EP3004095A1 - Triazolopyridines utilisées comme inhibiteurs de la thrombine pour traiter des maladies thromboemboliques - Google Patents

Triazolopyridines utilisées comme inhibiteurs de la thrombine pour traiter des maladies thromboemboliques

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Publication number
EP3004095A1
EP3004095A1 EP14728514.2A EP14728514A EP3004095A1 EP 3004095 A1 EP3004095 A1 EP 3004095A1 EP 14728514 A EP14728514 A EP 14728514A EP 3004095 A1 EP3004095 A1 EP 3004095A1
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EP
European Patent Office
Prior art keywords
alkyl
methyl
mmol
hydrogen
substituted
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Withdrawn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
EP14728514.2A
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German (de)
English (en)
Inventor
Swen Allerheiligen
Anja BUCHMÜLLER
Karen Engel
Christoph Gerdes
Kersten Matthias Gericke
Michael Gerisch
Stefan Heitmeier
Alexander Hillisch
Tom KINZEL
Philip Lienau
Bernd Riedl
Susanne Röhrig
Martina Victoria Schmidt
Julia Strassburger
Adrian Tersteegen
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
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Publication date
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Priority to EP14728514.2A priority Critical patent/EP3004095A1/fr
Publication of EP3004095A1 publication Critical patent/EP3004095A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention relates to substituted triazolopyridines and processes for their preparation and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular of cardiovascular diseases, preferably of thrombotic or thromboembolic diseases.
  • Blood clotting is a protective mechanism of the organism that can quickly and reliably "seal" defects in the vessel wall, thus preventing or minimizing blood loss, and bleeding after vascular injury is essentially through the coagulation system, which involves an enzymatic cascade It involves numerous clotting factors, each of which, once activated, converts the next inactive precursor to its active form, transforming the soluble fibrinogen into the insoluble fibrin at the end of the cascade Traditionally, one differentiates between the intrinsic and the extrinsic system in blood coagulation, which culminate in a concluding common reaction pathway, where factors Xa and IIa (thrombin) play key roles: Factor Xa bundles the signals of the two coagulation pathways because it is formed by Factor VIIa / Tissue Factor (extrinsic pathway) as well as the Tenase complex (intrinsic pathway) by reaction of Factor X.
  • Factor Xa bundles the signals of the two coagulation pathways because it is formed by Factor VII
  • the activated serine protease Xa cleaves prothrombin to thrombin, which transmits the cascade impulses to the coagulation status of the blood via a series of reactions: Thrombin splits fibrinogen directly into fibrin. It activates the factor ⁇ to factor XIIIa necessary for the stabilization of the fibrin clot.
  • thrombin is a potent trigger of platelet aggregation (via PAR-1 activation), which also makes a significant contribution to hemostasis.
  • TAFI thrombin-activatable fibrinolysis inhibitor
  • thrombin In addition to thrombin, which is freely present in the blood, bound forms are also known: During the formation of a fibrin clot, thrombin and prothrombinase (factor Xa in the complex) are bound to the fibrin skeleton. These enzyme molecules continue to have activity and can not be inhibited by the body's anti-thrombin III. Clots thus have a general procoagulant potential in this way.
  • thrombin is involved, in particular via the activation of PAR-1 receptors on endothelial cells, also in inflammatory processes which interact with the Coagulation system speeds up both 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 also occur in microangiopathic hemolytic anemias, extracorporeal blood circuits such as hemodialysis, and heart valve prostheses and stents.
  • thromboembolic disease remains among the most common causes of morbidity and mortality in most industrialized countries [Heart Disease: A Textbook of Cardiovascular Medicine, Eugene Braunwald, 5th Ed., 1997, WB Saunders Company, Philadelphia].
  • the anticoagulants known from the prior art ie substances for the inhibition or prevention of blood clotting, have various disadvantages.
  • 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.
  • 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 important: 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 minimal risk profile.
  • tissue-type plamogen activator (tPA) was worked out.
  • An object of the present invention is therefore to provide novel compounds as thrombin inhibitors for the treatment of cardiovascular diseases, in particular of thrombotic or thromboembolic diseases, in humans and animals, which have a broad therapeutic range and show good pharmacokinetic behavior.
  • WO2009 / 023179 describes inter alia the use of triazolopyridines for the treatment of the hepatitis C virus.
  • the invention relates to compounds of the formula
  • X is an oxygen atom, a sulfur atom or CH-R 6 , wherein
  • R 6 is hydrogen or hydroxy
  • R 2 is hydrogen, aminocarbonyl, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl or phenyl, in which alkyl and cycloalkyl may be substituted by a substituent selected from the group consisting of hydroxy, methoxy, Cyano, hydroxycarbonyl, aminocarbonyl, methylsulfonyl, difluoromethoxy and trifluoromethoxy, or in which alkyl and cycloalkyl can be substituted by 1 to 3 substituents fluorine,
  • R 3 is hydrogen or GC 4 - alkyl, or
  • R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring, in which the cyclobutyl ring and cyclopentyl ring may be substituted by a hydroxy substituent,
  • R 4 is hydrogen or C 1 -C 6 -alkyl in which alkyl may be substituted by one hydroxy substituent or in which alkyl may be substituted by from 1 to 3 fluoro substituents
  • R 5 is C 1 -C 4 alkyl
  • R 4 and R 5 together with the carbon atom to which they are attached form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring, wherein the cyclobutyl ring and cyclopentyl ring may be substituted with a hydroxy substituent,
  • R 7 is hydrogen or GC 6 - alkyl, in which alkyl may be substituted by a substituent selected from the group consisting of cyano, hydroxy and methoxy, or in which alkyl may be substituted by 1 to 3 substituents fluorine, is hydrogen, is hydrogen or C 1 -C 6 -alkyl, in which alkyl may be substituted by a substituent selected from the group consisting of hydroxy and cyano, or in which alkyl may be substituted by 1 to 3 substituents fluoro,
  • R 10 is hydrogen
  • R 11 is C 1 -C 4 -alkyl, in which alkyl may be substituted by one hydroxy
  • R 12 is hydrogen or C 1 -C 4 -alkyl, or
  • R 11 and R 12 together with the carbon atom to which they are attached form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring wherein the cyclobutyl ring and cyclopentyl ring may be substituted with a hydroxy, R 13 for hydroxymethyl or hydroxy substituent Hydroxyethyl stands,
  • R 14 is methoxy or ethoxy wherein methoxy and ethoxy may be substituted with 1 to 3 substituents selected from the group consisting of deuterium and fluorine, and R 15 is hydrogen, methyl or fluoromethyl, and their salts, solvates and solvates 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 the compounds of formula (I) mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds according to the invention may exist in different stereoisomeric forms, ie in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in the case of atropisomers).
  • the present invention therefore encompasses the enantiomers and diastereoisomers 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 Cl, 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; Due to the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes are particularly suitable for this purpose.
  • 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 the rules given 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. 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 according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic Malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • mineral acids for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic Malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and choline.
  • 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 am
  • solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water.
  • 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 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 6 carbon atoms, preferably 1 to 4 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, 1-methylpropyl, tert-butyl, n-pentyl, iso-pentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 Methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1-ethylbutyl and 2-ethylbutyl.
  • Cycloalkyl represents a monocyclic cycloalkyl group having 3 to 6 carbon atoms, by way of example and preferably cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • X is an oxygen atom or CH-R 6 , where * is the point of attachment to the carbonyl group, X is an oxygen atom or CH-R 6 , where
  • R 6 is hydrogen
  • R 2 is aminocarbonyl, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl, wherein alkyl and cycloalkyl may be substituted with one substituent selected from the group consisting of hydroxy, methoxy and hydroxycarbonyl, or wherein alkyl may be substituted with 1 to 3 Substituents fluorine, R 3 is hydrogen or Ci-C 4 alkyl, or
  • R 2 and R 3 together with the carbon atom to which they are attached form a cyclobutyl ring in which the cyclobutyl ring may be substituted by a hydroxy substituent
  • R 4 is hydrogen or C 1 -C 4 -alkyl, in which alkyl may be substituted by a hydroxy substituent,
  • R 5 is C 1 -C 4 -alkyl
  • R 7 is C 1 -C 4 -alkyl, in which alkyl may be substituted by a substituent methoxy,
  • R 8 is hydrogen
  • R 9 is C 1 -C 4 -alkyl
  • R 10 is hydrogen
  • R 11 is C 1 -C 4 -alkyl
  • R 12 is hydrogen
  • R 11 and R 12 together with the carbon atom to which they are attached form a cyclopropyl ring, R 13 is hydroxymethyl,
  • R 14 is ethoxy, wherein ethoxy may be substituted with 1 to 3 substituents selected from the group consisting of deuterium and fluorine, and R 15 is hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts.
  • R 1 is a group of the formula
  • X is an oxygen atom
  • R 2 is C 1 -C 4 -alkyl or cyclobutyl, wherein alkyl may be substituted with one substituent selected from the group consisting of hydroxy and methoxy, or wherein alkyl may be substituted with 1 to 3 substituents fluorine, and wherein cyclobutyl is substituted with a hydroxy substituent, R 3 is hydrogen or methyl, R 4 is hydrogen or methyl, and
  • R 5 is methyl, or
  • R 2 is methyl or ethyl, in which methyl and ethyl may be substituted by 1 to 3 substituents fluoro,
  • R 3 is hydrogen or methyl
  • R 4 is C 1 -C 4 -alkyl, wherein alkyl is substituted with a hydroxy substituent
  • R 5 is methyl
  • R 2 and R 3 together with the carbon atom to which they are attached form a cyclobutyl ring in which the cyclobutyl ring is substituted by a hydroxy substituent,
  • R 4 is hydrogen or methyl
  • R 5 is methyl
  • R 7 is methyl or ethyl, wherein methyl and ethyl may be substituted by a methoxy substituent
  • R 8 is hydrogen
  • R 9 is methyl or ethyl
  • R 10 is hydrogen
  • R 11 is methyl
  • R 12 is hydrogen, or
  • R 11 and R 1 together with the carbon atom to which they are attached form a cyclopropyl ring
  • R 13 is hydroxymethyl
  • R 14 is ethoxy, wherein ethoxy may be substituted with 1 to 3 substituents selected from the group consisting of deuterium and fluorine, and
  • R 15 is hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts. Preference is also given to compounds of the formula (II) in which R 1 is a group of the formula
  • X is an oxygen atom
  • R 2 is C 1 -C 4 -alkyl or cyclobutyl, wherein alkyl is substituted with a hydroxy substituent, and wherein cyclobutyl is substituted with hydroxy, R 3 is hydrogen, R 4 is hydrogen or methyl, and
  • R 5 is methyl, or
  • R 2 is methyl, wherein methyl may be substituted with 1 to 2 substituents fluoro
  • R 3 is hydrogen or methyl
  • R 4 is Ci-C 4 alkyl, wherein alkyl is substituted with a hydroxy substituent
  • R 5 is methyl, or
  • R 2 and R 3 together with the carbon atom to which they are attached form a cyclobutyl ring in which the cyclobutyl ring is substituted by a hydroxy substituent, R 4 is hydrogen, and
  • R 5 is methyl
  • R 7 is methyl
  • R s is hydrogen
  • R 9 is methyl or ethyl
  • R 10 is hydrogen, R 11 is methyl, R 12 is hydrogen, or R 11 and R 12 taken together with the carbon atom to which they are attached
  • R 13 is hydroxymethyl
  • R 14 is ethoxy, wherein ethoxy may be substituted with 1 to 3 substituents selected from the group consisting of deuterium and fluorine, and
  • R 15 is hydrogen, methyl or fluoromethyl, 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
  • X is an oxygen atom, a sulfur atom or CH-R 6 , where
  • R 6 is hydrogen or hydroxy
  • R 2 is hydrogen, aminocarbonyl, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl or phenyl, in which alkyl and cycloalkyl may be substituted by a substituent selected from the group consisting of hydroxy, methoxy, cyano, hydroxycarbonyl, aminocarbonyl, methylsulfonyl, Difluoromethoxy and trifluoromethoxy, or wherein alkyl and cycloalkyl may be substituted with 1 to 3 substituents fluorine,
  • R 3 is hydrogen or GC 4 - alkyl, or
  • R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring, in which the cyclobutyl ring and cyclopentyl ring may be substituted by a hydroxy substituent,
  • R 4 is hydrogen or GC 6 - alkyl, wherein alkyl may be substituted with a hydroxy substituent, or wherein alkyl may be substituted with 1 to 3 fluoro substituents, Ci-C alkyl, or R 4 and R 5 together with the carbon atom to which they are attached form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring wherein the cyclobutyl ring and cyclopentyl ring may be substituted with a hydroxy
  • R 7 substituent for hydrogen or GC 6 - is alkyl, wherein alkyl may be substituted with a substituent selected from the group consisting of cyano, hydroxy and methoxy, or wherein alkyl may be substituted with 1 to 3 substituents fluorine
  • R 8 is hydrogen, and
  • R 15 is hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts. Preference is given to compounds of the formula (I) in which R 1 is a group of the formula
  • X is an oxygen atom or CH-R 6 , where * is the point of attachment to the carbonyl group, X is an oxygen atom or CH-R 6 , where
  • R 6 is hydrogen
  • R 2 is aminocarbonyl, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl, wherein alkyl and cycloalkyl may be substituted with a substituent selected from the group consisting of hydroxy, methoxy and hydroxy carbonyl, or wherein alkyl may be substituted with 1 to 3 substituents fluorine,
  • R 3 is hydrogen or GC 4 - alkyl, or
  • R 2 and R 3 together with the carbon atom to which they are attached form a cyclobutyl ring in which the cyclobutyl ring may be substituted by a hydroxy substituent
  • R 4 is hydrogen or GC 4 -alkyl, in which alkyl may be substituted by a hydroxy substituent, R 5 is C 1 -C 4 -alkyl,
  • R 7 is Ci-C alkyl, wherein alkyl may be substituted with a substituent methoxy, R 8 is hydrogen, and R 15 is hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts.
  • R 1 is a group of the formula where the point of attachment to the carbonyl group is,
  • X is an oxygen atom
  • R 2 is C 1 -C 4 -alkyl or cyclobutyl, wherein alkyl may be substituted with one substituent selected from the group consisting of hydroxy and methoxy, or wherein alkyl may be substituted with 1 to 3 substituents fluoro, and wherein cyclobutyl is substituted with a substituent is hydroxy, R 3 is hydrogen or methyl, R 4 is hydrogen or methyl, and
  • R 5 is methyl, or
  • R is methyl or ethyl, in which methyl and ethyl may be substituted by 1 to 3 substituents fluorine, R 3 is hydrogen or methyl, R 4 is C 1 -C 4 -alkyl, wherein alkyl is substituted with a hydroxy substituent, and
  • R 5 is methyl, or
  • R 2 and R 3 together with the carbon atom to which they are attached form a cyclobutyl ring in which the cyclobutyl ring is substituted by a hydroxy substituent,
  • R 4 is hydrogen or methyl
  • R 5 is methyl
  • R 7 is methyl or ethyl, in which methyl and ethyl may be substituted by a methoxy substituent
  • R 8 is hydrogen
  • R 15 is hydrogen, methyl or fluoromethyl, Salts, their solvates and the solvates of their salts, are compounds of the formula (I) in which, for a group of the formula
  • X is an oxygen atom
  • R 2 is C 1 -C 4 -alkyl or cyclobutyl, wherein alkyl is substituted with a hydroxy substituent, and wherein cyclobutyl is substituted with hydroxy, R 3 is hydrogen, R 4 is hydrogen or methyl, and
  • R 5 is methyl, or
  • R 2 is methyl, wherein methyl may be substituted with 1 to 2 substituents fluoro
  • R 3 is hydrogen or methyl
  • R 4 is Ci-C 4 alkyl, wherein alkyl is substituted with a hydroxy substituent
  • R 5 is methyl, or
  • R 2 and R 3 together with the carbon atom to which they are attached form a cyclobutyl ring in which the cyclobutyl ring is substituted by a hydroxy substituent, R 4 is hydrogen, and
  • R 5 is methyl
  • R 7 is methyl
  • R 8 is hydrogen
  • R 15 is hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts. Preference is given to compounds of the formula (I) in which R 1 is a group of the formula
  • X is an oxygen atom, a sulfur atom or CH-R 6 , wherein
  • R 6 is hydrogen or hydroxy
  • R 2 is hydrogen, aminocarbonyl, C 1 -C 6 -alkyl, C 5 -C 6 -cycloalkyl or phenyl, in which alkyl and cycloalkyl may be substituted by a substituent selected from the group consisting of hydroxy, methoxy, cyano, hydroxycarbonyl, aminocarbonyl, methylsulfonyl, Difluoromethoxy and trifluoromethoxy, or wherein alkyl and cycloalkyl may be substituted with 1 to 3 substituents fluoro,
  • R 3 is hydrogen or C 1 -C 4 -alkyl, or R 2 and R 3 together with the carbon atom to which they are attached are
  • R 4 is hydrogen or C 1 -C 6 -alkyl in which alkyl may be substituted by one hydroxy substituent, or wherein alkyl may be substituted by from 1 to 3 fluoro substituents, R 5 is C 1 -C 4 alkyl, or R 4 and R 4 R 5 together with the carbon atom to which they are bound one
  • X is an oxygen atom or CH-R 6 , where
  • R 6 is hydrogen
  • R 2 is aminocarbonyl, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl, wherein alkyl and cycloalkyl may be substituted with a substituent selected from the group consisting of hydroxy, methoxy and hydroxycarbonyl, or wherein alkyl may be substituted with 1 to 3 substituents fluorine, R 3 is hydrogen or GC 4 - alkyl, or R 2 and R 3 together with the carbon atom to which they are attached one
  • R 4 is hydrogen or C 1 -C 4 -alkyl in which alkyl may be substituted by a hydroxy substituent
  • R 5 is C 1 -C 4 -alkyl
  • R 15 is hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts.
  • Preference is given to compounds of the formula (I) in which R 1 is a group of the formula
  • X is an oxygen atom
  • R 2 is C 1 -C 4 alkyl or cyclobutyl, wherein alkyl may be substituted with a substituent selected from
  • alkyl may be substituted with 1 to 3 substituents fluorine, and wherein cyclobutyl is substituted with a hydroxy substituent
  • R 3 is hydrogen or methyl
  • R 4 is hydrogen or methyl
  • R 5 is methyl, or R 2 is methyl or ethyl, in which methyl and ethyl may be substituted by 1 to 3 substituents fluorine, R 3 is hydrogen or methyl, R 4 is C 1 -C 4 -alkyl, in which alkyl is substituted by one hydroxy substituent, and
  • R 5 is methyl, or
  • R 2 and R 3 together with the carbon atom to which they are attached form a cyclobutyl ring in which the cyclobutyl ring is substituted by a hydroxy substituent,
  • R 4 is hydrogen or methyl
  • R 5 is methyl
  • R 15 is hydrogen, methyl or fluoromethyl, Salts, their solvates and the solvates of their salts, are compounds of the formula (I) in which, for a group of the formula
  • X is an oxygen atom
  • R 2 is C 1 -C 4 -alkyl or cyclobutyl wherein alkyl is substituted with a hydroxy substituent and wherein cyclobutyl is substituted with hydroxy
  • R 3 is hydrogen
  • R 4 is hydrogen or methyl
  • R 5 is methyl, or
  • R is methyl, wherein methyl may be substituted with 1 to 2 substituents fluoro, R 3 is hydrogen or methyl, R 4 is G-Ct-alkyl, wherein alkyl is substituted with a hydroxy substituent, and
  • R 5 is methyl, or
  • R 5 is methyl
  • R 15 is hydrogen, methyl or fluoromethyl
  • R 1 is a group of the formula
  • X is an oxygen atom
  • R 2 is C 1 -C 4 alkyl or cyclobutyl
  • alkyl is substituted with a hydroxy substituent
  • R 3 is hydrogen
  • R 4 is hydrogen or methyl
  • R 5 is methyl
  • R 15 is hydrogen, methyl or fluoromethyl
  • R 1 is a group of the formula
  • X is an oxygen atom
  • R 2 is methyl
  • R 3 is hydrogen or methyl
  • R 4 is C 1 -C 4 -alkyl
  • alkyl is substituted with a hydroxy substituent
  • R 5 is methyl
  • R 15 is hydrogen, methyl or fluoromethyl
  • R 2 and R 3 together with the carbon atom to which they are attached form a cyclobutyl ring in which the cyclobutyl ring is substituted by a hydroxy substituent, R 4 is hydrogen, and
  • R 5 is methyl
  • R 15 is hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts. Preference is given to compounds of the formula (I) in which R 1 is a group of the formula
  • R 7 is hydrogen or Ci-C 6 - alkyl, wherein alkyl may be substituted with a substituent selected from the group consisting of cyano, hydroxy and methoxy, or wherein alkyl may be substituted with 1 to 3 substituents fluorine, R 8 is hydrogen stands, and
  • R 15 is hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts. Preference is given to compounds of the formula (I) in which R 1 is a group of the formula
  • R 7 is Ci-C 4 alkyl, wherein alkyl may be substituted with a substituent methoxy, R 8 is hydrogen, and
  • R 15 is hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts. Preference is given to compounds of the formula (I) in which R 1 is a group of the formula
  • X is an oxygen atom
  • R 7 is methyl or ethyl, in which methyl and ethyl may be substituted by a methoxy substituent
  • R 8 is hydrogen
  • R 15 is hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts. Preference is given to compounds of the formula (I) in which R 1 is a group of the formula
  • R 7 is methyl
  • R 8 is hydrogen
  • R 15 is hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts. Preference is given to compounds of the formula (I) in which R 1 is a group of the formula
  • R 9 is hydrogen or GC 6 -alkyl, in which alkyl may be substituted by a substituent selected from the group consisting of hydroxy and cyano, or in which alkyl may be substituted by 1 to 3 substituents fluoro,
  • R 10 is hydrogen
  • R 11 is C 1 -C 4 -alkyl, in which alkyl may be substituted by a hydroxy substituent,
  • R 12 is hydrogen or C 1 -C 4 -alkyl, or R 11 and R 12 taken together with the carbon atom to which they are attached form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring, wherein the cyclobutyl ring and cyclopentyl ring may be substituted with a hydroxy substituent, and
  • R 15 is hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts. Preference is given to compounds of the formula (I) in which R 1 is a group of the formula
  • R 9 is C 1 -C 4 -alkyl
  • R 10 is hydrogen
  • R 11 is C 1 -C 4 -alkyl
  • R 12 is hydrogen, or
  • R 11 and R 12 together with the carbon atom to which they are attached form a cyclopropyl ring
  • R 15 is hydrogen, methyl or fluoromethyl, and their salts, their solvates, and the solvates of their salts. Preference is given to compounds of the formula (I) in which R 1 is a group of the formula
  • R 12 is hydrogen, or
  • R 11 and R 12 together with the carbon atom to which they are attached form a cyclopropyl ring
  • R 15 is hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts. Preference is given to compounds of the formula (I) in which R 1 is a group of the formula where * is the point of attachment to the carbonyl group,
  • R 13 is hydroxymethyl or hydroxyethyl
  • R 14 is methoxy or ethoxy, where methoxy and ethoxy may be substituted with 1 to 3 substituents selected from the group consisting of deuterium and fluorine, and
  • R 15 is hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts. Preference is given to compounds of the formula (I) in which R 1 is a group of the formula
  • R 13 is hydroxymethyl
  • R 14 is ethoxy, where ethoxy may be substituted by 1 to 3 substituents selected from the group consisting of deuterium and fluoro, and
  • R 15 is hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts.
  • R 1 and R 15 are as defined above. Also preferred is ⁇ 2 - [(3-chlorobenzyl) amino] -8-methoxy [1,2,4] triazolo [l, 5-a] pyridin-6-yl ⁇ [5- (3-hydroxycyclobutyl) -2- methylmorpholin-4-yl] methanone [diastereomer 3 + diastereomer 4] or
  • 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 has the abovementioned meaning, with compounds of the formula
  • R has the meaning given above, be reacted in the presence of a palladium catalyst.
  • the reaction according to process [A] 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 examples include carbodiimides such as ⁇ , ⁇ '-diethyl, A ⁇ W-dipropyl, A ⁇ W-diisopropyl, A ⁇ A ⁇ '- dicyclohexylcarbodiimide, ⁇ - (S-dimethylaminoisopropyl) -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-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamin
  • 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, dioxane, dimethylformamide, dimethyl sulfoxide or acetonitrile, or mixtures of the solvents mentioned, preference being given to dimethylformamide.
  • halogenated hydrocarbons such as dichloromethane or trichloromethane
  • hydrocarbons such as benzene
  • other solvents such as nitromethane, dioxane, dimethylformamide, dimethyl sulfoxide or acetonitrile, or mixtures of the solvents mentioned, preference being given to dimethylformamide.
  • the reaction according to process [B] is generally carried out under Buchwald-Hartwig conditions in the presence of a base, in inert solvents, preferably in a temperature range from 0 ° C to 200 ° C, preferably at 10 ° C to 150 ° C, at atmospheric pressure or at temperatures above the boiling point of the solvent at elevated pressure in closed reaction vessels (microwave tubes) or optionally in a microwave at temperatures above the boiling point of the solvent and under elevated pressure.
  • bases are alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal or alkaline earth metal hydroxides such as sodium, potassium or barium hydroxide, alkali metal or alkaline earth metal phosphates such as potassium phosphate, alkali metal alcoholates such as sodium or potassium -feri-butoxide and sodium methoxide, alkali phenolates such as sodium phenolate, amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide or organic amines such as l, 5-diazabicyclo [4.3.0] non-5- en (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), preferably cesium carbonate, potassium carbonate, sodium or potassium ieri-butoxide or lithium bis (trimethylsilyl) amide.
  • alkali metal or alkaline earth metal carbonates such as lithium, sodium,
  • Palladium catalysts are, for example, palladium on activated carbon, palladium (II) acetate, bis (dibenzylideneacetone) palladium (0), tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, bis - (acetonitrile) palladium (II) chloride, [1,1 * - bis (diphenylphosphino) ferrocene] dichloropalladium (II) and corresponding dichloromethane complex, optionally in combination with additional phosphine ligands such as 2,2'-bis (diphenylphosphino ) -l, 1'-binaphthyl (BINAP), (2-biphenyl) di-ieri-butylphosphine, Dicyclohexyl [2 ', 4', 6'-tris (1-methylethyl) bi
  • precatalysts such as chloro- [2- (dicyclohexylphosphine) -3,6-dimethoxy-2 ', 4', 6'-triisopropyl-l, -biphenyl] [2- (2-aminoethyl) - phenyl] palladium (II) (BrettPhos precatalyst) [cf. eg SL Buchwald et al., Chem.
  • phosphine ligands such as 2- (dicyclohexylphosphine) -3,6-dimethoxy-2 ', 4', 6'-triisopropyl-l, -biphenyl (BrettPhos) use, preferably bis (dibenzylidenacetone ) palladium (0) in combination with 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (xantphos) and also chloro- [2- (dicyclohexylphosphine) -3,6-dimethoxy-2 ', 4', 6 ''-triisopropyl-l, -biphenyl] [2- (2-aminoethyl) -phenyl] palladium (II) (BrettPhos precatalyst) or a mixture of chloro [2- (dicyclohexylphosphine)
  • Inert solvents are, for example, ethers such as 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, di-w-butyl ether, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as feri-butanol or amyl alcohols or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide ( DMSO), dimethylacetamide (DMA), toluene or acetonitrile, or mixtures of said solvents, is preferably ieri-butanol, 1,4-dioxane or toluene.
  • ethers such as 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, di-w-butyl ether, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as feri
  • the compounds of the formula ( ⁇ ) are known or can be prepared by reacting the compounds of the formula in which
  • R 15 has the meaning given above, and
  • R 16 is methyl, ethyl or tert-butyl, in the case that R 16 is methyl or ethyl, with a base and in the event that R 16 is tert-butyl, be reacted with an acid.
  • the reaction is generally carried out in inert solvents, preferably in a temperature range from 0 ° C to room temperature at atmospheric pressure.
  • 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, sodium hydroxide is preferred.
  • Acids are, for example, trifluoroacetic acid or hydrogen chloride in dioxane. If desired, triethylsilane may be added to the reaction mixture, the mixture of trifluoroacetic acid and triethylsilane being preferred.
  • Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, aceton
  • R is tert-butyl
  • R 15 is methyl or fluoromethyl, are reacted
  • R 16 is methyl, ethyl or tert-butyl, with the compound of formula be reacted in the presence of a reducing agent.
  • reaction according to method [C] is carried out as described for method [B].
  • reaction according to process [D] is generally carried out in inert solvents, preferably in a temperature range from 0 ° C to reflux of the solvent at atmospheric pressure.
  • Reducing agents are, for example, hydrides, such as complex borohydrides or aluminum hydrides, and boranes, such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride or borane-tetrahydrofuran, preferably sodium borohydride.
  • Inert solvents are, for example, alcohols, such as methanol, ethanol, n-propanol or isopropanol, or ethers, such as diethyl ether, dioxane, tetrahydrofuran, or other solvents, such as dimethylformamide, preference is given to ethanol.
  • the compounds of the formula (Va) are a subset of the compounds of the formula (V).
  • the compounds of the formula (IV) are known or can be prepared by reacting the compound of the formula
  • the reaction is carried out as described for method [A].
  • the compounds of the formula (X) 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 protease thrombin.
  • the compounds of this invention inhibit thrombin-catalyzed enzymatic cleavage of substrates that play an essential role in the activation of blood clotting, platelet aggregation (via platelet PAR-1 activation), and thrombin-induced inflammatory, fibrosis, and angiogenesis Take processes. 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.
  • cardiovascular diseases preferably thrombotic or thromboembolic diseases and / or thrombotic or thromboembolic complications.
  • TAFI thrombin-activatable fibrinolysis inhibitor
  • the compounds of the invention are suitable for the treatment and / or prophylaxis of diseases or complications that may arise or 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), heart attack with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI), stable angina pectoris, unstable angina pectoris, reocclusions and restenosis after coronary interventions such as angioplasty, stent implantation or aortocoronary bypass, but also thrombotic or thromboembolic disorders in other vessels leading to peripheral arterial occlusive diseases, pulmonary embolism, venous thromboembolism, venous thrombosis, especially in deep leg veins and renal veins, transient ischemic attacks as well as thrombotic stroke and thromboembolic stroke s.
  • ACS acute coronary syndrome
  • ST segment elevation ST segment elevation
  • non-STEMI non-STEMI
  • the stimulation of the coagulation system can be done by various causes or comorbidities.
  • the coagulation system in the context of surgical interventions, immobility, bed-rest, infections or cancer or cancer therapy, the coagulation system can be strongly stimulated and there are thrombotic complications, especially venous thrombosis.
  • 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 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
  • Thromboembolic complications also occur in microangiopathic hemolytic anemias, extracorporeal blood circuits such as hemodialysis, and heart valve prostheses.
  • the compounds according to the invention come into consideration in particular for the treatment of diseases in which the clot already exists, since, in particular, thrombin which is incorporated in the clot contributes to clot stability. Since the inhibition of these thrombin molecules accelerates clot degradation, the compounds of the invention can be used to treat existing clots. These clots can arise in the entire vascular system and lead to serious complications in various organs, in particular by ischemia, inflammatory reactions or embolization, such as myocardial infarction or cerebral infarction, but also pulmonary embolism or postthrombotic syndrome, especially after deep vein thrombosis.
  • the compounds according to the invention are therefore also suitable for the treatment of venous and arterial occlusions of the eye vessels which are caused by clots, for example age-related macular degeneration.
  • tissue plasminogen activator tPA
  • the compounds are suitable for adjuvant use in the context of thrombolytic therapy.
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of diseases in which micro-clot formations or fibrin deposits in cerebral vessels occur which can lead to dementias 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 of the thrombin action plays an essential role.
  • the mutual reinforcement of coagulation and inflammation can by the prevented compounds of the invention and therefore the probability of a thrombotic complication are significantly reduced.
  • 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 in a diabetic underlying disease, such as diabetic retinopathy or nephropathy.
  • the compounds of the present 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, particularly those undergoing major surgery or chemotherapy 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 (APAH), which is associated with collagenosis.
  • Idiopathic Pulmonary Arterial Hypertension formerly referred to as Primary Pulmonary Hypertension
  • FPAH Familial Pulmonary Arterial Hypertension
  • APAH Associated Pulmonary Arterial Hypertension
  • congenital systemic pulmonary shunt veins portal hypertension, HIV infections, the use of certain drugs and medications, with other diseases (thyroid diseases, 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.
  • diseases thyroid diseases, glycogen storage diseases, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy
  • 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.
  • 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 an infectious disease, and / or of Systemic Inflammatory Syndrome (SIRS), septic organ dysfunction, septic organ failure and Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury (ALI), Septic shock and / or septic organ failure.
  • SIRS Systemic Inflammatory Syndrome
  • ARDS Acute Respiratory Distress Syndrome
  • ALI Acute Lung Injury
  • 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
  • coagulation factors eg Factor X, prothrombin and fibrinogen
  • platelets are consumed, reducing the blood's ability to coagulate and causing severe bleeding.
  • the compounds according to the invention are particularly suitable for the treatment and / or prophylaxis of acute coronary syndrome (ACS), venous thromboembolism, venous thrombosis, in particular in deep leg veins and renal veins, pulmonary embolisms, stroke and / or thrombosis prophylaxis in the context of surgical interventions, in particular in the context surgical intervention in patients who have cancer.
  • ACS acute coronary syndrome
  • venous thromboembolism venous thrombosis
  • venous thrombosis in particular in deep leg veins and renal veins
  • pulmonary embolisms pulmonary embolisms
  • stroke and / or thrombosis prophylaxis in the context of surgical interventions, in particular in the context surgical intervention in patients who have cancer.
  • 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 according to the invention and one or more further 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 equipment, to coat artificial surfaces of medical devices and equipment used in vivo or ex vivo, or biological samples that may contain factor IIa.
  • 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 equipment, to coat artificial surfaces of medical devices and equipment used in vivo or ex vivo, or biological samples that may contain factor IIa.
  • 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 IIa, which is characterized in that an anticoagulatory effective amount of the compound of the invention is added.
  • Another object of the present invention 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 / vasodilator drugs in particular ACE (angiotensin converting enzyme) inhibitors such as captopril, lisinopril, enalapril, ramipril, cilazapril, benazepril, fosinopril, quinapril and perindopril, or AII (angiotensin ID 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-a
  • 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
  • anticoagulant substances anticoagulants
  • UHF heparin
  • LMWH low molecular weight heparin
  • tinzaparin certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, danaparoid, semuloparin (AVE 5026), adomiparin (M118) and EP -42,675 / ORG42675
  • Direct thrombin inhibitors DTI
  • Direct factor Xa inhibitors such as rivaroxaban, apixaban, edoxaban (DU-176b), betrixaban (PRT-54021), R-1663, darexaban (YM-150), otamixaban (FXV-673 / RPR)
  • letaxaban (TAK-442), razaxaban (DPC-906), DX-9065a, LY-517717, idraparinux and fondaparinux;
  • 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;
  • Recombinant human activated protein C such as Xigris; ⁇ As well as antiarrhythmics.
  • the present invention further relates to the combination of a compound of this invention with 5-chloro-A r - ( ⁇ (5 l S ') - 2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] - l, 3-oxazolidin-5-yl ⁇ -methyl) -2-thiophenecarboxamide (rivaroxaban) [WO 01/47919] having the structural formula
  • Another object of the present invention is the combination of
  • the compounds according to the invention can act systemically and / or locally. For this purpose, 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. For these administration routes, the compounds according to the invention can be administered in suitable administration forms.
  • the prior art is capable of rapidly and / or modifying the compounds according to the invention which release the compounds according to the invention in crystalline and / or amorphized and / or dissolved form, for example tablets (uncoated or coated tablets, for example, with enteric or delayed-dissolving or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (eg hard or soft gelatin capsules), dragees, granules, pellets, Powders, emulsions, suspensions, aerosols or solutions.
  • tablets uncoated or coated tablets, for example, with enteric or delayed-dissolving or insoluble coatings which control the release of the compound of the invention
  • tablets uncoated or coated tablets, for example, with enteric or delayed-dissolving or insoluble coatings which control the release of the compound of the invention
  • parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • suitable application forms include injection and fusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • the oral application is preferred.
  • Inhalation medicines including powder inhalers, nebulizers
  • nasal drops solutions, sprays
  • lingual, sublingual or buccal tablets to be applied, 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.
  • These adjuvants include, among others. Carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin ), Stabilizers (eg antioxidants such as ascorbic acid), dyes (eg inorganic pigments such as iron oxides) and flavor and / or odoriferous agents.
  • Carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodec
  • compositions containing at least one compound of the invention preferably together with one or more inert non-toxic, pharmaceutically suitable excipient, and their use for the purposes mentioned above.
  • Method 1A Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 ⁇ 50 x 1 mm; Eluent A: 1 L water + 0.25 mL 99% formic acid, eluent B: 1 L acetonitrile + 0.25 mL 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 2A Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 ⁇ 30 x 2 mm; Eluent A: 1 L water + 0.25 mL 99% formic acid, eluent B: 1 L acetonitrile + 0.25 mL 99% formic acid; Gradient: 0.0 min 90% A -> 1.2 min 5% A -> 2.0 min 5% A; Oven: 50 ° C; Flow: 0.60 mL / min; UV detection: 208-400 nm.
  • Method 3A Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 ⁇ 50 x 1 mm; Eluent A: 1 L water + 0.5 mL 50% formic acid, eluent B: 1 L acetonitrile + 0.5 mL 50% formic acid; Gradient: 0.0 min 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 4A Instrument MS: Waters (Micromass) Quattro Micro; Instrument HPLC: Agilent 1100 series; Column: YMC-Triart C18 3 ⁇ 50 x 3 mm; Eluent A: 1 L water + 0.01 mol ammonium carbonate, eluent B: 1 L 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 5A Instrument MS: Waters (Micromass) QM; Instrument HPLC: Agilent 1100 series; Column: Agient ZORBAX Extend-C18 3.0 x 50mm 3.5-micron; Eluent A: 1 L water + 0.01 mol ammonium carbonate, eluent B: 1 L 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 6A Instrument MS: Waters (Micromass) ZQ; Instrument HPLC: Agilent 1100 series; Column: Agient ZORBAX Extend-C18 3.0 x 50mm 3.5-micron; Eluent A: 1 L water + 0.01 mol ammonium carbonate, eluent B: 1 L 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 7A Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 ⁇ 50 x 1 mm; Eluent A: 1 L water + 0.25 mL 99% formic acid, eluent B: 1 L acetonitrile + 0.25 mL 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 8A Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 ⁇ 50 x 1 mm; Eluent A: 1 L water + 0.25 mL 99% formic acid, eluent B: 1 L acetonitrile + 0.25 mL 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.
  • GC-MS methods :
  • Method 1B Instrument: Thermo DFS, Trace GC Ultra; Column: Restek RTX-35, 15 m x 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 2B Instrument: Micromass GCT, GC6890; Column: Restek RTX-35, 15 m x 200 ⁇ x 0.33 ⁇ ; constant flow with helium: 0.88 mL / min; Oven: 70 ° C; Met: 250 ° C; Gradient: 70 ° C, 30 ° C / min -> 310 ° C (hold for 3 min).
  • Method IC Instrument: Thermo Fisher-Scientific DSQ; chemical ionization; Reactant gas NH 3 ; Source temperature: 200 ° C; Ionization energy 70eV.
  • Method 2C Instrument: Waters ZQ 2000; Electrospray ionization; Eluent A: 1 L water + 0.25 mL 99% formic acid, eluent B: 1 L acetonitrile + 0.25 mL 99% formic acid; 25% A, 75% B; Flow: 0.25 mL / min.
  • Method 1D Phase: Daicel Chiralpak AZ-H, 5 ⁇ 250 mm ⁇ 30 mm, eluent: isohexane / ethanol 50:50; Flow: 40 mL / min; Temperature: 20 ° C; UV detection: 220 nm.
  • Method 2D Phase: Daicel Chiralpak AZ-H, 5 ⁇ 250 mm x 30 mm, eluent: iso-hexane / ethanol 50:50; Flow: 40 mL / min, temperature: 25 ° C; UV detection: 220 nm.
  • Method 3D Phase: Daicel Chiralpak AD-H SFC, 10 ⁇ 250 mm x 20 mm, eluent: carbon dioxide / ethanol 70:30; Flow: 100 mL / min, makeup flow rate: 30 mL / min, baking pressure: 80 bar; Temperature: 40 ° C; UV detection: 220 nm.
  • Method 4P Phase: Daicel Chiralpak AD-H, 5 ⁇ 250 mm x 20 mm, eluent: iso-hexane / isopropanol 70:30; Flow: 20 mL / min; Temperature: 25 ° C; UV detection: 230 nm.
  • Method 5D Phase: Daicel Chiralpak AZ-H, 5 ⁇ 250 mm ⁇ 30 mm, eluent: iso-hexane / ethanol 90:10; Flow: 40 mL / min; Temperature: 25 ° C; UV detection: 220 nm.
  • Method 6D Phase: Daicel Chiralpak AY-H, 5 ⁇ 250 mm x 20 mm, eluent: iso-hexane / ethanol 90:10; Flow: 40 mL / min; Temperature: 40 ° C; UV detection: 220 nm.
  • Method 7D Phase: Daicel Chiralpak AS-H, 5 ⁇ 250 mm x 20 mm, eluent: iso-hexane / ethanol 70:30; Flow: 20 mL / min; Temperature: 25 ° C; UV detection: 230 nm.
  • Method 8D Phase: Daicel Chiralpak AZ-H, 5 ⁇ 250 mm x 30 mm, eluent: iso-hexane / ethanol 50:50; Flow: 20 mL / min; Temperature: 25 ° C; UV detection: 220 nm.
  • Method 9D Phase: Daicel Chiralpak OZ-H, 5 ⁇ m 250 mm ⁇ 20 mm, eluent: isohexane / ethanol 50:50; Flow: 15 mL / min; Temperature: 30 ° C; UV detection: 220 nm.
  • Method 10D Phase: Daicel Chiralpak OD-H, 5 ⁇ 250 mm ⁇ 20 mm, eluent: iso-hexane / ethanol 60:40; Flow: 20 mL / min; Temperature: 22 ° C; UV detection: 230 nm.
  • Method HD Phase: Daicel Chiralpak AD-H SFC, 10 ⁇ 250 mm x 20 mm, eluent: carbon dioxide / methanol 70:30; Flow: 100 mL / min, makeup flow rate: 30 mL / min, baking pressure: 80 bar; Temperature: 40 ° C; UV detection: 210 nm.
  • Method 12D Phase: Daicel Chiralcel AD-H, 5 ⁇ 250 mm x 20 mm; Eluent: iso-hexane / ethanol 50:50 + 0.2% diethylamine; Flow: 20 mL / min; Temperature: 20 ° C; UV detection: 220 nm.
  • Method 13D Phase: Daicel Chiralcel AD-H, 5 ⁇ 250 mm x 20 mm; Eluent: iso-hexane / isopropanol 50:50 + 0.2% diethylamine; Flow: 20 mL / min; Temperature: 20 ° C; UV detection: 230 nm.
  • Method 14D Phase: Daicel Chiralpak OD-H, 5 ⁇ 250 mm x 20 mm, eluent: iso-hexane / isopropanol 50:50; Flow: 20 mL / min; Temperature: 25 ° C; UV detection: 230 nm.
  • Method 15D Phase: Daicel Chiralpak IC, 5 ⁇ 250 mm x 20 mm, eluent: ieri-butyl methyl ether / methanol 50:50; Flow: 20 mL / min; Temperature: 25 ° C; UV detection: 220 nm.
  • Method 16D Phase: Daicel Chiralpak AY-H, 5 ⁇ 250 mm x 20 mm, eluent: iso-hexane / ethanol 50:50; Flow: 20 mL / min; Temperature: 20 ° C; UV detection: 230 nm.
  • Method 17D Phase: Daicel Chiralpak AS-H, 5 ⁇ 250 mm x 20 mm, eluent: iso-hexane / ethanol 90:10; Flow: 20 mL / min; Temperature: 25 ° C; UV detection: 220 nm.
  • Method 18D Phase: Daicel Chiralcel AZ-H, 5 ⁇ m 250 mm ⁇ 40 mm; Eluent: iso-hexane / ethanol 90: 10 + 0.2% diethylamine; Flow: 35 mL / min; Temperature: 25 ° C; UV detection: 230 nm.
  • Method 19D Phase: Daicel IA, 5 ⁇ 250 mm x 40 mm; Eluent: ferric butyl methyl ether / methanol 50:50; Flow: 20 mL / min; Temperature: 25 ° C; UV detection: 230 nm.
  • Method 20D Phase: Daicel Chiralcel AD-H, 5 ⁇ 250 mm x 20 mm; Eluent: iso-hexane / isopropanol 60:40 + 0.2% diethylamine; Flow: 20 mL / min; Temperature: 20 ° C; UV detection: 220 nm.
  • Method 21D Phase: Daicel Chiralpak IC, 5 ⁇ 250 mm x 20 mm, eluent: ieri-butyl methyl ether / methanol / acetonitrile 50:25:25; Flow: 15 mL / min; Temperature: 35 ° C; UV detection: 220 nm.
  • Method 22D Phase: Daicel Chiralcel AZ-H, 5 ⁇ 250 mm x 40 mm; Eluent: iso-hexane / ethanol 90: 10 + 0.2% diethylamine; Flow: 15 mL / min; Temperature: 30 ° C; UV detection: 220 nm.
  • Method 23D Phase: Daicel Chiralcel AD-H, 5 ⁇ 250 mm x 20 mm; Eluent: iso-hexane / isopropanol 50:50; Flow: 20 mL / min; Temperature: 40 ° C; UV detection: 210 nm.
  • Method 24D Phase: Daicel Chiralpak IC, 5 ⁇ 250 mm ⁇ 20 mm, eluent: acetonitrile / methanol 30:70; Flow: 30 mL / min; Temperature: 25 ° C; UV detection: 220 nm.
  • Method 25D Phase: Daicel Chiralpak OD-H, 5 ⁇ 250 mm x 20 mm, eluent: iso-hexane / ethanol 50:50; Flow: 20 mL / min, temperature: 20 ° C; UV detection: 220 nm.
  • Method 26D Phase: Daicel Chiralpak AS-H, 5 ⁇ 250 mm ⁇ 20 mm, eluent: isohexane / ethanol 70:30 + 0.2% diethylamine; Flow: 20 mL / min; Temperature: 20 ° C; UV detection: 220 nm.
  • Method 27D Phase: Daicel Chiralpak AD-H SFC, 5 ⁇ 250 mm x 30 mm, eluent: carbon dioxide / methanol 80:20; Flow: 100 mL / min, step gradient after 3 min for 1.5 min carbon dioxide / methanol 70:30; Makeup flow rate: 30 mL / min, baking pressure: 120 bar; Temperature: 40 ° C; UV detection: 210 nm.
  • Method 28D Phase: Daicel Chiralpak AS-H, 5 ⁇ m, 250 mm ⁇ 20 mm, eluent: 50% iso-hexane, 50% ethanol; Flow: 20 mL / min; Temperature: 25 ° C; Detection: 220 nm.
  • Method 29D Phase: Daicel Chiralpak OD-H, 5 ⁇ m, 250 mm ⁇ 4 mm, eluent: 95% iso-hexane, 5% ethanol + 1% diethylamine; Flow: 20 mL / min; Temperature: 40 ° C; Detection: 220 nm.
  • Method 30D Phase: Daicel Chiralpak AZ-H, 5 ⁇ m, 250 mm ⁇ 30 mm, eluent: 10% iso-hexane, 90% ethanol + 0.2% diethylamine; Flow: 40 mL / min; Temperature: 20 ° C; Detection: 220 nm.
  • Method 31D Phase: Daicel Chiralpak OD-H, 5 ⁇ m, 250 mm ⁇ 20 mm, eluent: 95% iso-hexane, 5% ethanol; Flow: 20 mL / min; Temperature: 40 ° C; Detection: 220 nm.
  • Method 32D Phase: Daicel Chiralpak AD-H, 5 ⁇ , 250 mm ⁇ 4 mm, eluent: 50% iso-hexane, 50% ethanol / isopropanol, 0.2% diethylamine; Flow: 1 mL / min; Temperature: 40 ° C; Detection: 230 nm.
  • Method 33D Phase: Daicel Chiralpak AS-H, 5 ⁇ m, 250 mm ⁇ 20 mm, eluent: 70% iso-hexane, 30% ethanol / isopropanol, 0.2% diethylamine; Flow: 20 mL / min; Temperature: 40 ° C; Detection: 230 nm.
  • Method 34D Phase: Daicel Chiralpak OZ-H, 5 ⁇ , 250 mm x 20 mm, eluent: 30% iso-hexane, 70% ethanol with 0.2% diethylamine; Flow: 15 mL / min; Temperature: 40 ° C; Detection: 220 nm.
  • Method 35D Phase: Daicel Chiralpak AS-H, 5 ⁇ m, 250 mm ⁇ 20 mm, eluent: 65% isohexane, 35% ethanol with 0.2% diethylamine; Flow: 20 mL / min; Temperature: 25 ° C; Detection: 220 nm.
  • Method 36D Phase: Daicel Chiralpak AS-H, 5 ⁇ m, 250 mm ⁇ 20 mm, eluent: 50% iso-hexane, 50% isopropanol; Flow: 20 mL / min; Temperature: 25 ° C; Detection: 220 nm.
  • Method 37D Phase: Daicel Chiralpak AS-H, 5 ⁇ m, 250 mm ⁇ 20 mm, eluent: 50% iso-hexane, 50% ethanol; Flow: 20 mL / min; Temperature: 25 ° C; Detection: 230 nm.
  • Method IE Phase: Daicel Chiralcel OZ-H, 5 ⁇ 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 50:50; Flow: 1 mL / min; Temperature: 30 ° C; UV detection: 220 nm.
  • Method 2E Phase: Daicel Chiralcel AZ-H, 5 ⁇ 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 50:50; Flow: 1 mL / min; Temperature: 30 ° C; UV detection: 220 nm.
  • Method 3E Phase: Daicel Chiralpak AD-H SFC, 5 ⁇ m 250 mm x 4.6 mm; Eluent: carbon dioxide / ethanol 70:30; Flow: 3 mL / min; Temperature: 30 ° C; UV detection: 220 nm.
  • Method 4E Phase: Daicel Chiralpak AD-H, 5 ⁇ 250 mm x 4.6 mm, eluent: iso-hexane / isopropanol 50:50; Flow: 1 mL / min; Temperature: 30 ° C; UV detection: 220 nm.
  • Method 5E Phase: LUX amylose-2, 5 ⁇ 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 90:10; Flow: 1 mL / min; Temperature: 30 ° C; UV detection: 220 nm.
  • Method 6E Phase: Daicel Chiralpak AS-H, 5 ⁇ 250 mm x 4.6 mm, eluent: iso-hexane / isopropanol 50:50; Flow: 1 mL / min; Temperature: 30 ° C; UV detection: 220 nm.
  • Method 7E Phase: Daicel Chiralcel OD-H, 5 ⁇ 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 80:20 + 0.2% diethylamine; Flow: 1 mL / min; Temperature: 40 ° C; UV detection: 220 nm.
  • Method 8E Phase: Daicel Chiralpak AD-H, 5 ⁇ 250 mm x 4.6 mm, eluent: iso-hexane / ethanol 50:50; Flow: 1 mL / min; Temperature: 30 ° C; UV detection: 220 nm.
  • Method 9E Phase: Daicel Chiralcel OZ-H, 5 ⁇ 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 50:50; Flow: 1 mL / min; Temperature: 40 ° C; UV detection: 220 nm.
  • Method 10E Phase: Daicel Chiralcel OD-H, 5 ⁇ 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 50:50; Flow: 1 mL / min; Temperature: 30 ° C; UV detection: 220 nm.
  • Method 11E Phase: Daicel Chiralpak AD-H SFC, 5 ⁇ 250 mm x 4.6 mm; Eluent: carbon dioxide / ethanol 70:30; Flow: 4 mL / min; Temperature: 30 ° C; UV detection: 220 nm.
  • Method 12E Phase: Daicel Chiralcel AD-H, 5 ⁇ 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 50:50 + 0.2% diethylamine; Flow: 1 mL / min; Temperature: 40 ° C; UV detection: 220 nm.
  • Method 13E Phase: Daicel Chiralpak OD-H, 5 ⁇ 250 mm x 4.6 mm, eluent: iso-hexane / isopropanol 50:50; Flow: 1 mL / min; Temperature: 25 ° C; UV detection: 220 nm.
  • Method 14E Phase: Daicel Chiralpak IC, 5 ⁇ m 250 mm ⁇ 4.6 mm, eluent: ieri-butyl methyl ether / methanol 50:50; Flow: 1 mL / min; Temperature: 30 ° C; UV detection: 220 nm.
  • Method 15E Phase: Daicel Chiralpak AY-H, 5 ⁇ 250 mm x 4.6 mm, eluent: iso-hexane / ethanol 50:50; Flow: 1 mL / min; Temperature: 45 ° C; UV detection: 220 nm.
  • Method 16E Phase: Daicel Chiralcel AZ-H, 5 ⁇ 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 90:10; Flow: 1 mL / min; Temperature: 30 ° C; UV detection: 220 nm.
  • Method 17E Phase: Daicel Chiralpak AS-H, 5 ⁇ 250 mm x 4.6 mm, eluent: iso-hexane / ethanol 90:10; Flow: 1 mL / min; Temperature: 30 ° C; UV detection: 220 nm.
  • Method 18E Phase: Daicel Chiralcel AZ-H, 5 ⁇ 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 90: 10 + 0.2% diethylamine; Flow: 1 mL / min; Temperature: 40 ° C; UV detection: 230 nm.
  • Method 19E Phase: Daicel IA, 5 ⁇ 250 mm x 4.6 mm; Eluent: ieri-butyl methyl ether / methanol 50:50; Flow: 1 mL / min; Temperature: 30 ° C; UV detection: 220 nm.
  • Method 20E Phase: Daicel Chiralcel AD-H, 5 ⁇ 250 mm x 4.6 mm; Eluent: iso-hexane / isopropanol 50:50 + 0.2% diethylamine; Flow: 1 mL / min; Temperature: 40 ° C; UV detection: 220 nm.
  • Method 2 IE Phase: Daicel Chiralpak IC, 5 ⁇ m 250 mm ⁇ 4.6 mm, eluent: ieri-butyl methyl ether / methanol 50:50; Flow: 1 mL / min; Temperature: 40 ° C; UV detection: 220 nm.
  • Method 22E Phase: Daicel Chiralpak IC, 5 ⁇ 250 mm x 4.6 mm, eluent: acetonitrile / methanol 30:70; Flow: 1 mL / min; Temperature: 30 ° C; UV detection: 220 nm.
  • Method 23E Phase: Daicel Chiralcel OD-H, 5 ⁇ 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 80:20; Flow: 1 mL / min; Temperature: 40 ° C; UV detection: 220 nm.
  • Method 24E Phase: Daicel Chiralcel OZ-H, 5 ⁇ , 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 50:50; Flow: 1 mL / min; Temperature: 30 ° C; UV detection: 220 nm.
  • Method 25E Phase: Daicel Chiralpak AD-H SFC, 5 ⁇ , 250 mm x 4.6 mm; Eluent: carbon dioxide / methanol 70:30; Flow: 3 mL / min; Temperature: 30 ° C; UV detection: 220 nm.
  • Method 26E Phase: Daicel Chiralpak AS-H, 5 ⁇ m, 250 mm ⁇ 4.6 mm, eluent: 50% iso-hexane, 50% ethanol; Flow: 1 mL / min; Temperature: 25 ° C; Detection: 220 nm.
  • Method 27E Phase: Daicel Chiralpak AS-H, 5 ⁇ m, 250 mm ⁇ 4.6 mm, eluent: 30% iso-hexane, 70% ethanol; Flow: 1 mL / min; Temperature: 30 ° C; Detection: 220 nm.
  • Method 28E Phase: Daicel Chiralpak OD-H, 5 ⁇ m, 250 mm ⁇ 4.6 mm, eluent: 95% iso-hexane, 5% ethanol; Flow: 1 mL / min; Temperature: 30 ° C; Detection: 220 nm.
  • Method 29E Phase: Daicel Chiralpak AD-H, 5 ⁇ m, 250 mm ⁇ 4 mm, eluent: 50% isohexane, 50% ethanol / isopropanol, 0.2% diethylamine; Flow: 1 mL / min; Temperature: 40 ° C; Detection: 230 nm.
  • Method 30E Phase: Daicel Chiralpak AS-H, 5 ⁇ m, 250 mm ⁇ 4 mm, eluent: 50% isohexane, 50% ethanol / isopropanol, 0.2% diethylamine; Flow: 1 mL / min; Temperature: 40 ° C; Detection: 230 nm.
  • Method 3 IE Phase: Daicel Chiralpak OZ-H, 5 ⁇ m, 250 mm ⁇ 4.6 mm, eluent: 30% isohexane, 70% ethanol + 0.2% diethylamine; Flow: 1 mL / min; Temperature: 40 ° C; Detection: 230 nm.
  • Method 32E Phase: Daicel Chiralpak AS-H, 5 ⁇ m, 250 mm ⁇ 4.6 mm, eluent: 50% iso-hexane, 50% ethanol with 0.2% diethylamine; Flow: 1 mL / min; Temperature: 40 ° C; Detection: 220 nm.
  • Method 33E Phase: Daicel Chiralpak AS-H, 5 ⁇ m, 250 mm ⁇ 4.6 mm, eluent: 50% iso-hexane, 50% isopropanol with 0.2% diethylamine; Flow: 1 mL / min; Temperature: 40 ° C; Detection: 220 nm.
  • Method 34E Phase: Daicel Chiralpak AS-H, 5 ⁇ m, 250 mm ⁇ 4.6 mm, eluent: 50% iso-hexane, 50% ethanol; Flow: 1 mL / min; Temperature: 30 ° C; Detection: 220 nm. Preparative purification:
  • Method 1F Phase: Sunfire C-18, 5 ⁇ 250 mm x 20 mm, eluent: water / acetonitrile gradient 80: 20-> 5:95, flow: 23.75 mL / min + constant addition of 2% formic acid, flow: 1.25 mL / min; UV detection: 210 nm.
  • Method 2F Phase: Sunfire C-18, 5 ⁇ 250 mm x 20 mm, eluent: water / acetonitrile 50:50 + 1% trifluoroacetic acid in water, flow: 25 mL / min; Temperature: 40 ° C; UV detection: 210 nm.
  • Method 3F Phase: Agilent Prep 100, Xbridge C18, 5 ⁇ 150 mm x 19 mm, eluent: water / acetonitrile 40:60, flow: 23.75 mL / min + constant addition of 2% ammonia solution, flow: 1.25 mL / min ; UV detection: 210 nm.
  • Preparative diastereomer separation on achiral phase Method IG: Phase: Sunfire C-18, 5 ⁇ 250 mm ⁇ 20 mm, eluent: water / methanol 60:40, flow: 60 mL / min, temperature: 23 ° C., UV detection: 210 nm.
  • Method 2G Phase: Sunfire C-18, 5 ⁇ 250 mm x 20 mm, eluent: acetonitrile / water / 1% trifluoroacetic acid in water 65: 30: 5, flow: 56 mL / min; Temperature: 23 ° C; UV detection: 210 nm.
  • Method 3G Phase: Kromasil 100 C-18, 5 ⁇ 250 mm ⁇ 20 mm, eluent: acetonitrile / water / 1% trifluoroacetic acid in water 20:64:16, flow: 23.8 mL / min ; Temperature: 40 ° C; UV detection: 210 nm.
  • the microwave reactor used was a Biotage Initiator Microwave Synthesizer single mode device.
  • the compounds according to the invention can be obtained in salt form, for example as trifluoroacetate, formate or ammonium salt, provided that the compounds according to the invention contain a sufficiently basic or acidic functionality.
  • salt can be converted into the corresponding free base or acid by various methods known to those skilled in the art.
  • the reaction solution was poured into 25% aqueous ammonia solution (100 mL) and then filtered through diatomaceous earth. The filtrate was treated with ieri-butyl methyl ether (200 mL), extracted and, after phase separation, the aqueous phase extracted again with ieri-butylmethyl ether (100 mL). The combined organic phases were dried over sodium sulfate, filtered and im Vacuum concentrated.
  • the crude product was dissolved in diethyl ether / tetrahydrofuran (5: 1, 60 mL) and then treated with 4 N hydrogen chloride solution in 1,4-dioxane (10.0 mL).
  • reaction solution was poured onto 2 M aqueous ammonia solution (4.85 L) and the precipitated salts were filtered off through a frit in vacuo.
  • the filtrate was mixed with ieri-butyl methyl ether (14 L) and water (50 L), extracted and the mixture was then added to the phase separation with 5% aqueous sodium chloride solution. After phase separation, the aqueous phase was re-extracted with tert-butyl methyl ether (5 L) and the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
  • Example 16A 2- ⁇ [(lR) -l- (3-chlorophenyl) ethyl] amino ⁇ -8-methoxy [l, 2,4] triazolo [l, 5-a] pyridine-6-carboxylic acid ieri-butyl ester [ enantiomerically pure isomer]
  • the tube was sealed and the reaction mixture was stirred for 2 h at 90 ° C in the microwave (Biotage Synthesizer).
  • the reaction solution was diluted with dichloromethane (20 mL), washed with 0.5 N aqueous hydrogen chloride solution (20 mL) and the organic phase was concentrated in vacuo.
  • the residue was purified by preparative RP-HPLC (acetonitrile / water). Yield: 34.3 mg (27% of theory).
  • the residue was taken up in acetonitrile and subjected to purification and diastereomer separation directly by preparative RP-HPLC (acetonitrile / water, isocratic).
  • the enantiomerically pure diastereomer 1 (minor isomer) was the compound eluting as the first component. Yield: 2.60 g (10% of theory, enantiomerically pure isomer 1).
  • the enantiomerically pure diastereomer 2 (main isomer) was the compound eluting as the second component. Yield: 9.00 g (35% of theory, enantiomerically pure isomer 2).
  • reaction solution was concentrated in vacuo, taken up in ethyl acetate, washed several times with water, once with 0.4 N aqueous hydrogen chloride solution, once with saturated aqueous sodium bicarbonate solution and again with water.
  • the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. Yield: 27.9 g (93% of theory, diastereomer ratio: about 1: 1).
  • target compound (diastereomer 2, racemate, major isomer): 1.95 g; Minor isomer: 698 mg.
  • Example 81A [1-Amino-3- (benzyloxy) cyclobutyl] methanol [diastereomer mixture, 2 isomers, cis / trans ca.
  • Example 84A [iraws-1-amino-3- (benzyloxy) cyclobutyl] mefhanol hydrochloride [enantiomerically pure trans diastereomer] xHCl
  • Example 112A Enantiomerically pure isomer 1
  • Example 113A enantiomerically pure isomer 2
  • 441 mg of Example 114A enantiomerically pure isomer 3
  • 457 mg of Example 115A enantiomerically pure isomer 4

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Abstract

L'invention concerne des triazolopyridines substituées et des procédés pour leur préparation, ainsi que leur utilisation pour préparer des médicaments destinés au traitement et/ou à la prévention de maladies, en particulier de maladies cardiovasculaires, de préférence de maladies thrombotiques ou thromboemboliques.
EP14728514.2A 2013-06-03 2014-06-02 Triazolopyridines utilisées comme inhibiteurs de la thrombine pour traiter des maladies thromboemboliques Withdrawn EP3004095A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP14728514.2A EP3004095A1 (fr) 2013-06-03 2014-06-02 Triazolopyridines utilisées comme inhibiteurs de la thrombine pour traiter des maladies thromboemboliques

Applications Claiming Priority (3)

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EP13170211 2013-06-03
PCT/EP2014/061307 WO2014195244A1 (fr) 2013-06-03 2014-06-02 Triazolopyridines utilisées comme inhibiteurs de la thrombine pour traiter des maladies thromboemboliques
EP14728514.2A EP3004095A1 (fr) 2013-06-03 2014-06-02 Triazolopyridines utilisées comme inhibiteurs de la thrombine pour traiter des maladies thromboemboliques

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EP (1) EP3004095A1 (fr)
JP (1) JP2016520113A (fr)
CN (1) CN105408331A (fr)
CA (1) CA2914040A1 (fr)
HK (1) HK1222648A1 (fr)
WO (1) WO2014195244A1 (fr)

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WO2019057946A1 (fr) 2017-09-25 2019-03-28 F. Hoffmann-La Roche Ag Composés aromatiques multi-cycliques utilisés en tant qu'inhibiteurs du facteur d
CA3105456A1 (fr) 2018-07-05 2020-01-09 Daiichi Sankyo Company, Limited Compose cyclique fusionne ayant une structure d'uree
WO2023098882A1 (fr) * 2021-12-02 2023-06-08 Beigene, Ltd. Procédés de synthèse de composés de morpholine 3,5-disubstituée chiraux et intermédiaires utiles dans ceux-ci

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US6303625B1 (en) * 1998-07-27 2001-10-16 Ortho-Mcneil Pharmaceutical, Inc. Triazolopyridines for the treatment of thrombosis disorders
DE19962924A1 (de) * 1999-12-24 2001-07-05 Bayer Ag Substituierte Oxazolidinone und ihre Verwendung
DE10220570A1 (de) * 2002-05-08 2003-11-20 Bayer Ag Carbamat-substituierte Pyrazolopyridine
JP2011528337A (ja) * 2008-07-18 2011-11-17 サノフイ−アベンテイス 新規トリアゾロ［４，３−ａ］ピリジン誘導体、これらの調製方法、医薬としてのこれらの使用、医薬組成物および、特にｍｅｔ阻害剤としての、新規使用
TWI453207B (zh) * 2008-09-08 2014-09-21 Signal Pharm Llc 胺基三唑并吡啶，其組合物及使用其之治療方法
WO2013049591A2 (fr) * 2011-09-29 2013-04-04 Verseon Corporation Composés doublement inhibiteurs et procédés d'utilisation de ceux-ci

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HK1222648A1 (zh) 2017-07-07
US20160108039A1 (en) 2016-04-21
JP2016520113A (ja) 2016-07-11
WO2014195244A1 (fr) 2014-12-11
CN105408331A (zh) 2016-03-16
CA2914040A1 (fr) 2014-12-11

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