EP1406908A1 - Morpholin-überbrückte pyrazolopyridinderivate - Google Patents
Morpholin-überbrückte pyrazolopyridinderivateInfo
- Publication number
- EP1406908A1 EP1406908A1 EP02745409A EP02745409A EP1406908A1 EP 1406908 A1 EP1406908 A1 EP 1406908A1 EP 02745409 A EP02745409 A EP 02745409A EP 02745409 A EP02745409 A EP 02745409A EP 1406908 A1 EP1406908 A1 EP 1406908A1
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- Prior art keywords
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- compound
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- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- 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
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- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- 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
- A61P25/06—Antimigraine agents
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- 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
- A61P25/20—Hypnotics; Sedatives
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- 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
- A61P25/22—Anxiolytics
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- 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
- A61P25/24—Antidepressants
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- 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
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- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- 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
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- 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
- A61P7/06—Antianaemics
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to new chemical compounds which stimulate soluble guanylate cyclase, their preparation and their use as medicaments, in particular as medicaments for the treatment of cardiovascular diseases.
- Cyclic guanosine monophosphate is one of the most important cellular transmission systems in mammalian cells. Together with nitrogen monoxide (NO), which is released from the endothelium and transmits hormonal 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 both 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 most likely contain one heme per heterodimer, which is part of the regulatory center. This is of central importance for the activation mechanism. NO can bind to the iron atom of the heme and so the
- 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.
- patho- The NO / cGMP system can be suppressed under physiological conditions, which can lead, for example, to high blood pressure, platelet activation, increased cell proliferation, endothelial dysfunction, atherosclerosis, angina pectoris, heart failure, thromboses, stroke and myocardial infarction.
- a NO-independent treatment option for such diseases aimed at influencing the cGMP signal path in organisms is a promising approach due to the expected high efficiency and few side effects.
- WO 98/16507, WO 98/23619, WO 00/06567, WO 00/06568, WO 00/06569 and WO 00/21954 pyrazolopyridine derivatives are described as stimulators of soluble guanylate cyclase.
- These patent applications also describe pyrazolo-pyridines which have a pyrimidine residue in the 3-position.
- These new pyrazolopyridine derivatives are distinguished by a pyrimidine residue in the 3-position which has a certain substitution pattern, namely a bridged morpholine residue in the 5-position of the pyrimidine ring and one or two amino groups in the 4-position or 4,6-position of the pyrimidine ring.
- R 2 represents H
- the compounds of formula (I) according to the invention can also be present in the form of their salts.
- salts with organic or inorganic bases or acids may be mentioned here.
- the compounds according to the invention can exist in the form of their possible hydrates.
- the compounds of the formula (I) according to the invention can be prepared by reacting the compound of the formula (H)
- R 1 is as defined above;
- R 1 is as defined above;
- R 1 is as defined above;
- R 1 is as defined above;
- R represents halogen
- the compound of formula (II) can be prepared according to the following reaction scheme:
- This pyridine derivative l- (2-fluorobenzyl) -IH-pyrazolo [3,4-b] pyridine-3-carboxylic acid ethyl ester is dehydrated by a multistage sequence consisting of converting the ester with ammonia into the corresponding amide converted with a dehydrating agent such as trifluoroacetic anhydride to the corresponding nitrile derivative, reaction of the nitrile derivative with sodium ethylate and final reaction with ammonium chloride in the compound of formula (II).
- the bicyclic system is built up, for example, by reacting the bishydroxymethyltetrahydrofuran derivative (activated as bistosylate) with benzlyamine via a nucleophilic substitution reaction under conditions conventionally used for such reactions.
- the reaction is preferably carried out in an organic solvent, for example a hydrocarbon, preferably an aromatic hydrocarbon and in particular toluene Use of a 2-5-fold excess of the amine preferably at normal pressure and stirring the reaction solution for several hours, for example 2 hours, at elevated temperature, for example 60-130 ° C., preferably 80-120 ° C., in particular 100 ° C.
- the bicyclic system is built up, for example, by an intramolecular nucleophilic substitution reaction of the two hydroxyl groups of the piperidine-2,6-dihydroxymethyl derivative under conditions conventionally used for such reactions.
- it is preferred to carry out the reaction under acidic conditions for example in the presence of concentrated sulfuric acid, preferably under normal pressure and stirring the reaction solution for several hours, for example 24 hours, at elevated temperature, for example 60-200 ° C., preferably 80-190 ° C. especially 175 ° C.
- the piperidine-2,6-dihydroxymethyl derivative required for this can be obtained from methyl pyridine-2,6-dicarboxylic acid by hydrogenation under conditions conventionally used for such reactions, for example with hydrogen over a palladium / activated carbon catalyst, to give the corresponding piperidine-2,6- dicarboxylic acid methyl ester, benzylation of the ring nitrogen with, for example, benzyl bromide (see Goldspink, Nicholas J .; Simpkins, Nigel S .; Beckmann, Marion; Syn.Lett .; 8; 1999; 1292 - 1294) and subsequent reduction of the carboxylic acid ester groups to the corresponding hydroxymethyl residues conditions conventionally used for such reactions, for example with lithium aluminum hydride in an organic solvent, for example an ether, preferably diethyl ether, using a 2-5-fold excess of the reducing agent, preferably at normal pressure and stirring the reaction solution for several hours, for example 3 hours, at elevated Temp erature, for example
- Protecting group under conditions conventionally used for such reactions gene for example with hydrogen on a palladium / activated carbon catalyst in an organic solvent, for example an alcohol, preferably ethanol, preferably under elevated pressure of 50-200 bar, preferably 100 bar, and stirring the reaction solution for several hours, for example 5 hours, at elevated temperature, for example 60-130 ° C, preferably 80-120 ° C, in particular 100 ° C, are converted into the corresponding bicyclic amines.
- an organic solvent for example an alcohol, preferably ethanol, preferably under elevated pressure of 50-200 bar, preferably 100 bar
- acetonitrile derivatives for example with haloacetonitriles and preferably with bromoacetonitrile, under conditions conventionally used for such reactions, for example in an organic solvent such as N, N-dimethylformamide (DMF), using a slight excess of the acetonitrile derivative in the presence of a base , for example an amine such as N, N-diisopropylethylamine, and a halide such as sodium iodide preferably at normal pressure and stirring the reaction solution for several hours, for example 24 hours, at elevated temperature, for example 40-130 ° C, preferably 40-100 ° C, in particular 60 ° C, to be converted to the corresponding N-methyl nitrile derivatives.
- a base for example an amine such as N, N-diisopropylethylamine
- a halide such as sodium iodide preferably at normal pressure and stirring the reaction solution for several hours, for example 24 hours, at elevated temperature, for
- the compounds of the formula (III) can finally be reacted with a formic acid ester, for example ethyl formate, under conditions conventionally used for such reactions, for example in an organic solvent, for example an ether, preferably a cyclic ether such as
- Tetrahydrofuran using a 2-5-fold excess of formic acid ester, preferably at normal pressure and stirring the reaction solution for several minutes, for example 20-60 minutes, at room temperature, and then acetylating with acetic anhydride in the presence of acetic acid under conventional for such reactions conditions used, for example under
- the compounds of formula (IV) are commercially available (e.g. from Mercachem) or can be prepared in a manner known to those skilled in the art.
- reaction of the compounds of the formulas (11) and (IV) to the compounds of the formula (V) can be carried out in an organic solvent, for example by using the reactants in equimolar amounts or using the compound of the formula (IV) in a slight excess a hydrocarbon, preferably an aromatic hydrocarbon and in particular
- Toluene preferably at normal pressure and stirring the reaction solution for several hours, for example 12 hours, at elevated temperature, for example 80-160 ° C., preferably 100-150 ° C., in particular 140 ° C.
- POCl 3 can preferably be used as the halogenating agent.
- reaction of the compounds of the formula (VI) to the compounds of the formula (I) according to the invention can be carried out by reaction of the compounds of the formula (VI) with aqueous ammonia solution, preferably at elevated pressure, for example by running the reaction in an autoclave so that the reaction proceeds under the autogenous pressure of the reaction mixture, and stirring the reaction solution for several hours, for example 12 hours, at elevated temperature, for example 80-160 ° C., preferably 100-150 ° C., in particular 140 ° C.
- the compound of formula (I) according to the invention enhances the action of substances which increase the cGMP level, such as EDRF (endothelium derived relaxing factor), NO donors, protoporphyrin LX, arachidonic acid or
- Arteriosclerosis asthmatic diseases and diseases of the genitourinary system such as prostate hypertrophy, erectile dysfunction, female sexual dysfunction, osteoporosis, gastroparesis and incontinence are used.
- the invention comprises the combination of the compounds of the formula (I) 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 develop their therapeutic effect through the release of NO or NO species. Sodium nitroprusside, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-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 11 pp. 150 to 155. These inhibitors potentiate the activity of the compounds according to the invention and increase the desired pharmacological effect.
- 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 placed individually in 5 ml organ baths with 37 ° C warm, carbogen-degassed Krebs-Henseleit solution of the following composition (mM): NaCl :
- Glucose 10. The contraction force is recorded with Statham UC2 cells, amplified and digitized via A / D converter (DAS-1802 HC, Keithley Instruments Kunststoff) and recorded in parallel on a line recorder. To create a contraction
- Phenylephrine added cumulatively to the bath in increasing concentration. After several control cycles, the substance to be examined is added to each
- 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.
- 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 pharmacokinetic parameters are calculated from the plasma concentration-time curves thus determined using conventional non-compartmental methods used for this.
- the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain the compound of the formula (I) according to the invention and processes for the preparation of these preparations.
- the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.
- the active compound according to the invention in total amounts of from about 0.01 to about 700, preferably from 0.01 to 100 mg / kg of body weight per 24 hours, if appropriate in the form multiple doses to achieve the desired results.
- a single dose contains the active ingredient according to the invention preferably in amounts of about 0.1 to about 80, in particular 0.1 to 30 mg / kg body weight.
- Carrier gas helium flow: 1.5 ml / min
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Physical Education & Sports Medicine (AREA)
- Psychology (AREA)
- Diabetes (AREA)
- Pulmonology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Reproductive Health (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Gynecology & Obstetrics (AREA)
- Anesthesiology (AREA)
- Addiction (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10132416A DE10132416A1 (de) | 2001-07-04 | 2001-07-04 | Neue Morpholin-überbrückte Pyrazolopyridinderivate |
DE10132416 | 2001-07-04 | ||
PCT/EP2002/006991 WO2003004503A1 (de) | 2001-07-04 | 2002-06-25 | Morpholin-überbrückte pyrazolopyridinderivate |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1406908A1 true EP1406908A1 (de) | 2004-04-14 |
Family
ID=7690582
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP02745409A Withdrawn EP1406908A1 (de) | 2001-07-04 | 2002-06-25 | Morpholin-überbrückte pyrazolopyridinderivate |
Country Status (6)
Country | Link |
---|---|
US (1) | US20040235863A1 (ja) |
EP (1) | EP1406908A1 (ja) |
JP (1) | JP2005501034A (ja) |
CA (1) | CA2452590A1 (ja) |
DE (1) | DE10132416A1 (ja) |
WO (1) | WO2003004503A1 (ja) |
Families Citing this family (40)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10220570A1 (de) | 2002-05-08 | 2003-11-20 | Bayer Ag | Carbamat-substituierte Pyrazolopyridine |
EP1763406B1 (de) | 2004-07-08 | 2014-04-23 | Sulzer Mixpac AG | Austragvorrichtung für eine einmal-anwendung |
DE102006043443A1 (de) | 2006-09-15 | 2008-03-27 | Bayer Healthcare Ag | Neue aza-bicyclische Verbindungen und ihre Verwendung |
DE102006054757A1 (de) * | 2006-11-21 | 2008-05-29 | Bayer Healthcare Ag | Neue aza-bicyclische Verbindungen und ihre Verwendung |
DE102007026392A1 (de) * | 2007-06-06 | 2008-12-11 | Bayer Healthcare Ag | Lösungen für die Perfusion und Konservierung von Organen und Geweben |
DE102008063992A1 (de) | 2008-12-19 | 2010-09-02 | Lerner, Zinoviy, Dipl.-Ing. | Neue aliphatisch substituierte Pyrazolopyridine und ihre Verwendung |
DE102009004245A1 (de) | 2009-01-09 | 2010-07-15 | Bayer Schering Pharma Aktiengesellschaft | Neue anellierte, Heteroatom-verbrückte Pyrazol- und Imidazol-Derivate und ihre Verwendung |
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 |
RS54433B1 (en) | 2009-11-27 | 2016-04-28 | Adverio Pharma Gmbh | PROCEDURE FOR THE PRODUCTION OF METHYL- {4,6-DIAMINO-2- [1- (2-FLUOROBENZYL) -1H-PYRAZOLO [3,4-B] PYRIDIN-3-IL] PYRIMIDIN-5-IL} METHYLCARBAMATE AND ITS Purification thereof ITS USE AS A PHARMACEUTICAL AGENCY |
DE102010021637A1 (de) | 2010-05-26 | 2011-12-01 | Bayer Schering Pharma Aktiengesellschaft | Substituierte 5-Fluor-1H-Pyrazolopyridine und ihre Verwendung |
EP2682394A1 (de) | 2010-07-09 | 2014-01-08 | Bayer Intellectual Property GmbH | 1H-Pyrazolo[3,4-b]pyridin-Triazine Verbindungen und ihre Verwendung zur Behandlung bzw. Prophylaxe von Herz-Kreislauf-Erkrankungen |
ES2572638T3 (es) | 2010-07-09 | 2016-06-01 | Bayer Intellectual Property Gmbh | 4-Aminopirimidinas condensadas y su uso como estimuladores de la guanilatociclasa soluble |
DE102010040233A1 (de) | 2010-09-03 | 2012-03-08 | Bayer Schering Pharma Aktiengesellschaft | Bicyclische Aza-Heterocyclen und ihre Verwendung |
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 |
CA2833698A1 (en) | 2011-04-21 | 2012-10-26 | Bayer Intellectual Property Gmbh | Fluoroalkyl-substituted pyrazolopyridines and use thereof |
KR20140040774A (ko) | 2011-05-30 | 2014-04-03 | 아스테라스 세이야쿠 가부시키가이샤 | 이미다조피리딘 화합물 |
PE20141582A1 (es) | 2011-09-02 | 2014-11-06 | Bayer Ip Gmbh | Pirimidinas anilladas sustituidas y uso de las mismas |
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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 |
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JP7101688B2 (ja) | 2016-10-11 | 2022-07-15 | バイエル・ファルマ・アクティエンゲゼルシャフト | sGC刺激薬とミネラルコルチコイド受容体拮抗薬とを含む組み合わせ |
CA3039735A1 (en) | 2016-10-11 | 2018-04-19 | Bayer Pharma Aktiengesellschaft | Combination containing sgc activators and mineralocorticoid receptor antagonists |
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WO2018188590A1 (en) | 2017-04-11 | 2018-10-18 | Sunshine Lake Pharma Co., Ltd. | Fluorine-substituted indazole compounds and uses thereof |
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DE19649460A1 (de) * | 1996-11-26 | 1998-05-28 | Bayer Ag | Neue substituierte Pyrazolderivate |
DE19834047A1 (de) * | 1998-07-29 | 2000-02-03 | Bayer Ag | Substituierte Pyrazolderivate |
DE19834044A1 (de) * | 1998-07-29 | 2000-02-03 | Bayer Ag | Neue substituierte Pyrazolderivate |
DE19846514A1 (de) * | 1998-10-09 | 2000-04-20 | Bayer Ag | Neue Heterocyclyl-methyl-substituierte Pyrazole |
DE19920352A1 (de) * | 1999-05-04 | 2000-11-09 | Bayer Ag | Substituiertes Pyrazolderivat |
DE10021069A1 (de) * | 2000-04-28 | 2001-10-31 | Bayer Ag | Substituiertes Pyrazolderivat |
-
2001
- 2001-07-04 DE DE10132416A patent/DE10132416A1/de not_active Withdrawn
-
2002
- 2002-06-25 WO PCT/EP2002/006991 patent/WO2003004503A1/de active Application Filing
- 2002-06-25 US US10/482,766 patent/US20040235863A1/en not_active Abandoned
- 2002-06-25 EP EP02745409A patent/EP1406908A1/de not_active Withdrawn
- 2002-06-25 CA CA002452590A patent/CA2452590A1/en not_active Abandoned
- 2002-06-25 JP JP2003510670A patent/JP2005501034A/ja active Pending
Non-Patent Citations (1)
Title |
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See references of WO03004503A1 * |
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WO2003004503A1 (de) | 2003-01-16 |
CA2452590A1 (en) | 2003-01-16 |
JP2005501034A (ja) | 2005-01-13 |
US20040235863A1 (en) | 2004-11-25 |
DE10132416A1 (de) | 2003-01-16 |
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