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EP3049407A1 - Dérivés de phénylalanine substitués servant de modulateurs du facteur xia - Google Patents

Dérivés de phénylalanine substitués servant de modulateurs du facteur xia

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Publication number
EP3049407A1
EP3049407A1 EP14771920.7A EP14771920A EP3049407A1 EP 3049407 A1 EP3049407 A1 EP 3049407A1 EP 14771920 A EP14771920 A EP 14771920A EP 3049407 A1 EP3049407 A1 EP 3049407A1
Authority
EP
European Patent Office
Prior art keywords
mmol
methyl
amino
substituted
dihydro
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Withdrawn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
EP14771920.7A
Other languages
German (de)
English (en)
Inventor
Ulrike RÖHN
Manuel ELLERMANN
Julia Strassburger
Astrid WENDT
Susanne Röhrig
Robert Alan WEBSTER
Martina Victoria Schmidt
Adrian Tersteegen
Kristin BEYER
Martina SCHÄFER
Anja BUCHMÜLLER
Christoph Gerdes
Michael Sperzel
Steffen SANDMANN
Stefan Heitmeier
Alexander Hillisch
Jens Ackerstaff
Carsten TERJUNG
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 Pharma AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Pharma AG filed Critical Bayer Pharma AG
Priority to EP14771920.7A priority Critical patent/EP3049407A1/fr
Publication of EP3049407A1 publication Critical patent/EP3049407A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to substituted phenylalanine derivatives and processes for their preparation and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular cardiovascular diseases and / or perioperative severe blood loss.
  • Blood clotting is a protective mechanism of the organism that can rapidly and reliably "seal" defects in the blood vessel wall, thus preventing or minimizing blood loss, and hemostasis following vascular injury is essentially through the coagulation system, where an enzymatic cascade becomes more complex 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 differentiates between the intrinsic and the extrinsic system in blood coagulation, which culminate in a final common pathway, where factors Xa and IIa (thrombin) play key roles: Factor Xa bundles the signals of the two ger because it is produced both by Factor VIIa / Tissue Factor (extrinsic pathway) and the Tenase complex (intrinsic pathway) by reaction of Factor X. The activated serine protease Xa cleaves prothrombin to thrombin, which
  • coagulation is initiated by binding of activated factor VIIa to tissue factor (TF).
  • TF tissue factor
  • the resulting complex activates factor X, which in turn leads to thrombin generation with subsequent production of fibrin and platelet activation (via PAR-1) as hemorrhagic end-products of hemostasis.
  • PAR-1 tissue factor
  • the rate of thrombin production is small and limited by the occurrence of TFPI as an inhibitor of the TF-FVIIa-FX complex.
  • a key component of the transition from initiation to amplification and propagation of coagulation is factor XIa.
  • Thrombin activated in positive feedback loops in addition to Factor V and Factor VIII and Factor XI to Factor XIa, which converts Factor IX to Factor IXa and on the thus generated Factor IXa / Factor VIIIa complex quickly larger amounts of Factor Xa produced. This triggers the production of large amounts of thrombin, which leads to strong thrombus growth and stabilizes the thrombus.
  • fibrinolysis Upon activation of plasminogen by tissue plasminogen activator (tPA), the active serine protease, plasmin, cleaves polymerized fibrin and thus degrades the thrombus. This process is called fibrinolysis - with plasmin as the key enzyme.
  • tissue plasminogen activator tPA
  • Uncontrolled activation of the coagulation system or defective inhibition of the activation processes can cause the formation of local thromboses or emboli in vessels (arteries, veins, lymphatics) or cardiac cavities. This can lead to serious thrombotic or thromboembolic disorders.
  • systemic hypercoagulability can lead to consumption coagulopathy in the context of disseminated intravascular coagulation.
  • Thromboembolic disorders are the most common cause of morbidity and mortality in most industrialized countries [Heart Disease: A Textbook of Cardiovascular Medicine, Eugene Braunwald, 5th Ed., 1997, W.B. Saunders Company, Philadelphia].
  • heparin In the therapy and prophylaxis of thromboembolic diseases, on the one hand 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, the known disadvantages described below can not thereby also be avoided be avoided, which consist in the therapy with heparin. Thus, heparin is orally ineffective and has only a comparatively low half-life.
  • 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 of action 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.
  • the therapeutic range is of central importance: The distance between the therapeutically effective dose for anticoagulation and the dose at which bleeding can occur should be as large as possible so that maximum therapeutic efficacy is achieved with a minimal risk profile.
  • factor XIa inhibitors In various in vivo models with, for example, antibodies as factor XIa inhibitors, but also in factor XIa knock-out models, the anti-thrombotic effect was demonstrated with little / no prolongation of bleeding time or increase in blood volume. In clinical trials Increased factor XIa levels were associated with an increased event rate. In contrast, factor XI deficiency (hemophilia C), unlike factor VIII or factor IXa (hemophilia A and B, respectively), did not result in spontaneous bleeding and was only seen during surgery and trauma. Instead, it showed protection against certain thromboembolic events.
  • W089 / 11852 describes inter alia substituted phenylalanine derivatives for the treatment of pancreatitis and WO 2007/070816 describes substituted thiophene derivatives as factor XIa inhibitors.
  • the invention relates to compounds of the formula
  • R 1 is a group of the formula
  • R 6 is 5-membered heteroaryl, wherein heteroaryl may be substituted with one substituent selected from the group consisting of oxo, chloro, cyano, hydroxy and C 1 -C 3 -alkyl, wherein alkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of hydroxy, amino, hydroxycarbonyl and methoxy, or wherein alkyl may be substituted with 1 to 7 fluorine substituents, or wherein alkyl is substituted with one substituent selected from the group consisting of hydroxy, amino, hydroxycarbonyl and methoxy and wherein Alkyl is additionally substituted by 1 to 6 substituents fluorine, R 7 is hydrogen, fluorine or chlorine,
  • R 8 and R 9 together with the carbon atoms to which they are attached form a 5-membered heterocycle, it being possible for the heterocycle to be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, chlorine, cyano, hydroxyl, C 3 alkyl, pyrazolyl and pyridyl, wherein alkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of hydroxy, amino, hydroxycarbonyl and methoxy, or wherein alkyl may be substituted with 1 to 7 substituents fluoro, or wherein alkyl is substituted with a substituent selected from the group consisting of hydroxy, amino, hydroxycarbonyl and methoxy and wherein alkyl is additionally substituted with 1 to 6 substituents fluoro,
  • R i of ur is hydrogen, fluorine or chlorine, is 9- or 10-membered bicyclic heteroaryl, wherein heteroaryl may be substituted by 1 to 3 substituents independently selected from the group consisting of oxo, fluorine, chlorine, cyano, trifluoromethyl, Hydroxy, amino, C 1 -C 3 -alkylamino, C 1 -C 3 -alkyl and C 3 -C 6 -cycloalkyl, wherein alkyl may be substituted by a substituent selected from the group consisting of amino and C 1 -C 3 -alkylamino, or for a group of the formula
  • R 4 is hydrogen, C 1 -C 4 -alkyl or benzyl
  • R 5 is hydrogen, C 1 -C 4 -alkyl or benzyl
  • R 3 is hydrogen, fluorine, chlorine, methyl or methoxy, and their salts, their solvates and the solvates of their salts.
  • Compounds of the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, as well as those of formula (I), hereinafter referred to as embodiment (e) and their salts, solvates and solvates of the salts, as far as it is in the compounds of formula (I), mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or, if appropriate, also as conformational isomers (enantiomers and / or diastereomers, including those of atropisomers).
  • the present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
  • the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 C1, 82 Br, 123 I, 124 I, 129 I and 131 I.
  • isotopic variants of a compound of the invention such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or drug distribution in the body; Because of the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes are particularly suitable for this purpose. Moreover, the incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention.
  • Isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and by the methods described below. Examples reproduced by appropriate isotopic modifications of the respective reagents and / or starting compounds are used.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, 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, N-methylpiperidine and choline.
  • 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.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but during their residence time in the body are converted to compounds of the invention (for example metabolically or hydrolytically).
  • the enantiomers can be separated either directly after the coupling of the L-phenylalanine intermediates with the amine H 2 NR 1 or at a later intermediate of the synthesis or else the compounds according to the invention.
  • the separation of the enantiomers is directly after the coupling of the L-phenylalanine intermediates with the amine
  • treatment includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, a disease, a disease, an injury or a medical condition , the unfolding, the course or progression of such conditions and / or the symptoms of such conditions.
  • therapy is understood to be synonymous with the term “treatment”.
  • prevention means the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or to get, experience, suffer or have the symptoms of such conditions.
  • the treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.
  • alkyl is a linear or branched alkyl radical having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, iso-propyl, 2-methyl-prop-1-yl, n-butyl and tert-butyl.
  • Alkoxy represents a linear or branched alkoxy radical having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, by way of example and preferably methoxy, ethoxy, n-propoxy, iso-propoxy, 2-methyl-prop-l-oxy, n-butoxy and teri-butoxy.
  • Alkylamino is an amino group having one or two independently selected identical or different linear or branched alkyl radicals, each having 1 to 3 carbon atoms, by way of example and preferably methylamino, ethylamino, n-propylamino, iso-propylamino, N, N Dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-iso-propyl-Nn-propylamino and N, N-diisopropylamino.
  • 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 radical.
  • Cycloalkyl represents a monocyclic cycloalkyl group having 3 to 6 carbon atoms, by way of example and preferably cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • 9- or 10-membered bicyclic heteroaryl in the definition of the radical R 2 is an aromatic or partially aromatic bicyclic radical having 9 or 10 ring atoms and up to 4 heteroatoms and / or hetero groups from the series S, O, ⁇ , SO and SO 2 , where a nitrogen atom can also form a ⁇ -oxide, by way of example and preferably benzimidazolyl, benzoxazolyl, benzthiazolyl, benzofuranyl, benzothiophenyl, indazolyl, pyrrolopyridinyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, quinazolyl, quinoxalinyl, 1H-imidazo [4,5 -b] pyridin-6-yl, l, 2,3,4-tetrahydropyrido [2,3-b] pyrazine-7-yl, 2,3-dihydro-1
  • 5-membered heteroaryl in the definition of the radical R 6 is an aromatic monocyclic radical having 5 ring atoms and up to 4 heteroatoms and / or hetero groups from the series S, O, N, SO and SO 2 , where a nitrogen atom is also an N- May be exemplified and preferably for thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl, more preferably triazolyl and tetrazolyl, most preferably tetrazolyl.
  • 5-membered heterocycle in the definition of the radicals R 8 and R 9 is a saturated, partially unsaturated or aromatic monocyclic radical having 5 ring atoms and up to 2 heteroatoms and / or hetero groups from the series S, O, N, SO and SO 2 where a nitrogen atom can also form an N-oxide.
  • This 5-membered heterocycle together with the phenyl ring to which it is attached is by way of example and preferably 2,3-dihydro-1-benzothiophene-5-yl, 1,3-dihydro-2-benzothiophene-5-yl, 2 , 3-dihydro-1-benzofuran-5-yl, 1,3-dihydro-2-benzofuran-5-yl, indolin-5-yl, isoindolin-5-yl, 2,3-dihydro-1H-indazole-5 -yl, 2,3-dihydro-1H-benzimidazol-5-yl, 1,3-dihydro-2,1-benzoxazol-5-yl, 2,3-dihydro-1,3-benzoxazol-5-yl, 1 , 3-Dihydro-2,1-benzothiazol-5-yl, 2,3-dihydro-1,3-benzothiazol-5-yl, 1H-benzimi
  • R 6 is 5-membered heteroaryl, wherein heteroaryl may be substituted with one substituent selected from the group consisting of oxo, chloro, cyano, hydroxy and C 1 -C 3 -alkyl, wherein alkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of hydroxy, amino, hydroxycarbonyl and methoxy, or wherein alkyl may be substituted with 1 to 7 fluorine substituents, or wherein alkyl is substituted with one substituent selected from the group consisting of hydroxy, amino, hydroxycarbonyl and methoxy and wherein Alkyl is additionally substituted by 1 to 6 substituents fluorine,
  • R 7 is hydrogen, fluorine or chlorine
  • R 8 and R 9 together with the carbon atoms to which they are attached form a 5-membered heterocycle, it being possible for the heterocycle to be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, chlorine, cyano, hydroxyl, C 3 alkyl, pyrazolyl and pyridyl, wherein alkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of hydroxy, amino, hydroxycarbonyl and methoxy, or wherein alkyl may be substituted with 1 to 7 substituents fluorine, or wherein alkyl is substituted with a substituent selected from the group consisting of hydroxy, amino, hydroxycarbonyl and methoxy and wherein alkyl is additionally substituted with 1 to 6 substituents fluoro,
  • R io is hydrogen, fluorine or chlorine
  • R 2 is 9- or 10-membered bicyclic heteroaryl, where heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, fluorine, chlorine, cyano, trifluoromethyl, hydroxy, amino, C 1 -C 3 - Alkylamino and C 1 -C 3 -alkyl, wherein alkyl may be substituted with one substituent selected from the group consisting of amino and C 1 -C 3 -alkylamino, or R : for a group of the formula
  • R 4 is hydrogen, C 1 -C 4 -alkyl or benzyl
  • R 5 is hydrogen, C 1 -C 4 -alkyl or benzyl
  • R 3 is hydrogen, fluorine, chlorine, methyl or methoxy, salts, their solvates and the solvates of their salts.
  • Compounds of the formula (I) in which R 1 is a group of the formula are preferred.
  • R 6 is 5-membered heteroaryl, wherein heteroaryl may be substituted with one substituent selected from the group consisting of oxo, chloro and C 1 -C 3 -alkyl, wherein alkyl may be substituted with 1 to 2 substituents independently selected from the group consisting of hydroxycarbonyl and methoxy, or wherein alkyl may be substituted with 1 to 7 fluorine substituents, or wherein alkyl is substituted with a hydroxy carbonyl substituent and wherein alkyl is additionally substituted with 1 to 6 fluorine substituents,
  • R 7 is hydrogen or fluorine
  • R 8 and R 9 together with the carbon atoms to which they are attached form a 5-membered heterocycle, where the heterocycle may be substituted by 1 to 2 substituents independently selected from the group consisting of oxo, chloro, hydroxy, Ci-C 3 Alkyl, pyrazolyl and pyridyl, wherein alkyl may be substituted with 1 to 2 substituents independently selected from the group consisting of hydroxycarbonyl and methoxy, or wherein alkyl may be substituted with 1 to 7 fluorine substituents, or wherein alkyl is substituted with one substituent hydroxycarbonyl and wherein alkyl is additionally substituted with 1 to 6 substituents fluorine,
  • R i of ur is hydrogen or fluorine, is 9- or 10-membered bicyclic heteroaryl, wherein heteroaryl may be substituted with 1 to 3 substituents independently selected from the group consisting of oxo, fluoro, chloro, hydroxy, amino, C 1 -C3- alkylamino and Ci-C 3 alkyl, which alkyl may be substituted with a substituent selected from the group consisting of amino and Ci-C3-alkylamino, or a group of the formula
  • R 4 is hydrogen, methyl or benzyl
  • R 5 is hydrogen, methyl or benzyl
  • R 3 is hydrogen, fluorine, methyl or methoxy, and their salts, their solvates and the solvates of their salts.
  • R 6 is 5-membered heteroaryl
  • R 7 is hydrogen or fluorine
  • R 8 and R 9 together with the carbon atoms to which they are attached form a 5-membered heterocycle, it being possible for the heterocycle to be substituted by a substituent oxo,
  • R 2 is 9- or 10-membered bicyclic heteroaryl wherein heteroaryl may be substituted with 1 to 2 substituents independently selected from the group consisting of oxo, amino and C 1 -C 3 -alkyl, wherein alkyl may be substituted with an amino substituent , or
  • R 2 is a group of the formula
  • R 4 is hydrogen or methyl
  • R 5 is hydrogen, methyl or benzyl
  • R 3 is hydrogen
  • R 1 is a group of the formula
  • R 6 is tetrazolyl
  • R 7 is hydrogen or fluorine
  • R 2 is benzimidazolyl, indazolyl, pyrrolopyridinyl, isoquinolinyl or tetrahydroquinolinyl, where benzimidazolyl, indazolyl, pyrrolopyridinyl, isoquinolinyl and tetrahydroquinolinyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, amino, methyl, ethyl, n- Propyl and iso-propyl, wherein ethyl, n-propyl and iso-propyl may be substituted with a substituent amino, or
  • R 2 is a group of the formula
  • R 4 is hydrogen or methyl
  • R 5 is hydrogen, methyl or benzyl
  • R 3 is hydrogen, and their salts, their solvates and the solvates of their salts.
  • R 1 is a group of the formula
  • R 6 is 5-membered heteroaryl, wherein heteroaryl may be substituted with one substituent selected from the group consisting of oxo, chloro and C 1 -C 3 -alkyl, wherein alkyl may be substituted with 1 to 2 substituents independently selected from the group consisting of hydroxycarbonyl and methoxy, or wherein alkyl may be substituted with 1 to 7 fluorine substituents, or wherein alkyl is substituted with a hydroxy carbonyl substituent and wherein alkyl is additionally substituted with 1 to 6 fluorine substituents,
  • R 7 is hydrogen or fluorine
  • R 8 and R 9 together with the carbon atoms to which they are attached form a 5-membered heterocycle, where the heterocycle may be substituted by 1 to 2 substituents independently selected from the group consisting of oxo, chloro, hydroxy, Ci-C 3 -Alkyl, pyrazolyl and pyridyl, wherein alkyl may be substituted with 1 to 2 substituents independently selected from the group consisting of hydroxycarbonyl and methoxy, or wherein alkyl may be substituted with 1 to 7 substituents fluoro, or wherein alkyl is substituted with a substituent hydroxycarbonyl and wherein alkyl is additionally substituted with 1 to 6 substituents fluoro,
  • R i of ur is hydrogen or fluorine
  • R 2 is 9- or 10-membered bicyclic heteroaryl, where heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, fluorine, chlorine, hydroxyl, amino, C 1 -C 3 -alkylamino, ci C 3 alkyl and C 3 -C 6 cycloalkyl, wherein alkyl may be substituted with one substituent selected from the group consisting of amino and C 1 -C 3 alkylamino, or a group of the formula
  • R 4 is hydrogen, methyl or benzyl
  • R 5 is hydrogen, methyl or benzyl
  • R 3 is hydrogen, fluorine, methyl or methoxy, and their salts, their solvates and the solvates of their salts.
  • Compounds of the formula (I) in which R 1 is a group of the formula are preferred where # is the point of attachment to the nitrogen atom,
  • R 6 is 5-membered heteroaryl
  • R 7 is hydrogen or fluorine
  • R 8 and R 9 together with the carbon atoms to which they are attached form a 5-membered heterocycle, it being possible for the heterocycle to be substituted by a substituent oxo,
  • R i of ur is hydrogen
  • R 2 is 9- or 10-membered bicyclic heteroaryl, wherein heteroaryl may be substituted by 1 to 2 substituents independently selected from the group consisting of oxo, amino, Ci-C3-alkyl, cyclopropyl and Cyclobutyl, wherein alkyl may be substituted with a substituent amino
  • R 3 is hydrogen, and their salts, their solvates and the solvates of their salts.
  • R 6 is tetrazolyl
  • R 7 is hydrogen or fluorine, or
  • R 1 is 2,3-dihydro-1H-indazol-6-yl, 2,3-dihydro-1H-benzimidazol-5-yl, 1H-benzimidazol-6-yl or 1H-indazol-6-yl, wherein 2 , 3-dihydro-1H-indazol-6-yl and 2,3-dihydro-1H-benzimidazol-5-yl may be substituted by a substituent oxo,
  • R 2 is benzimidazolyl, indazolyl, pyrrolopyridinyl, isoquinolinyl, tetrahydroquinolinyl, 1H-imidazo [4,5-b] pyridin-6-yl, 1,2,3,4-tetrahydropyrido [2,3-b] pyrazine-7-yl , 2,3-dihydro-1H-isoindol-5-yl, 2,3-dihydro-1H-indazol-6-yl, [l, 2,4] triazolo [l, 5-a] pyridin-6-yl or 3H-imidazo [4,5-b] pyridin-5-yl, wherein benzimidazolyl, indazolyl, pyrrolopyridinyl, isoquinolinyl, tetrahydroquinolinyl, 1H-imidazo [4,5-b] pyridin-6-yl, l, 2,3
  • R 3 is hydrogen, and their salts, their solvates and the solvates of their salts. Preference is also given to compounds of the formula (I) in which, for a group of the formula
  • R 6 is tetrazolyl
  • R 7 is hydrogen or fluorine
  • R 1 is 2,3-dihydro-1H-indazol-6-yl, where 2,3-dihydro-1H-indazol-6-yl may be substituted with one substituent oxo.
  • R 1 is 2,3-dihydro-1H-indazol-6-yl, 2,3-dihydro-1H-benzimidazol-5-yl, 1H-benzimidazol-6-yl or 1H-indazol-6-yl, wherein 2,3-dihydro-1H-indazol-6-yl and 2,3-dihydro-1H-benzimidazol-5-yl may be substituted with one substituent oxo.
  • R 2 is benzimidazolyl, indazolyl, pyrrolopyridinyl, isoquinolinyl or tetrahydroquinolinyl
  • benzimidazolyl, indazolyl, pyrrolopyridinyl, isoquinolinyl and tetrahydroquinolinyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, amino, methyl, ethyl, n-propyl and iso-propyl, wherein ethyl, n-propyl and iso-propyl may be substituted with a
  • R 2 is benzimidazolyl, indazolyl, pyrrolopyridinyl, isoquinolinyl, tetrahydroquinolinyl, 1H-imidazo [4,5-b] pyridin-6-yl, 1,2,3,4-tetrahydropyrido [2,3-b] pyrazine-7-yl , 2,3-dihydro-1H-isoindol-5-yl, 2,3-dihydro-1H-indazol-6-yl, [l, 2,4] triazolo [l, 5-a] pyridin-6-yl or 3H-
  • R 4 is hydrogen or methyl
  • R 5 is hydrogen, methyl or benzyl.
  • 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, where the compounds of the formula
  • R 1 , R 2 and R 3 have the meaning given above, be reacted with an acid.
  • the reaction is generally carried out in inert solvents, preferably in a temperature range from room temperature to 60 ° C at atmospheric pressure.
  • Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1, 2-dichloroethane, or ethers such as tetrahydrofuran or dioxane, preferably dioxane.
  • Acids are for example trifluoroacetic acid or hydrogen chloride in dioxane, preferred is hydrogen chloride in dioxane.
  • the compounds of formula (II) are known or can be prepared by
  • R 1 and R 3 have the abovementioned meaning
  • Q 1 is -B (OH) 2, a boronic acid ester, preferably boronic acid pinacol ester, or, with compounds of the formula
  • R 2 has the meaning given above, and X 1 is bromine or iodine, are reacted under Suzuki coupling conditions, or
  • R 1 and R 3 have the abovementioned meaning, and X 2 is bromine or iodine, with compounds of the formula Q-R 2 (VI), in which
  • R 2 has the meaning given above, and
  • Q 2 is -B (OH) 2
  • a boronic acid ester preferably boronic acid pinacol ester, or -BF 3 K + , are reacted under Suzuki coupling conditions, or
  • R 2 and R 3 have the abovementioned meaning, with compounds of the formula
  • reaction according to process [A] is generally carried out in inert solvents, in the presence of a catalyst, optionally in the presence of an additional reagent, optionally in a microwave, preferably in a temperature range from room temperature to 150 ° C at atmospheric pressure to 3 bar.
  • catalysts are conventional palladium catalysts for Suzuki reaction conditions, preferably catalysts such as e.g. Dichlorobis (triphenylphosphine) palladium, tetrakistriphenylphosphinepalladium (O), palladium (II) acetate / triscyclohexylphosphine, tris (dibenzylideneacetone) dipalladium, bis (diphenylphosphineferrocenyl) palladium (II) chloride, 1,3-bis (2,6-) diisopropylphenyl) imidazol-2-ylidene (1,4-naphthoquinone) palladium dimer, allyl (chloro) - (1,3-dimesityl-l, 3-dihydro-2H-imidazol-2-ylidene) palladium, palladium (II) acetate / Dicyclohexyl- (2 ', 4'
  • Additional reagents are for example potassium acetate, cesium, potassium or sodium carbonate, potassium tert-butoxide, cesium fluoride or potassium phosphate, which may be present in aqueous solution, preference is given to additional reagents such as potassium acetate or a mixture of potassium acetate and sodium carbonate.
  • Inert solvents are, for example, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons, such as benzene, xylene or toluene, or carboxamides, such as dimethylformamide or dimethylacetamide, alkylsulfoxides, such as dimethylsulfoxide, or N-methylpyrrolidone or acetonitrile, or mixtures of the solvents with alcohols, such as methanol or ethanol and / or water, preferred is toluene, dimethylformamide or dimethyl sulfoxide.
  • ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane
  • hydrocarbons such as benzene, xylene or toluene
  • carboxamides such as dimethylformamide or dimethylacetamide
  • alkylsulfoxides such as dimethylsulfoxide, or N-
  • the compounds of the formula (IV) are known, can be synthesized by known processes from the corresponding starting compounds or can be prepared analogously to the processes described in the Examples section.
  • reaction according to method [B] is carried out as described for method [A].
  • the compounds of the formula (VI) are known, can be synthesized by known processes from the corresponding starting compounds or can be prepared analogously to the processes described in the Examples section.
  • reaction according to process [C] is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 0 ° C to reflux of the solvent at atmospheric pressure.
  • Suitable dehydrating reagents for this purpose are, for example, carbodiimides, such as e.g. N, N'-diethyl, N, N'-dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylamino-isopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1, 2-oxazolium-3-sulphate or 2-tert.-butyl-5-methylisoxazolium perchlorate, or
  • Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines, e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preferred is diisopropylethylamine.
  • alkali carbonates e.g. Sodium or potassium carbonate
  • hydrogen carbonate e.g. Sodium or potassium carbonate
  • organic bases such as trialkylamines, e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preferred is diisopropylethylamine.
  • Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, or other solvents such as nitromethane, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, acetonitrile or pyridine, or Mixtures of the solvents, preferably tetrahydrofuran or dimethylformamide or a mixture of dimethylformamide and pyridine.
  • halogenated hydrocarbons such as dichloromethane or trichloromethane
  • hydrocarbons such as benzene
  • other solvents such as nitromethane, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, acetonitrile or pyridine
  • Mixtures of the solvents preferably tetrahydrofuran or dimethylformamide or a mixture of dimethylformamide and pyridine.
  • the compounds of the formula (VIII) are known, can be synthesized by known processes from the corresponding starting compounds or can be prepared analogously to the processes described in the Examples section.
  • the compounds of formula (III) are known or may be prepared by reacting compounds of formula (V) with 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi -l, 3,2-dioxaborolane.
  • the reaction is generally carried out in inert solvents, in the presence of a catalyst, optionally in the presence of an additional reagent, optionally in a microwave, preferably in a temperature range from room temperature to 150 ° C at atmospheric pressure to 3 bar.
  • Hydroylation in an acidic medium gives the corresponding boronic acids.
  • Working up with potassium hydrogen difluoride solution (KHF 2 solution) gives the corresponding trifluoroborates.
  • Catalysts are, for example, conventional palladium catalysts for the borylation of aryl halides, preferably catalysts such as e.g.
  • Additional reagents are for example potassium acetate, cesium, potassium or sodium carbonate, potassium or sodium tert-butoxide, cesium fluoride, potassium phosphate or potassium phenolate, preferably potassium acetate.
  • Inert solvents are, for example, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons, such as benzene, xylene or toluene, or carboxamides, such as dimethylformamide or dimethylacetamide, alkyl sulphoxides, such as dimethylsulphoxide, or Methylpyrrolidone or acetonitrile, preferably dioxane, dimethylformamide or dimethyl sulfoxide.
  • R 3 has the abovementioned meaning, and X 2 is bromine or iodine, are reacted with compounds of formula (VIII) in the presence of dehydrating reagents.
  • the compounds of the formula (IX) are known, can be synthesized by known processes from the corresponding starting compounds or can be prepared analogously to the processes described in the Examples section.
  • R 2 and R 3 have the abovementioned meaning
  • X 3 is methyl or ethyl, are reacted with a base.
  • the reaction is generally carried out in inert solvents, preferably in a temperature range from room temperature to the reflux of the solvent at atmospheric pressure.
  • Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane, trichloromethane, tetrachloromethane or 1,2-dichloroethane, alcohols, such as methanol or ethanol, ethers, such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, or other solvents, such as dimethylformamide. Dimethylacetamide, acetonitrile or pyridine, or mixtures of solvents, or mixtures of solvent with water, preferred is a mixture of tetrahydrofuran and water.
  • halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane or 1,2-dichloroethane
  • alcohols such as methanol or ethanol
  • ethers such as diethyl ether, methyl tert-but
  • Bases are, for example, alkali metal hydroxides such as sodium, lithium or potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or alcoholates such as potassium or sodium tert-butoxide, preferably sodium hydroxide or lithium hydroxide.
  • R 3 has the meaning given above, X 3 is methyl or ethyl, and X 4 is bromine or iodine, are reacted with compounds of formula (VI) under Suzuki coupling conditions. The reaction is carried out as described for method [A].
  • the compounds of the formula (XI) are known, can be synthesized by known processes from the corresponding starting compounds or can be prepared analogously to the processes described in the Examples section.
  • the compounds of the invention show an unpredictable, valuable pharmacological activity spectrum and a good pharmacokinetic behavior. These are compounds which influence the proteolytic activity of the serine proteases FXIa and kallikrein and optionally plasmin.
  • the compounds of the present invention inhibit the enzymatic cleavage of substrates which play an essential role in the activation of the blood coagulation cascade and the aggregation of platelets. If the compounds according to the invention inhibit plasmin activity, inhibition of fibrinolysis occurs. They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.
  • 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 cardiovascular diseases, preferably thrombotic or thromboembolic diseases and / or thrombotic or thromboembolic complications.
  • thromboembolic disorders include in particular diseases such as acute coronary syndrome (ACS), heart attack 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, stent implantation or aortocoronary bypass, peripheral arterial occlusive diseases, pulmonary embolism, venous thrombosis, especially in deep leg veins and renal veins, transient ischemic attacks and thrombotic and thromboembolic stroke.
  • ACS acute coronary syndrome
  • STEMI heart attack with ST segment elevation
  • non-STEMI non-STEMI
  • stable angina pectoris unstable Angina pectoris
  • reocclusions reocclusions and restenoses after coronary interventions
  • coronary interventions such as angioplasty, stent implantation or aortocoronary bypass, peripheral arterial occlusive diseases, pulmonary embolism, ve
  • the compounds of the invention 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 , in 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 according to the invention are suitable for the treatment and prevention of disseminated intravascular coagulation (DIC), which occur, inter alia, in the context of sepsis, but also as a result of operations, tumor diseases, burns or other injuries and can lead to severe organ damage through microthromboses.
  • DIC disseminated intravascular coagulation
  • Thromboembolic complications also occur in microangiopathic hemolytic anemias, extracorpo
  • the compounds according to the invention also have an influence on wound healing, for the prophylaxis and / or treatment of atherosclerotic vascular diseases and inflammatory diseases such as rheumatic diseases of the locomotor system, coronary heart diseases, cardiac insufficiency, hypertension, inflammatory diseases such as asthma, inflammatory lung diseases, Glomerulonephritis and inflammatory bowel diseases, such as Crohn's disease or ulcerative colitis, or acute renal failure into consideration, moreover, also for the prophylaxis and / or treatment of dementia diseases such.
  • atherosclerotic vascular diseases and inflammatory diseases such as rheumatic diseases of the locomotor system, coronary heart diseases, cardiac insufficiency, hypertension, inflammatory diseases such as asthma, inflammatory lung diseases, Glomerulonephritis and inflammatory bowel diseases, such as Crohn's disease or ulcerative colitis, or acute renal failure into consideration, moreover, also for the prophylaxis and / or treatment of dementia diseases such.
  • 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, especially those undergoing major surgery or chemo- or radiotherapy.
  • pulmonary hypertension covers certain forms of pulmonary hypertension as defined, for example, by the World Health Organization (WHO), such as pulmonary arterial hypertension, pulmonary hypertension in diseases of the left heart, pulmonary hypertension in pulmonary disease and / or hypoxia and pulmonary hypertension due to chronic thromboembolism (CTEPH).
  • WHO World Health Organization
  • CTEPH chronic thromboembolism
  • Pulmonary arterial hypertension includes idiopathic pulmonary arterial hypertension (IPAH, formerly referred to as primary pulmonary hypertension), familial pulmonary arterial hypertension (FPAH), and Associated pulmonary arterial hypertension (APAH) associated with collagenosis, congenital systemic pulmonary shunt veins, portal hypertension, HIV infection, use of certain drugs and medications, other diseases (thyroid disorders, glycogen storage disorders, Gaucher's disease, heredi telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy), with diseases with significant venous / capillary involvement, such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, as well as persistent pulmonary hypertension of newborns.
  • Pulmonary hypertension in left heart disease includes left atrial or ventricular disease and mitral or aortic valve failure.
  • Pulmonary hypertension in lung disease and / or hypoxia includes chronic obstructive pulmonary disease, interstitial lung disease, sleep apnea syndrome, alveolar hypoventilation, chronic altitude sickness, and plant-related malformations.
  • Pulmonary hypertension due to chronic thromboembolism includes thromboembolic occlusion of proximal pulmonary arteries, thromboembolic occlusion of distal pulmonary arteries, and non-thrombotic pulmonary embolisms (tumor, parasites, foreign bodies).
  • Another object of the present invention is the use of the compounds of the invention for the preparation of medicaments for the treatment and / or prophylaxis of pulmonary hypertension in sarcoidosis, histiocytosis X and Lymphangiomatosis.
  • the substances according to the invention are also suitable for the treatment of pulmonary and hepatic fibroses.
  • the compounds according to the invention also come for the treatment and / or prophylaxis of disseminated intravascular coagulation in the context of infectious disease and / or systemic inflammatory syndrome (SIRS), septic organ dysfunction, septic organ failure and multi-organ failure, acute respiratory distress syndrome (ARDS), acute lung Injury (ALI), septic shock and / or septic organ failure.
  • SIRS systemic inflammatory syndrome
  • septic organ dysfunction septic organ dysfunction
  • septic organ failure and multi-organ failure multi-organ failure
  • ARDS acute respiratory distress syndrome
  • ALI acute lung Injury
  • septic shock and / or septic organ failure septic shock and / or septic organ failure.
  • DIC Dispersed Intravascular Coagulation
  • Consumption Coagulopathy hereinafter referred to as "DIC”
  • endothelial damage can result in increased vascular permeability and leakage of fluid and proteins into the extravasal space.
  • organ failure e.g., renal failure, liver failure, respiratory failure, CNS deficits and cardiovascular failure
  • multiple organ failure may occur.
  • DIC DIC
  • the surface of damaged endothelial cells, foreign body surfaces or extravasated extravascular tissue causes massive activation of the coagulation system.
  • coagulation occurs in small vessels of various organs with hypoxia and subsequent organ dysfunction. This can be prevented by the compounds of the invention.
  • coagulation factors e.g., Factor X, prothrombin, and fibrinogen
  • platelets are consumed, which lowers the blood's ability to coagulate and cause severe bleeding.
  • the compounds according to the invention are also suitable for the prophylaxis and / or treatment of hyperfibrinolysis.
  • Prophylaxis and / or treatment can reduce or eliminate severe perioperative blood loss. Strong bleeding occurs in severe surgery, such as. Coronary artery bypass graft surgery, transplantation or hysterectomy, as well as trauma, haemorrhagic shock, or postpartum hemorrhage.
  • perioperative use of extracorporeal circulation systems or filter systems such as, for example, heart lung machine, hemofiltration, hemodialysis, extracorporeal membrane oxygenation or ventricular support system, such as artificial heart, may occur.
  • This also requires anticoagulation, to which the compounds of the invention can also be used.
  • the compounds according to the invention are also suitable for anticoagulation during the renal replacement procedure, for example in continuous veno-venous hemofiltration or intermittent hemodialysis.
  • the compounds according to the invention can also be used for the prevention of 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 which might contain Factor XIa.
  • 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 a therapeutically effective amount of a compound of the invention.
  • Another object of the present invention are the compounds of the invention for use in a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using a therapeutically effective amount of a compound of the invention.
  • Another object of the present invention are pharmaceutical compositions containing a compound of the invention and one or more other active ingredients.
  • Another object of the present invention is a method for preventing blood coagulation in vitro, especially in blood or biological samples that might contain factor XIa, 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 such as lovastatin (Mevacor), simvastatin (Zocor), pravastatin (pravachol), fluvastatin (Lescol) and atorvastatin (Lipitor);
  • Coronary / vasodilators especially ACE (angiotensin converting enzyme) inhibitors such as captopril, lisinopril, enalapril, ramipril, cilazapril, benazepril, fosinopril, quinapril and perindopril, or AII (angiotensin II) receptor antagonists such as embusartan , Losartan, valsartan, irbesartan, candesartan, eprosartan and temisarta, or beta-adrenoceptor antagonists such as carvedilol, alprenolol, bisoprolol, acebutolol, atenolol, betaxolol, carteolol, metoprolol, nadolol, penbutolol, pindolol, propranolol and timolol, or alpha- 1-adren
  • Plasminogen activators thrombolytics / fibrinolytics
  • thrombolysis / fibrinolysis-enhancing compounds such as inhibitors of the plasminogen activator inhibitor (PAI inhibitors) or inhibitors of the thrombin-activated fibrinolysis inhibitor (TAFI inhibitors) such as tissue plasminogen activator ( t-PA), streptokinase, reteplase and urokinase; anticoagulant substances (anticoagulants) such as heparin (UFH), low molecular weight heparin (LMWH) such as tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, danaparoid, semuloparin (AVE 5026), adomiparin (Ml 18) and EP-42675 / ORG42675; direct thrombin inhibitors (DTI) such as Pradaxa (D
  • Antiplatelet agents such as, for example, aspirin, ticlopidine (ticlid), clopidogrel (plavix), prasugrel, ticagrelor, cangrelor, elinogrel,
  • Fibrinogen receptor antagonists such as abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban and fradafiban;
  • Vasopressors such as norepinephrine, dopamine and vasopressin;
  • Inotropic therapy such as dobutamine
  • Corticosteroids such as hydrocortisone and fludrocortisone
  • Recombinant human activated protein C such as Xigris
  • blood products such as erythrocyte concentrates, platelet concentrates,
  • Combinations within the meaning of the invention not only pharmaceutical forms containing all components (so-called. Fixed combinations) and combination packs containing the components separated from each other, understood, but also simultaneously or temporally staggered applied components, if they are for prophylaxis and It is also possible to combine two or more active substances, ie two or more combinations.
  • the compounds according to the invention can act systemically and / or locally.
  • they can be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • 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 medicines including powder inhalers, nebulizers
  • nasal drops solutions, 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 (such as patches)
  • 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 excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitol oleate), 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) and flavor and / or odoriferous.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitol oleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example,
  • compositions containing at least one compound of the invention preferably together with one or more inert non-toxic, pharmaceutically suitable excipient, as well as their use for the purposes mentioned above.
  • Method 1 Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 ⁇ 50mm x 1mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A-> 1.2 min 5% A-> 2.0 min 5% A; Oven: 50 ° C; Flow: 0.40 ml / min; UV detection: 210 - 400 nm.
  • Method 2 Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 ⁇ 50 mm x 1 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 97% A -> 0.5 min 97% A -> 3.2 min 5% A -> 4.0 min 5% A Oven: 50 ° C; Flow: 0.3 ml / min; UV detection: 210 nm.
  • Method 3 Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 ⁇ 30 mm x 2 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A-> 1.2 min 5% A -> 2.0 min 5% A Furnace: 50 ° C; Flow: 0.60 ml / min; UV detection: 208-400 nm.
  • Method 4 Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 ⁇ 50 mm x 2.1 mm; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow: 0.8 ml / min; Temperature: 60 ° C; Injection: 2 ⁇ ; DAD scan: 210-400 nm; ELSD.
  • Method 5 Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 ⁇ 50 mm x 2.1 mm; Eluent A: water + 0.2% ammonia, eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow: 0.8 ml / min; Temperature: 60 ° C; Injection: 2 ⁇ ; DAD scan: 210-400 nm; ELSD.
  • Method 6 System: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; Column: Chromatorex C-18 125 mm ⁇ 30 mm, eluent A: 0.1% formic acid in water, eluent B: acetonitrile, gradient: A 95% / B 5% -> A 55% / B 45%; Flow: 150 ml / min; UV detection: 254 nm.
  • Method 7 System: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; Column: Chromatorex C-18 125 mm ⁇ 30 mm, eluent A: 0.1% formic acid in water, eluent B: acetonitrile; Gradient: A 90% / B 10% -> A 50% / B 50%; Flow: 150 ml / min; UV detection: 254 nm.
  • Method 8 System: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; Column: Chromatorex C-18 125 mm ⁇ 30 mm, eluent A: 0.1% formic acid in water, eluent B: acetonitrile; Gradient: A 85% / B 15% -> A 45% / B 55%; Flow: 150 ml / min; UV detection: 254 nm.
  • Method 9 System: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; Column: Chromatorex C-18 125 mm ⁇ 30 mm, eluent A: 0.1% formic acid in water, eluent B: acetonitrile; Gradient: A 80% / B 20% -> A 40% / B 60%; Flow: 150 ml / min; UV detection: 254 nm.
  • Method 10 Instrument: Waters autopurification system SQD; Column: Waters XBrigde C18 5 ⁇ 100 mm x 30 mm; Eluent A: water + 0.1% formic acid (99%), eluent B: acetonitrile; Gradient: 0-8.0 min 1-100% B, 8.0-10.0 min 100% B; Flow 50.0 ml / min; Temperature: RT; Injection: 2500 ⁇ ; DAD scan: 210-400 nm.
  • Method 11 Instrument: Waters autopurification system SQD; Column: Waters XBrigde C18 5 ⁇ 100 mm x 30 mm; Eluent A: water + 0.2% ammonia (32%), eluent B: acetonitrile; Gradient: 0-8.0 min 1-100% B, 8.0-10.0 min 100% B; Flow 50.0 ml / min; Temperature: RT; Injection: 2500 ⁇ ; DAD scan: 210-400 nm.
  • Method 12 Instrument MS: Waters (Micromass) QM; Instrument HPLC: Agilent 1100 series; Column: Agient ZORBAX Extend-C18 3.0mm x 50mm 3.5-micron; Eluent A: 1 l of water + 0.01 mol of ammonium carbonate, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 98% A-> 0.2 min 98% A -> 3.0 min 5% A ⁇ 4.5 min 5% A; Oven: 40 ° C; Flow: 1.75 ml / min; UV detection: 210 nm.
  • Method 13 Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 ⁇ 50 mm x 1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 95% A -> 6.0 min 5% A -> 7.5 min 5% A; Oven: 50 ° C; Flow: 0.35 ml / min; UV detection: 210 - 400 nm.
  • Method 14 Instrument MS: Waters (Micromass) Quattro Micro; Instrument HPLC: Agilent 1100 series; Column: YMC-Triart C18 3 ⁇ 50 mm x 3 mm; Eluent A: 1 l of water + 0.01 mol of ammonium carbonate, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 10 0% A-> 2.75 min 5% A-> 4.5 min 5% A; Oven: 40 ° C; Flow: 1.25 ml / min; UV detection: 210 nm.
  • Method 15 System: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; Column: Chromatorex C-18 125 mm x 30 mm; Eluent A: 0.1% formic acid in water, eluent B: acetonitrile, gradient: A 90% / B 10% -> A 50% / B 50%; Flow: 150 ml / min; UV detection: 254 nm.
  • Microwave The microwave reactor used was a Biotage TM initiator.
  • the compounds of the invention may be in salt form, for example as trifluoroacetate, formate or ammonium salt, if the Compounds according to the invention contain a sufficiently basic or acidic functionality.
  • a salt can be converted into the corresponding free base or acid by various methods known to those skilled in the art.
  • Weaker salts can be converted to the corresponding chlorides by addition of some hydrochloride.
  • the starting compounds and examples contain an L-phenylalanine derivative as the central building block, the corresponding stereocenter is described as (S) -configuration. Unless otherwise stated, it was not examined whether in individual cases in the coupling of the L-phenylalanine intermediate with the amine H2N-R 1 partial epimerization of the stereocenter took place. Thus, a mixture of the compounds of (S) -enantiomer and (R) -enantiomer according to the invention may be present. The main component is the respectively depicted (S) -enantiomer.
  • the reaction mixture was stirred into water and extracted three times with ethyl acetate.
  • the organic phase was washed with aqueous saturated sodium bicarbonate solution, aqueous saturated ammonium chloride solution, and aqueous saturated sodium chloride solution. It was dried over sodium sulfate and the solvent removed. 420 g (97% of theory) of the title compound were obtained.
  • the suspension was at 0 ° C dropwise with a 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide solution (50% in DMF, 16.9 g, 27 mmol) and then stirred for 16 h at RT.
  • the reaction mixture was stirred into ethyl acetate (13,000 ml) and extracted three times with water (1570 ml each). The organic phase was dried with sodium sulfate and the solvent removed.
  • the crude product was stirred with acetonitrile and filtered with suction. 11.4 g (78% of theory, 95% purity) of the title compound were obtained.
  • the suspension was treated with a 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide solution (50% in DMF, 2.2 ml, 3.7 mmol) and until added to the solution with DMF and then stirred for 16 h at RT.
  • the reaction mixture was stirred into ethyl acetate, washed twice with water and once with aqueous saturated sodium chloride solution.
  • the organic phase was dried with sodium sulfate and the solvent removed.
  • the crude product was stirred with acetonitrile and filtered with suction.
  • the residue was separated twice by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid).
  • the Crude product was stirred with methanol and filtered with suction. 202 mg (11% of theory) of the title compound were obtained.
  • the reaction mixture was treated with 1-bis-bis (diphenylphosphino) ferrocene-dichloroalladium (II) (267 mg, 0.16 mmol) and potassium acetate (1.9 g, 19.6 mmol) and heated at 110 ° C. for 24 h and 150 ° C. for 30 min C stirred in the microwave (Biotage initiator) and then further reacted as a crude product.
  • II 1-bis-bis (diphenylphosphino) ferrocene-dichloroalladium
  • the aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over sodium sulfate. The solvent was removed, the residue was slurried in dichloromethane, filtered, washed with acetonitrile and dried under high vacuum. 30 mg (17% of theory) of the title compound were obtained.
  • Example IIA Na / 7Aa - [(ira-i-4- ⁇ [(te ⁇ butoxycarbonyl) amino] methyl ⁇ cyclohexyl) carbonyl] -4- (2,4-dimethoxypyrinndin-5-yl) -N- [4- (2H-tetrazol-5-yl) phenyl] -L-phenylalaninamide trifluoroacetate
  • reaction mixture was heated at 120 ° C for 2 hours and cooled. Then lH-indazol-4-ylboronic acid (32 mg, 0.02 mmol) and 1, 1'-bis (diphenylphosphino) ferrocenedichloropalladium (II) (18 mg, 24 ⁇ ) were added again and heated at 120 ° C for 1.5 h.
  • the reaction solution was filtered through kieselguhr, partitioned between water and ethyl acetate and treated with 10% citric acid solution. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over sodium sulfate. The solvent was removed, the residue slurried in ethyl acetate, filtered, washed with acetonitrile and dried under high vacuum. 78 mg (48% of theory) of the title compound were obtained.
  • Example 21A Na / 7Aa - [(1 ⁇ -i-4- ⁇ [(te ⁇ Butoxycarbonyl) amino] methyl ⁇ cyclohexyl) carbonyl] -4- (1-methyl-1H-benzimidazol-5-yl) -N- [ 4- (2H-tetrazol-5-yl) phenyl] -L-phenylalaninamide
  • the suspension was treated with a 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide solution (50% in dimethylformamide, 7898 mg, 12 mmol) and until to the solution with dimethylformamide (20 ml) and then stirred for 16 h at RT.
  • the reaction mixture was stirred into ethyl acetate (600 ml), washed three times with water (300 ml) and once with saturated aqueous sodium chloride solution (250 ml).
  • the precipitate in the organic phase was filtered off and washed with ethyl acetate.
  • the solvent of the filtrate was removed and the residue was dried under high vacuum. 4021 mg (62% of theory) of the title compound were obtained.
  • reaction mixture was stirred at 120 ° C for 2 h.
  • the reaction mixture was mixed with water, the residue was filtered off, dried and purified by chromatography on silica gel (Biotage Isolera, SNAP ⁇ 375 g, eluent hexane / ethyl acetate / methanol). 391 mg (18% of theory) of the title compound were obtained.
  • reaction mixture was added for 2 h Stirred at 120 ° C.
  • the reaction mixture was filtered through aluminum oxide and chromatographically via HPLC (instrument: Labomatic HD3000, AS-3000, Labcol Vario 4000 Plus, Knauer DAD 2600, column: Waters XBrigde C18 5 ⁇ 150 mm x 50 mm, eluent A: water + 0.2% by volume.
  • Ammonia (32%), eluent B: acetonitrile; gradient: 0.00-1.00 min 10% B (flow: 50 to> 150 ml / min), 1-00-8.00 min 10-40% B (flow: 150 ml / min) , Temperature: RT; UV detection: 254 nm). 665 mg (28% of theory) of the title compound were obtained.
  • the suspension was admixed with a 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide solution (50% in ethyl acetate, 0.5 g, 0.8 mmol) and Stirred under reflux for 3 h.
  • the reaction mixture was mixed with water, the precipitate was filtered off with suction, dried under high vacuum and purified by chromatography via HPLC (Method 8). 29 mg (15% of theory) of the title compound were obtained.
  • Example 41A 3- [5- (4-Aminophenyl) -1H-l, 2,4-triazol-3-yl] -2,2,3,3-tetrailoropropanoic acid
  • Example 52A tert-Butyl ⁇ [ira-i-4 - ( ⁇ (25) -3- [4- (6-methyl-1,2,3,4-tetrahydropyrido [2,3-b] pyrazine-7-one yl) phenyl] -l-oxo-l - [(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) amino] propan-2-yl ⁇ carbamoyl) cyclohexyl] methyl ⁇ carbamate
  • reaction mixture was treated with DMSO (about 3 ml) and the ethyl acetate was removed on a rotary evaporator.
  • the residue was filtered through a Millipore filter and purified by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). 411.7 mg (53% of theory) of the title compound were obtained.
  • reaction mixture was diluted with water and made slightly acidic with 1N hydrochloric acid.
  • the mixture was extracted with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. 825 mg (96% of theory) of the title compound were obtained, which were used further without purification.
  • reaction mixture was stirred at 120 ° C for 2 h.
  • the reaction mixture was mixed with water, the residue was filtered off, dried and purified by chromatography on silica gel (Biotage Isolera, SNAP ⁇ 375 g, eluent hexane / ethyl acetate / methanol). 391 mg (18% of theory) of the title compound were obtained.
  • the solvent was removed on a rotary evaporator and the residue was dissolved in methanol (about 3 ml).
  • the solution was filtered through a MiUiporefilter and purified by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid).
  • the resulting material was taken up in methanol and 4M hydrogen chloride in 1, 4-dioxane (about 0.05 ml) was added.
  • the solvent was removed on a rotary evaporator and the residue was dried in a high vacuum. 24.3 mg (67% of theory) of the title compound were obtained.
  • the solution was again treated with 4M hydrogen chloride in 1,4-dioxane (0.2 ml, 0.8 mmol) and stirred at RT for a further 3 days.
  • the solvent was removed on a rotary evaporator and the residue was dissolved in DMSO / acetonitrile (about 3 ml).
  • the solution was filtered through a MiUiporefilter and purified by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid).
  • the resulting material was taken up in methanol and 4M hydrogen chloride in 1,4-dioxane (about 0.05 ml) added.
  • the solvent was removed on a rotary evaporator and the residue was dried in a high vacuum. 55 mg (66% of theory) of the title compound were obtained.
  • reaction mixture was stirred overnight at RT, treated with further 4M hydrogen chloride in dioxane (8.5 ⁇ , 33.9 ⁇ ), stirred for 2 h at RT until complete reaction and concentrated to dryness in vacuo. 12 mg (81% of theory) of the title compound were obtained.
  • a biochemical test system is used in which the reaction of a peptide factor Xla substrate is used to determine the enzymatic activity of human factor XIa.
  • Factor XIa from the peptic factor XIa substrate cleaves the C-terminal aminomethylcoumarin (AMC) whose fluorescence is measured. The determinations are carried out in microtiter plates.
  • Test substances are dissolved in dimethyl sulfoxide and serially diluted in dimethylsulfoxide (3000 ⁇ to 0.0078 ⁇ , resulting final concentrations in the test: 50 ⁇ to 0.00013 ⁇ ). 1 ⁇ each of the diluted substance solutions are placed in the wells of white microtiter plates from Greiner (384 wells). Subsequently, 20 ⁇ assay buffer (50 mmol / l Tris buffer pH 7.4, 100 mmol / l sodium chloride, 5 mmol / l calcium chloride, 0.1% bovine serum albumin) and 20 ⁇ factor XIa from Kordia (0.45 nM in assay buffer) are added successively.
  • assay buffer 50 mmol / l Tris buffer pH 7.4, 100 mmol / l sodium chloride, 5 mmol / l calcium chloride, 0.1% bovine serum albumin
  • 20 ⁇ factor XIa from Kordia (0.45 nM in assay buffer
  • test substances are tested for their inhibition of other human serine proteases, such as factor Xa, trypsin and plasmin.
  • factor Xa 1.3 nmol / l of Kordia
  • trypsin 83 mU / ml of Sigma
  • plasmin 0.1 ug / ml of Kordia
  • these enzymes are dissolved (50 mmol / l Tris buffer [C , C, C-tris (hydroxymethyl) -aminomethane], 100 mmol / l sodium chloride, 0.1% BSA [bovine serum albumin], 5 mmol / l calcium chloride, pH 7.4) and for 15 min with test substance in various concentrations in dimethyl sulfoxide and with dimethyl sulfoxide incubated without test substance.
  • the enzymatic reaction is started by adding the appropriate substrates (5 ⁇ / ⁇ Boc-Ile-Glu-Gly-Arg-AMC of Bachem for factor Xa and trypsin, 50 ⁇ / ⁇ MeOSuc-Ala-Phe-Lys-AMC from Bachem for plasmin). After an incubation period of 30 min at 22 ° C, 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 mixtures without test substance (excluding dimethylsulfoxide instead of test substance in dimethyl sulfoxide) and ICso values are calculated from the concentration-activity relationships. a.3) thrombin generation assay (thrombogram)
  • thrombin generation assay is determined in vitro in human plasma (Octaplas® from Octapharma).
  • Hemker thrombin generation assay the activity of thrombin in clotting plasma is determined by measuring the fluorescent cleavage products of substrate 1-1140 (Z-Gly-Gly-Arg-AMC, Bachem). The reactions are carried out in the presence of varying concentrations of test substance or the corresponding solvent. Reagents from the company Thrombinoscope are used to start the reaction (30 pM or 0.1 pM recombinant tissue factor, 24 ⁇ M phospholipids in HEPES).
  • Thrombin Calibrator from the company Thrombinoscope is used, whose amidolytic activity is required for calculating the thrombin activity in a sample with an unknown amount of thrombin.
  • the test is carried out according to the manufacturer (Thrombionsocpe BV): 4 ⁇ of the test substance or the solvent, 76 ⁇ plasma and 20 ⁇ PPP reagent or thrombin calibrator are incubated for 5 min at 37 ° C. After addition of 20 ⁇ M 2.5 mM thrombin substrate in 20 mM Hepes, 60 mg / ml BSA, 102 mM calcium chloride, the thrombin generation is measured every 20 seconds for 120 min. The measurement is carried out with a fluorometer (Fluoroskan Ascent) from Thermo Electron, which is equipped with a 390/460 nM filter pair and a dispenser.
  • Fluorometer Fluoroskan Ascent
  • the thrombogram is calculated and graphically displayed and the following parameters are calculated: lag time, time to peak, peak, ETP (endogenous thrombin potential) and start tail a.4) Determination of the anticoagulant effect
  • the anticoagulant activity of the test substances is determined in vitro in human and animal plasma (eg mouse, rat, rabbit, porcine and canine plasma).
  • human and animal plasma eg mouse, rat, rabbit, porcine and canine plasma.
  • blood is removed using a 0.11 molar sodium citrate solution as a template in a mixing ratio of sodium citrate / blood 1/9.
  • the blood is mixed well immediately after collection and centrifuged for 15 minutes at approximately 4000 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 with a commercially available test kit (Neoplastin® from Boehringer Mannheim or Hemoliance® RecombiPlastin from Instrumentation Laboratory).
  • test compounds are incubated for 3 minutes at 37 ° C with the plasma. Subsequently, coagulation is triggered by the addition of thromboplastin and the time of coagulation is determined. The concentration of test substance is determined which causes a doubling of the prothrombin time.
  • the activated partial thromboplastin time is determined in the presence of varying concentrations of test substance or the corresponding solvent with a commercially available test kit (C.K. Perst from the company Diagnostica Stago).
  • the test compounds are incubated for 3 minutes at 37 ° C with the plasma and the PTT reagent (cephalin, kaolin). Subsequently, coagulation is triggered by addition of a 25 mM aqueous calcium chloride solution and the time of coagulation is determined.
  • the concentration of test substance is determined which causes a 1.5-fold prolongation of the aPTT. Effect data from this test are listed in Table B below:
  • Tissue factor (TF) (1 pM) and tissue plasminogen activator (tPA) (40 nM) are pipetted together with 12.5 mM aqueous calcium chloride solution and substance in plasma. After clot formation, the subsequent clot lysis is determined photometrically over a period of 30 minutes. a.6) Measurement of plasmin inhibition
  • a biochemical test system is used in which the reaction of a peptidic plasmin substrate is used to determine the enzymatic activity of human plasmin. Plasmin separates from the peptic plasmin substrate the C-terminal aminomethylcoumarin (AMC), whose fluorescence is measured. The determinations are carried out in microtiter plates. Test substances are dissolved in dimethyl sulfoxide and serially diluted in dimethylsulfoxide (3000 ⁇ to 0.0078 ⁇ , resulting final concentrations in the test: 50 ⁇ to 0.00013 ⁇ ). 1 ⁇ each of the diluted substance solutions are placed in the wells of white microtiter plates from Greiner (384 wells).
  • the antithrombotic activity of FXIa inhibitors is tested in an arterial thrombosis model.
  • the thrombus formation is triggered by chemical damage to a portion of the carotid artery in the rabbit.
  • the ear bleeding time is determined.
  • Male rabbits (Crl: KBL (NZW) BR, Charles River) under a diet of 2.2-2.5 kg body weight are administered by intramuscular administration of xylazine and ketamine (Rompun, Bayer, 5 mg / kg and Ketavet, Pharmacia & Upjohn GmbH , 40 mg / kg body weight) anesthetized.
  • Anesthesia is further assisted by intravenous administration of the same preparations (bolus: continuous infusion) via the right ear vein.
  • the vascular damage is produced by wrapping a piece of filter paper (10 mm x 10 mm) on a Parafilm® (25 mm x 12 mm) strip around the carotid artery without affecting the blood flow.
  • the filter paper contains 100% of a 13% solution of ferrous chloride (Sigma) in water. After 5 minutes, the filter paper is removed and the vessel rinsed twice with aqueous 0.9% sodium chloride solution. 30 minutes after the injury, the carotid artery is dissected out in the area of the damage and any thrombotic material is removed and weighed.
  • test substances are either administered intravenously via the femoral vein anesthetized or orally by gavage to the awake animals each 5 min or 2 h before damage.
  • the ear bleeding time is determined 2 minutes after the injury to the carotid artery.
  • the left ear is shaved and a defined section of 3 mm in length (blade Art.No. 10-150-10, Martin, Tuttlingen, Germany) is set parallel to the longitudinal axis of the ear. Care is taken not to injure any visible vessel. Any escaping blood is collected at 15-second intervals with accurately weighed pieces of filter paper without touching the wound directly.
  • the bleeding time is calculated as the time from placement of the incision to the time when no more blood is detectable on the filter paper.
  • the leaked blood volume is calculated after weighing the pieces of filter paper.
  • the determination of the antifibrinolytic activity in vivo is carried out in hyper-fibrinoly tables. Following anesthesia and catheterization of the animals, hyper-fibinolysis is initiated by infusion of tissue plasminogen activator (tPA) (8 mg / kg / h). 10 minutes after the beginning of the tPA infusion, the substances are administered as an iv bolus. After another 15 minutes, the tPA infusion is terminated and a tail transsection performed. The subaquale bleeding (37 ° C tempered physiological sodium chloride solution) is observed over 30 minutes and determines the bleeding time.
  • tPA tissue plasminogen activator
  • the substances according to the invention can, for example, be converted into pharmaceutical preparations as follows:
  • composition
  • Example 1 100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of corn starch, 10 mg of polyvinylpyrrolidone (PVP) and 2 mg of magnesium stearate.
  • lactose monohydrate
  • corn starch 50 mg of corn starch
  • PVP polyvinylpyrrolidone
  • composition Composition:
  • a single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension. production:
  • the rhodigel is suspended in ethanol, the compound of Example 1 is added to the suspension. While stirring, the addition of water. Until the swelling of the Rhodigels swirling is about 6 h stirred.
  • 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.
  • Lv.-Solution The compound of the invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g., isotonic sodium chloride solution, glucose solution 5% and / or polyethylene glycol 400 / water 30% m / m).
  • a physiologically acceptable solvent e.g., isotonic sodium chloride solution, glucose solution 5% and / or polyethylene glycol 400 / water 30% m / m.
  • the solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

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Abstract

L'invention concerne des dérivés de phénylalanine substitués et des procédés pour leur préparation, ainsi que leur utilisation pour la préparation de médicaments pour le traitement et/ou la prophylaxie de maladies, notamment de maladies cardiovasculaires et/ou de fortes pertes sanguines péri-opératoires.
EP14771920.7A 2013-09-26 2014-09-24 Dérivés de phénylalanine substitués servant de modulateurs du facteur xia Withdrawn EP3049407A1 (fr)

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UY35971A (es) 2014-01-31 2015-07-31 Bristol Myers Squibb Company Una Corporación Del Estado De Delaware Macrociclos con grupos p2? aromáticos como inhibidores del factor xia
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CN107074821B (zh) 2014-09-04 2020-05-22 百时美施贵宝公司 为fxia抑制剂的二酰胺大环化合物
US9453018B2 (en) 2014-10-01 2016-09-27 Bristol-Myers Squibb Company Pyrimidinones as factor XIa inhibitors
WO2016146605A1 (fr) * 2015-03-19 2016-09-22 Bayer Pharma Aktiengesellschaft Dérivés de phénylalanine substitués
US10344039B2 (en) 2015-10-29 2019-07-09 Merck Sharp & Dohme Corp. Macrocyclic spirocarbamate derivatives as factor XIa inhibitors, pharmaceutically acceptable compositions and their use
TW201808908A (zh) 2016-08-22 2018-03-16 美商默沙東藥廠 因子XIa抑制劑
US20250002507A1 (en) 2021-10-14 2025-01-02 Vanderbilt University 7,8-dihydro-5h-1,6-naphthyridine derivatives as positive allosteric modulators of the muscarinic acetylcholine receptor m4 for treating neurological and psychiatric disorders
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