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EP2032567A1 - Hétérocycles substitués et son utilisation - Google Patents

Hétérocycles substitués et son utilisation

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Publication number
EP2032567A1
EP2032567A1 EP07725590A EP07725590A EP2032567A1 EP 2032567 A1 EP2032567 A1 EP 2032567A1 EP 07725590 A EP07725590 A EP 07725590A EP 07725590 A EP07725590 A EP 07725590A EP 2032567 A1 EP2032567 A1 EP 2032567A1
Authority
EP
European Patent Office
Prior art keywords
group
hydrogen
formula
alkyl
compound
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Withdrawn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
EP07725590A
Other languages
German (de)
English (en)
Inventor
Michael Härter
Tobias Wunberg
Susanne Röhrig
Stefan Heitmeier
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
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Filing date
Publication date
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Publication of EP2032567A1 publication Critical patent/EP2032567A1/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Withdrawn legal-status Critical Current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
    • 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
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the invention relates to novel substituted heterocycles, 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.
  • 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, transforming the soluble fibrinogen into the insoluble fibrin at the end of the cascade Traditionally, one distinguishes between the intrinsic and extrinsic systems in the blood coagulation, which culminate in a final 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 invention relates to compounds of the formula
  • n is the number 1, 2 or 3
  • A is a 5-membered heteroaryl or a 5-membered heterocyclyl
  • heteroaryl and heterocyclyl are bonded to the phenyl ring in 1 or 2 position and heteroaryl and heterocyclyl themselves have a 1,3-linkage with the phenyl ring and the carbonylaminomethyl group, and
  • heteroaryl and heterocyclyl may be substituted by a substituent R 8 ,
  • R 8 is attached to the neighboring atom of the atom to which the carbonylamino-methyl group is bonded and has a 1,4-linkage to the phenyl ring
  • R 8 alkylamino 4 -Al- is halogen, hydroxy, amino, Ci-C 4 alkyl, QC 4 -alkoxy, Ci-C, hydroxycarbonyl, aminocarbonyl, Ci-C 4 alkoxycarbonyl, Ci-C 4 alkyl aminocarbonyl , aminosulfonyl, alkylaminosulfonyl C 4 or C 4 -alkyl- sulfonyl 1 -C
  • alkyl, alkylamino and alkylaminosulfonyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, amino, Ci-C 4 alkoxy, Cj-Q-alkylamino, hydroxycarbonyl, aminocarbonyl, Ci-C 4 alkoxycarbonyl , C 1 -C 4 -alkylaminocarbonyl and a 5- or 6-membered heterocyclyl bonded via a nitrogen atom,
  • alkylaminocarbonyl may be substituted with a substituent wherein the substituent is selected from the group consisting of
  • R 1 represents hydrogen, cyano, hydroxy, C r C 4 alkyl, C r C 4 alkylcarbonyl, C 3 -C 7 - cycloalkylcarbonyl, phenylcarbonyl, 4- to 7-membered heterocyclylcarbonyl or 5- or 6-membered heteroarylcarbonyl group,
  • R 2 represents hydrogen, fluorine, chlorine, cyano, hydroxy, amino, trifluoromethyl, trifluoromethoxy, C r C 4 alkyl, C r C 4 alkoxy, C r C 4 alkoxymethyl, Ci-C 4 alkylamino, C 3 - C 6 cycloalkyl, aminocarbonyl, Ci-C 4 alkoxycarbonyl or Cj -C 4 - alkylaminocarbonyl is, R 3 is hydrogen, fluorine, chlorine, cyano, hydroxyl, amino, trifluoromethyl, trifluoromethoxy, C r C 4 alkyl, Ci-C 4 alkoxy, C 1 -C 4 -AlkOXyTnCtIIyI, C r C 4 alkylamino, C 3 C 6 -Cycloalkyl, aminocarbonyl, C 1 -C 4 -alkoxycarbonyl or C 1 -C 4 -alkylaminocarbonyl,
  • R 4 is a group of the formula
  • R 5 represents hydrogen, fluorine, chlorine, cyano, ethynyl, C r C 4 alkyl, C r C 4 alkoxy or C 3 - C 6 cycloalkyl,
  • R 6 is hydrogen, amino, C 1 -C 4 -alkyl, C 1 -C 4 -alkylamino or C 1 -C 6 -cycloalkyl,
  • R 7 is hydrogen, fluorine, chlorine, amino or C 1 -C 4 -alkyl
  • 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 formula below and their salts, solvates and solvates of the salts encompassed by formula (I) and those of the 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 not suitable for pharmaceutical applications themselves, but can be used, for example, for the isolation or purification of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid acetic acid, trifluoroacetic acid, propionic 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.
  • alkali metal salts for example sodium and potassium salts
  • alkaline earth salts for example calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms 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.
  • Atoms such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs includes compounds which are themselves biologically active or may be inactive, but during their residence time in the body to be converted into compounds of the invention (for example, metabolically or hydrolytically).
  • Alkylaminocarbonyl, alkylaminosulfonyl and alkylsulfonyl is a linear or branched alkyl radical having usually 1 to 4, preferably 1 or 2 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl and tert-butyl.
  • Alkoxy is exemplified and preferably methoxy, ethoxy, n-propoxy, isopropoxy and tert-butoxy.
  • Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents, by way of example and by preference methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, N, N-dimethylamino, N, N-diethylamino, N-ethyl-N- methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino and N-tert-butyl-N-methyl-amino.
  • C 1 -C 3 -alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having in each case 1 to 3 carbon atoms per alkyl substituent.
  • Alkoxycarbonyl is exemplified and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
  • Alkylaminocarbonyl is an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents, by way of example and by way of preference for methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl- N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-Nn-propylaminocarbonyl and N-tert-butyl-N-methylaminocarbonyl.
  • C 1 -C 5 -alkylaminocarbonyl is, for example, a monoalkylamino-carbonyl radical having 1 to 3 carbon atoms or a dialkylaminocarbonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.
  • Alkylaminosulfonyl is an alkylaminosulfonyl radical having one or two (independently selected) alkyl substituents, by way of example and by way of preference for methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl, tert-butylaminosulfonyl, N, N-dimethylaminosulfonyl, N, N-diethylaminosulfonyl, N-ethyl-N- methylaminosulfonyl, N-methyl-N-propylaminosulfonyl, N-isopropyl-Nn-propylaminosulfonyl and N-tert-butyl-N-methylamino sulfonyl.
  • C 1 -C 3 -alkylaminosulfonyl is, for example, a monoalkylaminosulfonyl radical having 1 to 3 carbon atoms or a dialkylaminosulfonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.
  • Alkylsulfonyl is, by way of example and by way of preference, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl and tert-butylsulfonyl.
  • Cycloalkyl represents a cycloalkyl group having usually 3 to 7 carbon atoms, preferably having 3 to 5 carbon atoms, by way of example and preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Heterocvclyl is a monocyclic radical having 5 or 6 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series N, O, S, SO, SO 2 .
  • the heterocyclyl radicals may be saturated or partially unsaturated. Preference is given to heterocyclyl radicals having up to two heteroatoms from the series O, N and S, such as, by way of example and by way of preference, tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, isoxazolinyl and morpholinyl.
  • Heteroaryl is an aromatic, monocyclic radical having 5 ring atoms and up to 4 heteroatoms from the series S, O and N, by way of example and preferably for thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl and pyrazolyl.
  • 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.
  • the end point of the line next to each one * is not a carbon atom or a CH 2 group but is part of the bond to the atom to which R 4 is attached is.
  • the end point of the line next to each of which is a # 1 or # 2 does not stand for a carbon atom or a CH 2 group but is part of the bond to the atom to which A is bound.
  • n is the number 1, 2 or 3
  • A is a 5-membered heteroaryl or partially unsaturated 5-membered heterocyclyl, where heteroaryl and heterocyclyl are bonded to the phenyl ring in 1 or 2 position and heteroaryl and heterocyclyl themselves have a 1,3-linkage with the phenyl ring and the carbonylaminomethyl group,
  • heteroaryl and heterocyclyl may be substituted by a substituent R 8 ,
  • R 8 is attached to the neighboring atom of the atom to which the carbonylaminomethyl group is attached and has a 1, 4-linkage to the phenyl ring
  • R 8 is amino, C r C 4 alkyl, C r C 4 alkoxy, C r C 4 alkoxymethyl, CpC 4 - alkylamino, Ci-C4-alkylaminomethyl, hydroxycarbonyl, hydroxycarbonyl methyl, hydroxycarbonylethyl, aminocarbonyl, aminocarbonylmethyl , amino carbonylethyl, C] -C 4 alkoxycarbonyl, Ci-C4-alkoxycarbonylmethyl, C 4 oxycarbonylethyl -AIk-, Ci-C4-alkylaminocarbonyl, Ci-C 4 -Alkylaminocarbonylmethyl, Ci-C 4 -Alkylaminocarbonylethyl, Aminosulfonyl, C 1 -C 4 -alkylaminosulfonyl or C 1 -C 4 -alkylsulfonyl,
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy and
  • ethylaminocarbonyl and propylaminocarbonyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, amino and C 1 -C 4 -alkylamino,
  • R 1 is hydrogen, cyano, hydroxy or C 1 -C 4 -alkyl
  • R 2 represents hydrogen, fluorine, chlorine, cyano, C r C 4 alkyl or C r C 4 -alkoxy
  • R 3 represents hydrogen, fluorine, chlorine, cyano, hydroxy, C, -C 4 alkyl, C, -C 4 alkoxy, C 1 -C 4 oxymethyl -AIk-, cyclopropyl, aminocarbonyl, C r C 4 -alkoxycarbonyl or C 1 -C 4 -alkylaminocarbonyl,
  • R 4 is a group of the formula
  • R 5 is fluorine, chlorine, ethynyl, methyl or methoxy
  • R 7 is hydrogen
  • n is the number 1 or 2
  • A is a group of the formula
  • # 1 is the point of attachment to the phenyl ring, and is attached to the phenyl ring in 1 position
  • # 2 is the point of attachment to the carbonylaminomethyl group
  • R 8 is hydrogen, C r C 4 alkyl, Ci-C 4 alkoxy, Ci-C4 alkoxymethyl, C r C 4 alkyl amino, Ci-C4-alkylaminomethyl, hydroxycarbonyl, hydroxycarbonylmethyl,
  • Aminocarbonyl, aminocarbonylmethyl, C] -C 4 alkoxycarbonyl, C r C carbonylmethyl 4 alkoxy, Ci-C4-alkylaminocarbonyl or C 4 alkylaminocarbonyl is methyl
  • alkyl may be substituted with a substituent wherein the substituent is selected from the group consisting of hydroxy and amino,
  • ethylaminocarbonyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, amino and C 1 -C 4 -alkylamino,
  • R 1 is hydrogen
  • R 2 is hydrogen or fluorine
  • R 3 is hydrogen, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methoxymethyl or cyclopropyl,
  • R 4 is a group of the formula
  • R 5 is fluorine, chlorine or methyl
  • R 7 is hydrogen
  • n is the number 1
  • A is a group of the formula
  • # 1 is the point of attachment to the phenyl ring, and is attached to the phenyl ring in 1 position,
  • R 8 is hydrogen, hydroxymethyl, aminomethyl, Ci-C4-alkyl, Ci-C 4 alkoxy, Ci-C4 alkoxymethyl, Ci-C4-alkylaminomethyl, hydroxycarbonyl, Aminocarb- onyl, C] -C 4 -alkoxycarbonyl , Ci-C4-alkylaminocarbonyl, Hydroxyethylaminocarb- onyl or C] -C 4 -Alkylaminoethylaminocarbonyl,
  • R 1 is hydrogen
  • R 2 is hydrogen or fluorine
  • R 3 is hydrogen, fluorine, chlorine, methyl or methoxy
  • R 4 is a group of the formula
  • R 5 is chlorine
  • R 7 is hydrogen
  • # 1 is the attachment site to the phenyl ring, and is attached to the phenyl ring in 1 position,
  • R 8 represents hydrogen, hydroxymethyl, aminomethyl, hydroxycarbonyl, aminocarbony, C 1 -C 4 -alkoxycarbonyl or C 1 -C 4 -alkylaminocarbonyl.
  • R 3 is hydrogen, fluorine, chlorine, methyl or methoxy.
  • R 5 is chlorine and R 7 is hydrogen.
  • 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
  • n, A, R 2 , R 3 and R 4 have the abovementioned meaning
  • n, A, R 2 , R 3 and R 4 have the abovementioned meaning
  • PG is a hydroxy-protecting group, preferably trimethylsilyl or tert-butyldimethylsilyl,
  • n, A, R 2 , R 3 and R 4 have the abovementioned meaning
  • PG is a hydroxy-protecting group, preferably trimethylsilyl or tert-butyldimethylsilyl,
  • n, A, R 2 , R 3 and R 4 have the abovementioned meaning
  • R 1 is C r C 4 alkyl, C r C 4 -alkylcarbonyl, C 3 -C 7 cycloalkylcarbonyl, phenylcarbonyl, 4- to 7-membered heterocyclylcarbonyl or 5- or 6-membered heteroarylcarbonyl,
  • R 1 is cyano or C 1 -C 4 -alkyl
  • G is a leaving group, preferably phenoxy or methylthio
  • the compounds of the formula (I) in which R 1 is hydrogen may, if appropriate, be reacted with the appropriate solvents and / or bases or acids to form their salts, their solvates and / or the solvates of their salts.
  • the free base of the salts can be obtained, for example, by chromatography on a reversed-phase column with an acetonitrile-water gradient with addition of a base, in particular by using an RP 18 Phenomenex Luna C 18 (2) column and diethylamine as base, or by dissolving the salts in an organic solvent and shaking with aqueous solutions of basic salts such as sodium bicarbonate.
  • the salts are dissolved in water and the addition of sodium bicarbonate solution precipitates the base.
  • 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.
  • reaction according to process [A] is generally carried out in inert solvents, preferably in a temperature range from -20 0 C to 5O 0 C at atmospheric pressure.
  • Inert solvents are, for example, tetrahydrofuran, dichloromethane or acetonitrile or mixtures of these solvents.
  • Acids are, for example, strong inorganic or organic acids such as hydrogen fluoride, hydrogen chloride, hydrogen bromide, methanesulfonic acid, trifluoromethanesulfonic acid or trifluoroacetic acid.
  • reaction of the first stage according to process [B] is generally carried out in inert solvents, preferably in a temperature range from -20 0 C to 50 0 C at atmospheric pressure.
  • Inert solvents are, for example, tetrahydrofuran, dichloromethane or acetonitrile or mixtures of these solvents.
  • bases examples include inorganic bases such as alkali metal 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.
  • cleavage of trimethylsilyl or tert-butyldimethylsilyl as preferably used hydroxy-protecting groups (PG) in the second stage according to process [B] is generally carried out in tetrahydrofuran as a solvent, preferably with the aid of tetra-n-butylammonium fluoride (TBAF), preferably in a temperature range of 0 0 C to 40 0 C at atmospheric pressure.
  • TBAF tetra-n-butylammonium fluoride
  • the reaction of the third stage according to process [B] is generally carried out in inert solvents, preferably in a temperature range from -20 0 C to 50 0 C at atmospheric pressure.
  • Inert solvents are, for example, tetrahydrofuran, dichloromethane or acetonitrile or mixtures of these solvents.
  • Acids are, for example, strong inorganic or organic acids such as hydrogen fluoride, hydrogen chloride, hydrogen bromide, methanesulfonic acid, trifluoromethanesulfonic acid or trifluoroacetic acid.
  • the reaction of the second and third stages according to process [B] is particularly preferably carried out using an acid-labile hydroxy protecting group, such as trimethylsilyl or tert-butyldimethylsilyl, in the presence of an excess of acid as a one-pot reaction, in inert solvents, preferably in one Temperature range from -20 0 C to 50 0 C at atmospheric pressure, without isolation of the intermediate of the compounds of formula (V).
  • an acid-labile hydroxy protecting group such as trimethylsilyl or tert-butyldimethylsilyl
  • Inert solvents are, for example, tetrahydrofuran, dichloromethane or acetonitrile or mixtures of these solvents.
  • Acids are, for example, strong inorganic or organic acids such as hydrogen fluoride, hydrogen chloride, hydrogen bromide, methanesulfonic acid, trifluoromethanesulfonic acid or trifluoroacetic acid.
  • the implementation of the first stage according to method [C] is generally carried out in analogy to literature methods, as described in, for. B. Hetenyi, et al., J. Org. Chem. 2003, 68, 2175-2182, D. Douglass, J. Amer. Chem. Soc. 1934, 56, 719, F.B. Dains et al., J. Amer. Chem. Soc. 1925, 47, 1981-1989 or F.B. Dains et al., J. Amer. Chem. Soc. 1922, 44, 2637-2643.
  • reaction according to process [D] is generally carried out analogously to processes known from the literature, as described in, for. B. Maezaki, A. Furusawa, S. Uchida, T. Tanaka, Tetrahedron 2001, 57, 9309-9316, G. Berecz, J. Reiter, G. Argay, A. Kaiman, J. Heterocycl. Chem. 2002, 39, 319-326, R. Evers, M. Michalik, J. Prakt. Chem. 1991, 333, 699-710, R. Mohr, A. Buschauer, W. Schunack, Arch. Pharm.
  • reaction according to process [E] is generally carried out analogously to processes known from the literature, as described in, for example, US Pat. BG Zinner, G. Nebel, Arch. Pharm. Ber. Dtsch. Ges. 1970, 303, 385-390.
  • the compounds of formulas (VI) and (VE) are known or can be synthesized by known methods from the corresponding starting compounds.
  • the compounds of the formula (IH) are known or can be prepared from the compounds of the formula (II) by introducing the protective group PG according to conditions known to the person skilled in the art.
  • trimethylsilyl or tert-butyldimethylsilyl as preferably used hydroxy-protecting groups is generally carried out by reaction with trimethylsilyl chloride, tert-butyldimethylsilyl chloride or tert-butyldimethylsilyl trifluoromethanesulfonate in tetrahydrofuran, dimethylformamide or dichloromethane as solvent, preferably in Presence of imidazole or 2,6-dimethylpyridine, preferably in a temperature range from 0 0 C to 40 0 C at atmospheric pressure.
  • the compounds of the formula (IT) are known or can be prepared by reacting compounds of the formula
  • R 2 , R 3 and R 4 have the meaning given above, and
  • X 1 is bromine or iodine
  • the reaction is generally carried out in inert solvents with the addition 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, preference is given to copper (I) iodide.
  • bases are potassium phosphate, potassium carbonate or cesium carbonate, potassium phosphate is preferred.
  • Diamine ligands are, for example, 1,2-diamines, such as N, N'-dimethylethylenediamine.
  • the compounds of the formula (VIII) are known or can be synthesized by methods known to those skilled in the art for the synthesis of the heterocycle A from the corresponding starting compounds.
  • the compounds of the formula (EX) are known or can be synthesized by known processes from the corresponding starting compounds.
  • the nitrogen of the amide in compounds of formulas (II), (ffl), (IV), (V) and (VHf) may optionally be protected during the reaction with a protecting group known to those skilled in the art, preferably a 2,4-dimethoxybenzyl Group which is cleaved under the conditions of the last stage of the synthesis of the compounds of formula (I).
  • the compounds of the invention show an unpredictable, valuable pharmacological activity spectrum.
  • 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 Restenoses 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 Restenoses after 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 aids and devices, 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 compound of the invention and one or more other active ingredients are pharmaceutical compositions containing a compound of the invention 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 blockers; Substances that cause an increase in cyclic guanosine monophosphate (cGMP), such as soluble guanylate cyclase stimulators;
  • ACE angiotensin converting enzyme
  • AII angiotensin II receptor antagonists
  • ⁇ -adrenoceptor antagonists alpha 1-adrenoceptor antagonists
  • diuretics Calcium channel blockers
  • cGMP cyclic guanosine monophosphate
  • Plasminogen activators thrombolytics / fibrinolytics
  • thrombolysis / fibrinolysis enhancing compounds such as inhibitors of plasminogen activator inhibitor (P AI 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 / ⁇ ia antagonists);
  • compositions containing at least one compound of the invention are pharmaceutical 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. For this purpose, they can be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, 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.
  • Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
  • tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates
  • capsules e.g. Soft gelatin capsules
  • dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation 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, 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 conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients 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).
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers for example antioxidants such as ascorbic acid
  • dyes for example inorganic pigments such as, for example, iron oxides
  • flavor and / or odoriferous agents for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers for example antioxidants such as ascorbic acid
  • dyes for example inorganic pigments such as, for example, iron oxides
  • flavor and / or odoriferous agents for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers for example antioxidants such as ascorbic acid
  • dyes for example inorganic pigments such as, for example, iron oxides
  • 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.
  • 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 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 5 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; 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: 208-400 nm.
  • Method 6 Column: GROM-SIL 120 ODS-4 HE, 10 ⁇ M, 250 mm x 30 mm; Running Means 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. f% Aqueous Formic Acid 95T5 " (27-34 min), Acetonitrile / 0.1% Aqueous Formic Acid 10:90 (34-38 min), Flow: 50 ml / min, Temperature: 22 ° C, UV Detection: 254 nm.
  • the mixture is allowed to come to RT and added again with the same amounts of aminoethanol, copper (I) iodide, potassium phosphate and NN-dimethylethylenediamine. It is heated to inerting for a further 20 hours to reflux. After this time, allow to cool to RT. It is mixed with water and extracted with ethyl acetate. The organic extract is washed successively with water and saturated brine. It is dried over anhydrous magnesium sulfate, filtered and the filtrate is freed from the solvent in vacuo. The residue is purified by preparative HPLC (Method 6).
  • the reaction mixture is diluted with dichloromethane and washed successively with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous sodium sulfate, filtering and removal of the solvent on a rotary evaporator, the residue is dissolved in acetonitrile and mixed with the same volume of water. The product fails. It is filtered off with suction and dried under high vacuum. 71 mg (64% of theory) of the title compound are obtained.
  • Example 6A Analogously to the process described under Example 6A, 12.5 g (48.06 mmol) of the compound from Example 16A are converted to 6.37 g (40% of theory, based on 90% purity) of the title compound. Instead of 60 0 C, the mixture is stirred at 80 0 C.
  • Example 7A Analogously to the process described under Example 7A, 6.30 g (21.14 mmol) of the compound from Example 17A are converted to 9.5 g (62% of theory, based on 62% purity) of the title compound.
  • Example 8A Analogously to the process described under Example 8A, 9.5 g (21.13 mmol) of the compound from Example 18A are converted to 5.14 g (37% of theory) of the title compound.
  • 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, reference being made to the test methods of Examples Bal) and Ba2) described below for the selectivity test methods.
  • a biochemical test system is constructed in which the reaction of a factor Xa substrate is used to determine the enzymatic activity of human factor Xa.
  • Factor Xa breaks down from the peptic substrate aminomethylcoumarin, which is measured fluorescently. The determinations are carried out in microtiter plates.
  • Substances to be tested are dissolved in various concentrations in dimethyl sulfoxide and incubated for 15 min with human factor Xa (1.3 nmol / l dissolved in 50 mmol / l Tris buffer [C, C, C]).
  • Tris (hydroxymethyl) -aminomethane 100 mmol / l NaCl, 0.1% BSA [bovine serum albumin], pH 8.
  • the substrate (5 .mu.mol / 1 Boc-Ile-Glu-Gly-Arg-AMC from Bachern) is added. After an incubation of 30 min, the sample is at a
  • test substances are tested for their inhibition of other human serine proteases, such as trypsin and plasmin.
  • trypsin 83 mU / ml from Sigma
  • plasmin 0.1 ⁇ g / ml from Kordia
  • trypsin 83 mU / ml from Sigma
  • plasmin 0.1 ⁇ g / ml from Kordia
  • these enzymes are dissolved (50 mmol / l Tris buffer [C, C, C tris (hydroxymethyl) aminomethane ], 100 mmol / 1 NaCl, 0.1% BSA [bovine serum albumin], 5 mmol / l calcium chloride, pH 7.4) and incubated for 15 min with test substance in various concentrations in dimethyl sulfoxide and with dimethyl sulfoxide without test substance.
  • the enzymatic reaction is then started by addition of the appropriate substrates (5 ⁇ mol / 1 Boc-Ile-Glu-Gly-Arg-AMC from Bachern for trypsin, 50 ⁇ mol / 1 MeOSuc-Ala-Phe-Lys-AMC from Bachern for plasmin).
  • the fluorescence is measured (excitation: 360 nm, emission: 460 nm).
  • the measured emissions of the test mixtures with test substance are compared with the test batches without test substance (excluding dimethyl sulfoxide instead of test substance in dimethylsulfoxide) and IC 50 values are calculated from the concentration-activity relationships.
  • 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.
  • 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 the pH and adjust to pH 4.6 if necessary.
  • Dimethyl sulfoxide e.g., Baker Art. No. 7157,2500
  • Preparation of the starting solution for calibration solutions (stock solution): Approximately 0.5 mg of the active substance is accurately weighed into a 2 ml Eppendorf Safe-Lock tube (Eppendorf Art. No. 0030 120,094), to which a concentration of 600 ⁇ g / ml is added with DMSO ( eg 0.5 mg of active ingredient + 833 ⁇ l of DMSO) and shaken to complete dissolution by means of a vortexer.
  • Calibration solution 2 (2.5 ⁇ g / ml): 100 ⁇ l of the calibration solution 1 are mixed with 700 ⁇ l of DMSO and homogenized.
  • Sample solution for solubility up to 10 g / l in PBS buffer pH 7.4 Approximately 5 mg of the active ingredient are weighed exactly into a 2 ml Eppendorf Safe-Lock tube (Eppendorf Art. No. 0030 120,094) and added to a concentration of 5 g / l mixed with PBS buffer pH 7.4 (eg 5 mg of active ingredient + 500 ul PBS buffer pH 7.4).
  • Sample solution for solubility up to 10 g / l in acetate buffer pH 4.6 Approximately 5 mg of the active substance are weighed exactly into a 2 ml Eppendorf Safe-Lock tube (Eppendorf Art. No. 0030 120,094) and added to a concentration of 5 g / l added with acetate buffer pH 4.6 (eg 5 mg of active ingredient + 500 .mu.l of acetate buffer pH 4.6).
  • Sample solution for solubility up to 10 g / l in water Approximately 5 mg of the active substance are weighed exactly into a 2 ml Eppendorf Safe-Lock tube (Eppendorf Art. No. 0030 120,094) and added to a concentration of 5 g / l with water added (eg 5 mg of active ingredient + 500 ul of water).
  • sample solutions thus prepared for 24 hours at 1400 rpm by means of a temperature shaker (for example, Eppendorf Thermomixer comfort Art. No. 5355 000.011 with interchangeable block Art. Nr. 5362.000.019) shaken at 20 0 C. 180 ⁇ l of each of these solutions are removed and transferred to Beckman Polyallomer Centrifuge Tubes (Art. No. 343621). These solutions are centrifuged for 1 hour at about 223,000 * g (eg Beckman Optima L-90K ultracentrifuge with Type 42.2 Ti rotor at 42,000 rpm).
  • a temperature shaker for example, Eppendorf Thermomixer comfort Art. No. 5355 000.011 with interchangeable block Art. Nr. 5362.000.019) shaken at 20 0 C. 180 ⁇ l of each of these solutions are removed and transferred to Beckman Polyallomer Centrifuge Tubes (Art. No. 343621). These solutions are centrifuged for 1 hour at about 223,000 * g
  • 100 ⁇ l of the supernatant are taken from each sample solution and diluted 1: 5, 1: 100 and 1: 1000 with the solvent used in each case (water, PBS buffer 7.4 or acetate buffer pH 4.6). Each dilution is bottled in a suitable vessel for HPLC analysis.
  • Agilent 1100 with DAD (Gl 315A), quat. Pump (Gl 31 IA), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); Column: Phenomenex Gemini C18, 50 x 2 mm, 5 ⁇ ; Temperature: 40 ° C .; Eluent A: water / phosphoric acid pH 2; Eluent B: acetonitrile; Flow rate: 0.7 ml / min; Gradient: 0-0.5 min 85% A, 15% B; Ramp: 0.5-3 min 10% A, 90% B; 3-3.5 min 10% A, 90% B; Ramp: 3.5-4 min 85% A, 15% B; 4-5 minutes 85% A, 15% B.
  • Agilent 1100 with DAD (Gl 315A), quat. Pump (Gl 31 IA), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); Column: VDSoptilab Kromasil 100 C18, 60 x 2.1 mm, 3.5 ⁇ ; Temperature: 30 ° C .; Eluent A: water + 5 ml perchloric acid / l; Eluent B: acetonitrile; Flow rate: 0.75 ml / min; Gradient: 0-0.5 min 98% A, 2% B; Ramp: 0.5-4.5 min 10% A, 90% B; 4.5-6 min 10% A, 90% B; Ramp: 6.5-6.7 min 98% A, 2% B; 6.7-7.5 min 98% A, 2% B.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • the mixture of 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 according to the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.
  • the compound of the invention is dissolved in a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%).
  • a physiologically acceptable solvent e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%.
  • the solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

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Abstract

L'invention concerne des hétérocycles substitués de formule (I), son procédé de fabrication, son utilisation pour le traitement et/ou la prophylaxie de maladies, ainsi que son utilisation pour la fabrication de médicaments pour le traitement et/ou la prophylaxie de maladies, notamment de maladies thromboemboliques.
EP07725590A 2006-05-31 2007-05-25 Hétérocycles substitués et son utilisation Withdrawn EP2032567A1 (fr)

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DE102006025319A DE102006025319A1 (de) 2006-05-31 2006-05-31 Substituierte Heterozyklen und ihre Verwendung
PCT/EP2007/004694 WO2007137792A1 (fr) 2006-05-31 2007-05-25 Hétérocycles substitués et son utilisation

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EP2921481A1 (fr) 2011-12-27 2015-09-23 Bayer Intellectual Property GmbH Dérivés d'acide de 4-piperidine
EP3078378B1 (fr) 2015-04-08 2020-06-24 Vaiomer Utilisation d'inhibiteurs du facteur xa destinés à réguler la glycémie

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DE102005042583A1 (de) * 2005-09-08 2007-03-15 Bayer Healthcare Ag Iminooxazolidin-Derivate und ihre Verwendung
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