EP3271332A1 - Dérivés d'oxopyridine comme inhibiteurs du facteur xia pour le traitement de la thrombose - Google Patents

Dérivés d'oxopyridine comme inhibiteurs du facteur xia pour le traitement de la thrombose

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Publication number
EP3271332A1
EP3271332A1 EP16709921.7A EP16709921A EP3271332A1 EP 3271332 A1 EP3271332 A1 EP 3271332A1 EP 16709921 A EP16709921 A EP 16709921A EP 3271332 A1 EP3271332 A1 EP 3271332A1
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EP
European Patent Office
Prior art keywords
diseases
formula
prophylaxis
treatment
mmol
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Withdrawn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
EP16709921.7A
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German (de)
English (en)
Inventor
Susanne Röhrig
Henrik Teller
Stefan Heitmeier
Karl-Heinz Schlemmer
Jan Stampfuss
Alexander Hillisch
Adrian Tersteegen
Eloisa JIMENEZ NUNEZ
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Bayer Pharma AG
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Bayer Pharma AG
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Publication of EP3271332A1 publication Critical patent/EP3271332A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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 substituted oxopyridine 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, preferably of thrombotic or thromboembolic diseases and of edema, as well as of ophthalmological diseases.
  • 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 in this first phase 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 activates in positive feedback loops in addition to Factor V and Factor VIII, Factor XI to Factor XIa, Factor IXa converts Factor IXa, and Factor IXa so generated / Factor VIIIa complex the factor X activation and thus in turn, strongly stimulates thrombin generation, leading to severe thrombus growth and stabilizing the thrombus.
  • activation of the coagulation system can take place on, in particular, negatively charged surfaces, which include not only surface structures of foreign cells (for example bacteria) but also artificial surfaces such as vascular prostheses, stents and extracorporeal circuits.
  • Activation of factor ⁇ (FXII) to factor Xüa first activates on the surface, activating cellI factor XI to factor XIa. This leads, as described above, to further activation of the coagulation cascade.
  • factor Xlla also activates bound plasma pro-kallikrein to plasma kallikrein (PK) which, on the one hand, leads to further factor XII activation in a potentiation loop, resulting in an overall increase in the initiation of the coagulation cascade.
  • PK is an important bradikinin-releasing protease, which among other things leads to an increase in endothelial permeability.
  • Other substrates described include prorenin and prourokinase, whose activation may affect the regulatory processes of the renin-angiotensin system and fibrinolysis. Thus, the activation of PK is an important link between coagulative and inflammatory processes.
  • 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.
  • systemic hypercoagulability can lead to system-wide thrombus formation and eventually to consumption coagulopathy in the context of disseminated intravascular coagulation.
  • Thromboembolic complications may also be found in extracorporeal blood circuits such. B. during hemodialysis, as well as in vascular or heart valve prostheses and stents occur.
  • thromboembolic diseases In the course of many cardiovascular and metabolic diseases systemic factors, such as hyperlipidemia, diabetes or smoking, due to blood flow changes with stasis, such as in atrial fibrillation, or due to pathological vascular wall changes, eg endothelial dysfunction or atherosclerosis, lead to an increased tendency of coagulation and platelet activation. This undesirable and excessive activation of coagulation can lead to thromboembolic diseases and thrombotic complications with life-threatening conditions by formation of fibrin and platelet-rich thrombi. In this case, inflammatory processes may be involved. Thromboembolic diseases therefore remain among the most common causes of morbidity and mortality in most industrialized countries countries.
  • the anticoagulants known in the art i.
  • Substances for inhibiting or preventing blood clotting have various disadvantages.
  • An efficient treatment method or prophylaxis of thrombotic / thromboembolic diseases therefore proves to be very difficult and unsatisfactory in practice.
  • 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, 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. In addition, there is a high risk of bleeding, in particular cerebral hemorrhage and bleeding may occur in the gastrointestinal tract, and it can lead to thrombocytopenia, alopecia medicomentosa or osteoporosis.
  • heparins Although low molecular weight heparins have a lower probability of developing heparin-induced thrombocytopenia, they can only be administered subcutaneously. This also applies to fondaparinux, a synthetically produced, selective factor Xa inhibitor with a long 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, because of the high risk of bleeding and the narrow therapeutic index but a complex individual attitude and observation of the patient is necessary. In addition, other side effects such as gastrointestinal disturbances, hair loss and skin necrosis are described.
  • PK plasma kallikrein
  • diabetic retinopathy is based primarily on a microvascular weakness, resulting in a basal membrane thickening of the vessels and the loss of vascular sheathing pericytes, later vascular occlusion with retinal ischemia, which due to the induced retinal hypoxia to increased vascular permeability with subsequent training of a Macular edema and, due to all the processes involved, may lead to blindness of the patient.
  • HAE hereditary angioedema
  • Cl-esterase inhibitor In hereditary angioedema (HAE), reduced formation of the physiological kallikrein inhibitor Cl-esterase inhibitor leads to uncontrolled plasma kallikrein activation and thus inflammation with fulminant edema formation and severe pain. From animal experiments there is evidence that the inhibition of plasma kallikrein inhibits the increased vascular permeability and thus can prevent the formation of macular edema or diabetic retinopathy or improve the acute symptoms of HAE. Oral plasma kallikrein inhibitors could also be used to prevent HAE.
  • IBD chronic inflammatory bowel disease
  • the kinakines generated by plasma kallikrein play a major role. Their pro-inflammatory effect via activation of bradykinin receptors induces and potentiates the disease process.
  • antithrombotic and antiinflammoric principles may be particularly attractive for many diseases to increase the mutual amplification of To prevent coagulation and inflammation.
  • An object of the present invention is therefore to provide novel compounds for the treatment of cardiovascular diseases, in particular thrombotic or thromboembolic diseases, and / or edematous diseases, and / or ophthalmological diseases, in particular diabetic retinopathy or macular edema, in humans and Animals that have a broad therapeutic range.
  • WO 2006/030032 describes inter alia substituted pyridinones as allosteric modulators of the mGluR2 receptor and WO 2008/079787 describes substituted pyridin-2-ones and their use as glucokinase activators.
  • WO 2014/154794, WO 2014/160592, WO 2015/011087 and WO 2015/063093 describe substituted oxopyridine derivatives as factor XIa inhibitors for the treatment of thromboses.
  • the invention relates to compounds of the formula
  • R is a group of the formula
  • R 6 is chlorine, cyano, difluoromethyl or difluoromethoxy
  • R ' is hydrogen or fluorine
  • R 2 is chlorine or methoxy, is ethyl, wherein ethyl is substituted with a substituent selected from the group consisting of tert-butoxy, iso-propoxy, C3-C6 cycloalkyloxy and 4- to 6-membered oxo-heterocyclyloxy, wherein tert-butoxy and iso-propoxy substituted may be substituted with 1 to 3 fluorine substituents, and wherein cycloalkyloxy and oxo-heterocyclyloxy may be substituted with 1 to 2 substituents independently selected from the group consisting of fluorine and methyl, represents hydrogen, represents a group of formula
  • R 9 is hydroxycarbonyl
  • R 10 is hydrogen or fluorine
  • their salts, their solvates and the solvates of their salts are hydrogen or fluorine
  • 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 the compounds of formula (I) mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds according to the invention can exist in different stereoisomeric forms, ie in the form of configuration isomers or given also as conformational isomers (enantiomers and / or diastereomers, including those in 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 according to 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 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I.
  • Certain isotopic variants of a compound of the invention may be useful, for example, for the study of the mechanism of action or drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes are particularly suitable for this purpose.
  • 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 an increase in half-life in the body or a reduction in 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 methods known to the person skilled in the art, for example by the methods described below and the rules reproduced in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. But are also included salts that are not suitable for pharmaceutical applications but for example for the isolation or purification of the Compounds according to the invention can be used.
  • 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, -methylmorpholine, arginine, lysine, ethylenediamine, -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).
  • 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 the symptoms of such conditions get to know, to suffer or to have.
  • the treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.
  • Cycloalkyl represents a monocyclic cycloalkyl group having 3 to 6 carbon atoms, by way of example and preferably cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Cycloalkyloxy is a monocyclic cycloalkyl group which is bonded via an oxygen atom having 3 to 6 carbon atoms, by way of example and preferably cycloalkyloxy may be mentioned cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
  • 4- to 6-membered oxo-heterocyclyloxy in the definition of the radical R 3 is a saturated monocyclic radical having 4 to 6 ring atoms, in which a ring atom is an oxygen atom and which is bonded via an oxygen atom, by way of example and preferably for oxetanyloxy, tetrahydrofuranyloxy and tetrahydro-2H-pyranyloxy.
  • the end point of the line next to each one * does not represent a carbon atom or a CEh group but is part of the bond to the atom to which R 1 is attached ,
  • R 1 is a group of the formula
  • R ' is hydrogen, is methoxy, ethyl, wherein ethyl is substituted with a substituent selected from the group consisting of tert-butoxy, iso-propoxy and cyclobutyloxy, wherein cyclobutyloxy may be substituted by a methyl substituent, is hydrogen , for a group of the formula
  • # is the point of attachment to the nitrogen atom, is hydroxycarbonyl
  • R 10 is hydrogen, and their salts, their solvates and the solvates of their salts.
  • R is a group of the formula
  • R 6 is chlorine
  • R 7 is cyano or difluoromethoxy
  • R 8 is hydrogen
  • R 2 is methoxy
  • R 3 is ethyl, wherein ethyl is substituted with a substituent selected from the group consisting of tert-butoxy, iso-propoxy and cyclobutyloxy,
  • R 4 is hydrogen
  • R 5 is a group of the formula
  • R 9 is hydroxycarbonyl
  • R 10 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 R 1 is a group of the formula
  • R 6 is chlorine
  • R 7 is cyano
  • R 8 is hydrogen. Preference is also given to compounds of the formula (I) in which R 3 is ethyl, where ethyl is substituted by one substituent tert-butoxy.
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • 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
  • R 1 , R 2 , R 3 , R 4 and R 10 have the abovementioned meaning
  • R 14 is tert-butyl
  • R L , R 2 , R 3 , R 4 and R 10 are as defined above and R 9 is hydroxycarbonyl
  • R 1 , R 2 , R 3 , R 4 and R 10 have the abovementioned meaning
  • R 14 is methyl or ethyl
  • R 1 , R 2 , R 3 , R 4 and R 10 are as defined above, and R 9 is hydroxycarbonyl, are reacted.
  • the reaction according to process [A] 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 dichloromethane.
  • Acids are for example trifluoroacetic acid or hydrogen chloride in dioxane, preferred is trifluoroacetic acid.
  • the reaction according to process [B] is generally carried out in inert solvents, preferably in a temperature range from room temperature to reflux of the solvent under normal pressure.
  • Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride 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 or a mixture of methanol and water.
  • halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane
  • alcohols such as methanol or ethanol
  • ethers such as diethyl ether, methyl
  • 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 lithium hydroxide or cesium carbonate.
  • R 1 , R 2 and R 3 have the abovementioned meaning, with compounds of the formula
  • R 4 and R 10 have the abovementioned meaning
  • R 14 is methyl, ethyl or tert-butyl, are reacted in the presence of a dehydrating reagent.
  • the reaction is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 0 ° C. to room temperature at atmospheric pressure.
  • dehydrating reagents include carbodiimides such as ⁇ , ⁇ '-diethyl, / V, / V'-dipropyl, / V, / V'-diisopropyl, A ⁇ 'dicyclohexylcarbodiimide, / V- (3-dimethylamino - isopropyl) - / V'-ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), cyclohexylcarbodiimide '-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2- Oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate,
  • Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines, e.g. Triethylamine, -methylmorpholine, / V-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • the condensation is carried out with diisopropylethylamine.
  • Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane or trichloromethane, hydrocarbons, such as benzene, or other solvents, such as nitromethane, dioxane, dimethylformamide, dimethyl sulfoxide or acetonitrile. It is likewise possible to use mixtures of the solvents. Particularly preferred is dimethylformamide.
  • the compounds of formula (IV) are known or can be synthesized by known methods from the corresponding starting compounds.
  • R 1 , R 2 and R 3 have the abovementioned meaning
  • R 15 is tert-butyl, reacted with an acid, or
  • R 1 , R 2 and R 3 have the abovementioned meaning
  • R 15 is methyl, ethyl or benzyl, are reacted with a base.
  • reaction according to method [C] is carried out as described for method [A].
  • reaction according to process [D] is carried out as described for process [B].
  • the compounds of the formula (V) are known or can be prepared by reacting compounds of the formula
  • R 1 and R 2 have the meaning given above, and
  • R 15 is methyl, ethyl, benzyl or tert-butyl, with compounds of the formula
  • R 3 has the meaning given above, and
  • X is chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy or para-toluenesulfonyloxy.
  • the reaction is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from -78 ° C. to room temperature at atmospheric pressure.
  • Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride 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 tetrahydrofuran.
  • bases are potassium or sodium tert-butylate, sodium hydride, n-butyl lithium or bis (trimethylsilyl) lithium amide; bis (trimethylsilyl) lithium amide is preferred.
  • the compounds of the formula (VII) 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 formula (VI) are known or can be prepared by reacting compounds of the formula
  • R 1 and R 2 have the abovementioned meaning, with compounds of the formula in which
  • R 15 is methyl, ethyl, benzyl or tert-butyl
  • X 2 is chloro, bromo, iodo, methanesulphonyloxy or trifluoromethanesulphonyloxy.
  • the reaction is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from room temperature to reflux of the solvents under atmospheric pressure.
  • Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride 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 dimethylformamide.
  • halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane
  • alcohols such as methanol or ethanol
  • ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane,
  • 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 potassium or sodium tert-butoxide, sodium hydride or a mixture of these bases or a mixture of sodium hydride and lithium bromide, is preferred Potassium carbonate or sodium hydride.
  • alkali metal hydroxides such as sodium, lithium or potassium hydroxide
  • alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or potassium or sodium tert-butoxide
  • sodium hydride or a mixture of these bases or a mixture of sodium hydride and lithium bromide is preferred Potassium carbonate or sodium hydride.
  • the compounds of formula (IX) are known or can be synthesized by known methods from the corresponding starting compounds.
  • R 1 and R 2 have the abovementioned meaning, be reacted with pyridinium hydrochloride or pyridinium hydrobromide.
  • the reaction is generally carried out in inert solvents, preferably in a temperature range from 80 ° C to 120 ° C at atmospheric pressure.
  • Inert solvents are, for example, hydrocarbons, such as benzene, or other solvents, such as nitromethane, dioxane, dimethylformamide, dimethyl sulfoxide or acetonitrile. It is likewise possible to use mixtures of the solvents. Particularly preferred is dimethylformamide.
  • the compounds of the formula (X) are known or can be prepared by reacting compounds of the formula
  • R 2 has the meaning given above, and
  • Q 1 is -B (OH) 2 , a boronic acid ester, preferably boronic acid pinacol ester, or -BF 3 ⁇ K + , with compounds of the formula
  • R 1 has the meaning given above, and
  • X 3 is chlorine, bromine or iodine, are reacted under Suzuki coupling conditions.
  • 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.
  • Catalysts are for example customary for Suzuki reaction conditions palladium catalysts, preference is given to catalysts such as dichlorobis (triphenylphosphine) palladium, tetrakistriphenylphosphinepalladium (O), palladium (II) acetate / triscyclohexylphosphine, tris (dibenzylideneacetone) dipalladium, bis (diphenylphosphanferrocenyl) palladium - (II) chloride, l, 3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene (1,4-naphthoquinone) palladium dimer, allyl
  • 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 carbonate or aqueous potassium phosphate solution.
  • 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 tetrahydrofuran, dioxane or acetonitrile.
  • 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,
  • 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 protease factor XIa (FXIa) and / or the serine protease plasma kallikrein (PK).
  • FXIa serine protease factor XIa
  • PK serine protease plasma kallikrein
  • the compounds of the present invention inhibit FXIa and / or PK catalyzed enzymatic cleavage of substrates that play important roles in activating blood clotting, platelet aggregation via reduction of thrombin required for PAR-1 activation of platelets, and in inflammatory processes in particular, including an increase in vascular permeability.
  • 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, and / or ophthalmological diseases, in particular of diabetic retinopathy or macular edema, and / or inflammatory diseases, especially those associated with excessive plasma kallikrein activity, such as hereditary angioedema (HAE) or chronic inflammatory diseases, especially of the intestine, such. Crohn's disease.
  • diseases in particular cardiovascular diseases, preferably thrombotic or thromboembolic diseases and / or thrombotic or thromboembolic complications, and / or ophthalmological diseases, in particular of diabetic retinopathy or macular edema, and / or inflammatory diseases, especially those associated with excessive plasma kallikrein activity, such as hereditary angioedema (HAE) or chronic
  • Factor XIa is an important coagulation enzyme that can be activated by both thrombin and factor XIIa (FXIIa), and is thus involved in two major processes of coagulation: it is a central component of the transition from initiation to coagulation Amplification and propagation of coagulation: Thrombin activated in positive feedback loops in addition to Factor V and Factor VIII and Factor XI to Factor XIa, the factor ⁇ to Factor Ka converts and the thus generated factor Ka / Factor VIIIa complex the Factor X activation and thus in turn, strongly stimulates thrombin generation, leading to severe thrombus growth and stabilizing the thrombus.
  • factor XIa is an important component of the intrinsic initiation of coagulation:
  • the activation of the coagulation system can also be carried out on particularly negatively charged surfaces, which include not only surface structures of foreign cells (eg bacteria) but also artificial surfaces such as vascular prostheses, stents and extracorporeal circuits.
  • TF tissue factor
  • FXII factor ⁇
  • FXIIa factor XIIa
  • factor XIIa also activates plasma pro-kallikrein into plasma kallikrein (PK) as part of intrinsic activation, which among other things leads to further factor ⁇ activation in the context of a potentiation loop, resulting in an overall increase in the initiation of the coagulation cascade on surfaces.
  • a PK-inhibiting activity of a compound according to the invention will therefore reduce the coagulation via surface activation and thus act anticoagulatory.
  • An advantage could be the combination of factor XIa and PK inhibitory activity, which allows a balanced antithrombotic effect.
  • the compounds according to the invention are therefore suitable for the treatment and / or prophylaxis of diseases or complications which may arise due to clot formation.
  • thrombotic or thromboembolic diseases include diseases which occur both in the arterial and in the venous vascular bed and can be treated with the compounds according to the invention, in particular diseases in the coronary arteries of the heart, such as acute coronary syndrome (ACS).
  • ACS acute coronary syndrome
  • the coagulation system can be greatly stimulated and there are thrombotic complications, especially venous thrombosis come.
  • the compounds according to the invention are therefore suitable for thrombosis prophylaxis in the context of surgical interventions in patients who have a cancer.
  • the compounds according to the invention are therefore also suitable for thrombosis prophylaxis in patients with an activated coagulation system, for example under the stimulation situations described.
  • the compounds of the invention are therefore also useful in the prevention and treatment of cardiogenic thromboembolisms, such as brain ischemia, stroke and systemic thromboembolism and ischaemia, in patients with acute, intermittent or persistent cardiac arrhythmias, such as atrial fibrillation, and in patients undergoing cardioversion patients with valvular heart disease or with artificial heart valves.
  • cardiogenic thromboembolisms such as brain ischemia, stroke and systemic thromboembolism and ischaemia
  • patients with acute, intermittent or persistent 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 and by contact of the blood with extraneous surfaces within extracorporeal blood circuits, such as hemodialysis, extracorporeal membrane oxygenation (ECMO), left ventricular assist device (LVAD), and similar procedures.
  • ECMO extracorporeal membrane oxygenation
  • LVAD left ventricular assist device
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of diseases in which micro clots or fibrin deposits occur in brain vessels, which can lead to dementia diseases such as, for example, vascular dementia or Alzheimer's disease.
  • dementia diseases such as, for example, vascular dementia or Alzheimer's disease.
  • the clot can contribute to the disease both via occlusions and via the binding of further disease-relevant factors.
  • the compounds according to the invention are particularly suitable for the treatment and / or prophylaxis of diseases in which not only the procoagulant but also the proinflammatory component plays an essential role.
  • the mutual reinforcement of coagulation and inflammation can be prevented by the compounds according to the invention and therefore the probability of a thrombotic complication can be decisively reduced.
  • Both the factor XIa-inhibitory component (via inhibition of thrombin production) and the PK-inhibitory component can contribute to the anticoagulant and anti-inflammatory action (for example via bradikinin).
  • the treatment and / or prophylaxis in the context of atherosclerotic vascular diseases inflammation in the context of rheumatic diseases of the musculoskeletal system, inflammatory diseases of the lung, such as pulmonary fibrosis, inflammatory diseases of the kidney, such as glomerulonephritis, inflammatory diseases of the intestine, such as Crohn's disease or ulcerative colitis, or diseases that may be present as part of a diabetic underlying disease, such as diabetic retinopathy or nephropathy into consideration.
  • kinins generated by plasma kallikrein play a major role. Their pro-inflammatory effect via activation of bradykinin receptors induces and potentiates the disease process.
  • Studies in Crohn's disease patients show a correlation between the kallikrein concentration in the intestinal epithelium and the degree of intestinal inflammation. Activation of the kallikrein-kinin system has also been observed in animal studies.
  • An inhibition of bradykinin synthesis by kallikrein inhibitors could therefore also be used for the prophylaxis and / or treatment of inflammatory bowel disease.
  • the compounds of the invention can be used to inhibit tumor growth and metastasis, and to prevent and / or treat thromboembolic complications such as venous thromboembolism in tumor patients, especially those undergoing major surgery or chemo- or radiotherapy.
  • the compounds according to the invention are also suitable for the prophylaxis and / or treatment of pulmonary hypertension.
  • pulmonary hypertension in the context of the present invention includes pulmonary arterial hypertension, pulmonary hypertension in diseases of the left heart, pulmonary hypertension in lung disease and / or hypoxia and pulmonary hypertension due to chronic thromboembolism (CTEPH).
  • 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 (AP AH), which is associated with collagenosis , congenital systemic pulmonary shunt veins, portal hypertension, HIV infections, the use of certain drugs and medications, with other diseases (thyroid disorders, glycogen storage diseases, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy), with diseases with a significant venous capillary involvement such as pulmonary veno-occlusive disease and pulmonary-capillary hemangiomatosis, as well as persistent pulmonary hypertension of newborns.
  • Idiopathic Pulmonary Arterial Hypertension Idiopathic Pulmonary Arterial Hypertension (IPAH, formerly referred to as Primary Pulmonary Hypertension), Familial
  • 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 causes massive activation of the coagulation system on the surface of damaged endothelial cells, foreign body surfaces or cross-linked extravascular tissue.
  • coagulation occurs in small vessels of various organs with hypoxia and subsequent organ dysfunction.
  • coagulation factors eg Factor X, prothrombin and fibrinogen
  • platelets are consumed, reducing the blood's ability to coagulate and causing severe bleeding.
  • Compounds of the invention which inhibit plasma kallikrein alone or in combination with factor XIa are additionally contemplated for the treatment and / or prophylaxis of diseases in the course of which plasma kallikrein is involved.
  • plasma kallikrein is an important bradikinin-releasing protease, thus leading inter alia to an increase in endothelial permeability.
  • the compounds can thus be used for the treatment and / or prophylaxis of diseases associated with edema formation, such as, for example, ophthalmological diseases, in particular diabetic retinopathy or macular edema, or hereditary angioedema.
  • ophthalmological diseases include in particular diseases such as diabetic retinopathy, diabetic macular edema (DME), macular edema, macular edema associated with retinal venous occlusion, age-related macular degeneration (AMD), choroidal neovascularization (CNV), choroidal neovascular membranes (CNVM), cystoid macular edema (cystoid macula edema, CME), epiretinal membranes (ERM) and macular perforations, myopia-associated choroidal neovascularization, angioid or vascular streaks, retinal detachment, atrophic Changes in the retinal pigment epithelium, hypertrophic changes in the retinal pigment epithelium, retinal venous occlusion, choroidal retinal venous occlusion, retinitis pigmentosa, Stargardt's disease, prematurity retinopathy, diabetic macular
  • the compounds of the invention for primary prophylaxis of thrombotic or thromboembolic diseases and / or inflammatory diseases and / or diseases with increased vascular permeability in patients in question in which gene mutations lead to increased activity of the enzymes or increased levels of zymogens and these by appropriate tests / measurements of the Enzyme activity or zymogen concentrations are detected.
  • 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.
  • 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.
  • the compounds of the invention may also be used to prevent coagulation ex vivo, e.g. to protect organs to be transplanted from organ damage caused by clot formation and to protect the organ recipient from thromboemboli from the transplanted organ, to preserve blood and plasma products, to clean / pretreat catheters and other medical devices and devices, to coat artificial surfaces of medical devices and equipment used in vivo or ex vivo, or biological samples that might contain factor XIa or plasma kallikrein.
  • Another object of the present invention is a method for the prevention of blood coagulation in vitro, in particular in blood or biological samples containing factor XIa or plasma kallikrein or both enzymes, 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 drugs 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 in particular 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-adrenoceptor antagonists such as prazosin, bunazosin, doxazosin and terazosin, or diuretics such as hydrochlorothiazide, furosemide, bumetanide, piretanide, to
  • Plasminogen activators thrombolytics / fibrinolytics
  • thrombolysis / fibrinolysis-enhancing compounds such as inhibitors of plasminogen activator inhibitor (PAI inhibitors) or inhibitors of thrombin-activated fibrinolysis inhibitor (TAFI inhibitors) such as tissue plasminogen activator (t-PA, such as Actilyse ®), streptokinase, reteplase and urokinase or plasminogen modulating substances that lead to increased plasmin formation; 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 / ORG4
  • Platelet adhesion inhibitors such as GPVI and / or GPIb antagonists such as Revacept or Caplacizumab;
  • Fibrinogen receptor antagonists such as abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban and fradafiban; Recombinant human activated protein C such as xigris or recombinant thrombomodulin;
  • Inhibitors of VEGF and / or PDGF signaling pathways such as aflibercept, ranibizumab, bevacizumab, KH-902, pegaptanib, ramucirumab, squalamine, or
  • Inhibitors of Angiopoietin-Tie signaling pathways such as AMG386; ⁇ Inhibitors of Tie2 receptor tyrosine kinase;
  • Inhibitors of integrin signaling pathways such as volociximab, cilengitide, and ALG1001;
  • Inhibitors of PI3K Akt-mTor signaling pathways such as XL-147, perifosine, MK2206, sirolimus, temsirolimus and everolimus;
  • Corticosteroid such as anecortave, betamethasone, dexamethasone, triamcinolone, fluocinolone and fluocinolone acetonide;
  • inhibitors of the ALKl-Smadl / 5 signaling pathway such as ACE041
  • Cyclooxygenase inhibitors such as bromfenac and nepafenac;
  • Inhibitors of the kallikrein kinin system such as safotibant and ecallantide
  • Inhibitors of sphingosine-1-phosphate signaling pathways such as sonepcizumab; ⁇ Inhibitors of the complement C5a receptor such as eculizumab;
  • Inhibitors of the 5HTla receptor such as tandospirone
  • inhibitors of the Ras-Raf-Mek-Erk signaling pathway • inhibitors of the Ras-Raf-Mek-Erk signaling pathway; Inhibitor of MAPK signaling pathways; Inhibitors of FGF signaling pathways; Inhibitor of endothelial cell proliferation; Apoptosis-inducing agents;
  • Photodynamic therapy consisting of an active substance and the action of light, the active substance being, for example, verteporfin.
  • “Combinations” in the sense 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 / or It is also possible to combine two or more active substances with each other, that is to say two or more combinations in each case.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • absorption e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • the drug application forms containing the active ingredient in crystalline and / or amorphized and / or dissolved form such as eye drops, sprays and lotions (eg solutions, suspensions, vesicular / colloidal systems, emulsions, aerosols), powder for eye drops, sprays and lotions (eg milled active ingredient, mixtures, lyophilisates, precipitated active substance), semi-solid eye preparations (eg hydrogels, in-situ hydrogels, creams and ointments), eyeliners (solid and semi-solid preparations, eg bioadhesives, films / wasters, tablets, contact lenses).
  • eye drops eg solutions, suspensions, vesicular / colloidal systems, emulsions, aerosols
  • powder for eye drops sprays and lotions
  • sprays and lotions eg milled active ingredient, mixtures, lyophilisates, precipitated active substance
  • semi-solid eye preparations eg hydrogels, in-situ
  • the intraocular administration comprises e.g. intravitreal subretinal, subscleral, intrachoroidal, subconjunctival, retrobulbar and subtenal administration.
  • intraocular administration are according to the state of the art functioning fast and / or modified or controlled drug-releasing application forms containing the active ingredient in crystalline and / or amorphized and / or dissolved form, such.
  • Injections and concentrates for injections eg solutions, suspensions, vesicular colloidal systems, emulsions, powders for injections (eg milled active ingredient, mixtures, lyophilisates, precipitated active substance), gels for injections (semi-solid preparations, eg hydrogels, in-situ hydrogels) and implants (solid preparations, eg biodegradable and non-biodegradable implants, implantable pumps).
  • 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 dode
  • 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 ⁇ 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 90% A -> 1.2 min 5% A -> 2.0 min 5% A; Oven: 50 ° C; Flow: 0.40 ml / min; UV detection: 208-400 nm.
  • Method 2 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 3 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 4 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 100% A-> 2.75 min 5% A-> 4.5 min 5% A; Oven: 40 ° C; Flow: 1.25 ml / min; UV detection: 210 nm.
  • Method 5 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 6 Instrument MS: Waters (Micromass) ZQ; 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 7 Instrument: Thermo DFS, Trace GC Ultra; Column: Restek RTX-35, 15 mx 200 ⁇ x 0.33 ⁇ ; constant flow with helium: 1.20 ml / min; Oven: 60 ° C; Met: 220 ° C; Gradient: 60 ° C, 30 ° C / min -> 300 ° C (hold for 3.33 min).
  • Method 8 Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; Column: Waters Acquity UPLC HSS T3 1.8 ⁇ 50 mm x 2.1 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 90% A-> 0.3 min 90% A -> 1.7 min 5% A -> 3.0 min 5% A; Oven: 50 ° C; Flow: 1.20 ml / min; UV detection: 205-305 nm.
  • Method 9 Instrument: Thermo Scientific DSQII, Thermo Scientific Trace GC Ultra; Column: Restek RTX-35MS, 15 m x 200 ⁇ x 0.33 ⁇ ; constant flow with helium: 1.20 ml / min; Oven: 60 ° C; Inlet: 220 ° C; Gradient: 60 ° C, 30 ° C / min - »300 ° C (hold for 3.33 min).
  • Method 10 Device Type MS: Thermo Scientific FT-MS; Device type UHPLC +: Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.1 mm x 75 mm, C18 1.8 ⁇ ; Eluent A: 1 liter of water + 0.01% of formic acid; Eluent B: 1 liter acetonitrile + 0.01% formic acid; Gradient: 0.0 min 10% B -> 2.5 min 95% B -> 3.5 min 95% B; Oven: 50 ° C; Flow: 0.90 ml / min; UV detection: 210 nm / Optimum Integration Path 210-300 nm.
  • Microwave reactor used was an Emrys TM Optimizer single mode device.
  • 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.
  • the aqueous phase was acidified with aqueous hydrochloric acid (2M), usually precipitating, which was filtered, washed with water and dried.
  • the aqueous phase was extracted three times with ethyl acetate.
  • the combined organic phases were dried (sodium or magnesium sulfate), filtered and concentrated in vacuo.
  • the reaction mixture was treated with dioxane (about 6 ml / mmol) and stirred at 110 ° C for several hours until substantially complete reaction.
  • the reaction mixture was then filtered through Celite, the filtrate concentrated in vacuo.
  • the residue was mixed with water.
  • the organic phase was washed once with water and once with saturated aqueous sodium chloride solution, dried (sodium or magnesium sulfate), filtered and concentrated in vacuo.
  • the crude product was then purified either by normal phase chromatography (cyclohexane-ethyl acetate mixtures or dichloromethane-methanol mixtures) or preparative RP-HPLC (water-acetonitrile gradient or water-methanol gradient).
  • the crude product was then purified either by normal phase chromatography (cyclohexane-ethyl acetate mixtures or dichloromethane-methanol mixtures) or preparative RP-HPLC (water-acetonitrile gradient or water-methanol gradient).
  • the crude product was then optionally purified either by normal phase chromatography (eluent: cyclohexane-ethyl acetate mixtures or dichloromethane-methanol mixtures) or preparative RP-HPLC (water-acetonitrile gradient or water-methanol gradient).
  • the crude product was then purified either by flash chromatography (silica gel-60, eluent: cyclohexane-ethyl acetate mixtures or dichloromethane-methanol mixtures) or preparative HPLC (Reprosil C18, water-acetonitrile gradient or water-methanol gradient).
  • the crude product was then purified either by normal phase chromatography (cyclohexane-ethyl acetate mixtures or dichloromethane-methanol mixtures) or preparative RP-HPLC (water-acetonitrile gradient or water-methanol gradient).
  • aqueous phase was extracted with ethyl acetate.
  • the combined organic phases were dried (sodium sulfate or magnesium sulfate), filtered and concentrated under reduced pressure.
  • the crude product was then purified either by normal phase chromatography (cyclohexane-ethyl acetate mixtures or dichloromethane-methanol mixtures) or preparative RP-HPLC (water-acetonitrile gradient or water-methanol gradient).
  • Example 6 (enantiomer 2): Chiral HPLC: R t 3.35 min; 99% ee.
  • 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 ⁇ l of assay buffer (50 mM Tris / HCl pH 7.4, 100 mM sodium chloride, 5 mM 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 mM Tris / HCl pH 7.4, 100 mM sodium chloride, 5 mM calcium chloride, 0.1% bovine serum albumin
  • 20 ⁇ factor XIa from Kordia (0.45 nM in assay buffer
  • the enzyme reaction is started by adding 20 ⁇ l of the factor XIa substrate Boc-Glu (OBzl) -Ala-Arg-AMC (10 ⁇ l in assay buffer) dissolved in assay buffer, for 30 min at room temperature (22 ° C) and then a fluorescence measurement carried out (excitation: 360 nM, emission: 460 nM).
  • the measured emissions of the test mixtures with test substance are compared with those of control preparations without test substance (excluding dimethyl sulfoxide instead of test substance in dimethylsulfoxide) and calculated from the concentration-effect relationships IC 50 values.
  • Action data from this test are listed in Table A below:
  • 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 NaCl, 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 then started by addition of the appropriate substrates (5 ⁇ / ⁇ Boc-Ile-Glu-Gly-Arg-AMC from 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 batch with test substance are compared with the control batches without test substance (excluding dimethyl sulfoxide instead of test substance in dimethylsulfoxide) and IC 50 values are calculated from the concentration-effect relationships. a.3) thrombin generation assay (thrombogram)
  • Thrombogram thrombin generation assay according to Hemker
  • Octaplas® from Octapharma
  • 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 phosphohpids in HEPES). In addition, a 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 manufacturer's instructions (Thrombionocpe BV): 4 ⁇ of test substance or 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, equipped with a 390/460 nm filter pair and a dispenser.
  • a 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 effect of the test substances is determined in vitro in human and rat 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). The 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 (PTT Reagent from Roche).
  • 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 the addition of 25 mM calcium chloride and the time of coagulation is determined.
  • the concentration of test substance is determined which causes a 50% prolongation or a doubling of the APTT. a.5) Determination of plasma kallikrein activity
  • Plasma kallikrein inhibition of the substances according to the invention is a biochemical test system, in which the reaction of a peptidic plasma kallikrein substrate is used to determine the enzymatic activity of human plasma kallikrein.
  • Plasma kallikrein separates from the peptic plasma kallikrein substrate the C-terminal aminomethyl coumarin (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).
  • assay buffer 50 mM Tris / HCl pH 7.4, 100 mM sodium chloride solution, 5 mM calcium chloride solution, 0.1% bovine serum albumin
  • 20 ⁇ M plasma kallikrein from Kordia 0.6 nM in assay buffer
  • the enzyme reaction is started by addition of 20 .mu.l of the substrate dissolved in assay buffer H-Pro-Phe-Arg-AMC (10 .mu.in in assay buffer) from Bachem, incubated for 30 min at room temperature (22 ° C.) and then a fluorescence measurement carried out (excitation: 360 nm, emission: 460 nm).
  • the activity of the compounds according to the invention are characterized by means of an in vitro permeability assay on "human umbilical venous cells” (HUVEC) (EC IS: Electric Cell-substrate Impedance Sensing; Applied Biophysics, Inc., Troy, NY), differences in transendothelial electrical resistance (TEER) across an endothelial cell monolayer plated over gold electrodes can be continuously measured.
  • HUVECs are sown on a 96-well sensor electrode plate (96W1E, Ibidi GmbH, Martinsried). Hyperpermeability of the resulting confluent cell monolayer is induced by stimulation with kininogen, prekallikrein and factor ⁇ (per 100 nM).
  • the compounds according to the invention are added before the addition of the substances indicated above.
  • the usual concentrations of the compounds are 1 x 10 "10 to 1 x 10" 6 M.
  • a.7) Determination of in vitro permeability of endothelial cells In another Hyperpermeabilticians model, the activity of the substances is determined in the modulation of the macromolecular permeability.
  • HUVECs are seeded on a fibronectin-coated Transwell filter membrane (24-well plates, 6.5 mm insert with 0.4 ⁇ polycarbonate membrane, Costar # 3413). The filter membrane separates the upper from the lower cell culture space with the confluent endothelial cell layer at the bottom of the upper cell culture space.
  • FITC-Dextan 250 g / ml 40 kDa FITC-Dextan (Invitrogen, D1 844) is added to the medium of the upper room.
  • the hyperpermeability of the monolayer layer is induced by stimulation with kininogen, prekallikrein and factor XII (100 nM each).
  • Medium samples are taken every 30 minutes from the lower chamber and the relative fluorescence, as a parameter for the changes of the macromolecular permeability as a function of time, determined with a fluorimeter.
  • the compounds according to the invention are added before the addition of the substances indicated above.
  • the usual Konzentationen the compounds are 1 x 10 "10 to 1 x 10" 6 M.
  • the compounds are 1 x 10 "10 to 1 x 10" 6 M.
  • b) Determination of the antithrombotic effect (in vivo)
  • b. Arterial thrombosis model (iron (II) chloride-induced thrombosis
  • 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. Simultaneously, the ear bleeding time is determined.
  • 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 containing 100 ⁇ ⁇ of a 13% solution of iron (II) 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.
  • the 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.
  • pigmented rats of the Brown-Norway strain which show no signs of ophthalmological diseases, are selected and randomly assigned to treatment groups.
  • the animals are anesthetized by intraperitoneal injection (15 mg / kg xylazine and 80 mg / kg ketamine).
  • the choroidal Neovascularization triggered by a 532 nm argon laser photocoagulator at six defined points around the optic nerve (50-75 ⁇ m diameter, 150 mW intensity, 100 ms duration).
  • test substance and the corresponding vehicle are either systemically administered orally or intraperitoneally or administered locally to the eye by repeated administration as eye drops or intravitreal injection.
  • vehicle eg PBS, isotonic saline
  • the body weight of all animals is determined before the start of the study, and then daily during the study.
  • angiography is performed by means of a fluorescence fundus chamber (eg Kowe, HRA). Under narcosis and after pupil dilation, a 10% sodium fluorescein dye is injected subcutaneously (sc). 2-10 minutes later, images of the fundus are taken. The extent of extravasation / edema, represented by the leakage of fluorescein, is assessed by two to three allied observers, grading from severities 0 (no extravasation) to 3 (strong staining beyond the actual lesion). After killing the animals on day 23, the eyes are removed and fixed in 4% paraformaldehyde solution for one hour at room temperature.
  • HRA fluorescence fundus chamber
  • the retina is gently peeled out and the sclera-choroid complex is stained with a FITC-isolectin B4 antibody and then placed flat on an object carrier.
  • the preparations thus obtained are evaluated by means of a fluorescence microscope (Apotom, Zeiss) at an excitation wavelength of 488 nm.
  • the area or volume of the choroidal neovascularization (in ⁇ 2 or ⁇ 3 ) is calculated by morphometric analysis using Axiovision 4.6 software. c.2) Testing the efficacy of substances in the oxygen-induced retinopathy model
  • oxygen-induced retinopathy is a valuable animal model for the study of pathological retinal angiogenesis.
  • This model is based on the observation that hyperoxia during early postnatal development in the retina leads to the arrest or slow down of the growth of normal retinal blood vessels. Once the animals return to normoxic room air after a 7-day hyperoxic phase, this is equivalent to relative hypoxia as the retina lacks the normal vessels required to ensure adequate supply of neural tissue under normoxic conditions.
  • the resulting ischemic situation leads to abnormal neovascularization, which bears some resemblance to pathophysiological neovascularization in ocular diseases such as wet AMD.
  • the evoked neovascularization is very reproducible, quantifiable and important Parameters for the study of disease mechanisms and possible treatments for various forms of retinal diseases.
  • the aim of this study is to investigate the efficacy of daily systemically administered doses of the test compound on the growth of retinal vessels in the oxygen-induced retinopathy model.
  • Newborns of C57B1 / 6 mice and their mothers are exposed to hyperoxia (70% oxygen) on postnatal day 7 (PD7) for 5 days.
  • PD7 postnatal day 7
  • the mice are kept under normoxic conditions (room air, 21% oxygen) until PD17.
  • the mice are treated daily with the test substance or the appropriate vehicle.
  • all mice are anesthetized with isoflurane and then killed by cervical dislocation. The eyes are removed and fixed in 4% formalin.
  • test substances are injected with the respective test substances as bolus (in rats) or infusion (in dogs or monkeys).
  • the preferred formulation of the test substances in rats is plasma / dimethyl sulfoxide in the ratio 99: 1.
  • the infusion solution of the test substance in dogs and monkeys consists of polyethylene glycol / ethanol / water in the ratio 50/10/40.
  • the application volume in rats is 2-10 ml / kg, 0.5-2 ml / kg in dogs and monkeys.
  • Test animals will be sampled with blood in sodium EDTA-containing tubes at the following times: at bolus dose 0.033, 0.083, 0.167, 0.25, 0.283, 0.333, 0.5, 0.75, 1, 2, 3, 5, 7, 24 hours after administration of the test substance and in infusions 0.083, 0.167, 0.25, 0.283, 0.333, 0.5, 0.75, 1, 2, 3, 5, 7, 24 hours after administration of the test substance.
  • the blood samples are centrifuged for 10 minutes at 1280 g after taking off.
  • the supernatant (plasma) is removed and either further processed directly or frozen for later sample preparation.
  • sample preparation mix 50 ⁇ plasma with 250 ⁇ acetonitrile (the precipitating reagent acetonitrile also contains the internal standard ISTD for subsequent analytical determination) and then allow to stand at room temperature for 5 minutes. Thereafter, the mixture is centrifuged for 3 minutes at 16000 g. The supernatant is removed and mixed with 500 .mu. ⁇ of a matched to the run medium buffer.
  • LC-MS / MS analysis eg liquid chromatography with a gemini 5 ⁇ C18 110A 50 mm x 3 mm (or 150 mm x 3 mm) column of Phenomenex; Mass spectrometry with an API 5500 or API 6500; SCIEX, Canada
  • LC-MS / MS analysis eg liquid chromatography with a gemini 5 ⁇ C18 110A 50 mm x 3 mm (or 150 mm x 3 mm) column of Phenomenex; Mass spectrometry with an API 5500 or API 6500; SCIEX, Canada
  • the concentration ratio of whole blood to plasma is also determined for a respective test substance.
  • the test substance is incubated with a specific concentration for 20 minutes in whole blood. Subsequently, the preparation of the samples as described above to determine the concentration of the test substance in the plasma. The set concentration divided by the measured concentration in the plasma gives the parameter Cb / Cp.
  • the pharmacokinetic parameters are calculated by non-compartmental analysis (NCA). The algorithms for calculating the parameters are defined in an internal process description and are based on rules published in general pharmacokinetic textbooks.
  • CL pharmacokinetic parameters clearance
  • Vss volume of distribution
  • CLblood (blood clearance)
  • CLblood CLplasma / (Cb / Cp)
  • Vss Vss CLplasma * MRViv
  • AUMC AUMC AUMC (O-tlast) + tlast * Clast, cakulatedA «+ Clast.calculated / ⁇ ⁇ 2 ⁇ ⁇ Rate constant for the terminal phase; is calculated from the logarithmic linear regression of unweighted data from the terminal phase with data points above the detection limit C)
  • exemplary embodiments of pharmaceutical compositions
  • the substances according to the invention can 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 25) (BASF, Germany) and 2 mg of magnesium stearate.
  • 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.
  • a sterile pharmaceutical preparation for topical application to the eye can be prepared by reconstitution of a lyophilizate of the compound of the invention in sterile saline solution.
  • a preservative for such a solution or suspension For example, benzalkonium chloride, thiomersal or phenylmercuric nitrate in a concentration range of 0.001 to 1 weight percent are suitable.
  • a sterile pharmaceutical preparation for topical application to the eye can be prepared by reconstitution of a lyophilizate of the compound of the invention in sterile saline.
  • a preservative for such a solution or suspension for example, benzalkonium chloride, thiomersal or phenylmercuric nitrate in a concentration range of 0.001 to 1% by weight is suitable.

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Abstract

L'invention concerne des dérivés d'oxopyridine substitués et des procédés pour les préparer ainsi que leur utilisation pour produire des médicaments destinés au traitement et/ou à la prophylaxie de maladies, en particulier de maladies cardiovasculaires, de préférence de maladies thrombotiques ou encore de maladies thromboemboliques et de l'œdème ainsi que de maladies ophtalmiques.
EP16709921.7A 2015-03-19 2016-03-15 Dérivés d'oxopyridine comme inhibiteurs du facteur xia pour le traitement de la thrombose Withdrawn EP3271332A1 (fr)

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ES2722423T3 (es) * 2014-09-24 2019-08-12 Bayer Pharma AG Derivados de oxopiridina sustituidos
KR20200141445A (ko) 2018-04-10 2020-12-18 바이엘 파마 악티엔게젤샤프트 치환된 옥소피리딘 유도체
AU2019304392A1 (en) * 2018-07-19 2021-01-28 Jiangsu Hengrui Medicine Co., Ltd. Method for preparing coagulation factor XIa inhibitor and intermediate thereof
EP3898634A1 (fr) 2018-12-21 2021-10-27 Bayer Aktiengesellschaft Dérivés d'oxopyridine substitués
WO2020127504A1 (fr) 2018-12-21 2020-06-25 Bayer Aktiengesellschaft Dérivés d'oxopyridine substitués
CN116947818B (zh) * 2023-09-18 2023-12-19 成都施贝康生物医药科技有限公司 一种氧代吡啶类化合物、中间体及其制备方法和用途

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WO2014160592A2 (fr) * 2013-03-27 2014-10-02 Merck Sharp & Dohme Corp. Inhibiteurs du facteur xia
TWI633089B (zh) * 2013-03-28 2018-08-21 拜耳製藥股份有限公司 經取代的酮基吡啶衍生物
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ES2722423T3 (es) * 2014-09-24 2019-08-12 Bayer Pharma AG Derivados de oxopiridina sustituidos
WO2016046157A1 (fr) * 2014-09-24 2016-03-31 Bayer Pharma Aktiengesellschaft Dérivés de pyridobenzazépine et de pyridobenzazocine inhibant le facteur xia
EP3197889B1 (fr) * 2014-09-24 2018-08-01 Bayer Pharma Aktiengesellschaft Dérivés d'oxopyridine substitués
CA2961981A1 (fr) * 2014-09-24 2016-03-31 Bayer Pharma Aktiengesellschaft Derives d'oxopyridine substitues
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WO2016046166A1 (fr) * 2014-09-24 2016-03-31 Bayer Pharma Aktiengesellschaft Dérivés d'oxopyridine substitués
JO3703B1 (ar) * 2015-07-09 2021-01-31 Bayer Pharma AG مشتقات أوكسوبيريدين مستبدلة
US20180250280A1 (en) * 2015-09-04 2018-09-06 Bayer Pharma Aktiengesellschaft Substituted oxopyridine derivatives
PT3486242T (pt) * 2016-08-31 2022-01-06 Jiangsu Hengrui Medicine Co Derivado de oxopicolinamida, método de preparação para esse fim e utilização farmacêutica do mesmo

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CA2979937A1 (fr) 2016-09-22
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