EP1819701A1 - Iminocarbamates cycliques et leur utilisation - Google Patents

Iminocarbamates cycliques et leur utilisation

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Publication number
EP1819701A1
EP1819701A1 EP05815274A EP05815274A EP1819701A1 EP 1819701 A1 EP1819701 A1 EP 1819701A1 EP 05815274 A EP05815274 A EP 05815274A EP 05815274 A EP05815274 A EP 05815274A EP 1819701 A1 EP1819701 A1 EP 1819701A1
Authority
EP
European Patent Office
Prior art keywords
formula
mmol
compounds
compound
phenyl
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Withdrawn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
EP05815274A
Other languages
German (de)
English (en)
Inventor
Susanne Röhrig
Jens Pohlmann
Sabine Arndt
Mario Jeske
Metin Akbaba
Elisabeth Perzborn
Christoph Gerdes
Karl-Heinz Schlemmer
Arounarith Tuch
Mario Lobell
Peter Nell
Nils Burkhardt
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 Healthcare AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Healthcare AG filed Critical Bayer Healthcare AG
Publication of EP1819701A1 publication Critical patent/EP1819701A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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

Definitions

  • the present application relates to novel cyclic iminocarbamates, processes for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the production of medicaments for the treatment and / or prophylaxis of diseases, in particular thromboembolic diseases.
  • Blood clotting is a protective mechanism of the organism that can quickly and reliably "seal" defects in the blood vessel wall, thus preventing or minimizing blood loss, and bleeding after vascular injury is essentially through the coagulation system, which involves an enzymatic cascade It involves numerous clotting factors, each of which, once activated, converts the next inactive precursor to its active form, and at the end of the cascade converts the soluble fibrinogen into the insoluble fibrin Traditionally, one distinguishes between the intrinsic and the extrinsic system of blood coagulation, which culminate in a concluding common pathway, in which the factor Xa, which is formed by the proenzyme factor X, plays a key role, as both coagulation pathway The activated serine protease Xa splits prothrombin into thrombin.
  • thrombin in turn splits fibrinogen to fibrin. Subsequent cross-linking of the fibrin monomers leads to the formation of blood clots and thus to haemostasis. In addition, thrombin is a potent trigger of platelet aggregation, which also makes a significant contribution to hemostasis.
  • Hemostasis is subject to a complex regulatory mechanism.
  • An uncontrolled activation of the coagulation system or a defective inhibition of the activation processes can cause the formation of local thromboses or embolisms in vessels (arteries, veins, lymphatics) or cardiac cavities. This can lead to serious thromboembolic diseases.
  • hypercoagulability - systemically - in case of consumption coagulopathy can lead to disseminated intravascular coagulation.
  • Thromboembolic complications also occur in microangiopathic hemolytic anemias, extracorporeal blood circuits such as hemodialysis, and heart valve prostheses.
  • thromboembolic disease is the leading cause of morbidity and mortality in most industrialized countries [Heart Disease: A Textbook of Cardiovascular Medicine, Eugene Braunwald, 5th Ed., 1997, WB Saunders Company, Philadelphia].
  • the known from the prior art anticoagulants, ie substances for the inhibition or prevention of blood clotting, have various, often serious disadvantages.
  • 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. 2002, 27, 669-683; HA Wieland, V. Laux, D. Kozian, M.
  • the object of the present invention is to provide novel substances for controlling diseases, in particular thromboembolic diseases.
  • the present invention relates to compounds of the general formula (I)
  • n is the number 1, 2 or 3
  • R 1 is hydrogen, (C r C4) alkyl, (C r C4) alkanoyl, cyano or hydroxy;
  • R 2 and R 3 are identical or different and independently of one another represent hydrogen, fluorine, chlorine, cyano, (C 1 -C 3 ) -alkyl, cyclopropyl, trifluoromethyl, hydroxy, (C 1 -C 3 ) -alkoxy, trifluoromethoxy or amino stand,
  • A is a phenylene or 5- or 6-membered heteroarylene ring, wherein the two carboxamide groups -CO-NH-phenyl and -CO-NH-Z on adjacent Ring atoms of the phenylene or heteroarylene ring are located and phenylene and heteroarylene may additionally be substituted by halogen and / or (Ci-C 4 ) alkyl,
  • Z is phenyl, pyridyl, pyrimidinyl, pyrazinyl or thienyl, each one or two times, identically or differently, by substituents selected from the group of
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
  • the present invention encompasses all tautomeric forms.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoracetic, propionic, lactic Malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • mineral acids for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoracetic, propionic, lactic Malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms, such as, by way of example and by way of illustration, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salt
  • solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically).
  • (C 1 -C 4) -AlkVl and (C 1 -C 4 -alkyl in the context of the invention represent a straight-chain or branched alkyl radical having 1 to 4 or 1 to 3 carbon atoms, preferably a straight-chain or branched alkyl radical having 1 to 3 carbon atoms and are preferably: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and tert-butyl.
  • (C 1 -C 6 -alkoxy in the context of the invention represents a straight-chain or branched alkoxy radical having 1 to 3 carbon atoms and may be mentioned by way of example and preferably: methoxy, ethoxy, n-propoxy and isopropoxy.
  • (C j -CdValkanoyl [(Ci-C 4 ) acyl] in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, which carries a doubly bonded oxygen atom in the 1-position and linked via the 1-position
  • an alkanoyl radical having 2 or 3 carbon atoms may be mentioned by way of example and preferably: formyl, acetyl, propionyl, n-butyryl and isobutyryl.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.
  • 5- or 6-membered heteroarylene is a bivalent, monocyclic, aromatic heterocycle (heteroaromatic) having a total of 5 or 6 ring atoms and up to three identical or different ring heteroatoms from the series N, O and / or S, wherein the two carboxamide groups, independently of each other, in each case via a ring carbon atom or a ring nitrogen atom are linked to heteroaryls.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.
  • a particular embodiment of the invention comprises compounds of the formula (I) in which
  • R 1 is hydrogen, (C, -C 4) alkyl, (C r C 4) is alkanoyl or cyano.
  • n for the number 1 or 2
  • R 1 is hydrogen
  • R 2 is hydrogen
  • R 3 is hydrogen, fluorine or methyl.
  • A is a group of the formula
  • R 4 is hydrogen, halogen or (C r C 4) alkyl
  • R ' is hydrogen or (C r C 4 ) -alkyl
  • # and * denote the sites of attachment to the -CO-NH-phenyl and -CO-NH-Z moieties.
  • A is a group of the formula
  • R 5 is hydrogen or (C r C 4 ) -alkyl
  • # and * denote the sites of attachment to the -CO-NH-phenyl and -CO-NH-Z moieties.
  • Z is a group of the formula
  • R 6 is fluorine, chlorine, cyano, methyl or ethynyl
  • $ means the point of attachment to the nitrogen atom.
  • n for the number 1 or 2
  • R 1 is hydrogen
  • R * is hydrogen
  • R J is hydrogen, fluorine or methyl
  • A is a group of the formula
  • A is a group of the formula
  • # and * are the linking sites with the -CO-NH-phenyl and the -CO-NH-Z grouping.
  • the invention further provides a process for the preparation of the compounds according to the invention of the formula (I) in which R 1 is hydrogen, which comprises reacting compounds of the formula (II)
  • PG is a hydroxy-protecting group, preferably trimethylsilyl or tert-butyldimethylsilyl,
  • n, A, PG, Z, R and R have the meanings given above,
  • n, A, Z, R 2 and R 3 have the meanings given above,
  • n, A, PG, Z, R and R have the meanings given above,
  • n, A, Z, R 2 and R 3 have the meanings given above,
  • Inert solvents for process step (II) + (III) - »(IV) are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether,
  • Hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions,
  • Halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichlorethylene or chlorobenzene, or other solvents such as ethyl acetate, pyridine,
  • Suitable condensing agents for amide formation in process step (II) + (III) -> (IV) are, for example, carbodiimides such as N.N'-diethyl, NN'-dipropyl, N, N'-diisopropyl, N, N ' Dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), or phosgene derivatives such as N.N'-carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5 -phenyl-l, 2-oxazolium-3-sulfate or 2-ter / -butyl-5-methyl-isoxazolium perchlorate, or
  • the process step (II) + (DT) ⁇ (IV) is generally carried out in a temperature range from -2O 0 C to + 60 0 C, preferably from 0 0 C to + 4O 0 C.
  • the reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
  • reaction sequence (VI) -> (VIT) -> (IA) in total is particularly preferred using an acid-labile hydroxy-protecting group, such as trimethylsilyl or tert-butyl-dimethylsilyl, in the presence of an excess of acid as a one-pot reaction, without Isolation of the intermediate (VII), performed.
  • an acid-labile hydroxy-protecting group such as trimethylsilyl or tert-butyl-dimethylsilyl
  • Suitable inert solvents for process steps (V) ⁇ (IA), (IV) ⁇ (VI) and (VII) ⁇ (IA) are in particular tetrahydrofuran, dichloromethane or acetonitrile or mixtures of these Solvent. These process steps are generally carried out in a temperature range of -20 0 C to +50 0 C, preferably from 0 0 C to + 4O 0 C is performed. The reactions can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.
  • Suitable acids in process steps (V) -> (IA) and (VII) -> (IA) and the reaction sequence (VI) -> (VE) -> (IA) are in particular strong inorganic or organic acids such as, for example, hydrogen fluoride, Hydrogen chloride, hydrogen bromide, methanesulfonic acid, trifluoromethanesulfonic acid or trifluoroacetic acid.
  • the process step (IV) - »(VI) is preferably carried out in the presence of a base.
  • a base for this purpose, in particular inorganic bases such as alkali or alkaline earth metal carbonates or bicarbonates such as lithium, sodium, potassium, calcium or cesium carbonate or sodium or potassium bicarbonate, or alkali metal hydrides such as sodium hydride are suitable.
  • the compounds of the formula (II) can be synthesized, for example, by methods customary in the literature by reacting a carboxylic anhydride of the formula (VIII)
  • the compounds of the invention show an unpredictable, valuable spectrum of pharmacological activity.
  • the compounds according to the invention are selective inhibitors of the blood coagulation factor Xa, which act in particular as anticoagulants.
  • the compounds of the invention have favorable physicochemical properties, such as good solubility in water and physiological media, 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 following coronary interventions such as angioplasty or aortocoronary bypass, peripheral arterial occlusive disease, 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 following coronary interventions such as angioplasty or aortocoronary bypass
  • the substances are therefore also useful in the prevention and treatment of cardiogenic thromboembolism, such as brain ischemia, stroke and systemic thromboembolism and ischaemia, in patients with acute, intermittent or persistent cardiac arrhythmias, such as atrial fibrillation, and those undergoing cardioversion patients with valvular heart disease or with artificial heart valves.
  • cardiogenic thromboembolism such as brain ischemia, stroke and systemic thromboembolism and ischaemia
  • cardiac arrhythmias such as atrial fibrillation
  • the compounds of the invention are suitable for the treatment of disseminated intravascular coagulation (DIC).
  • DIC disseminated intravascular coagulation
  • 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.
  • the compounds of the present invention can inhibit tumor growth and metastasis, microangiopathies, age-related macular degeneration, diabetic retinopathy, diabetic nephropathy and other microvascular diseases and for the prevention and treatment of thromboembolic complications such as venous thromboembolism in tumor patients, particularly those that undergo major surgery or chemo- or radiotherapy.
  • the compounds of the invention may also be used to prevent coagulation ex vivo, e.g. for the preservation of blood and plasma products, for the cleaning / pretreatment of catheters and other medical devices and equipment, for the coating of artificial surfaces of in vivo or ex vivo used medical devices and devices or for 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 an anticoagulatory effective amount of the compound of the invention.
  • 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 anticoagulatory effective amount of the compound of the invention is added.
  • compositions containing a erf ⁇ ndungs- proper compound and one or more other active ingredients are pharmaceutical compositions containing a erf ⁇ ndungs- proper compound and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
  • suitable combination active ingredients may be mentioned by way of example and preferably: Lipid-lowering agents, in particular HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors;
  • Coronary / vasodilators especially ACE (angiotensin converting enzyme) inhibitors; AII (angiotensin II) receptor antagonists; ⁇ -adrenoceptor antagonists; alpha 1-adrenoceptor antagonists; diuretics; Calcium channel B loose; Substances that one
  • cGMP cyclic guanosine monophosphate
  • plasminogen activators thrombolytics / fibrinolytics
  • thrombolysis / fibrinolysis-enhancing compounds such as inhibitors of plasminogen activator inhibitor (PAI inhibitors) or inhibitors of thrombin-activated fibrinolysis inhibitor (TAFI inhibitors);
  • anticoagulant substances anticoagulants
  • platelet aggregation inhibiting substances platelet aggregation inhibitors, antiplatelet agents
  • Fibrinogen receptor antagonists (glycoprotein IIb / IIIa antagonists);
  • compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as tablets (uncoated or coated Tablets, for example with enteric or delayed-dissolving or insoluble coatings controlling the release of the compound of the invention), rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (eg hard or soft gelatin capsules), dragees, granules, pellets, powders , Emulsions, suspensions, aerosols or solutions.
  • tablets uncoated or coated Tablets, for example with enteric or delayed-dissolving or insoluble coatings controlling the release of the compound of the invention
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicaments including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (eg plasters)
  • milk pastes, foams, powdered powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg antioxidants such as ascorbic acid
  • dyes eg inorganic pigments such as iron oxides
  • flavor and / or odoriferous include, among others.
  • Excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl
  • the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
  • 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 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: 5O 0 C; UY detection: 210 nm.
  • Device type MS Micromass ZQ
  • Device type HPLC HP 1100 Series
  • UV DAD Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm
  • Eluent A 1 liter of water + 0.5 ml of 50% ant acid
  • eluent B 1 liter acetonitrile + 0.5 ml 50% formic acid
  • Flow 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min
  • Oven 5O 0 C
  • UV detection 210 nm.
  • Device type MS Micromass ZQ
  • Device type HPLC Waters Alliance 2795; Column: Merck Chromolith SpeedROD RP-18e 50 mm x 4.6 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 10% B ⁇ 3.0 min 95% B ⁇ 4.0 min 95% B; Oven: 35 ° C; Flow: 0.0 min 1.0 ml / min ⁇ 3.0 min 3.0 ml / min ⁇ 4.0 min 3.0 ml / min; UV detection: 210 nm.
  • Method 7 Method 7:
  • 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 keep min), 50 ° C min ⁇ 120 0 C, 16 ° C min ⁇ 250 0 C, 30 ° C (1.7 min hold) / / / min ⁇ 300 0C.
  • a solution of 101 g (716 mmol) of 4-fluoro-atrophenol in 500 ml of ethanol is mixed with 130 ml (2.15 mol, 3 eq.) Of 2-aminoethanol and 274 ml (1.57 mol, 2.2 eq.) Of N, N-diisopropylethylamine.
  • the reaction mixture is stirred at 50 ° C. overnight, then admixed with a further 86 ml (1.43 mol, 2.0 eq.) Of 2-aminoethanol and 249 ml (1.43 mol, 2.0 eq.) Of N, N-diisopropylethylamine and stirred for a further 12 h at 50 ° 0 C stirred.
  • the reaction solution is concentrated in vacuo and the residue is stirred with 600 ml of water. The resulting precipitate is filtered off, washed several times with water and dried.
  • the free base is obtained by stirring a solution of the corresponding salt (Example 1, 2 or 3) in THF with saturated aqueous sodium bicarbonate solution and subsequent extraction with dichloromethane.
  • the suspension is stirred for 2 d at 40 0 C and then diluted with 6 ml of water and 10 ml of dichloromethane. After phase separation, the organic phase is washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is stirred in diethyl ether, filtered and the solid dried in vacuo.
  • X is CH 3 SO 2 OH
  • the suspension is stirred for 2 d at 4O 0 C and then diluted with 3 ml of water and 4 ml of dichloromethane. After phase separation, the organic phase is washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is stirred in diisopropyl ether, filtered and the solid dried in vacuo.
  • the regioisomer mixture from example 9A (as crude product, about 27 mmol) and 7.2 g (27 mmol) of the compound from example IA are reacted.
  • the crude product obtained is purified by preparative RP-HPLC [column: Kromasil 100 C 18, 5 ⁇ m, 250 mm x 20 mm; Eluent: water / acetonitrile 1: 9], the two regioisomeric products being separated (see also Example 13).
  • the suspension is stirred for 4 d at 40 0 C and then diluted with 17 ml of water and 23 ml of dichloromethane. After phase separation, the organic phase is washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is stirred in diisopropyl ether, filtered and the solid dried in vacuo.
  • the regioisomer mixture from example 9A (as crude product, about 27 mmol) and 7.2 g (27 mmol) of the compound from example IA are reacted.
  • the crude product obtained is purified by preparative RP-HPLC [column: Kromasil 100 Cl 8, 5 ⁇ m, 250 mm ⁇ 20 mm; Eluent: water / acetonitrile 1: 9], the two regioisomeric products being separated (see also Example 12).
  • the suspension is stirred for 4 d at 40 0 C and then diluted with 2.5 ml of water and 3.5 ml of dichloromethane. After phase separation, the organic phase is washed with saturated aqueous sodium bicarbonate solution, over Dried magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane / methanol 200: 1).
  • reaction mixture is to come to RT, stirred for 15 min at RT, cooled again to 0 0 C and then treated with a solution of 90 mg (0:22 mmol) of 5 - [( ⁇ 4 - [(2 - ⁇ [TE7 " ⁇ -butyl (dimethyl) silyl] oxy ⁇ ethyl) amino] phenyl ⁇ amino) carbonyl] -1H-imidazole-4-carboxylic acid methyl ester.
  • the suspension is stirred for 2 d at 40 0 C and then diluted with 3 ml of water and 5 ml of dichloromethane. After phase separation, the organic phase is washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative RP-HPLC.
  • X is CH 3 SO 2 OH
  • the compounds according to the invention act in particular as selective 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.
  • “Selective” refers to those coagulation factor Xa inhibitors in which the IC 50 values for factor Xa inhibition are at least 100-fold smaller than the IC 50 values for the inhibition of other serine proteases, in particular plasmin and trypsin in which, with regard to the selectivity test methods, reference is made to the test methods of Examples Bal) and Ba2) described below.
  • the enzymatic activity of human factor Xa is measured by 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 with test substance are compared with the control batches without test substance and from this the IC 50 values are calculated.
  • test substances are tested for their inhibition of other human serine proteases, such as trypsin and plasmin.
  • trypsin 500 mU / ml
  • plasmin 3.2 nmol / l
  • the anticoagulant effect of the test substances is determined in vitro in human and rabbit plasma.
  • blood is taken off using a 0.11 molar sodium citrate solution as a template in a sodium citrate / blood mixing ratio of 1: 9.
  • the blood is mixed well immediately after collection and centrifuged for 10 minutes at about 2500 g.
  • the supernatant is pipetted off.
  • the prothrombin time (PT, synonyms: thromboplastin time, quick test) is determined in the presence of varying concentrations of test substance or the corresponding solvent using a commercial test kit (Hemoliance ® RecombiPlastin, from Instrumentation Laboratory.).
  • the test compounds are incubated for 3 minutes at 37 ° C. with the plasma.
  • Fasted rabbits (strain: ESD: NZW) are anesthetized by intramuscular administration of a Rompun / Ketavet solution (5 mg / kg or 40 mg / kg).
  • the thrombus formation is in an arteriovenous shunt based on that of CN.
  • Berry et al. [Semin. Thromb. Hemost. 1996, 22, 233-241].
  • the left jugular vein and the right carotid artery are dissected free.
  • An extracorporeal shunt is placed between the two vessels by means of a 10 cm long venous catheter.
  • This catheter is centered in another 4 cm long polyethylene tube (PE 160, Becton Dickenson) which incorporates a roughened and looped nylon thread to create a thrombogenic surface.
  • PE 160 polyethylene tube
  • Becton Dickenson a polyethylene tube
  • the extracorporeal circuit is maintained for 15 minutes. Then the shunt is removed and the nylon thread with the thrombus weighed immediately. The net weight of the nylon thread was determined before the start of the test.
  • the test substances are administered either intravenously via an ear vein or orally by gavage prior to application of the extracorporeal circuit.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • the mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are mixed after drying with the magnesium stearate for 5 minutes.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the compression.
  • a single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.
  • the rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.
  • a single dose of 100 mg of the compound according to the invention corresponds to 20 g of oral solution.
  • the compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.
  • the compound of the invention is dissolved at a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%).
  • a physiologically acceptable solvent e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%.
  • the solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

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Abstract

La présente invention concerne de nouveaux iminocarbamates cycliques de formule (I) dans laquelle R1, R2, R3, A, Z et n ont les significations indiquées dans les revendications, un procédé de production desdits composés, leur utilisation dans le traitement et/ou la prophylaxie de maladies ainsi que leur utilisation dans la production de médicaments destinés au traitement et/ou à la prophylaxie de maladies, en particulier de maladies thromboemboliques.
EP05815274A 2004-12-02 2005-11-22 Iminocarbamates cycliques et leur utilisation Withdrawn EP1819701A1 (fr)

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DE102004058062A DE102004058062A1 (de) 2004-12-02 2004-12-02 Cyclische Iminocarbamate und ihre Verwendung
PCT/EP2005/012465 WO2006058630A1 (fr) 2004-12-02 2005-11-22 Iminocarbamates cycliques et leur utilisation

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CA (1) CA2589740A1 (fr)
DE (1) DE102004058062A1 (fr)
WO (1) WO2006058630A1 (fr)

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DE102004059219A1 (de) * 2004-12-09 2006-06-14 Bayer Healthcare Ag Pyrazindicarbonsäureamide und ihre Verwendung
DE102006025318A1 (de) * 2006-05-31 2007-12-06 Bayer Healthcare Ag Dihydro-pyrrolopyridin-, Dihydro-pyrrolopyridazin- und Dihydro-pyrrolopyrimidin-Derivate und ihre Verwendung
DE102006025319A1 (de) * 2006-05-31 2007-12-06 Bayer Healthcare Aktiengesellschaft Substituierte Heterozyklen und ihre Verwendung
ES2633766T3 (es) 2011-10-28 2017-09-25 Lumena Pharmaceuticals Llc Inhibidores de reciclaje de ácido biliar para el tratamiento de enfermedades de hígado colestático pediátrico
UY36060A (es) 2014-04-02 2015-10-30 Bayer Pharma AG Compuestos de azol sustituidos con amida
EP3078378B1 (fr) 2015-04-08 2020-06-24 Vaiomer Utilisation d'inhibiteurs du facteur xa destinés à réguler la glycémie
WO2017055316A1 (fr) * 2015-10-01 2017-04-06 Bayer Pharma Aktiengesellschaft Composés azole à substitution amido

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AU2001273040A1 (en) * 2000-06-27 2002-01-08 Du Pont Pharmaceuticals Company Factor xa inhibitors
ATE368643T1 (de) * 2001-03-30 2007-08-15 Millennium Pharm Inc Faktor xa benzamidin inhibitoren

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US20080214533A1 (en) 2008-09-04

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