la guanylate cyclase soluble
EP2635576B1 (fr) Carbamates substitués par des benzyles et leur utilisation
DE102012200352A1 (de) Substituierte, annellierte Imidazole und Pyrazole und ihre Verwendung
EP2682394A1 (fr) 1H-pyrazolo[3,4-b]pyridin-triazines et leur utilisation pour le traitement ou la prévention des maladies cardio-vasculaires
EP2635577A1 (fr) 6-fluoro-1h-pyrazolo[4,3-b]pyridines substituées et leur utilisation
DE102006043443A1 (de) Neue aza-bicyclische Verbindungen und ihre Verwendung
EP2822951A1 (fr) Azabicyles substitués et leur utilisation
EP2024361A1 (fr) 3-tétrazolylindazoles et 3-tétrazolylpyrazolopyridines et leur utilisation
DE102006054757A1 (de) Neue aza-bicyclische Verbindungen und ihre Verwendung
WO2012152630A1 (fr) Imidazopyridazines substituées et leur utilisation
WO2012010578A1 (fr) Méthyle-pyrimidin-5-ylcarbamates substitués et leur utilisation
WO2012010577A1 (fr) Oxazolidinones et oxazinanones substituées et leur utilisation
WO2012010576A1 (fr) Diaminopyrimidines substituées par du carbamate et leur utilisation
WO2017121692A1 (fr) Sulfamides substitués et leur utilisation
DE102011075399A1 (de) Substituierte Imidazopyridine und Imidazopyridazine und ihre Verwendung
DE102011007890A1 (de) Fluoralkyl-substituierte Pyrazolopyridine und ihre Verwendung
DE102011007891A1 (de) Annellierte 4-Aminopyrimidine und ihre Verwendung
DE102012200351A1 (de) Substituierte annellierte Pyrimidine und ihre Verwendung
DE102011078715A1 (de) Heteroaryl-substituierte Pyrazolopyridine und ihre Verwendung
DE102011082041A1 (de) Substituierte annellierte Pyrimidine und ihre Verwendung

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20110809

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BAYER INTELLECTUAL PROPERTY GMBH

17Q First examination report despatched

Effective date: 20130102

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20130713