EP2167495A1 - Oxazolidinones substitués et leur utilisation - Google Patents

Oxazolidinones substitués et leur utilisation

Info

Publication number
EP2167495A1
EP2167495A1 EP08759100A EP08759100A EP2167495A1 EP 2167495 A1 EP2167495 A1 EP 2167495A1 EP 08759100 A EP08759100 A EP 08759100A EP 08759100 A EP08759100 A EP 08759100A EP 2167495 A1 EP2167495 A1 EP 2167495A1
Authority
EP
European Patent Office
Prior art keywords
substituent
alkyl
hydrogen
alkoxy
hydroxy
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Withdrawn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
EP08759100A
Other languages
German (de)
English (en)
Inventor
Susanne Röhrig
Michael Härter
Mark Jean Gnoth
Georges Von Degenfeld
Elke Dittrich-Wengenroth
Anja BUCHMÜLLER
Swen Allerheiligen
Elisabeth Perzborn
Christoph Gerdes
Karl-Heinz Schlemmer
Metin Akbaba
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Bayer Schering 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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=39765012&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP2167495(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Bayer Schering Pharma AG filed Critical Bayer Schering Pharma AG
Publication of EP2167495A1 publication Critical patent/EP2167495A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates to novel substituted oxazolidinones, processes for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular thromboembolic diseases
  • the blood coagulation is a protective mechanism of the organism, with the help of which defects in the vascular wall can be "sealed” so that blood loss can be avoided or minimized
  • the hemostasis after Geflubrication essentially by the coagulation system, in which an enzymatic cascade of complex reactions of Triggering plasma proteins Involved here are numerous blood-cell factors, each of which, once activated, converts the next inactive precursor to its active form.
  • the transformation of the soluble fibrogen into the insoluble fibrin, resulting in a blood clot is traditionally different in the blood coagulation between the intrinsic and the extnnsic system, which end in a final common reaction pathway, the factor Xa, which is formed by the proenzyme factor X, plays a key role, since it connects the two pathways of gene formation activated protease Xa cleaves prothrombin to thrombin The resulting thrombin in turn cleaves fibrinogen to fibrin Subsequent crosslinking of the Fib ⁇ n monomers leads to the formation of blood vessels and thus to haemostasis In addition, thrombin is a potent trigger of platelet aggregation, which also makes a considerable contribution in the case of hemostasis
  • Hamostasis is subject to a complex regulatory mechanism
  • An uncontrolled activation of the coagulation system or a defective inhibition of activation processes can cause the formation of local thrombosis or embolism in vessels (arteries, veins, lymphatics) or cardiac cavities. This can lead to serious thromboembolic disease.
  • hypercoagulabihtat - Systemic - lead to disseminated intravascular coagulation in case of consumption coagulopathy
  • Thromboembolic complications also occur in microangiopathic hemolytic anemias, extracorporeal blood circulation, such as hemodialysis, and heart valve prostheses
  • thromboembolic disorders are the leading cause of morbidity and mortality in most industrialized countries [Heart Disease A Textbook of Cardiovascular Medicine, Eugene Braunwald, 5 Edition, 1997, WB Saunders Company, Philadelphia]
  • anticoagulants ie substances for the inhibition or prevention of blood clotting
  • An efficient method of treatment or prophylaxis of thromboembolic diseases therefore proves to be very difficult and unsatisfactory in practice.
  • heparin is used, which is administered parenterally or subcutaneously. Due to more favorable pharmacokinetic properties, although increasingly low molecular weight heparin is nowadays increasingly preferred; However, this also the known disadvantages described below can not be avoided, which consist in the therapy with heparin. Thus, heparin is orally ineffective and has only a comparatively low half-life. Since heparin simultaneously inhibits several factors of the blood coagulation cascade, there is an unselective effect.
  • a second class of anticoagulants are the vitamin K antagonists. These include, for example, 1, 3-indandiones, but especially compounds such as warfarin, phenprocoumon, dicumarol and other coumarin derivatives, which are unsuitable for the synthesis of various products of certain vitamin K-dependent coagulation factors in the liver. Due to the mechanism of action, the effect is only very slow (latency until the onset 36 to 48 hours). Although the compounds can be administered orally, due to the high risk of bleeding and the narrow therapeutic index, a complex individual adjustment and observation of the patient is necessary [J. Hirsh, J. Dalen, D.R.
  • factor Xa is one of the most important targets for anticoagulant drugs [J. Hauptmann, J. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S., Thrombosis Research 1999, 93, 203; SAV Raghavan, M. Dikshit, "Recent Advances in the Status and Targets of Antithrombotic Agents" Drugs Fut.
  • the therapeutic range is of central importance for antithrombotic drugs.
  • the distance between the therapeutically effective dose of inhibition and the dose at which bleeding can occur should be as large as possible so that maximum therapeutic efficacy is achieved with a minimal risk profile
  • the therapeutic range of an antithrombotic Active substance depends on the change in the plasma level of an active substance during the course of the day after taking the medication.
  • the peak-to-trough ratio can be used as a measure, ie the ratio between the maximum level after taking the medication and the maximum level at the end of the treatment interval.
  • This peak-to-trough ratio should be as small as possible so that diminished maximum levels prevent the occurrence of bleeding and ensure antithrombotic efficacy through sufficiently high levels end of the entire treatment interval is ensured
  • the invention relates to compounds of the formula
  • R 1 is a group of the formula
  • R 4 is hydrogen or C 1 -C 3 -alkyl
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, CpC 3 alkoxy and C3-C6 cycloalkyloxy,
  • R 5 is hydrogen, hydroxy, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy or C 3 -C 6 -cycloalkyloxy, wherein alkyl and alkoxy may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, CpC 3 - alkoxy and C 3 -C 6 -CyClOAlCyIoXy,
  • R 6 is hydrogen, hydroxy, C, -C 3 alkyl, C r C 3 alkoxy or C 3 -C 6 cycloalkyloxy group
  • alkyl and alkoxy may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, CpC 3 - alkoxy and C 3 -C 6 cycloalkyloxy,
  • R 7 is hydrogen, C r C 3 alkyl or C 3 -C 6 cycloalkyl
  • C 2 -C 3 alkyl may be substituted with a substituent, wherein the
  • Substituent is selected from the group consisting of hydroxy, CpC 3 - alkoxy and C 3 -C 6 cycloalkyloxy,
  • R 8 is hydrogen, C 1 -C 3 -alkyl or C 3 -C 6 -cycloalkyl
  • C 2 -C 3 -alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, CpC 3 -
  • R 9 is hydrogen, C 1 -C 3 -alkyl or C 3 -C 6 -cycloalkyl
  • C 2 -C 3 -alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, CpC 3 - alkoxy and C 3 -C 6 -cycloalkyloxy,
  • R 10 is hydrogen, C 1 -C 3 -alkyl or C 3 -C 6 -cycloalkyl
  • C 2 -C 3 -alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, CpC 3 - alkoxy and C 3 -C 6 -cycloalkyloxy,
  • R 11 represents hydrogen, hydroxy, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy or C 3 -C 6 -cycloalkyloxy,
  • alkyl and alkoxy may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, CpC 3 - alkoxy and C 3 -C ⁇ -cycloalkyloxy, R 12 is hydrogen, C r C 3 alkyl or C 3 -C 6 cycloalkyl,
  • C 2 -C 3 -alkyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxy, C 1 -C 3 -alkoxy and C 3 -C 6 -cycloalkyloxy,
  • R 2 is fluorine, chlorine, cyano, trifluoromethyl or trifluoromethoxy
  • R 3 is hydrogen, chlorine, methyl, ethyl, n-propyl, methoxy, ethoxy or methoxymethyl,
  • 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 as well as those 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
  • the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore encompasses the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform constituents can be isolated in a known manner
  • Suitable salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are not suitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds according to the invention
  • Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, eg salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoracetic 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, for example and preferably, 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 with 1 to 16 C atoms, such as, by
  • 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 the solvates in which coordination takes place with water present invention hydrates preferred
  • prodrugs of the compounds according to the invention.
  • prodrugs comprises compounds which themselves may 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 per se and "Alk” and "alkyl” in alkoxy represents a linear alkyl radical having usually 1 to 3, preferably 1 or 2 carbon atoms, by way of example and preferably methyl, ethyl and n-propyl
  • Alkoxy is exemplary and preferably methoxy, ethoxy and n-propoxy
  • Cycloalkyl is a cycloalkyl group having usually 3 to 6 carbon atoms, preferably having 3 to 5 carbon atoms, by way of example and preferably cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl
  • Cycloalkyloxy represents a cycloalkyloxy group having usually 3 to 6 carbon atoms, preferably having 3 to 5 carbon atoms, by way of example and preferably cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy
  • R 1 is a group of the formula
  • R 4 is hydrogen
  • R 5 r C 3 alkyl or C r C 3 alkoxy stands for hydrogen, hydroxy, C
  • alkyl and alkoxy may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy and C r C 3 alkoxy,
  • R 6 is hydrogen, C, -C 3 alkyl or C, -C r alkoxy
  • alkyl and alkoxy may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy and C 1 -C 3 alkoxy,
  • R s is hydrogen, C r C 3 alkyl or C 3 -C 5 cycloalkyl, Wonn C 2 -C 3 alkyl which may be substituted with a substituent, whereby the substituent is selected from the group consisting of hydroxy and Ci-C 3 -, alkoxy
  • R 9 is hydrogen, C 1 -C 3 -alkyl or C 3 -C 6 -cycloalkyl
  • Substituent is selected from the group consisting of hydroxy and CpC 3 - alkoxy,
  • R 10 is hydrogen, C 1 -C 3 -alkyl or C 3 -C 6 -cycloalkyl
  • C 2 -C 3 -alkyl can be substituted by a substituent, where the substituent is selected from the group consisting of hydroxy and CpC 3 -
  • R 2 is fluorine or chlorine
  • R 3 is hydrogen, methyl or methoxymethyl
  • R 1 is a group of the formula
  • R 5 is hydrogen, hydroxy or hydroxymethyl
  • R 6 represents hydrogen, methyl, hydroxymethyl, 2-hydroxyeth-1-yl or 2-hydroxyeth-1-oxy,
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen or methyl
  • R 10 is methyl, ethyl or 2-hydroxyeth-1-yl
  • R 2 is fluorine or chlorine
  • R 3 is hydrogen or methyl
  • R 1 is a group of the formula
  • R 4 is hydrogen
  • R 5 is hydrogen, hydroxy or hydroxymethyl
  • R 6 is hydroxymethyl or 2-hydroxyeth-l -oxy
  • R 2 is fluorine or chlorine
  • R 3 is hydrogen or methyl, and their salts, their solvates, and the solvates of their salts.
  • R 4 is hydrogen
  • R 5 is hydrogen, hydroxy or hydroxymethyl
  • R 6 is hydroxymethyl, 2-hydroxyeth-1-yl or 2-hydroxyeth-1 -oxy. Preference is also given to compounds of the formula (I) in which R 1 is a group of the formula
  • R 4 is hydrogen
  • R 5 is hydrogen, hydroxy or hydroxymethyl.
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen or methyl.
  • R 10 is methyl, ethyl or 2-hydroxyeth-1-yl.
  • the invention further provides a process for the preparation of the compounds of the formula (I), or their salts, their solvates or the solvates of their salts, wherein
  • X is halogen, preferably bromine or chlorine, or hydroxy
  • hydroxy groups are protected during the process, for example by a silyl protective group, these are known to the person skilled in the art after completion of the process [A] or [B] Methods split off, z. B. by reaction with tetrabutylammonium fluoride in a solvent such. B. tetrahydrofuran.
  • the free base of the salts can be obtained, for example, by chromatography on a reversed-phase column with an acetonitrile-water gradient with the addition of a base, in particular by using a RPl 8 Phenomenex Luna Cl 8 (2) column and diethylamine as base, or by Dissolve the salts in an organic solvent and shake with aqueous solutions of basic salts such as sodium bicarbonate.
  • the invention further provides a process for the preparation of the compounds of the formula (I) or their solvates, in which salts of the compounds or solvates of the salts of the compounds are converted into the compounds by chromatography with addition of a base.
  • the reaction of the first stage according to process [A] is generally carried out in inert solvents, in the presence of a Lewis acid, preferably in a temperature range from room temperature to reflux of the solvent at atmospheric pressure.
  • Inert solvents are, for example, polar, aprotic solvents such as, for example, acetonitrile, butyronitrile, dichloromethane or chloroform, preference being given to acetonitrile.
  • Lewis acids are, for example, magnesium perchlorate, ytterbium (IH) trifluoromethanesulfonate or aluminum trichloride, preference being given to magnesium perchlorate.
  • reaction of the second stage according to process [A] is generally carried out in inert solvents, in the presence of a base, preferably in a temperature range from room temperature to reflux of the solvent at atmospheric pressure.
  • Inert solvents are, for example, polar, aprotic solvents such as, for example, acetonitrile or butyronitrile.
  • bases are strong, tertiary amine bases such as, for example, 4-yl, N-dimethylaminopyridine.
  • reaction is generally carried out in inert solvents, optionally in the presence of a base, preferably in a temperature range from -30 0 C to 50 0 C at atmospheric pressure.
  • inert solvents are, for example, tetrahydrofuran, methylene chloride, pyridine, dioxane or dimethylformamide, preference is given to tetrahydrofuran or methylene chloride.
  • bases are triethylamine, diisopropylethylamine or N-methylmorpholine, preference is given to diisopropylethylamine.
  • reaction is generally carried out in inert solvents, in the presence of a dehydrating reagent, if appropriate in the presence of a base, preferably in a temperature range from -3O 0 C to 50 0 C at atmospheric pressure.
  • Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane or trichloromethane, hydrocarbons, such as benzene, nitromethane, dioxane, dimethylformamide or acetonitrile. It is also possible to use Gernische of the solvents. Particularly preferred is dichloromethane or dimethylformamide.
  • Carbodiimides such as N, N'-diethyl, N, N, dipropyl, N, N'-diisopropyl, NN'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide are suitable as dehydrating reagents hydrochloride (EDC), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3 sulphate or 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride,
  • Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, yV-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • alkali carbonates e.g. Sodium or potassium carbonate
  • hydrogen carbonate e.g. Sodium or potassium carbonate
  • organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, yV-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • the condensation is carried out with HATU or with EDC in the presence of HOBt.
  • the compounds of formulas (II) and (VI) are known or can be synthesized by known methods from the corresponding starting compounds.
  • the compounds of the formula (UI) in which the group of the formula R 1 is bonded via a nitrogen atom to the phenyl ring are known or can be prepared by reacting compounds of the formula
  • the reaction generally takes place in inert solvents, in the presence of a copper (I) salt, a base and a diamine ligand, preferably in a temperature range from 60 ° C. to the reflux of the solvent under atmospheric pressure.
  • Inert solvents are, for example, aprotic solvents such as toluene, dioxane, tetrahydrofuran or dimethylformamide, preference is given to dioxane.
  • Copper (I) salts are, for example, copper (I) iodide, copper (I) chloride or copper (I) oxide, preferred is copper (I) iodide.
  • Diamine ligands are, for example, 1,2-diamines such as N, N'-dimethylethylenediamine or 1,2-diaminocyclohexane, preferably N, N'-dimethylethylenediamine
  • R 7 , R s and R 12 have the abovementioned meaning
  • the reaction of the first stage is generally carried out in inert solvents, preferably in a temperature range from -30 0 C to 0 0 C at atmospheric pressure
  • the reaction of the second stage is generally carried out in inert solvents, preferably in a temperature range from room temperature to the reflux of the solvent at atmospheric pressure
  • Inert solvents for both reaction steps are, for example, ethers, such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, optionally mixed with hydrocarbons, such as, for example, hexane, preference being given to tetrahydrofuran
  • Strong bases are, for example, sec-butylthiium, tert-butylthiium, lithium diisopropylamide or lithium hexamethyldisilazide, preferably sec-butylthonium
  • the zinc salt is, for example, zinc chloride
  • Palladium complexes are formed in-situ from palladium compounds and ligands Suitable palladium compounds are, for example, palladium (II) acetate, palladium (II) chloride, bis (t-phenylphosphine) palladium (II) chloride, tetrakis (tphenylphosphine) palladium (0 ), Bis (dibenzylidenactone) palladmm (O), preferred is bis (dibenzylhdenactone) palladium (0)
  • Ligands are for example 2-dicyclohexylphosphino-2 '- (N r / V-dimethylamino) biphenyl, Bmaphthyl or N-heterocyclic carbene ligand, preferably 2-dicyclohexylphosphino-2'- (N, N-dimethylamino) biphenyl
  • the reaction of the first stage is generally carried out in inert solvents, optionally in the presence of some water, in the presence of a base and a palladium catalyst, and optionally in the presence of a ligand, preferably in a temperature range from 4O 0 C to the reflux of the solvent at atmospheric pressure
  • Inert solvents are, for example, ethers, such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, preferably 1,2-dimethoxyethane
  • Base for example Nat ⁇ umcarbonat, Kahumcarbonat or cocium carbonate, preferably a 2-molar solution of Nat ⁇ umcarbonat in water
  • Palladium compounds are, for example, palladium (II) acetate, palladium (EI) chloride, bis (tphenylphosphine) palladium (II) chloride, tetrakis (tnphenylphosphine) palladium (0), preferably tetrakis (tnphenylphosphine) palladium (0)
  • Ligands for example, hydrolysis-stable Phosphinhganden such as T ⁇ phenylphosphin
  • the reaction of the second stage is generally carried out in inert solvents, in the presence of an acid, preferably in a temperature range from 0 ° C. to room temperature at normal pressure
  • Inert solvent-acid mixtures are, for example, hydrochloric acid in dioxane or toluenoic acid in dichloromethane. Hydrochloric acid in dioxane is preferred at room temperature
  • the compounds of formula (Iu) can be prepared by reacting in compounds of formula (Iu).
  • the reaction is generally carried out with a reducing agent in inert solvents, preferably in a temperature range from room temperature to the reflux of the solvent at atmospheric pressure to 3 bar
  • Reducing agents are for example palladium on activated carbon and hydrogen, Zinndichlo ⁇ d or Titant ⁇ chlo ⁇ d, preferably palladium on activated carbon and hydrogen or Zinndichlo ⁇ d
  • Inert solvents are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butyl ether.
  • ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butyl ether.
  • Butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine, as solvent are preferably methanol, ethanol, iso-propanol or in the case of Zinndichlo ⁇ d in dimethylformamide
  • the phthalimide protecting group is cleaved.
  • the reaction is generally carried out with an aqueous methylamine solution or a hydrazine hydrate solution in ethanol, preferably with an aqueous methylamine solution under reflux of the solvent at atmospheric pressure.
  • the compounds of the formula (XII) are known, can be prepared from the corresponding epoxides as described under process [A] or can be synthesized by known processes from the corresponding starting compounds.
  • the compounds of the invention show an unpredictable, valuable spectrum of pharmacological activity.
  • the compounds according to the invention are inhibitors of the blood coagulation factor Xa, which act in particular as anticoagulants.
  • the compounds according to the invention have favorable physicochemical properties and a broad therapeutic range, which is advantageous for their therapeutic use.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, preferably of thromboembolic diseases and / or thromboembolic complications.
  • thromboembolic disorders include in particular diseases such as myocardial infarction with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI), stable angina pectoris, unstable angina pectoris, reocclusions and Restenosis after coronary interventions such as angioplasty or aortocoronary bypass, peripheral arterial occlusive diseases, pulmonary embolism, deep venous thrombosis and renal vein thrombosis, transient ischemic attacks and thrombotic and thromboembolic stroke.
  • diseases such as myocardial infarction with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI)
  • stable angina pectoris such as myocardial infarction with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI)
  • unstable angina pectoris unstable angina pectoris
  • reocclusions and Restenosis after coronary interventions such as angioplasty or aortocoronary bypass
  • the substances are therefore also useful in the prevention and treatment of cardiogenic thromboembolic events, such as brain ischemia, stroke and systemic thromboembolic and ischaemias, in patients with acute, intermittent or persistent cardiac arrhythmias, such as atrial fibrillation, and those undergoing cardioversion in patients with valvular heart disease or with artificial heart valves
  • Thromboembolic complications also occur in microangiopathic hemolytic anemias, extracorporeal blood circuits such as hemodialysis, and heart valve prostheses
  • the compounds according to the invention are also suitable for the prophylaxis and / or treatment of atherosclerotic vascular diseases and inflammatory diseases such as rheumatic diseases of the musculoskeletal system, moreover also for the prophylaxis and / or treatment of Alzheimer's disease Tumor growth and metastasis, in microangiopathies, age-related macular degeneration, diabetic retinopathy, diabetic nephropathy and other microvascular diseases and in the prevention and treatment of thromboembolic complications, such as venous thromboembolic, in tumor patients, especially those undergoing major surgery or chemotherapy. or undergo radiotherapy
  • the compounds according to the invention are also suitable for the prophylaxis and / or treatment of pulmonary hypertension
  • pulmonary hypertension includes certain forms of pulmonary hypertension. Examples include pulmonary arterial hypertension, pulmonary hypertension in diseases of the left heart, pulmonary hypertension in pulmonary disease and / or hypoxia, and pulmonary hypertension due to chronic thromboembolism (CTEPH).
  • CTEPH chronic thromboembolism
  • pulmonary arterial hypertension covers certain forms of pulmonary hypertension, such as those defined by the World Health Organization (WHO) (Chnical Classification of Pulmonary Hypertensives, Venice, 2003).
  • WHO World Health Organization
  • Pulmonary arterial hypertension includes idiopathic pulmonary arterial hypertension (IP AH, also referred to as primary pulmonary hypertension), familial pulmonary arterial hypertension (FPAH) and associated pulmonary arterial hypertension (APAH), which is associated with collagen, congenital systemic pulmonary shunt veins, portal hypertension, HIV infections, the use of certain drugs and medicines, with other diseases (thyroid diseases, glycogen storage diseases, Gaucher disease, medical telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy), with diseases with significant venous / capillary involvement, such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, as well as persistent pulmonary hypertension in newborns.
  • IP AH idiopathic pulmonary arterial hypertension
  • FPAH familial pulmonary arterial hypertension
  • APAH pulmonary arterial hypertension
  • diseases with significant venous / capillary involvement such as pulmonary veno-occlusive disease and pulmonary
  • Pulmonary hypertension in left heart disease includes left atrial or ventricular disease and mitral or aortic valve failure.
  • Pulmonary hypertension in lung disease and / or hypoxia includes chronic obstructive pulmonary disease, interstitial lung disease, sleep apnea syndrome, alveolar hypoventilation, chronic altitude sickness, and plant-related malformations.
  • Pulmonary hypertension due to chronic thromboembolism includes thrombembolic occlusion of proximal pulmonary arteries, thromboembolic occlusion of distal pulmonary arteries, and non-thrombotic pulmonary embolisms (tumor, parasites, foreign bodies).
  • Another object of the present invention is the use of factor Xa inhibitors for the preparation of medicaments for the treatment and / or prophylaxis of pulmonary hypertension in sarcoidosis, histiocytosis X and Lymphangiomatosis.
  • the substances according to the invention are also suitable for the treatment of pulmonary and hepatic fibroses.
  • the compounds according to the invention also come for the treatment and / or prophylaxis of sepsis (or septicemia), systemic inflammatory syndrome (SIRS), septic organ dysfunction, septic organ failure and multi-organ failure, Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury (ALI), Septic shock, DIC ("Disseminated Intravascular Coagulation", or “Consumption Coagulopathy”) and / or septic organ failure.
  • SIRS systemic inflammatory response syndrome
  • DIC Dispersed Intravascular Coagulation
  • Consumption Coagulopathy hereinafter referred to as "DIC”
  • DIC Consption Coagulopathy
  • it may endothelially damage with increase in vascular permeabilization and escape of fluid and proteins into the extravascular space.
  • an organ failure eg kidney failure, liver failure, respiratory failure, central nervous deficits and cardiovascular failure
  • Septic shock refers to the occurrence of a blood pressure reduction that requires treatment. which favors a further organ damage and is accompanied by a worsening of the prognosis
  • Pathogens can be bacteria (gram-negative and gram-positive), fungi, viruses and / or eukaryotes.
  • the portal of entry or pneumonia can be eg pneumonia, urinary tract infection, peritonitis.
  • the infection may, but not necessarily, be accompanied by bacteremia
  • DIC and / or SIRS can occur as a result of sepsis, but also as a result of surgeries, tumors, burns or other injuries.
  • DIC leads to the upper compartment of damaged endothelial cells, foreign body surfaces or extravasated extravascular tissue as a result of massive activation of the gene system
  • Ge ⁇ nnungsmiden eg factor X, prothrombin and fibrinogen
  • platelets whereby the coagulability of the blood is reduced and severe bleeding can occur
  • the therapy of sepsis consists on the one hand in the consequent elimination of the infectious cause, eg by operative herdsan ist and antibiosis on the other hand it consists in the temporary intensive medical support of the impaired organ systems therapies of the various stages of this disease are described eg in the following publication (Dellinger et al, Ctt Care Med 2004, 328, 858-873) There are no proven effective therapies for DICs
  • compositions containing a compound according to the invention and one or more further active compounds, in particular for the treatment and / or prophylaxis of the abovementioned diseases are by way of example and by way of example • Antibiotic therapy
  • antibiotics or antifungal drug combinations may be considered, either as a calculated therapy (before the presence of the microbial condition) or as a specific therapy
  • Fluid therapy for example, cystalloids or colloidal fluids
  • Vasopressors eg B Norepinephrine, Dopamine or Vasopressin
  • Corticosteroids eg B hydrocortisone, or fludrocortisone
  • Blood products eg B red blood cell concentrates, platelet concentrates, erythropietin or fresh frozen plasma
  • Sedation eg B Diazepam, Lorazepam, Midazolam or Propofol Opioids eg B Fentanyl, Hydromorphone, Morphine, Mepe ⁇ din or Rermfentanil NSATDs eg B Ketorolac, Ibuprofen or Acetaminophen Neuromuscular blockade eg B Pancuronmm
  • Renal replacement therapy eg continuous veno-venous hemofiltration or intermittent hemodialysis dopamine low-dose for renal protection
  • anticoagulants eg for thrombosis prophylaxis or in renal replacement therapy, eg unfractionated heparins, low molecular weight heparin, hepannoids, hirudin, bivirudin or argatroban
  • the compounds according to the invention can also be used ex vivo to prevent coagulation, for example for the preservation of blood and plasma products, for the purification / pretreatment of catheters and other medical aids and devices, for the coating of artificial surfaces used in vivo or ex vivo medical devices and devices or biological samples containing factor Xa
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases
  • Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using ellg an anticoagulato ⁇ sch effective amount of the inventive compound
  • Another object of the present invention is a method for preventing blood coagulation in vitro, especially in blood or biological samples containing factor Xa, which is characterized in that an anticoagulation effective amount of the compound of the invention is added
  • Another object of the present invention are combinations of
  • Platelet aggregation inhibitors are, for example, acetylsalicylic acid (such as aspirin), ticlopidine (ticlid), clopidogrel (Plavix) and prasugrel,
  • glycoprotein IIb / IIIa antagonists such as abciximab, eptifibatide, tirof ⁇ ban, lamif ⁇ ban, lefradafiban and fradafiban.
  • Anticoagulant substances are for example heparin (UFH), low molecular weight heparins (LMWH) such as tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, danaparoid,
  • UHF heparin
  • LMWH low molecular weight heparins
  • ORG42675 (Organon International Ine, Company World Wide Website 2007, April),
  • DTI direct thrombin inhibitors
  • Direct thrombin inhibitors are, for example:
  • Plasminogen activators include tissue plasminogen activator (t-PA), streptokinase, reteplase and urokinase.
  • lipid lowering agents are HMG-CoA- (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors such as lovastatin (Mevacor, US 4,231,938), simvastatin (Zocor, US Pat 4,444,784), pravastatin (Pravachol, US 4,346,227), fluvastatin (Lescol, US 5,354,772) and atorvastatin (L ⁇ itor, US 5,273,995)
  • HMG-CoA- (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors such as lovastatin (Mevacor, US 4,231,938), simvastatin (Zocor, US Pat 4,444,784), pravastatin (Pravachol, US 4,346,227), fluvastatin (Lescol, US 5,354,772) and atorvastatin (L ⁇ itor, US 5,273,995)
  • Coronary / vasodilators are particularly ACE (angiotensin converting enzyme) inhibitors such as Captop ⁇ l, Lisinopril, Enalapril, Ramipril, Cilazapril, Benazepril, Fosinopril, Quinapril and Penndop ⁇ l, or AH (angiotensin II) receptor antagonists such as Embusartan (US 5,863,930), losartan, valsartan, irbesartan, candesartan, eprosartan and temisartan, or ⁇ -adrenoceptor antagonists such as carvedilol, alprenolol, bisoprolol, acebutolol, atenolol, betaxolol, carteolol, metoprolol, nadolol, penbutolol, pindolol, propranolol and timolol or alpha-1-a
  • compositions containing at least one inventive compound usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above
  • compositions containing a compound according to the invention and one or more further of the aforementioned combination active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases
  • 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, pulmonarily, 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 forms of aphcation
  • suitable forms of aphcation which contain the compounds according to the invention in crystalline and / or amorphized and / or dissolved form, such as tablets (non-toxic). coated 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, films / lyophilisates, capsules (eg hard or soft gelatin capsules), dragees rapidly disintegrating in the oral cavity , Granules, pellets, powders, emulsions, suspensions, aerosols or solutions
  • the parenteral administration can be done bypassing a Resorptionsschnttes (eg, intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with involvement of a resorption (eg, intramuscular, subcutaneous, mtracutan, percutan or intrape ⁇ toneal)
  • a Resorptionsschnttes eg, intravenous, intraarterial, intracardiac, intraspinal or intralumbar
  • a resorption eg, intramuscular, subcutaneous, mtracutan, percutan or intrape ⁇ toneal
  • parenteral administration are suitable as application forms, inter alia and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders
  • z B inhalable drugs including powder inhalers, Nebuhzer
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets to be applied films / wafers or capsules
  • Supposito ⁇ en ear or eye preparations
  • vaginal capsules For example, suspensions (lotions, mixtures of sponges), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg plaster), milk, pastes, foams, scattering powders, implants or stents
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients include, inter alia, carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (eg liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (for example antioxidants such as ascorbic acid), dyes (eg inorganic pigments such as iron oxides) and flavor and / or odorants
  • carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents eg liquid polyethylene glycols
  • emulsifiers and dispersing or wetting agents for example sodium dodecyl sul
  • the dosage is about 001 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
  • Method 1 Instrument: HP 1100 with DAD Detection; Column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 ⁇ m; Eluent A: 5 ml perchloric acid (70%) / 1 water, eluent B: acetonitrile; Gradient: 0 min 2% B ⁇ 0.5 min 2% B ⁇ 4.5 min 90% B ⁇ 6.5 min 90% B -> 6.7 min 2% B ⁇ 7.5 min 2% B; Flow: 0.75 ml / min; Column temperature: 30 ° C .; UV detection: 210 nm.
  • Method 2 Instrument: HP 1100 with DAD Detection; Column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 ⁇ m; Eluent A: 5 ml perchloric acid (70%) / 1 water, eluent B: acetonitrile; Gradient: 0 min 2% B -> 0.5 min 2% B ⁇ 4.5 min 90% B ⁇ 9 min 0% B ⁇ 9.2 min 2% B ⁇ 10 min 2% B; Flow: 0.75 ml / min; Column temperature: 30 ° C .; UV detection: 210 nm.
  • Method 3 Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A ⁇ 2.5 min 30% A ⁇ 3.0 min 5% A ⁇ 4.5 min 5% A; 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.
  • Method 4 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; Gradient: 0.0 min 90% A ⁇ 2.5 min 30% A ⁇ 3.0 min 5% A -> 4.5 min 5% A; 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.
  • Method 5 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; 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; Gradient: 0.0 min 90% A ⁇ 2.5 min 30% A ⁇ 3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C .; UV detection: 208-400 nm.
  • Method 6 Instrument: Micromass Platform LCZ with HPLC Agilent Series 1 100; Column: Thermo HyPURITY Aquastar 3 ⁇ 50 mm x 2.1 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 100% A -> 0.2 min 100% A ⁇ 2.9 min 30% A ⁇ 3.1 min 10% A ⁇ 5.5 min 10% A; Oven: 50 ° C .; Flow: 0.8 ml / min; UV detection: 210 nm.
  • Method 7 Instrument: HP 1 100 with DAD Detection; Column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 ⁇ m; Eluent A: 5 ml perchloric acid (70%) / 1 water, eluent B: acetonitrile; Gradient: 0 min 2% B ⁇ 0.5 min 2% B ⁇ 4.5 min 90% B -> 15 min 90% B ⁇ 15.2 min 2% B ⁇ 16 min 2% B; Flow: 0.75 ml / min; Column temperature: 30 ° C .; UV detection: 210 nm.
  • Method 8 Device Type MS: Waters ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Onyx Monolithic C18, 100 mm x 3 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A ⁇ 2 min 65% A ⁇ 4.5 min 5% A ⁇ 6 min 5% A; Flow: 2 ml / min; Oven: 4O 0 C; UV detection: 210 nm.
  • Method 9 Instrument: Micromass GCT, GC6890; Column: Restek RTX-35MS, 30 m ⁇ 250 ⁇ m ⁇ 0.25 ⁇ m; constant flow with helium: 0.88 ml / min; Oven: 6O 0 C; Inlet: 250 ° C; Gradient: 6O 0 C (0.30 min hold), (1.7 min hold) 50 ° C / min ⁇ 120 0 C, 16 ° C / min ⁇ 250 0 C, 30 ° C / min ⁇ 300 0C.
  • Method 10 Instrument: Micromass GCT, GC6890; Column: Restek RTX-35, 15 m ⁇ 200 ⁇ m ⁇ 0.33 ⁇ m; constant flow with helium: 0.88 ml / min; Oven: 70 ° C; Inlet: 25O 0 C; Gradient: 70 0 C, 30 ° C / min ⁇ 310 0 C (3 min hold).
  • Method 1 Column: GROM-SIL 120 ODS-4 HE, 10 ⁇ M, 250 mm x 30 mm; Flow: 50 ml / min; Mobile phase and gradient program: acetonitrile / 0.1% aqueous formic acid 10:90 (0-3 min), acetonitrile / 0.1% aqueous formic acid 10:90 ⁇ 95: 5 (3-27 min), acetonitrile / 0.1% aqueous formic acid 95: 5 ( 27-34 min), acetonitrile / 0.1% aqueous formic acid 10:90 (34-38 min); Temperature: 22 ° C; UV detection: 254 nm.
  • Eme solution of 673 mg (3 00 mmol) of the compound of Example 9A in 10 ml of anhydrous DMF is treated with 543 mg (3 60 mmol) tert -Butyldimethylsilylchlo ⁇ d and 306 mg (4 50 mmol) of imidazole and stirred at room temperature After two hours Most of the DMF is removed on a rotary evaporator, the residue is taken up in dichloromethane and washed with water. Drying over anhydrous magnesium sulfate, filtration and rotary evaporation gives 963 mg (95% of theory) of the title compound
  • this solution of zinc enolate is transferred via a syringe in another flask, in which a solution of 1.50 g (3.60 mmol), 103 mg (0.180 mmol) of bis (dibenzylideneacetone) palladium (0) and 106 mg (0.270 mmol) of 2-dicyclohexylphosphino-2'- ( ⁇ fN-dimethylamino) biphenyl is in 8 ml of anhydrous THF. The reaction mixture is heated to reflux for 19 hours.
  • the THF is removed on a rotary evaporator, the residue taken up with ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous sodium sulfate, filtering, and rotary evaporation, the product is purified by flash chromatography over silica gel with cyclohexane / ethyl acetate 1: 1 as eluent. 1.12 g (78% of theory) of the title compound are obtained.
  • Residue is purified by suction filtration through silica gel with cyclohexane / ethyl acetate 20 1 ⁇ 1 l as eluent. 9 43 g (66% of theory) of the title compound are obtained
  • Example 8A Analogously to the process described under Example 8A, from 854 mg (1.79 mmol) of the product from Example 18A and 429 mg (1.97 mmol) of the compound from Example 4A, 785 mg (63% of theory) of the title compound are obtained.
  • the reaction time is 2 days.
  • Example 8A Analogously to the process described under Example 8A, from 161 mg (0.718 mmol) of the product from Example 27A and 259 mg (1.15 mmol) of the compound from Example 4A, 212 mg (65% of theory) of the title compound are obtained and, at the same time, 27 mg (17% of theory) of the compound of Example 27A recovered.
  • the reaction time is 40 hours.
  • Example 6A Analogously to the process described under Example 6A, 1.5 g (3.59 mmol) of the compound from Example 5A and 0.77 g (6.74 mmol) of 1-methyltetrahydropyrimidine-2 (// f) -one (CAS No. 10166-54-8) to 1.28 g (88% of theory) of the title compound.
  • the reaction time is 40 hours.
  • Example 44A 109 mg (0.453 mmol) of the hydrochloride from Example 44A are converted into the free base as described in Example 42A. Subsequently, the aniline thus obtained is reacted with 109 mg (0.498 mmol) of the compound from Example 4A to 110 mg (57% of theory) of the title compound analogously to the process described under Example 8 A.
  • the organic extract is added After drying over anhydrous sodium sulfate, it is filtered and the filtrate is freed from the solvent on a rotary evaporator.
  • the crude product is first freed from coarse impurities by means of suction filtration over silica gel with cyclohexane / ethyl acetate 5 1 ⁇ 1 l as the eluent. Subsequently, the product is purified by preparative HPLC isolated. 2.1 g of the crude product obtained are dissolved in 5 ml of acetonitrile and in 10 portions of chromatographies.
  • the diastereomeric mixture from example 2 is separated on a preparative scale by chromatography into the pure diastereomers. For this purpose, 390 mg of the compound from Example 2 are dissolved in 30 ml of the mobile phase and chromatographed in 75 portions. 161 mg (41% of theory) of the title compound (diastereomer 1) and 169 mg (43% of theory) of diastereomer 2 are obtained.
  • the diastereomeric mixture from example 2 is separated on a preparative scale by chromatography into the pure diastereomers. For this purpose, 390 mg of the compound from Example 2 are dissolved in 30 ml of the mobile phase and chromatographed in 75 portions. 169 mg (43% of theory) of the title compound (diastereomer 2) and 161 mg (43% of theory) of diastereomer 1 are obtained.
  • the diastereomer mixture from example 5 is separated on a preparative scale by chromatography into the pure diastereomers.
  • 432 mg of the compound from Example 5 are dissolved in a mixture of 10 ml of methanol, 10 ml of rerr.-butyl methyl ether and 5 ml of acetonitrile and chromatographed in ten portions.
  • 182 mg (42% of theory) of the title compound (diastereomer 1) and 156 mg (36% of theory) of diastereomer 2 are obtained.
  • the diastereomeric enzyme of Example 5 is chromatographically separated on a preparative scale into the pure diastereomers.
  • 432 mg of the compound from Example 5 are dissolved in a mixture of 10 ml of methanol, 10 ml of tert-butyl methyl ether and 5 ml of acetomeltin and chromatographed in ten portions mg (36% of theory) of the title compound (diastereomer 2) and 182 mg (42% of theory) of diastereomer 1 were obtained
  • the diastereomer mixture from Example 8 is separated on a preparative scale by chromatography into the pure diastereomers. For this purpose, 223 mg of the compound from Example 8 are dissolved in 20 ml of the solvent and chromatographed in 50 portions. 105 mg (47% of theory) of the title compound (diastereomer 1) and 114 mg (51% of theory) of diastereomer 2 are obtained.
  • the diastereomer mixture from Example 8 is separated by chromatography on a preparative scale into the pure diastereomers. 223 mg of the compound from Example 8 are dissolved in 20 ml of the solvent and chromatographed in 50 portions. 114 mg (51% of theory) of the title compound ( Diastereomer 2) and 105 mg (47% of theory) of diastereomer 1 were obtained.
  • a solution of 179 mg (0.367 mmol) of the product from Example 56A in 1.9 ml of THF is admixed with 1.9 ml of water, 92 ⁇ l of a 2.5% solution of osmium tetraoxide in tert-butanol and 235 mg (1.10 mmol) of sodium periodate.
  • the reaction mixture is stirred for 15 hours at room temperature. It is then diluted with water and extracted with dichloromethane. The organic extract is filtered after drying over anhydrous magnesium sulfate and freed from the solvent on a rotary evaporator.
  • Chromathography method Column: Kromasil 100C18, 5 ⁇ m, 250 mm x 20 mm; Flow: 25 ml / min; Temperature: 40 ° C .; UV detection: 210 nm; Eluent: water / acetonitrile 3: 1.
  • the compounds of the invention act in particular as inhibitors of the blood coagulation factor Xa and do not inhibit or only at significantly higher concentrations, other serine proteases such as plasmin or trypsin.
  • FXa human factor Xa
  • the enzymatic activity of human factor Xa is measured by the reaction of a FXa-specific chromogenic substrate.
  • the factor Xa cleaves from the chromogenic substrate p-nitroaniline.
  • the determinations are carried out in microtiter plates as follows:
  • the control is pure DMSO.
  • the chromogenic substrate 150 .mu.mol / 1 Pefachrome ® FXa from Pentapharm
  • the absorbance at 405 nm is determined. The extinctions of the test mixtures containing test substance are compared with the control mixtures without test substance from
  • FXa human factor Xa
  • Substances to be tested are dissolved in dimethyl sulfoxide at various concentrations and incubated for 15 min with human FXa (1.3 nmol / l dissolved in 50 mmol / l Tris buffer [C, C, C]).
  • test substances are tested for their inhibition of other human secretions such as thrombin, trypsin and plasmin.
  • thrombin 75 mU / ml
  • trypsin 500 mU / ml
  • plasmin 3.2 nmol / 1
  • test substances are tested for their inhibition of other human secretions such as thrombin, trypsin and plasmin.
  • thrombin (0.06 nmol / 1 von Kordia)
  • trypsin 83 mU / ml from Sigma
  • Plas ⁇ un (0 1 ug / ml of Kordia)
  • these enzymes are dissolved (50 mmol / 1 T ⁇ s buffer [C, C, C-T ⁇ s (hydroxymethyl) -aminomethan] , 100 mmol / 1 NaCl, 0 1% BSA [bovine serum albumin], 5 mmol / l Calciumchlo ⁇ d, pH 7 4) and incubated for 15 min with Prufsubstanz in various concentrations in dimethyl sulfoxide and with Dimethylsulföxid without Prufsubstanz then the enzymatic reaction by addition of the respective substrates (5
  • the Antikoagulatonsche effect of Prufsubstanzen is determined in vitro in human and rabbit plasma
  • blood is removed using a 0 11 molar Nat ⁇ umcitrat solution as a template in a mixing ratio Nat ⁇ umcitrat / blood 1 9
  • the blood is mixed well immediately after the decrease and at 10 minutes about 2500 g zent ⁇ fugiert
  • the supernatant is pipetted off
  • the prothrombin time (PT, synonyms thromboplastin time, Quick-Test) is determined in the presence of varying concentrations of Prufsubstanz or the corresponding solvent with a commercial test kit (Hemohance ® RecombiPlastin, Fa Instrumentation Laboratory)
  • the test compounds are 3 minutes incubated with the plasma at 37 ° C.
  • coagulation is triggered by the addition of thromboplastin and the time of coagulation is determined.
  • the concentration of test substance is determined which causes a doubling of the prothrombin time
  • thrombin In Thrombin Generation Assay according to Hemker, the activity of thrombin in clotting plasma is determined by measuring the fluorescent cleavage products of substrate I-1 140 (Z-Gly-Gly-Arg-AMC, Bachern). The reactions are carried out in 20 mM Hepes, 60 mg / ml BSA, 102 mM CaCl 2 , pH 7 5 at 37 ° C.
  • the reactions are carried out in Immulon 2HB clear U-bottom 96-well plates (Thermo Electron) in a total volume of 100 ⁇ l
  • PPP platelet poor plasma
  • PRP platelet-rich plasma
  • a Cahbrator is needed whose amidolytic activity for the calculation of Thrombin activity in a sample with an unknown amount of thrombin is also required.
  • the cahbrator enables the correction of the data with respect to the donor vein distilate (different staining of the plasmid) as), the variability of the measuring device, the "inner filter effect" and the substrate consumption
  • the measurement is carried out with a fluorometer (Fluoroskan Ascent) from Thermo Electron, which is equipped with a 390/460 nM filter pair and a dispenser.
  • Test procedure Dissolve lyophilisates Incubate MTP for 5 min at 37 ° C., prepare FIuCa (70 ⁇ l 1-1140 + 2800 ⁇ l Fluo buffer (20 mM HEPES, 102 mM CaCl 2 , 60 mg / ml BSA), (PPP reagent, PRP reagent, cahbrator). pH 7 5) per plate), starting the program, spooling the dispenser and filling the system with FluoCa, adding 20 ⁇ l FluoCa per well and measuring the thrombin generation, 120 min every 20s (or in animal plasma every 10 s) "Thrombinoscope software" calculates and plots the thrombogram.
  • FIuCa 70 ⁇ l 1-1140 + 2800 ⁇ l Fluo buffer (20 mM HEPES, 102 mM CaCl 2 , 60 mg / ml BSA), (PPP reagent, PRP reagent, cahbrator). pH 7 5) per
  • lag time time to start thrombin generation
  • ttPeak time to peak, peak to peak
  • peak maximum thrombin kin ntration
  • ETP endogenous thrombin potential, the area under the curve
  • start tail time at which the thrombin concentration goes back to 0
  • Thrombin-antithrombin complexes are a measure of thrombin endogenously formed by coagulation activation TAT are determined by means of an ELISA assay (Enzygnost TAT micro, Dade-Beh ⁇ ng). Plasma is obtained from citrated blood by centrifugation Plasma is added to 50 ⁇ l of TAT sample buffer, shaken briefly and incubated for 15 min at room temperature. The samples are aspirated and the well washed 3 times with wash buffer (300 ⁇ l / well) The plate is tapped between washings Add conjugate solution (100 ⁇ l) and incubate for 15 minutes at room temperature.
  • endotoxin-induced inflammatory response can be demonstrated by the increase in inflammatory mediators in plasma, for example interleukins (1, 6, 8 and 10), tumor necrosis factor alpha or monocyte chemoattractant protein. 1 ELISAs or the Lummex system can be used for this purpose
  • Fasting rabbits (Esd NZW strain) are anesthetized by intramuscular administration of a Rompun / Ketavet solution (5 mg / kg or 40 mg / kg) Thrombus formation is induced in an arteriovenous shunt following CN Berry et al [Semin Thromb Hemost 1996 For this the left vena jugula ⁇ s and the right carotid artery are dislocated.
  • An extracorporeal shunt is placed between the two vessels by means of a 10 cm long venous catheter. This catheter is in the middle in another, 4 cm long Polyethylene tubing (PE 160, Becton Dickenson) incorporating a roughened and looped nylon thread to create a thrombogenic surface.
  • PE 160 Polyethylene tubing
  • the extracorporeal circuit is maintained for 15 minutes. Then the shunt is removed and the nylon thread with the thrombus weighed immediately Nylon filament was determined before the start of the test. The test substances are tested before application the extracorporeal circulation administered either intravenously via an ear vein or orally by gavage
  • the antithrombotic efficacy of the substances is investigated in an established venous thrombosis model (method s also Ref 1 -3) in rats Venous thrombi are produced by a combination of blood flow arrest and thromboplastm injection Male rats (HSD CPB WU, Harlan Winkelmann) with a Weight of 220g-260g are fasted overnight. Water is available ad libitum.
  • a xylazine / ketamine mixture (5 ml / kg) (Rompun Bayer 12 mg / kg, Ketavet Pharmacia & Upjohn GmbH, 50 mg / kg) anesthetized
  • the left vena jugula ⁇ s and the abdominal vena cava are freeprepared
  • a catheter is inserted into the vena jugula ⁇ s
  • a loop is placed around the vena cava proximally and distally at a distance of 8-10 mm in order to later set this vein section
  • Thromboplastm Neoplastin Plus, Diagnostica Stago, Roche
  • the vena cava is ligated, first proximally, then distally after 30 seconds.
  • the harvested vein segment is excised 15 minutes after thromboplastm
  • test substances are administered either intravenously via the contralateral jugular vein as a single bolus or as a bolus followed by continuous infusion or orally by means of a gavage, prior to application of the extracorporeal circuit and tail tip incision.
  • Fasting rats are anesthetized by intraperitoneal administration of thiobarbital sodium (inactin) (180 mg / kg).
  • a catheter (PE 190) is pushed into the abdominal aorta and blood collected for the determination of the substance plasma concentration as well as the ex-vivo specific
  • Blood clotting (FXa, PT, aPTT, thrombin generation assay, etc.). Substance administration was carried out orally at various times before taking blood. It will be the substances in the
  • PBS buffer pH 7.4 90.00 g NaCl pa (eg Merck Art. No. 1.06404.1000), 13.61 g KH 2 PO 4 pa (eg Merck Art. No. 1.04873.1000) and 83.35 g IN NaOH (eg Bernd Kraft GmbH Art. No. 01030.4000) into a 1 1 volumetric flask, fill up with water and stir for about 1 hour.
  • NaCl pa eg Merck Art. No. 1.06404.1000
  • KH 2 PO 4 pa eg Merck Art. No. 1.04873.1000
  • 83.35 g IN NaOH eg Bernd Kraft GmbH Art. No. 01030.4000
  • Acetate buffer pH 4.6 Weigh out 5.4 g sodium acetate x 3 H 2 O pa (eg Merck Art. No. 1.06267.0500) into a 100 ml volumetric flask, dissolve in 50 ml water, add 2.4 g glacial acetic acid, make up to 100 ml with water , Check pH value and adjust to pH 4.6 if necessary.
  • Dimethyl sulfoxide e.g., Baker Art. No. 7157,2500
  • Calibration solution 2 (2 5 ⁇ g / ml) 100 ⁇ l of Kahb ⁇ erlosung 1 are mixed with 700 ⁇ l of DMSO and homogenized
  • the sample solutions thus prepared are shaken for 24 hours at 1400 rpm in a temperature shaker (for example, Eppendorf Thermomixer comfort Art. No. 5355 000.011 with shift block Nr. 5362.000.019) at 20 0 C. 180 ⁇ l of these solutions are taken in each case and transferred to Beckman Polyallomer Centrifuge Tubes (Item No. 343621). These solutions are centrifuged for 1 hour at approximately 223,000 ⁇ g (eg Beckman Optima L-90K ultra-centrifuge with Type 42 2 Ti rotor at 42,000 rpm ).
  • the samples are analyzed by RP-HPLC. Quantification is done by a two-point calibration curve of the test compound in DMSO. Loss is expressed in mg / l

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Communicable Diseases (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne de nouveaux oxazolidinones substitués de formule (I), des procédés pour leur fabrication, leur utilisation pour le traitement et/ou la prévention de maladies et leur utilisation pour la fabrication de médicaments destinés au traitement et/ou à la prévention de maladies, notamment de maladies thromboemboliques. Formule (I) avec R'= formule (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) ou (Ii).
EP08759100A 2007-06-20 2008-06-07 Oxazolidinones substitués et leur utilisation Withdrawn EP2167495A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102007028320A DE102007028320A1 (de) 2007-06-20 2007-06-20 Substituierte Oxazolidinone und ihre Verwendung
PCT/EP2008/004564 WO2008155034A1 (fr) 2007-06-20 2008-06-07 Oxazolidinones substitués et leur utilisation

Publications (1)

Publication Number Publication Date
EP2167495A1 true EP2167495A1 (fr) 2010-03-31

Family

ID=39765012

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08759100A Withdrawn EP2167495A1 (fr) 2007-06-20 2008-06-07 Oxazolidinones substitués et leur utilisation

Country Status (26)

Country Link
US (1) US20100184767A1 (fr)
EP (1) EP2167495A1 (fr)
JP (1) JP2010530385A (fr)
KR (1) KR20100029213A (fr)
CN (1) CN101772496A (fr)
AR (1) AR067058A1 (fr)
AU (1) AU2008266527A1 (fr)
BR (1) BRPI0813263A2 (fr)
CA (1) CA2692172A1 (fr)
CL (1) CL2008001703A1 (fr)
CO (1) CO6251282A2 (fr)
CR (1) CR11169A (fr)
DE (1) DE102007028320A1 (fr)
DO (1) DOP2009000287A (fr)
EC (1) ECSP099806A (fr)
GT (1) GT200900318A (fr)
IL (1) IL202073A0 (fr)
MA (1) MA31570B1 (fr)
MX (1) MX2009013710A (fr)
PA (1) PA8784101A1 (fr)
PE (1) PE20090333A1 (fr)
RU (1) RU2010101302A (fr)
TN (1) TN2009000484A1 (fr)
TW (1) TW200914447A (fr)
UY (1) UY31136A1 (fr)
WO (1) WO2008155034A1 (fr)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102464658B (zh) * 2010-11-03 2014-04-16 天津药物研究院 噁唑烷酮衍生物及其制备方法和用途
CA2824885A1 (fr) 2011-01-19 2012-07-26 Bayer Intellectual Property Gmbh Proteines de liaison a des inhibiteurs de facteurs de coagulation
CZ2012114A3 (cs) * 2012-02-17 2013-02-20 Zentiva, K.S. Zpusob prípravy rivaroxabanu zalozený na úspore 1,1´ -karbonyldiimidazolu
AU2013250801A1 (en) * 2012-04-16 2014-11-06 Sun Pharmaceutical Industries Limited Process for the preparation of rivaroxaban and intermediates thereof
RU2701156C9 (ru) 2012-07-18 2019-12-18 Саншайн Лейк Фарма Ко., Лтд. Азотсодержащие гетероциклические производные и их применение в фармацевтических препаратах
CN102746250B (zh) * 2012-07-24 2016-03-02 瑞阳制药有限公司 N-[[3-(3-氟-4-吗啉基-4-基-苯基)-2-恶唑酮基-5-基]甲基]-2-甲氨基-苯甲酰胺的制备方法
CN103833724A (zh) * 2012-11-20 2014-06-04 上海医药工业研究院 一种5-氯噻吩-2-甲酰氯的制备方法
CN103242307B (zh) * 2013-05-17 2015-08-12 天津药物研究院有限公司 一种噁唑烷酮类衍生物晶型ⅰ及其制备方法和用途
WO2014183667A1 (fr) * 2013-05-17 2014-11-20 天津药物研究院 Solvate d'acide acétique de dérivé d'oxazolidinone, procédé de préparation dudit solvate, et application associée
US9981940B2 (en) 2013-06-20 2018-05-29 Bayer Cropscience Aktiengesellschaft Aryl sulfide derivatives and aryl sulfoxide derivatives as acaricides and insecticides
CN105722830B (zh) 2013-06-20 2019-06-04 拜耳作物科学股份公司 作为杀螨剂和杀昆虫剂的芳基硫醚衍生物和芳基亚砜衍生物
TW201542532A (zh) 2013-07-08 2015-11-16 Bayer Cropscience Ag 作為殺蟲劑的六員ｃ－ｎ－鍵結之芳基硫化物及芳基亞碸衍生物
CN104016975B (zh) * 2014-06-27 2017-01-11 深圳翰宇药业股份有限公司 利伐沙班的制备方法
CN104447729A (zh) * 2014-12-05 2015-03-25 广东东阳光药业有限公司 噁唑烷酮类化合物及其在药物中的应用
EP3078378B1 (fr) 2015-04-08 2020-06-24 Vaiomer Utilisation d'inhibiteurs du facteur xa destinés à réguler la glycémie
IL275443B (en) * 2018-02-26 2022-07-01 Sumitomo Chemical Co Production method for an oxazolidinan compound
KR102422628B1 (ko) 2020-03-20 2022-07-18 마인도어 사회적협동조합 보드 게임 도구

Family Cites Families (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4231938A (en) 1979-06-15 1980-11-04 Merck & Co., Inc. Hypocholesteremic fermentation products and process of preparation
US4444784A (en) 1980-08-05 1984-04-24 Merck & Co., Inc. Antihypercholesterolemic compounds
DK149080C (da) 1980-06-06 1986-07-28 Sankyo Co Fremgangsmaade til fremstilling af derivater af ml-236b-carboxylsyre
US5354772A (en) 1982-11-22 1994-10-11 Sandoz Pharm. Corp. Indole analogs of mevalonolactone and derivatives thereof
FI94339C (fi) 1989-07-21 1995-08-25 Warner Lambert Co Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi
DE4319041A1 (de) 1992-10-23 1994-04-28 Bayer Ag Trisubstituierte Biphenyle
DE19642255A1 (de) 1996-10-14 1998-04-16 Bayer Ag Verwendung von 1-Benzyl-3-(substituierten-hetaryl) -kondensierten Pyrazol-Derivaten
AU736303B2 (en) 1996-10-14 2001-07-26 Bayer Aktiengesellschaft New heterocyclylmethyl-substituted pyrazol derivates
DE19649460A1 (de) 1996-11-26 1998-05-28 Bayer Ag Neue substituierte Pyrazolderivate
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
DE19834045A1 (de) 1998-07-29 2000-02-03 Bayer Ag (4-Amino-5-ethylpyrimidin-2-yl)-1-(2-fluorbenzyl)-1H-pyrazolo[3,4-b]pyridin
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
DE19942809A1 (de) 1999-09-08 2001-03-15 Bayer Ag Verfahren zur Herstellung substituierter Pyrimidinderivate
DE19943635A1 (de) 1999-09-13 2001-03-15 Bayer Ag Neuartige Aminodicarbonsäurederivate mit pharmazeutischen Eigenschaften
DE19943634A1 (de) 1999-09-13 2001-04-12 Bayer Ag Neuartige Dicarbonsäurederivate mit pharmazeutischen Eigenschaften
DE19943639A1 (de) 1999-09-13 2001-03-15 Bayer Ag Dicarbonsäurederivate mit neuartigen pharmazeutischen Eigenschaften
DE19943636A1 (de) 1999-09-13 2001-03-15 Bayer Ag Neuartige Dicarbonsäurederivate mit pharmazeutischen Eigenschaften
DE19962924A1 (de) * 1999-12-24 2001-07-05 Bayer Ag Substituierte Oxazolidinone und ihre Verwendung
DE10129725A1 (de) * 2001-06-20 2003-01-02 Bayer Ag Kombinationstherapie substituierter Oxazolidinone
DE10300111A1 (de) 2003-01-07 2004-07-15 Bayer Healthcare Ag Verfahren zur Herstellung von 5-Chlor-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophencarboxamid
GB0405272D0 (en) 2004-03-09 2004-04-21 Trigen Ltd Compounds
DE102005047558A1 (de) * 2005-10-04 2008-02-07 Bayer Healthcare Ag Kombinationstherapie substituierter Oxazolidinone zur Prophylaxe und Behandlung von cerebralen Durchblutungsstörungen
DE102005050497A1 (de) 2005-10-21 2007-04-26 Bayer Healthcare Ag Difluorphenol-Derivate und ihre Verwendung
DE102005050376A1 (de) 2005-10-21 2007-05-31 Bayer Healthcare Ag Dicarbonsäure-Derivate und ihre Verwendung
DE102005050375A1 (de) 2005-10-21 2007-04-26 Bayer Healthcare Ag Tetrazol-Derivate und ihre Verwendung
DE102005050377A1 (de) 2005-10-21 2007-04-26 Bayer Healthcare Ag Heterocyclische Verbindungen und ihre Verwendung
DE102005050498A1 (de) 2005-10-21 2007-06-06 Bayer Healthcare Aktiengesellschaft Cyclopropylessigsäure-Derivate und ihre Verwendung
DE102007028406A1 (de) * 2007-06-20 2008-12-24 Bayer Healthcare Ag Substituierte Oxazolidinone und ihre Verwendung
DE102007032345A1 (de) * 2007-07-11 2009-01-15 Bayer Healthcare Ag Aminoacyl-Prodrugs
DE102007032347A1 (de) * 2007-07-11 2009-01-15 Bayer Healthcare Ag Aminoacyl-Prodrugs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008155034A1 *

Also Published As

Publication number Publication date
DOP2009000287A (es) 2010-01-31
CR11169A (es) 2010-07-01
MA31570B1 (fr) 2010-08-02
GT200900318A (es) 2010-10-04
PA8784101A1 (es) 2009-02-09
MX2009013710A (es) 2010-02-01
JP2010530385A (ja) 2010-09-09
DE102007028320A1 (de) 2008-12-24
TN2009000484A1 (en) 2011-03-31
CA2692172A1 (fr) 2008-12-24
RU2010101302A (ru) 2011-07-27
ECSP099806A (es) 2010-01-29
BRPI0813263A2 (pt) 2014-12-30
WO2008155034A1 (fr) 2008-12-24
UY31136A1 (es) 2009-01-30
KR20100029213A (ko) 2010-03-16
AR067058A1 (es) 2009-09-30
CO6251282A2 (es) 2011-02-21
AU2008266527A1 (en) 2008-12-24
TW200914447A (en) 2009-04-01
PE20090333A1 (es) 2009-04-15
US20100184767A1 (en) 2010-07-22
CL2008001703A1 (es) 2008-12-26
IL202073A0 (en) 2010-06-16
CN101772496A (zh) 2010-07-07

Similar Documents

Publication Publication Date Title
EP2167495A1 (fr) Oxazolidinones substitués et leur utilisation
EP2167499B1 (fr) Oxazolidinones substituées et leur utilisation
EP1928867B1 (fr) Dérivés d'acide 2-aminoéthoxyacétique et utilisation pour le traitement de maladies thromboemboliques
EP2170877B1 (fr) (oxazolidinon-5-yl-méthyl)-2-thiophène-carboxamides substitués et leur utilisation dans le domaine de la coagulation sanguine
WO2014154794A1 (fr) Dérivés de l'oxopyridine substitués et, utilisation desdits dérivés dans le traitement des maladies cardiovasculaires
EP2029546B1 (fr) Hétérocycles substitués par un aryle et leur utilisation
DE102009022896A1 (de) Substituierte Piperidine
EP2173744B1 (fr) (oxazolidinon-5-yl-méthyl)-2-thiophène-carboxamides substitués et leur utilisation dans le domaine de la coagulation sanguine
EP1824844B1 (fr) Amides d'acide dicarboxylique de pyrazine et leur utilisation
WO2007051532A1 (fr) Derives de phenylene-bis-oxazolidine et leur utilisation en tant qu’anticoagulant
DE102004058062A1 (de) Cyclische Iminocarbamate und ihre Verwendung
DE102006025316A1 (de) Isoindolin-1-on-, Isoindolin-3-on- und Isoindolin-1,3-dion-Derivate und ihre Verwendung
WO2007137800A1 (fr) Dérivés d'isoindolin-1-one, d'isoindolin-3-one et d' isoindolin-1,3-dione et leur utilisation
EP2032567A1 (fr) Hétérocycles substitués et son utilisation
DE102005018690A1 (de) Imino-oxazolidine 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: 20100120

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 MT NL NO PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA MK RS

17Q First examination report despatched

Effective date: 20100531

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: 20101211