WO2004009590A1 - 4-aminosubstituierte pyrimidinderivate - Google Patents
4-aminosubstituierte pyrimidinderivate Download PDFInfo
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- WO2004009590A1 WO2004009590A1 PCT/EP2003/007236 EP0307236W WO2004009590A1 WO 2004009590 A1 WO2004009590 A1 WO 2004009590A1 EP 0307236 W EP0307236 W EP 0307236W WO 2004009590 A1 WO2004009590 A1 WO 2004009590A1
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the present invention relates to new 4-amino-substituted pyrimidine derivatives which stimulate soluble guanylate cyclase, processes for their preparation and their use for the preparation of medicaments, in particular medicaments for the treatment of diseases of the central nervous system.
- Cyclic guanosine monophosphate is one of the most important cellular signal transmission systems in mammalian cells. Together with nitrogen monoxide (NO), which is released from the endothelium and transmits hormone-like and mechanical signals, it forms the NO / cGMP system.
- the guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triposphate (GTP).
- GTP guanosine triposphate
- the previously known representatives of this family can be divided into two groups according to structural features and the type of ligand: the particulate guanylate cyclases that can be stimulated by natriuretic peptides and the soluble guanylate cyclases that can be stimulated by NO.
- the soluble guanylate cyclases consist of two subunits and contain at least one heme per heterodimer.
- the heme groups are part of the regulatory center and are of central importance for the activation mechanism.
- NO can be bound to the iron atom of the heme and thus significantly increase the activity of the enzyme.
- Hem-free preparations cannot be stimulated by NO.
- CO can also be bound to the iron central atom of the heme, whereby the stimulation by CO is significantly less than that by NO.
- guanylate cyclase plays a decisive role in different physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion and neuronal signal transmission as well as in diseases which are based on a disturbance of the above-mentioned processes. Under patho- the NO / cGMP system can be suppressed under physiological conditions. In Alzheimer's patients, for example, the NO-stimulated activity of soluble guanylate cyclase in the brain (cortex cerebralis) is greatly reduced.
- a NO-independent treatment option aimed at influencing the cGMP signaling pathway in organisms is a promising approach for the stimulation of soluble guanylate cyclase due to the expected high efficiency and few side effects.
- Such compounds have a very high in vitro activity with regard to the stimulation of soluble guanylate cyclase.
- these compounds were found to have some in terms of their in vivo properties, such as their behavior in the liver, their pharmacokinetic behavior, their dose-response relationship and their metabolic pathway
- the present invention relates to the compounds of the formula
- R 1 is hydrogen or fluorine
- R Ci-C ö alkyl which can be substituted by C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 5- to 6-membered heteroaryl, where C 6 -C ⁇ o Aryl and 5- to 6-membered heteroaryl optionally substituted with up to 3 radicals selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxyl, trifluoromethoxy,
- preferred salts are physiologically acceptable salts of the compounds according to the invention.
- Physiologically acceptable salts of the compounds according to the invention can include acid addition salts of the compounds with mineral acids, carboxylic acids or sulfonic acids. be acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
- Physiologically acceptable salts can also be salts with conventional bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts, derived from ammonia or organic amines such as, for example, diethylamine, triemylamine, ethyldisopropylamine, procaine , Dibenzylamine, N-methylmorpholine, dmydroabiemylamine, 1-ephenamine or methylpiperidine.
- alkali metal salts for example sodium or potassium salts
- alkaline earth metal salts for example calcium or magnesium salts
- ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triemylamine, ethyldisopropylamine, procaine , Dibenzylamine, N-methylmorpholine, dmydroabiemylamine, 1-
- Solvates of the compounds according to the invention are stoichiometric compositions of the compounds or their salts with solvents, e.g. Water, ethanol.
- Ci-Ce-alkyl represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, ter butyl, n-pentyl and n-hexyl.
- C 1 -C 6 alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms.
- Non-hermetic examples include methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
- j -Cip-aryl represents an aromatic radical having 6 to 10 carbon atoms. Non-limiting examples include phenyl and naphthyl.
- C -C 8 cycloalkyl stands for cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl.
- Non-limiting examples include cyclopropyl, cyclopentyl and cyclohexyl.
- Halogen stands for fluorine, chlorine, bromine and iodine. Fluorine, chlorine and
- 5- to 6-membered heteroaryl represents an aromatic, monocyclic radical
- heteroaryl radical can be bonded via a carbon or nitrogen.
- Non-limiting examples include thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl,
- radicals in the compounds according to the invention are substituted, the radicals, unless otherwise specified, can be substituted one or more times in the same or different ways. A substitution with up to three identical or different ones
- Another embodiment of the invention relates to compounds of the formula (I)
- R 1 is hydrogen or fluorine, R 2 -C 5 alkyl, which may be substituted by methoxy, ethoxy, isopropoxy, cyclopropyl
- the invention further relates to processes for the preparation of the compounds according to the invention, according to which compounds of the formula
- Formula (I) optionally reacted with the corresponding (i) solvents and / or (ii) bases or acids to give their solvates, salts and / or solvates of the salts.
- the process according to the invention is preferably carried out in a temperature range from 40 to 100 ° C. at normal pressure.
- Inert solvents are, for example, ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons such as benzene, xylene or toluene, nitroaromatics such as nitrobenzene, optionally N-alkylated carboxamides such as dimethylformamide, dimethylacetamide, alkyl sulfoxides such as dimethyl sulfoxide or
- Lactams such as N-methylpyrrolidone. Solvents from the series of dimethylformarnide and dimethyl sulfoxide are preferred.
- R 1 has the meanings given above and
- R 3 represents straight-chain CrCe alkyl
- the process according to the invention is preferably carried out in a temperature range from 50 to 150 ° C. at normal pressure.
- the compounds of the formula (VI) are commercially available, known or can be prepared by known processes.
- the compound of formula (V) is known from WO 00/06569.
- the compounds according to the invention show an unforeseeable, valuable spectrum of pharmacological activity.
- the compounds in the invention increase the cGMP levels in neurons and thus represent active substances for combating diseases in the central nervous system which are characterized by disorders of the NO / cGMP system.
- they are suitable for improving perception, concentration performance, learning performance, or memory performance after cognitive disorders, such as occur particularly in situations / diseases / syndromes such as "mild cognitive impairment", age-related learning and memory disorders, age-associated memory loss, vascular dementia, Traumatic brain injury, stroke, Dementia that occurs after strokes ("post stroke dementia”), post-traumatic craniocerebral trauma, general concentration disorders, concentration disorders in children with learning and memory problems, Alzheimer's disease, dementia with Lewy bodies, dementia with degeneration of the frontal lobes including des 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, HIN dementia, schizophrenia with dementia or Kor
- the compounds according to the invention also lead to vascular relaxation, platelet aggregation inhibition and to a reduction in blood pressure and to an increase in the coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and an intracellular increase in cGMP.
- the compounds according to the invention can increase the action of substances which increase the cGMP level, for example EDRF (endothelium derived relaxing factor), factorO donors, protoporphyrin LX, arachidonic acid or phenylhydrazine derivatives.
- cardiovascular diseases such as for the treatment of high blood pressure and heart failure, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, of arrhythmias, for the treatment of thromboembolic diseases and ischemia such as myocardial infarction, stroke, transitory and ischemic attacks , peripheral circulatory disorders, prevention of restenosis like after
- Thrombolysis therapies by, for example, use in stents, percutaneously transluminal angioplasties (PTA), percutaneously transluminal coronary angioplasties (PTCA), bypass operations and for the treatment of arteriosclerosis, asthmatic diseases, osteoporosis, gastroparesis, glaucoma and diseases of the genitourinary system such as incontinence incontinence, such as incontinence incontinence, such as incontinence incontinence Dysfunction and female sexual dysfunction are used. They are also suitable for the treatment of diseases of the central nervous system such as anxiety, tension and depression, central nervous system-related sexual dysfunctions and sleep disorders, as well as for the regulation of pathological disorders in the intake of food, beverages and addictive substances.
- PTA percutaneously transluminal angioplasties
- PTCA percutaneously transluminal coronary angioplasties
- bypass operations for the treatment of arteriosclerosis, asthmatic diseases, osteoporosis, gastroparesis, glaucoma
- the compounds according to the invention are suitable for regulating cerebral blood flow and can be effective agents for combating migraines.
- the compounds according to the invention are also suitable for the prophylaxis and control of the consequences of cerebral infarction (apoplexia cerebri) such as stroke, cerebral ischemia and cranial-brain trauma.
- the compounds according to the invention can also be used to combat painful conditions.
- the compounds according to the invention have an anti-inflammatory effect.
- the invention comprises the combination of the compounds according to the invention with organic nitrates and NO donors.
- Organic nitrates and NO donors in the context of the invention are generally substances which release NO or NO vaporizers.
- Sodium nitroprusside, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SDSf-1 are preferred.
- the invention also includes combination with compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP).
- cGMP cyclic guanosine monophosphate
- These are in particular inhibitors of phosphodiesterases 1, 2 and 5; Nomenclature according to Beavo and Reifsnyder (1990) TiPS H pp. 150 to 155. These inhibitors potentiate the activity of the compounds according to the invention and increase the desired pharmacological effect.
- the in vitro effect of the compounds according to the invention can be shown in the following assays:
- Rat embryos (embryonic day 17-19) are decapitated, the cerebrum is dissected and incubated for 30 min at 37 ° C with 5 mL papain solution and 250 ⁇ L DNAse (Papain kit from Cell-System), homogenized using a Pasteur pipette and 5 min at 1200 U. / min centrifuged. The supernatant is removed and the cell pellet is resuspended (in 2.7 mL EBSS [Earl's balanced salt solution], 300 ⁇ L ovomucoid / albumin
- test buffer 154 mM NaCl, 5.6 mM KC1, 2.3 mM CaCl 2 '2H 2 O, 1 mM MgCl 2 , 5.6 mM Glucose, 8.6 mM HEPES (4- (2-hydroxyethyl) piperazin-l-ethanesulfonic acid), pH ⁇ ).
- test buffer 100 ⁇ L / well of test substance are dissolved in test buffer and then 100 ⁇ L / well LBMX (3-isobutyl-l-methyrxanthine; dissolved in 50 mM ethanol, diluted with test buffer to a final concentration of 100 ⁇ M). After 20 min incubation at 37 ° C., the test buffer is replaced by 200 ⁇ L / well lysis buffer (cGMP EIA RPN 226 from Amersham Pharmacia Biotech), and the cGMP content of the lysates is determined using an EIA test kit.
- LBMX 3-isobutyl-l-methyrxanthine
- Rabbits are anesthetized and bled by the blow of the neck.
- the aorta is removed, adherent tissue is removed, divided into 1.5 mm wide rings and individually pretensioned in 5 ml organ baths at 37 ° C, carbo-rubbed brought gaster Krebs-Henseleit solution of the following composition (mM): NaCl: 119; KC1: 4.8; CaCl 2 x 2 H 2 O: 1; MgSO 4 x 7 H 2 O; 1.4; KH 2 PO 4 : 1.2; NaHCO3: 25; Glucose: 10.
- the contraction force is recorded with Statham UC2 cells, strengthened and digitized via A / D converter (DAS-1802 HC, Keithley Instruments Munich) and recorded in parallel on a line recorder.
- DAS-1802 HC Keithley Instruments Kunststoff
- Rats are anesthetized, heparinized and the liver perfused in situ through the portal vein.
- the primary rat hepatocytes are then obtained ex vivo from the liver using collagenase solution.
- 210 6 hepatocytes per ml were incubated at 37 ° C., each with the same concentration of the compound to be examined.
- the decrease in the substrate to be examined over time was determined bioanalytically (HPLC / UV, HPLC / fluorescence or LC / MSMS) at 5 times in each case in the period from 0-15 min after the start of incubation.
- the clearance was calculated from this using the cell number and liver weight.
- the substance to be examined is administered intravenously as a solution to rats via the tail vein. Blood is drawn from the rats at specified times, this is heparinized and plasma is obtained therefrom by conventional measures. The substance is bioanalytically quantified in plasma. The plasma concentration-time curves thus determined become conventional ones for this used non-compartmentalized methods calculated the pharmacokinetic parameters.
- Trial 1 but handled without substance or vehicle application.
- the test substances are applied directly after Trial 1.
- the social memory is measured in Trial 2 after 24 hours.
- Makrolon held. 4 minutes before testing, a box consisting of two aluminum side walls, an AJun rear wall and a plexiglass front (63x41x40 cm) is placed over the cage and the lid of the cage removed. A young animal is placed in the cage with the adult rats, and the social interaction (e.g. sniffing) is recorded over a period of 2 minutes using a stopwatch. After that the social interaction (e.g. sniffing) is recorded over a period of 2 minutes using a stopwatch. After that the social interaction (e.g. sniffing) is recorded over a period of 2 minutes using a stopwatch. After that the social interaction (e.g. sniffing) is recorded over a period of 2 minutes using a stopwatch. After that the social interaction (e.g. sniffing) is recorded over a period of 2 minutes using a stopwatch. After that the social interaction (e.g. sniffing) is recorded over a period of 2 minutes using a stopwatch. After that the social interaction (e.g. sniffing) is recorded over a
- Trial 2 The experiment is repeated after 24 h in the same way as in Trial 1 with the same animals. The difference between the social interaction time in Trial 1 and Trial 2 is taken as a measure of the social memory.
- the compounds according to the invention are suitable for use as medicaments for humans and animals.
- the present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically suitable auxiliaries and excipients, contain one or more compounds according to the invention, or which consist of one or more compounds according to the invention, and processes for the preparation of these preparations.
- the compounds according to the invention should be present in these preparations in a concentration of 0.1 to 99.5% by weight, preferably 0.5 to 95% by weight, of the total mixture.
- the pharmaceutical preparations can also contain other active pharmaceutical ingredients.
- the pharmaceutical preparations listed above can be prepared in a customary manner by known methods, for example using the excipient or excipients.
- the new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
- the therapeutically active compound should be in a concentration of about 0.5 to
- the formulations can be prepared, for example, by diluting the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, ziB. in the case of loading Using water as a diluent, organic solvents can optionally be used as auxiliary solvents.
- the application can be carried out in a customary manner, preferably orally, transdermally or parenterally, in particular perlingually or intravenously. But you can also by
- Formulation and the time or interval at which the administration takes place In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day.
- Method C Instrument: Micromass Quattro LCZ, HP1100; Column: Symmetry C 18, 50 mm x 2.1 mm, 3.5 ⁇ m; Eluent A: acetonitrile + 0.1% formic acid, eluent B: water + 0.1% formic acid; Gradient: 0 min 10% A ⁇ 4 min 90% A - »6 min 90% A; Oven: 40 ° C; Flow: 0.5 ml / min; UV detection: 208-400 nm.
- 6-methyl-4-pyrimidinol (Example II, step 1) is obtained after chromatography of the crude product over silica gel (eluent: DCM / methanol 100: 1) 4.10 g (83% of theory) of
- reaction mixture is diluted with 0.20 ml DMSO and then purified by preparative HPLC. 41 mg (98% of theory) of the product are obtained.
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Abstract
Description
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2004522410A JP2005537274A (ja) | 2002-07-18 | 2003-07-07 | 4−アミノ置換ピリミジン誘導体 |
EP03740426A EP1525203A1 (de) | 2002-07-18 | 2003-07-07 | 4-aminosubstituierte pyrimidinderivate |
US10/521,540 US7410973B2 (en) | 2002-07-18 | 2003-07-07 | 4-amino-substituted pyrimidine derivatives |
AU2003281477A AU2003281477A1 (en) | 2002-07-18 | 2003-07-07 | 4-amino-substituted pyrimidine derivatives |
CA002492726A CA2492726A1 (en) | 2002-07-18 | 2003-07-07 | 4-amino-substituted pyrimidine derivatives |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10232571.5 | 2002-07-18 | ||
DE10232571A DE10232571A1 (de) | 2002-07-18 | 2002-07-18 | 4-Aminosubstituierte Pyrimidinderivate |
Publications (2)
Publication Number | Publication Date |
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WO2004009590A1 true WO2004009590A1 (de) | 2004-01-29 |
WO2004009590A8 WO2004009590A8 (de) | 2005-05-12 |
Family
ID=30010151
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/EP2003/007236 WO2004009590A1 (de) | 2002-07-18 | 2003-07-07 | 4-aminosubstituierte pyrimidinderivate |
Country Status (7)
Country | Link |
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US (1) | US7410973B2 (de) |
EP (1) | EP1525203A1 (de) |
JP (1) | JP2005537274A (de) |
AU (1) | AU2003281477A1 (de) |
CA (1) | CA2492726A1 (de) |
DE (1) | DE10232571A1 (de) |
WO (1) | WO2004009590A1 (de) |
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DE102011082041A1 (de) | 2011-09-02 | 2013-03-07 | Bayer Pharma AG | Substituierte annellierte Pyrimidine und ihre Verwendung |
WO2013030288A1 (de) | 2011-09-02 | 2013-03-07 | Bayer Intellectual Property Gmbh | Substituierte annellierte pyrimidine und ihre verwendung |
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2002
- 2002-07-18 DE DE10232571A patent/DE10232571A1/de not_active Withdrawn
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2003
- 2003-07-07 WO PCT/EP2003/007236 patent/WO2004009590A1/de active Application Filing
- 2003-07-07 AU AU2003281477A patent/AU2003281477A1/en not_active Abandoned
- 2003-07-07 CA CA002492726A patent/CA2492726A1/en not_active Abandoned
- 2003-07-07 JP JP2004522410A patent/JP2005537274A/ja not_active Withdrawn
- 2003-07-07 US US10/521,540 patent/US7410973B2/en not_active Expired - Fee Related
- 2003-07-07 EP EP03740426A patent/EP1525203A1/de not_active Withdrawn
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DE19846514A1 (de) * | 1998-10-09 | 2000-04-20 | Bayer Ag | Neue Heterocyclyl-methyl-substituierte Pyrazole |
WO2002042301A1 (de) * | 2000-11-22 | 2002-05-30 | Bayer Aktiengesellschaft | Neue pyridin-substituierte pyrazolopyridinderivate |
Non-Patent Citations (1)
Title |
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STRAUB, A. ET AL: "NO-Independent stimulators of soluble guanylate cyclase", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2001), 11(6), 781-784, XP004230931 * |
Cited By (28)
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DE102007026392A1 (de) | 2007-06-06 | 2008-12-11 | Bayer Healthcare Ag | Lösungen für die Perfusion und Konservierung von Organen und Geweben |
DE102011082041A1 (de) | 2011-09-02 | 2013-03-07 | Bayer Pharma AG | Substituierte annellierte Pyrimidine und ihre Verwendung |
WO2013030288A1 (de) | 2011-09-02 | 2013-03-07 | Bayer Intellectual Property Gmbh | Substituierte annellierte pyrimidine und ihre verwendung |
CN104812762A (zh) * | 2012-01-11 | 2015-07-29 | 拜耳药业股份公司 | 取代的环状嘧啶和三嗪以及它们的用途 |
DE102012200360A1 (de) | 2012-01-11 | 2013-07-11 | Bayer Intellectual Property Gmbh | Substituierte Triazine und ihre Verwendung |
DE102012200349A1 (de) | 2012-01-11 | 2013-07-11 | Bayer Intellectual Property Gmbh | Substituierte annellierte Pyrimidine und Triazine und ihre Verwendung |
WO2013104598A2 (de) | 2012-01-11 | 2013-07-18 | Bayer Intellectual Property Gmbh | Substituierte, annellierte imidazole und pyrazole und ihre verwendung |
WO2013104703A1 (de) | 2012-01-11 | 2013-07-18 | Bayer Pharma Aktiengesellschaft | Substituierte annellierte pyrimidine und triazine und ihre verwendung |
WO2013104597A1 (de) | 2012-01-11 | 2013-07-18 | Bayer Intellectual Property Gmbh | Substituierte triazine derivate und ihre verwendung als stimulatoren der löslichen guanylatcyclase |
WO2013104598A3 (de) * | 2012-01-11 | 2013-10-10 | Bayer Intellectual Property Gmbh | Substituierte, annellierte imidazole und pyrazole und ihre verwendung |
US9505786B2 (en) | 2012-01-11 | 2016-11-29 | Bayer Pharma Aktiengesellschaft | Substituted annulated triazines and use thereof |
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US9133191B2 (en) | 2012-01-11 | 2015-09-15 | Bayer Intellectual Property Gmbh | Substituted triazine derivatives and use thereof as stimulators of soluble guanylate cyclase |
DE102012200351A1 (de) | 2012-01-11 | 2013-07-11 | Bayer Pharma Aktiengesellschaft | Substituierte annellierte Pyrimidine und ihre Verwendung |
WO2014131741A1 (de) | 2013-03-01 | 2014-09-04 | Bayer Pharma Aktiengesellschaft | Benzyl-substituierte pyrazolopyridine und ihre verwendung |
JP2016513129A (ja) * | 2013-03-01 | 2016-05-12 | バイエル・ファルマ・アクティエンゲゼルシャフト | ベンジル−置換ピラゾロピリジンおよびその使用 |
WO2014131760A1 (de) | 2013-03-01 | 2014-09-04 | Bayer Pharma Aktiengesellschaft | Trifluormethyl-substituierte annellierte pyrimidine und ihre verwendung |
WO2015004105A1 (de) | 2013-07-10 | 2015-01-15 | Bayer Pharma Aktiengesellschaft | Benzyl-1h-pyrazolo[3,4-b]pyridine und ihre verwendung |
US9605008B2 (en) | 2013-07-10 | 2017-03-28 | Bayer Pharma Aktiengesellschaft | Benzyl-1H-pyrazolo[3,4-b]pyridines and use thereof |
WO2015106268A1 (en) | 2014-01-13 | 2015-07-16 | Ironwood Pharmaceuticals, Inc. | USE OF sGC STIMULATORS FOR THE TREATMENT OF NEUROMUSCULAR DISORDERS |
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Also Published As
Publication number | Publication date |
---|---|
JP2005537274A (ja) | 2005-12-08 |
AU2003281477A1 (en) | 2004-02-09 |
DE10232571A1 (de) | 2004-02-05 |
US20060014951A1 (en) | 2006-01-19 |
EP1525203A1 (de) | 2005-04-27 |
CA2492726A1 (en) | 2004-01-29 |
WO2004009590A8 (de) | 2005-05-12 |
US7410973B2 (en) | 2008-08-12 |
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