EP3004086A1 - Substituierte benzoxazole - Google Patents

Substituierte benzoxazole

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Publication number
EP3004086A1
EP3004086A1 EP14727212.4A EP14727212A EP3004086A1 EP 3004086 A1 EP3004086 A1 EP 3004086A1 EP 14727212 A EP14727212 A EP 14727212A EP 3004086 A1 EP3004086 A1 EP 3004086A1
Authority
EP
European Patent Office
Prior art keywords
methyl
hydrogen
substituted
alkyl
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Withdrawn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
EP14727212.4A
Other languages
German (de)
English (en)
French (fr)
Inventor
Swen Allerheiligen
Anja BUCHMÜLLER
Karen Engel
Christoph Gerdes
Kersten Matthias Gericke
Michael Gerisch
Stefan Heitmeier
Alexander Hillisch
Tom KINZEL
Phlip 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
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Pharma AG filed Critical Bayer Pharma AG
Priority to EP14727212.4A priority Critical patent/EP3004086A1/de
Publication of EP3004086A1 publication Critical patent/EP3004086A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to substituted benzoxazoles 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.
  • 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.
  • WO 98/37075 describes, inter alia, benzoxazole derivatives with an amidinobenzylamino substituent as thrombin inhibitors.
  • Amidino-substituted thrombin inhibitors have a short half-life and low oral bioavailability. As such, the compounds are only suitable for parenteral use and must be used as prodrugs when given orally (A. Casimiro-Garcia, DA Dudley, RJ Heemstra, KJ Filipski, CF Bigge, JJ Edmunds, Expert Opin. Ther. 16 (2), 119-145).
  • WO 2007/140982 describes the use of benzoxazoles as thrombin inhibitors.
  • EP-A 0 535 521 describes the use of benzoxazoles as leukotriene biosynthesis inhibitors for the treatment of inflammatory diseases.
  • the invention relates to compounds of the formula
  • R is a group of the formula
  • X represents an oxygen atom, a sulfur atom or CH-R 6 , where 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, trifluoromethoxy and cyclopropyl, in which cyclopropyl may itself be substituted by a hydroxy substituent, or in which alkyl and cycloalkyl may be substituted by from 1 to 3 fluoro substituents,
  • 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 fluorine substituents, R 5 is C 1 -C 4 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 substituent,
  • R 7 is hydrogen or C 1 -C 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 fluoro,
  • R 8 is hydrogen
  • R 9 is hydrogen or Ci-Cö-alkyl, wherein alkyl may be substituted with a substituent selected from
  • R 11 and R 12 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 13 is methyl, ethyl, (3-fluoroazetidin-1-yl) carbonyl, (3,3-difluoroazetidin-1-yl) carbonyl or morpholin-4-ylcarbonyl, wherein methyl and ethyl are substituted with a substituent selected from the group consisting of cyano and hydroxy,
  • R 14 is hydrogen, methoxy, ethoxy or cyclopropyloxy, where methoxy and ethoxy may be substituted by from 1 to 3 substituents selected from the group consisting of deuterium and fluoro,
  • R 15 is hydrogen or methyl
  • R 16 is hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts.
  • Compounds of the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, as well as the compounds 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 of the invention may exist in different stereoisomeric forms depending on their structure, i.
  • the present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
  • the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
  • isotopes used in 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, to study 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;
  • 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 of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid acetic acid, trifluoroacetic acid, propionic acid
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms.
  • alkali metal salts for example sodium and potassium salts
  • alkaline earth salts for example calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms.
  • Atoms such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and choline.
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but during their residence time in the body are converted to compounds of the invention (for example metabolically or hydrolytically).
  • 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, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl Butyl, n-pentyl, isopentyl, 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.
  • the formulas of the group, which may stand for R 1 is the end point of the line, next to each a * is not a carbon atom or a CEh group but is part of the bond to the atom to which R 1 is attached ,
  • 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 hydrogen, GC 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, hydroxycarbonyl, difluoromethoxy and cyclopropyl, in which cyclopropyl in turn be substituted may be substituted with one hydroxy substituent, or wherein alkyl may be substituted with from 1 to 3 fluorine substituents, 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, wherein the cyclobutyl ring may be substituted with a hydroxy, R 4 is hydrogen or GC 4 alkyl, wherein alkyl may be substituted with 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 methoxy substituent, R 8 is hydrogen,
  • R 9 is C 1 -C 4 -alkyl, in which alkyl may be substituted by a substituent selected from the group consisting of cyano and aminocarbonyl,
  • R 10 is hydrogen, R 11 is C 1 -C 4 -alkyl,
  • R 12 is hydrogen or Ci-C - alkyl, or
  • R 11 and R 12 together with the carbon atom to which they are attached form a cyclopropyl ring
  • R 13 is methyl, ethyl, (3-fluoroazetidin-1-yl) carbonyl, (3,3-difluoroazetidin-1-yl) carbonyl or morpholin-4-ylcarbonyl wherein methyl and ethyl are substituted by a substituent selected from the group consisting of cyano and hydroxy,
  • R 14 is hydrogen, ethoxy or cyclopropyloxy, wherein ethoxy may be substituted with 1 to 3 substituents selected from the group consisting of deuterium and fluorine,
  • R 15 is hydrogen or methyl
  • R 16 is hydrogen or methyl
  • 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
  • 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 one Substituents hydroxy, R 3 is hydrogen or methyl,
  • R 4 is hydrogen or methyl
  • R 5 is methyl, or
  • R 2 is methyl or ethyl, wherein methyl or ethyl may be substituted with 1 to 3 substituents fluoro
  • R 3 is hydrogen or methyl
  • R 4 is GC 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 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 9 is methyl or ethyl, in which methyl and ethyl may be substituted by a substituent selected from the group consisting of cyano and aminocarbonyl, 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 methyl, in which methyl is substituted by a hydroxy substituent
  • R 14 is ethoxy or cyclopropyloxy, wherein ethoxy may be substituted with 1 to 3 substituents selected from
  • R 15 is hydrogen
  • R 16 is hydrogen or methyl, and their salts, their solvates and the solvates of their salts.
  • R 2 is C 1 -C 4 -alkyl or cyclobutyl, wherein alkyl is substituted with a hydroxy substituent, and wherein cyclobutyl is substituted with a hydroxy
  • R 3 is hydrogen
  • R 4 is hydrogen or methyl
  • 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 one Substituents hydroxy, and
  • R 5 is methyl, or
  • R: and R 3 together with the carbon atom to which they are attached form a cyclobutyl ring, wherein the cyclobutyl ring is substituted with a substituent hydroxy,
  • R 4 is hydrogen
  • R 5 is methyl
  • R 7 is methyl
  • R 8 is hydrogen
  • R 9 is methyl or ethyl, in which methyl may be substituted by a cyano substituent, R 10 is hydrogen,
  • R 11 is methyl, 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 13 is methyl, in which methyl is substituted by a hydroxy substituent
  • R 14 is ethoxy or cyclopropyloxy, wherein ethoxy may be substituted by 1 to 3 substituents selected from the group consisting of deuterium and fluoro,
  • R 15 is hydrogen
  • R 16 is hydrogen or methyl, 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 where * is the point of attachment to the carbonyl group, 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, trifluoromethoxy and cyclopropyl, in which cyclopropyl may itself be substituted by a hydroxy substituent, or in which alkyl and cycloalkyl may be substituted by from 1 to 3 fluoro substituents,
  • R 3 is hydrogen or C 1 -C 4 -alkyl
  • 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, wherein alkyl may be substituted with a substituent hydroxy, or wherein alkyl may be substituted with 1 to 3 substituents fluoro, R 5 is Ci-C 4 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 Ci-Ce-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 16 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 or CH-R 6 , where R 6 is hydrogen
  • R 2 is hydrogen, GC 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, hydroxycarbonyl, difluoromethoxy and cyclopropyl, in which cyclopropyl in turn be substituted can with one
  • R 2 and R 3 together with the carbon atom to which they are attached form a cyclobutyl ring, wherein the cyclobutyl ring may be substituted with a hydroxy
  • R 4 is hydrogen or GC 4 alkyl, wherein alkyl may be substituted with a substituent hydroxy
  • 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 16 is hydrogen or methyl, 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 2 is C i -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 hydroxy, 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 or 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
  • 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, wherein methyl and ethyl may be substituted by a methoxy substituent, R s is hydrogen, and
  • R 16 is hydrogen or methyl, 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
  • 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 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, 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
  • R 5 is methyl
  • R 7 is methyl
  • R 8 is hydrogen
  • R 16 is hydrogen or methyl, 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 represents an oxygen atom, a sulfur atom or CH-R 6 , where 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, trifluoromethoxy and cyclopropyl, in which cyclopropyl may itself be substituted by a hydroxy substituent, or in which alkyl and cycloalkyl may be substituted by from 1 to 3 fluoro substituents,
  • 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 fluorine substituents, R 5 is C 1 -C 4 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 substituent, and
  • R 16 is hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts.
  • 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 hydrogen, GC 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, hydroxycarbonyl, difluoromethoxy and cyclopropyl, in which cyclopropyl in turn be substituted may be substituted with a hydroxy substituent, or wherein alkyl may be substituted with from 1 to 3 fluoro substituents, hydrogen or GC is t-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 16 is hydrogen or methyl
  • 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 or 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 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 16 is hydrogen or methyl
  • R 1 is a group of the formula
  • X is an oxygen atom
  • R 2 is G-Ci-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 2 is methyl
  • 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, or
  • R : 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 16 is hydrogen or methyl, 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
  • alkyl is substituted with a hydroxy substituent
  • R 3 is hydrogen
  • R 4 is hydrogen or methyl
  • R 5 is methyl
  • R 16 is hydrogen or methyl
  • 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, wherein alkyl is substituted with a hydroxy substituent
  • R 5 is methyl
  • R 16 is hydrogen or methyl, 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
  • 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
  • R 5 is methyl, and R 16 is hydrogen or methyl, 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 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 wherein alkyl may be substituted by 1 to 3 substituents fluoro, R 8 is hydrogen, and R 16 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 * is the point of attachment to the carbonyl group
  • R 7 is C 1 -C 4 -alkyl, in which alkyl may be substituted by a substituent methoxy
  • R 8 is hydrogen
  • R 16 is hydrogen or methyl, 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 7 is methyl or ethyl, in which methyl and ethyl may be substituted by a methoxy substituent
  • R 8 is hydrogen
  • R 16 is hydrogen or methyl
  • R 7 is methyl
  • R 8 is hydrogen
  • R 16 is hydrogen or methyl
  • R 9 is hydrogen or C 1 -C 6 -alkyl, in which alkyl may be substituted by a substituent selected from the group consisting of hydroxy, cyano and aminocarbonyl, 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 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 16 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
  • R 9 is Ci-Gi-alkyl, wherein alkyl may be substituted with a substituent selected from the group consisting of cyano and aminocarbonyl,
  • R 10 is hydrogen
  • R 11 is C 1 -C 4 -alkyl
  • R 12 is hydrogen or GC 4 alkyl, or R 11 and R 12 together with the carbon atom to which they are attached are
  • R 16 is hydrogen or methyl, 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 9 is methyl or ethyl, wherein methyl and ethyl may be substituted with a substituent selected from the group consisting of cyano and aminocarbonyl,
  • R 10 is hydrogen
  • R 11 is methyl, R 12 is hydrogen, or
  • R 11 and R 12 together with the carbon atom to which they are attached form a cyclopropyl ring, and R 16 represents hydrogen or methyl, and their salts, their solvates and the solvates of their salts.
  • R 1 is a group of the formula
  • R 9 is methyl or ethyl, in which methyl may be substituted by a cyano substituent
  • R 10 is hydrogen, R 11 is methyl,
  • R 12 is hydrogen, or
  • R 11 and R 12 together with the carbon atom to which they are attached form a cyclopropyl ring, and R 16 represents hydrogen or methyl, and their salts, their solvates and the solvates of their salts.
  • R 1 is a group of the formula
  • R 13 is methyl, ethyl, (3-fluoroazetidin-1-yl) carbonyl, (3,3-difluoro-azetidin-1-yl) carbonyl or morpholin-4-ylcarbonyl wherein methyl and ethyl are substituted with one substituent selected from Group consisting of cyano and hydroxy,
  • R 14 is hydrogen, methoxy, ethoxy or cyclopropyloxy, where methoxy and ethoxy may be substituted by from 1 to 3 substituents selected from the group consisting of deuterium and fluoro,
  • R 15 is hydrogen or methyl
  • R 16 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
  • R 13 is methyl, ethyl, (3-fluoroazetidin-1-yl) carbonyl, (3,3-difluoro-azetidin-1-yl) carbonyl or morpholin-4-ylcarbonyl wherein methyl and ethyl are substituted with one substituent selected from Group consisting of cyano and hydroxy,
  • R 14 is hydrogen, ethoxy or cyclopropyloxy, where ethoxy may be substituted by 1 to 3 substituents selected from the group consisting of deuterium and fluorine,
  • R 15 is hydrogen or methyl
  • R 16 is hydrogen or methyl, 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 13 is methyl, in which methyl is substituted by a hydroxy substituent
  • R 14 is ethoxy or cyclopropyloxy, where ethoxy may be substituted by 1 to 3 substituents selected from deuterium and fluoro group,
  • R is hydrogen
  • R 16 is hydrogen or methyl, and their salts, their solvates and the solvates of their salts.
  • R 1 and R 15 are as defined above. It is also preferable
  • the invention further provides a process for the preparation of the compounds of the formula (I), or their salts, their solvates or the solvates of their salts, where the compounds of the formula
  • R-- H ( ⁇ ), in which R 1 has the meaning given above, be reacted with Dehydratmaschinesreagenzien.
  • 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.
  • Suitable dehydrating reagents for this purpose are, for example, carbodiimides, such as e.g.
  • 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 or 4-dimethylaminopyridine.
  • Triethylamine N-methylmorpholine, N-methylpiperidine
  • 4-dimethylaminopyridine or diisopropylethylamine preferred is diisopropylethylamine or 4-dimethylaminopyridine.
  • Preference is given to the combination of HATU and diisopropylethylamine or N- ⁇ -dimethylamino-isopropyl-N'-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine.
  • EDC
  • 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, dimethylformamide being preferred.
  • 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, dimethylformamide being preferred.
  • the compounds of the formula ( ⁇ ) 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 compound of the formula (II) is known or can be prepared by reacting the compounds of the formula
  • R 17 is methyl or ethyl, are reacted with a base.
  • 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.
  • 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 17 is methyl or ethyl, with compounds of the formula
  • R has the meaning given above, be reacted in the presence of a base.
  • the reaction is generally carried out in inert solvents, preferably in a temperature range from room temperature to the reflux of the solvent at atmospheric pressure.
  • 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.
  • thrombin As a key enzyme at the end of the coagulation cascade, thrombin translates the impulses from the cascade into the coagulation status of the blood via a series of reactions.
  • the conversion of fibrinogen to insoluble fibrin leads to fibrin clot formation, which is stabilized by the factor XHIa, which is also activated by thrombin.
  • TAFI thrombin-activatable fibrinolysis inhibitor
  • TAFIa thrombin inhibits the dissolution of the clot in the complex with thrombomodulin.
  • Activation of the factors V and Vin leads to the potentiation of thrombin production and thus to the enhancement of the Clotting reaction.
  • thrombin is a potent trigger of platelet aggregation (via PAR-1 activation), which also makes a significant contribution to hemostasis.
  • 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
  • acute, intermittent or persistent cardiac arrhythmias such as atrial fibrillation, and those undergoing cardioversion
  • 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. Due to the observed synergistic effects with ly therapeutic principles such as the tissue plasminogen activator (tPA), the compounds for adjuvant use in a thrombolytic therapy.
  • tissue plasminogen activator tPA
  • 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 be prevented by the compounds according to the invention and therefore the probability of a thrombotic complication can be decisively 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 occur in the May be present in the context of 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.
  • 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
  • pulmonary embolisms stroke and / or thrombosis prophylaxis
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using a therapeutically effective amount of a compound of the invention.
  • Another object of the present invention are the compounds of the invention for use in a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using a therapeutically effective amount of a compound of the invention.
  • Another object of the present invention are pharmaceutical compositions containing a compound of the invention and one or more other active ingredients.
  • 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, for example, lovastatin (Mevacor), simvastatin (Zocor), pravastatin
  • HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors
  • lovastatin Mevacor
  • simvastatin Zocor
  • ACE angiotensin converting enzyme
  • captopril lisinopril
  • enalapril ramipril
  • cilazapril benazepril
  • fosinopril quinapril and perindopril
  • 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, pindo
  • 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 such as heparin (UFH), low molecular weight heparin (LMWH) such as tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, danaparoid, semuloparin (AVE 5026), adomiparin (M118) and EP-42675 / ORG42675; Direct thrombin inhibitors (DTI) such as Pradaxa (Dabigatran), Atecegatran (AZD-0837), DP-4088, SSR-182289 A, argatroban, bivalirudin and Tanogitran (BIBT-986 and prodrug BIBT-1011), hirudin;
  • DTI Direct thrombin inhibitors
  • Direct factor Xa inhibitors such as rivaroxaban, apixaban, edoxaban (DU-176b), betrixaban (PRT-54021), R-1663, darexaban (YM-150), otamixaban (FXV-673 / RPR-130673), letaxaban ( TAK-442), razaxaban (DPC-906), DX-9065a, LY-517717, idraparinux and fondaparinux;
  • platelet aggregation-inhibiting substances such as acetylsalicylic acid (such as aspirin), Ticlopidine (Ticlid), Clopidogrel (Plavix), Prasugrel, Ticagrelor, Cangrelor, Elinogrel, Vorapaxar;
  • Fibrinogen receptor antagonists such as abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban and fradafiban; Recombinant human activated protein C such as Xigris;
  • the present invention further relates to the combination of a compound of this invention with 5-chloro-A r - ( ⁇ (5 l R 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
  • 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.
  • parenteral administration can be done bypassing a resorption step (eg intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with the involvement of a Absorption (eg intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • a resorption step eg intravenous, intraarterial, intracardiac, intraspinal or intralumbar
  • a Absorption eg intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal.
  • suitable application forms include injection and infusion 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 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 for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecylsulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odoriferous include, among others.
  • Excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl
  • 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 1A Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 ⁇ 50 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 2A Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 ⁇ 30 x 2 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A -> 1.2 min 5% A -> 2.0 min 5% A; 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 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 4A Instrument MS: Waters (Micromass) Quattro Micro; Instrument HPLC: Agilent 1 100 series; Column: YMC-Triart C18 3 ⁇ 50 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 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 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 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 liter of water + 0.01 mol Ammonium carbonate, eluent B: 1: 1 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 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 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 Instrumeit: Waters ZQ 2000; Electrospray ionization; 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; 25% A, 75% B; Flow: 0.25 ml / min.
  • Method 1D Phase: Daicel Chiralpak AZ-H, 5 ⁇ 250 mm x 30 mm, eluent: iso-hexane / 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 ⁇ 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 ⁇ m 250 mm ⁇ 30 mm, eluent: isohexane / 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 ⁇ 20 mm, eluent: isohexane / 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 ⁇ 250 mm x 20 mm, eluent: iso-hexane / 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 / in-propanol 50:50 + 0.2% diethylamine; Flow: 20 ml / min; Temperature: 20 ° C; UV detection: 230 nm.
  • Method 14D Phase: Daicel Chiralpak OD-H, 5 ⁇ m 250 mm ⁇ 20 mm, eluent: isohexane / 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 ⁇ 250 mm x 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 / in-propanol 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 / in-propanol 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 ⁇ 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 AD-H, 5 ⁇ 250 mm x 20 mm, eluent: iso-hexane / ethanol 30:70; Flow: 20 ml / min, temperature: 40 ° C; UV detection: 210 nm.
  • Method 29D Phase: Daicel Chiralcel AD-H, 5 ⁇ 250 mm x 20 mm; Eluent: iso-hexane / ethanol 50:50; Flow: 20 ml / min; Temperature: 40 ° C; UV detection: 210 nm.
  • Method 30D Phase: Daicel Chiralpak AS-H, 5 ⁇ 250 mm x 20 mm, eluent: iso-hexane / ethanol 50:50; Flow: 20 ml / min, temperature: 35 ° C; UV detection: 230 nm.
  • Method 31D Phase: Daicel Chiralcel AD-H, 5 ⁇ 250 mm x 20 mm; Eluent: iso-hexane / ⁇ -propanol 50:50; Flow: 20 ml / min; Temperature: 25 ° C; UV detection: 230 nm.
  • Method 32D Phase: Daicel Chiralpak OD-H, 5 ⁇ 250 mm x 20 mm, eluent: iso-hexane / w-propanol 80:20; Flow: 20 ml / min, temperature: 25 ° C; UV detection: 220 nm.
  • Method 33D Phase: Daicel Chiralpak AY-H, 5 ⁇ m 250 mm ⁇ 20 mm, eluent: isohexane / w / propanol 50:50 + 0.2% diethylamine; Flow: 15 ml / min, temperature: 40 ° C; UV detection: 220 nm.
  • Method 34D Phase: Daicel Chiralcel AD-H, 5 ⁇ 250 mm x 20 mm; Eluent: iso-hexane / ⁇ -propanol 50:50; Flow: 20 ml / min; Temperature: 20 ° C; UV detection: 220 nm.
  • Method 35D Phase: Daicel Chiralpak OZ-H, 5 ⁇ 250 mm x 20 mm, eluent: iso-hexane / ethanol 50:50; Flow: 20 ml / min, temperature: 25 ° C; UV detection: 220 nm.
  • Method 36D Phase: Daicel Chiralcel AD-H, 5 ⁇ 250 mm x 20 mm; Eluent: ethanol + 0.2% acetic acid / acetonitrile + 0.2% acetic acid 90:10; Flow: 20 ml / min; Temperature: 25 ° C; UV detection: 230 nm.
  • Method 37D Phase: Daicel Chiralpak ID, 5 ⁇ 250 mm ⁇ 20 mm, eluent: ieri-butyl methyl ether / methanol 70:30; Flow: 20 ml / min, temperature: 25 ° C; UV detection: 230 nm.
  • Method 38D Phase: Daicel Chiralcel AZ-H, 5 ⁇ 250 mm x 20 mm; Eluent: iso-hexane / n-propanol 50:50 + 0.2% diethylamine; Flow: 20 ml / min; Temperature: 45 ° C; UV detection: 220 nm.
  • Method 39D Phase: Daicel Chiralpak ID, 5 ⁇ 250 mm x 20 mm, eluent: ieri-butyl methyl ether / methanol 70:30; Flow: 20 ml / min, temperature: 20 ° C; UV detection: 230 nm.
  • Method 40D Phase: Daicel Chiralcel AZ-H, 5 ⁇ m 250 mm ⁇ 40 mm; Eluent: ethanol; Flow: 13 ml / min; Temperature: 45 ° C; UV detection: 220 nm.
  • Method 41D Phase: Daicel Chiralcel AD-H, 5 ⁇ 250 mm x 20 mm; Eluent: iso-hexane / n-propanol 50:50 + 0.2% diethylamine; Flow: 20 ml / min; Temperature: 25 ° C; UV detection: 220 nm.
  • Method 42D Phase: Daicel Chiralpak OZ-H, 5 ⁇ 250 mm x 20 mm, eluent: isohexane ethanol 30:70 + 0.2% diethylamine; Flow: 15 ml / min, temperature: 40 ° C; UV detection: 220 nm.
  • Method 43D Phase: Daicel Chiralcel OD-H, 5 ⁇ 250 mm x 40 mm; Eluent: iso-hexane / in-propanol 90: 10 + 0.2% diethylamine; Flow: 20 ml / min; Temperature: 25 ° C; UV detection: 220 nm.
  • Method 44D Phase: Daicel Chiralcel AZ-H, 5 ⁇ 250 mm x 40 mm; Eluent: iso-hexane / ethanol 80:20 + 0.2% diethylamine; Flow: 20 ml / min; Temperature: 25 ° C; UV detection: 220 nm.
  • Method 45D Phase: Daicel Chiralpak AZ-H, 5 ⁇ 250 mm x 20 mm, eluent: iso-hexane / ethanol 70:30; Flow: 20 ml / min, temperature: 40 ° C; UV detection: 220 nm.
  • Method 46D Phase: Daicel Chiralpak OZ-H, 5 ⁇ m 250 mm ⁇ 20 mm, eluent: isohexane / ethanol 25:75; Flow: 15 ml / min, temperature: 40 ° C; UV detection: 220 nm.
  • Method 47D Phase: Daicel Chiralpak IC, 5 ⁇ 250 mm x 20 mm, eluent: ieri-butyl methyl ether / methanol 50:50; Flow: 20 ml / min, temperature: 30 ° C; UV detection: 220 nm.
  • Method 48D Phase: Daicel IA, 5 ⁇ 250 mm x 40 mm; Eluent: ieri-butyl methyl ether / methanol 50:50; Flow: 20 ml / min; Temperature: 30 ° C; UV detection: 220 nm.
  • Method 49D 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 50D Phase: Daicel Chiralpak IC, 5 ⁇ , 250 mm x 20 mm, eluent: 50% iso-hexane, 50% ethanol; Flow: 15 ml / min; Temperature: 40 ° C; Detection: 220 nm.
  • Method 51D Phase: Daicel Chiralpak OD-H, 5 ⁇ m, 250 mm ⁇ 4 mm, eluent: 95% isohexane, 5% ethanol + 1% diethylamine; Flow: 20 ml / min; Temperature: 40 ° C; Detection: 220 nm.
  • Method 52D Phase: Daicel Chiralpak AZ-H, 5 ⁇ m, 250 mm x 30 mm, eluent: 10% iso-hexane, 90% ethanol + 0.2% diethylamine; Flow: 40 ml / min; Temperature: 20 ° C; Detection: 220 nm.
  • Method 53D 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 54D Phase: Daicel Chiralpak IC, 5 ⁇ m, 250 mm ⁇ 20 mm, eluent: 70% acetonitrile, 30% methanol with 0.2% diethylamine; Flow: 15 ml / min; Temperature: 45 ° C; Detection: 220 nm.
  • Method 55D Phase: Daicel Chiralpak OD-H, 5 ⁇ m, 250 mm ⁇ 20 mm, eluent: 70% iso-hexane, 30% ethanol with 2% diethylamine; Flow: 20 ml / min; Temperature: 25 ° C; Detection: 220 nm.
  • Method 56D Phase: Daicel Chiralpak OD-H, 5 ⁇ m, 250 mm ⁇ 20 mm, eluent: 50% isohexane, 50% ethanol with 0.2% diethylamine; Flow: 15 ml / min; Temperature: 40 ° C; Detection: 220 nm.
  • Method 57D Phase: Daicel Chiralpak OD-H, 5 ⁇ m, 250 mm ⁇ 20 mm, eluent: 50% iso-hexane, 50% ethanol; Flow: 20 ml / min; Temperature: 25 ° C; Detection: 220 nm.
  • Method 58D Phase: Daicel Chiracel OZ-H, 5 ⁇ , 250 mm x 20 mm, eluent: 50% iso-hexane, 50% iso-ethanol; Flow: 15 ml / min; Temperature: 40 ° C; Detection: 220 nm.
  • Method 59D Phase: Daicel Chiralpak IC-H, 5 ⁇ m, 250 mm ⁇ 20 mm, eluent: 50% tert-butyl methyl ether, 50% methanol; Flow: 20 ml / min; Temperature: 25 ° C; Detection: 220 nm.
  • Method 60D Phase: Daicel Chiracel OD-H, 5 ⁇ m, 250 mm ⁇ 20 mm, eluent: 70% iso-hexane, 30% isopropanol; Flow: 20 ml / min, temperature: 25 ° C; Detection: 220 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 ⁇ 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 ⁇ 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 ⁇ 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 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 / in-propanol 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 AD-H, 5 ⁇ 250 mm x 4.6 mm, eluent: iso-hexane / ethanol 30:70; Flow: 1 ml / min, temperature: 40 ° C; UV detection: 220 nm.
  • Method 27E Phase: Daicel Chiralpak AD-H, 5 ⁇ m 250 mm ⁇ 4.6 mm, eluent: isohexane / ethanol 50:50; Flow: 1 ml / min, temperature: 40 ° C; UV detection: 220 nm.
  • Method 28E Phase: Daicel Chiralpak AS-H, 5 ⁇ 250 mm x 4.6 mm, eluent: iso-hexane / ⁇ -propanol 50:50; Flow: 1 ml / min, temperature: 40 ° C; UV detection: 220 nm.
  • Method 29E Phase: Daicel Chiralpak OD-H, 5 ⁇ 250 mm x 4.6 mm, eluent: iso-hexane where propanol 80:20; Flow: 1 ml / min, temperature: 30 ° C; UV detection: 220 nm.
  • Method 30E Phase: Daicel Chiralpak AY-H, 5 ⁇ 250 mm x 4.6 mm, eluent: iso-hexane wo- Propanol 50:50; Flow: 1 ml / min, temperature: 40 ° C; UV detection: 220 nm.
  • Method 3 IE Phase: Daicel Chiralpak AD-H, 5 ⁇ 250 mm x 4.6 mm, eluent: iso-hexane / ⁇ -propanol 50:50; Flow: 1 ml / min, temperature: 25 ° C; UV detection: 230 nm.
  • Method 32E Phase: Daicel Chiralcel AD-H, 5 ⁇ 250 mm x 4.6 mm; Eluent: ethanol + 0.2% acetic acid / acetonitrile + 0.2% acetic acid 90:10; Flow: 1 ml / min; Temperature: 25 ° C; UV detection: 230 nm.
  • Method 33E Phase: Daicel Chiralpak ID, 5 ⁇ 250 mm ⁇ 4 mm, eluent: ieri-butyl methyl ether / methanol 70:30; Flow: 1 ml / min, temperature: 40 ° C; UV detection: 220 nm.
  • Method 34E Phase: Daicel Chiralcel AZ-H, 5 ⁇ 250 mm x 4.6 mm; Eluent: iso-hexane / in-propanol 50:50 + 0.2% diethylamine; Flow: 1 ml / min; Temperature: 45 ° C; UV detection: 220 nm.
  • Method 35E Phase: Daicel Chiralpak ID, 5 ⁇ 250 mm ⁇ 4 mm, eluent: ieri-butyl methyl ether / methanol 70:30; Flow: 1 ml / min, temperature: 30 ° C; UV detection: 220 nm.
  • Method 36E Phase: Daicel Chiralcel AZ-H, 5 ⁇ 250 mm x 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Temperature: 45 ° C; UV detection: 220 nm.
  • Method 37E Phase: Daicel Chiralpak OZ-H, 5 ⁇ 250 mm x 4.6 mm, eluent: isohexane / ethanol 30:70 + 0.2% diethylamine; Flow: 1 ml / min, temperature: 40 ° C; UV detection: 230 nm.
  • Method 38E Phase: Daicel Chiralcel OD-H, 5 ⁇ 250 mm x 4.6 mm; Eluent: iso-hexane / in-propanol 90: 10 + 0.2% diethylamine; Flow: 1 ml / min; Temperature: 25 ° C; UV detection: 220 nm.
  • Method 39E Phase: Daicel Chiralpak AZ-H, 5 ⁇ 250 mm x 4.6 mm, eluent: iso-hexane / ethanol 70:30; Flow: 1 ml / min, temperature: 30 ° C; UV detection: 220 nm.
  • Method 40E Phase: Daicel Chiralpak OZ-H, 5 ⁇ 250 mm ⁇ 4.6 mm, eluent: iso-hexane / ethanol 25:75; Flow: 1 ml / min, temperature: 40 ° C; UV detection: 220 nm.
  • Method 4 IE Phase: Daicel Chiralpak OZ-H, 5 ⁇ 250 mm x 4.6 mm, eluent: iso-hexane / ethanol 20:80; Flow: 1 ml / min, temperature: 40 ° C; UV detection: 220 nm.
  • Method 42E 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 43E Phase: Daicel Chiralpak IC, 5 ⁇ , 250 mm x 4.6 mm, eluent: 50% iso-hexane, 50% ethanol; Flow: 1 ml / min; Temperature: 40 ° C; Detection: 220 nm.
  • Method 44E Phase: Daicel Chiralpak AS-H, 5 ⁇ , 250 mm x 4.6 mm, eluent: 30% iso-hexane, 70% ethanol; Flow: 1 ml / min; Temperature: 30 ° C; Detection: 220 nm.
  • Method 45 E 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 46E Phase: Daicel Chiralpak IC, 5 ⁇ m, 250 mm ⁇ 4.6 mm, eluent: ethanol + 0.2% diethylamine; Flow: 1 ml / min; Temperature: 45 ° C; Detection: 235 nm.
  • Method 47E Phase: Daicel Chiralpak OD-H, 5 ⁇ m, 250 mm ⁇ 4 mm, eluent: 50% iso-hexane, 50% ethanol + 0.2% diethylamine; Flow: 1 ml / min; Temperature: 40 ° C, detection: 220 nm.
  • Method 48E Phase: Daicel Chiralpak OD-H, 5 ⁇ m, 250 mm ⁇ 4 mm, eluent: 50% iso-hexane, 50% ethanol + 0.2% diethylamine; Flow: 1 ml / min; Temperature: 40 ° C; Detection: 220 nm.
  • Method 49E Phase: Daicel Chiralpak OD-H, 5 ⁇ , 250 mm x 4.6 mm, eluent: 50% iso-hexane, 50% ethanol; Flow: 1 ml / min; Temperature: 30 ° C; Detection: 220 nm.
  • Method 50E Phase: Daicel Chiralpak OZ-H, 5 ⁇ , 250 mm x 4.6 mm, eluent: 60% iso-hexane, 40% ethanol; Flow: 1 ml / min; Temperature: 30 ° C; Detection: 220 nm.
  • Method 5 IU Phase: Daicel Chiralpak IC-H, 5 ⁇ m, 250 mm ⁇ 4.6 mm, eluent: 50% tert-butyl methyl ether, 50% methanol; Flow: 1 ml / min; Temperature: 30 ° C; Detection: 220 nm.
  • Method 52E Phase: Daicel Chiralpak OD-H, 5 ⁇ , 250 mm x 4.6 mm, eluent: 70% iso-hexane, 30% iso-propanol, flow: 1 ml / min; Temperature: 30 ° C; Detection: 220 nm.
  • 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 30:70; Flow: 25 ml / min; Temperature: 24 ° C; UV detection: 210 nm.
  • Method 3F Phase: Sunfire C-18, 5 ⁇ 250 mm x 20 mm, eluent: water / methanol / 1% ammonia in water 32: 60: 8; Flow: 25 ml / min; Temperature: 25 ° C; UV detection: 210 nm.
  • Method 4F Phase: Shield C-18, 5 ⁇ 100 mm x 190 mm, water / methanol / 1% trifluoroacetic acid in water 48:40:12; Flow: 23.8 ml / min; Temperature: 40 ° C; UV detection: 210 nm.
  • Method 5F Phase: Shield C-18.5 ⁇ 100 mm x 190 mm, water / acetonitrile Gradient 90: 10 ⁇ 5:95; Flow: 25 ml / min; Temperature: 23 ° C; UV detection: 210 nm.
  • Method 6F Phase: X-Bridge C-18.5 ⁇ 150 mm x 19 mm, eluent: water / acetonitrile gradient 95: 5-> 5:95, flow: 23.75 ml / min + constant Addition of 2% ammonia in water; Flow: 1.25 ml / min; Temperature: 23 ° C; UV detection: 210 nm.
  • Method 7F Phase: Daiso C-18 Bio, 10 ⁇ 300 mm x 100 mm, eluent: water, 0.1% TFA / acetonitrile isocratic 20:80; Flow: 250 ml / min; Temperature: 20 ° C; UV detection: 210 nm.
  • Method 8F Phase: Kromasil 100 C18, 5 ⁇ m, 250 mm ⁇ 20 mm, eluent: 24% water, 70% methanol; Flow: 23.75 ml / min, addition of 6% 1% trifluoroacetic acid with 1.25 ml / min flow; Temperature: 40 ° C; Detection: 210 nm.
  • Method IG Phase: Sunfire C-18.5 ⁇ 250 mm x 20 mm, eluent: water / methanol 60:40, flow: 60 ml / min, temperature: 23 ° C, UV detection: 210 nm.
  • Method 2G Phase: Sunfire C18, 5 ⁇ , 150 mm x 19 mm, eluent: 60% water, 40% methanol; from 10.00 min 23% water, 77% methanol, from 10.10 min 60% water, 40% methanol; Flow: 23.75 ml / min, addition of 0.1% 2% formic acid with 1.25 ml / min flow; Temperature: 25 ° C; Detection: 220 nm.
  • Method 3G Phase: Sunfire C18, 5 ⁇ , 250 mm x 20 mm, eluent: 65% water, 35% acetonitrile; Flow: 23.75 ml / min, addition of 0.1% 2% trifluoroacetic acid with 1.25 ml / min flow; Temperature: 23 ° C; Detection: 210 nm.
  • Microwave A single-mode Biotage Initiator Microwave Synthesizer was used as the microwave reactor.
  • 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 reaction mixture was cautiously treated with water, the phases were separated and the aqueous phase extracted with dichloromethane. The collected organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo.
  • the crude product (2.40 g) was dissolved in A ⁇ N-dimethylformamide (10 ml) under argon at RT to a 0.5 N solution of lithium cyanide in A ⁇ N-dimethylformamide (20 ml, 10 mmol). The reaction mixture was first stirred at RT overnight, then stirred at 60 ° C. for a further night and then at 80 ° C. for 2 d.
  • the reaction solution was concentrated in vacuo and the residue was taken up in ethyl acetate and water. After separation of the phases, the aqueous phase was extracted twice with ethyl acetate. The collected organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo.
  • the crude product was purified by means of two preparative RP-HPLC (acetonitrile / water + 0.1% formic acid). Yield: 430 mg (14% of theory over two stages).
  • the target compound is described as a racemate in the Zhu patent, Gui-Dong et al., US 20060229289, 2006, but with sodium hexamethyldisilazide solution.
  • reaction solution was diluted with ethyl acetate, washed three times with water, once with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution.
  • organic phase was dried over sodium sulfate, filtered and concentrated in vacuo.
  • the crude product obtained was purified by flash chromatography on silica gel (cyclohexane / ethyl acetate 7: 3 - 1: 1). Yield: 2.55 g (40% of theory).
  • reaction solution was then carefully added dropwise into saturated aqueous sodium bicarbonate solution, the phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
  • the crude product was taken up in tetrahydrofuran (40.0 ml) and admixed with 15.5 ml (15.5 mmol) of tetra-w-butylammonium fluoride solution (1.0 M in tetrahydrofuran). It was stirred overnight at RT and then the reaction solution was concentrated in vacuo.
  • reaction solution was diluted with ethyl acetate, washed once with water, three times with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution.
  • organic phase was dried over sodium sulfate, filtered and concentrated in vacuo.
  • the resulting crude product was purified by flash chromatography on silica gel (cyclohexane / ethyl acetate 20: 1 - 1: 1). Yield: 2.22 g (68% of theory).
  • Example 58A 1- [4-Benzyl-5- (fluoromethyl) -2-methylmorpholin-2-yl] -propan-2-ol Trifluoroacetate [diastereomer 1, 2 isomers + diastereomer 2, 2 isomers + diastereomer 3, 2 isomers + diastereomer 4 , 2 isomers]
  • reaction solution was taken up in ethyl acetate and diluted with water. After separation of the phases, the organic phase was washed with 1 N aqueous sodium sulfite solution (2 ⁇ 400 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 23.6 g of crude product.
  • Enantiomerically pure isomer 1 was eluted as a first compound. Yield: 1.34 g (28% of theory, enantiomerically pure isomer 1). Enantiomerically pure isomer 2 was eluted as a second compound. Yield: 2.28 g (47% 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).
  • reaction mixture was admixed with saturated aqueous ammonium chloride solution and extracted with ethyl acetate.
  • the collected organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo.
  • the crude product was purified by preparative RP-HPLC (acetonitrile / water). Yield: 3.68 g (43% of theory).

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