EP2079708A2 - Acylaminoimidazoles et acylaminothiazoles - Google Patents

Acylaminoimidazoles et acylaminothiazoles

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Publication number
EP2079708A2
EP2079708A2 EP07818862A EP07818862A EP2079708A2 EP 2079708 A2 EP2079708 A2 EP 2079708A2 EP 07818862 A EP07818862 A EP 07818862A EP 07818862 A EP07818862 A EP 07818862A EP 2079708 A2 EP2079708 A2 EP 2079708A2
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EP
European Patent Office
Prior art keywords
substituents
alkyl
substituted
group
phenyl
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Withdrawn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
EP07818862A
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German (de)
English (en)
Inventor
Marcus Bauser
Anja BUCHMÜLLER
Georges Von Degenfeld
Elke Dittrich-Wengenroth
Christoph Gerdes
Mark Jean Gnoth
Dirk Gottschling
Stefan Heitmeier
Martin Hendrix
Johannes KÖBBERLING
Dieter Lang
Ulrich Rester
Uwe Saatmann
Adrian Tersteegen
Astrid BRÜNS
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Bayer AG
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Bayer Healthcare AG
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Publication of EP2079708A2 publication Critical patent/EP2079708A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to acylaminoimidazoles and acylaminothiazoles and to processes for their preparation and to their use for the production of medicaments for the treatment and / or prophylaxis of diseases, in particular of cardiovascular diseases, preferably of thromboembolic diseases.
  • Blood clotting is a protective mechanism of the organism that can quickly and reliably "seal" defects in the blood vessel wall, thus preventing or minimizing blood loss, and bleeding after vascular injury is essentially through the coagulation system, which involves an enzymatic cascade It involves numerous clotting factors, each of which, once activated, converts the next inactive precursor to its active form, transforming the soluble fibrinogen into the insoluble fibrin at the end of the cascade Traditionally, a distinction is made in the blood clotting between the intrinsic and the extrinsic system, which result in a final common pathway, where the active enzyme Factor Xa is formed from the ptsoenzyme factor X.
  • the activated serine protease Xa cleaves prothromb
  • the resulting thrombin in turn splits fibrinogen into fibrin.
  • Subsequent cross-linking of the fibrin monomers leads to the formation of blood clots and thus to haemostasis.
  • thrombin is a potent trigger of platelet aggregation via the proteolytic activation of platelet receptors, which also makes a significant contribution to hemostasis.
  • Other functions of thrombin that contribute to blood coagulation are the stabilization of the fibrin clot via the activation of factor XIII, the enhancement of the coagulation reaction via the activation of cofactors V and VIII, and the inhibition of fibrinolysis via the activation of procarboxypeptidase B (syn. TAFI ).
  • proteolytic activation of the protein C thrombin can counteract an excessive activity of the coagulation cascade and thus an excessive hemostasis (thrombosis)
  • Hemostasis is subject to a complex regulatory mechanism.
  • An uncontrolled activation of the coagulation system or a defective inhibition of the activation processes can cause the formation of local thromboses or embolisms in vessels (arteries, veins, lymphatics) or cardiac cavities. This can lead to serious thromboembolic diseases.
  • hypercoagulability - systemically - in a consumption coagulopathy can lead to disseminated intravascular coagulation.
  • thromboembolic Complications also occur in microangiopathic hemolytic anemias, extracorporeal blood circuits, such as hemodialysis, and heart valve prostheses.
  • Thromboembolic disorders are the most common cause of morbidity and mortality in most industrialized countries [Heart Disease: A Textbook of Cardiovascular Medicine, Eugene Braunwald, 5th Ed., 1997, W.B. Saunders Company, Philadelphia].
  • heparin is used, which is administered parenterally or subcutaneously. Due to more favorable pharmacokinetic properties, although increasingly low molecular weight heparin is nowadays increasingly preferred; However, this also the known disadvantages described below can not be avoided, which consist in the therapy with heparin. Thus, heparin is orally ineffective and has only a comparatively low half-life. Since heparin simultaneously inhibits several factors of the blood coagulation cascade, there is an unselective effect.
  • a second class of anticoagulants are the vitamin K antagonists. These include, for example, 1,3-indandiones, but especially compounds such as warfarin, phenprocoumon, dicumarol and other coumarin derivatives, which are unsuitable for the synthesis of various products of certain vitamin K-dependent coagulation factors in the liver. Due to the mechanism of action, the effect is only very slow (latency until the onset 36 to 48 hours). Although the compounds can be administered orally, due to the high risk of bleeding and the narrow therapeutic index, a complex individual adjustment and observation of the patient is necessary [J. Hirsh, J.
  • An object of the present invention is therefore to provide novel compounds as thrombin inhibitors for the treatment of cardiovascular diseases, in particular of thromboembolic diseases, in humans and animals, which have a large therapeutic range.
  • WO 2005/092864 describes structurally similar imidazole derivatives and their use for the treatment of neurodegenerative and neurological diseases, such. Alzheimer's.
  • WO 02/053161 describes the use of imidazole and thiazole derivatives for the treatment of fibrotic diseases.
  • the invention relates to compounds of the formula
  • X is NH or S, - A -
  • R 1 is phenyl or 5- or 6-membered heteroaryl
  • phenyl and heteroaryl may be substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, Ci-C 4 alkyl, Ci-C 4 alkoxy, -C 4 alkylamino, C r C 4 -alkylthio and C r C 4 alkylcarbonyl,
  • R 2 is phenyl or 5- or 6-membered heteroaryl
  • phenyl and heteroaryl may be substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, Ci-C 4 alkyl, Ci-C 4 alkoxy, C r C 4 alkylamino, C r C 4 -alkylthio and C r C 4 alkylcarbonyl,
  • R 3 is hydrogen or methyl
  • R 4 is C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl or C 3 -C 6 -cycloalkyl,
  • alkyl and alkenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, amino carbonyl, CpC 4 alkoxy, Ci-C 4 -Alkylamino and C 3 -C 6 -cycloalkyl,
  • R 3 and R 4 are joined together and, with the atoms to which they are attached, form a pyrrolidine ring or a 1,3-thiazolidine ring,
  • substituents where the substituents are independently selected from the group consisting of halogen, hydroxy, amino, CpC 4 alkyl, C 2 -C 4 alkenyl, Ci-C 4 - alkoxy and C r C 4 alkylamino,
  • R 5 is hydrogen, halogen, hydroxy, amino, C, -C 6 alkyl, C r C 6 alkoxy, C r C 6 - alkylamino, CpC ö alkylcarbonyloxy, Ci-Q-alkylcarbonylamino or 5- to 7-membered
  • alkyl and alkylamino may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, amino, Hydroxycarbonyl, Ci-C ö alkylamino, C] -C 4 -alkoxycarbonyl and 5- to 7-membered heterocyclyl,
  • heterocyclyl may in turn be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, oxo,
  • heterocyclyl can be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxyl, amino, cyano, nitro, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C 1 -C 4 -alkyl, QC 4 -alkoxy, C] -C 4 alkylamino, Ci-C 4 - alkylthio, Ci-C4-alkylcarbonyl, Ci-C 4 alkoxycarbonyl, Ci-C4-alkylcarbonylamino, Cp
  • R 4 and R 5 are joined together and form a pyrrolidinone ring with the atoms to which they are attached
  • pyrrolidinone ring may be substituted with 1 to 2 substituents, wherein the
  • Substituents independently of one another are selected from the group consisting of hydroxy, amino, QQ-alkyl, Cj-C 4 -alkoxy and C] -C 4 -alkylamino,
  • R 6 is phenyl, 5- or 6-membered heteroaryl or 5-7-membered heterocyclyl
  • phenyl and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of
  • heterocyclyl can be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxyl, amino, cyano, nitro, oxo, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, CpC 4 -
  • R 5 and R 6 are joined together and together with the carbon atom to which they are attached form a group of the formula
  • R 7 and R 8 are joined together and together with the carbon atom to which they are attached form a cyclopentane ring or cyclohexane ring,
  • cyclopentane ring and the cyclohexane ring may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, C 1 - C 4 alkyl, C r C 4 - Alkoxy and C] -C 4 alkylamino,
  • R 3 and R 5 are not both simultaneously attached to R 4 and
  • 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 of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
  • the present invention encompasses all tautomeric forms.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. 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 are those forms of the compounds according to the invention which, in solid or liquid state, are characterized by coordination with solvents. complex molecules form a complex. 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 which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically).
  • Alkylcarbonyloxy, alkylaminocarbonyl, alkylsulfonyh, alkylsulfinyl, alkoxycarbonyl and alkoxycarbonylamino are a linear or branched alkyl radical having 1 to 6, preferably 1 to 4, carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl, n-butyl , tert-butyl, n-pentyl and n-hexyl.
  • Alkenyl represents a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms. Preference is given to a straight-chain or branched alkenyl radical having 2 to 4, particularly preferably 2 to 3, carbon atoms. Examples which may be mentioned are: vinyl, allyl, n-prop-1-en-1-yl and n-but-2-en-1-yl.
  • Alkoxy is exemplary and preferably methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy and tert-butoxy.
  • Alkylamino is an alkylamino radical having one or two (independently selected) alkyl substituents, by way of example and by preference methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-N-propylamino, N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn Hexyl-N-methyl-amino.
  • C 1 -C 3 -alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkyla
  • Alkylthio is exemplified and preferably methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.
  • Alkylcarbonyl is exemplified and preferably methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-burylcarbonyl and tert-butylcarbonyl.
  • Alkylcarbonylamino is, by way of example and by way of preference, methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino and tert-butylcarbonylamino.
  • Alkylcarbonyloxy is by way of example and preferably methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, iso-propylcarbonyloxy, n-butylcarbonyloxy and tert-butylcarbonyloxy.
  • Alkylaminocarbonyl is an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents, by way of example and by preference for methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N, N-dimethylaminocarbonyl, NN- Diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-N-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-Nn-pentylaminocarbonyl and Nn-hexyl-N-
  • C 1 -C 3 -alkylaminocarbonyl is, for example, a monoalkylamino-carbonyl radical having 1 to 3 carbon atoms or a dialkylaminocarbonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.
  • Alkylsulfonyl is exemplified and preferably methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl and tert-butylsulfonyl.
  • Alkylsulfinyl is exemplified and preferably methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, iso-propylsulfinyl, n-butylsulfinyl and tert-butylsulfinyl.
  • Alkoxycarbonyl is exemplified and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
  • Alkoxycarbonylamino is by way of example and preferably methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino, tert-butoxycarbonylamino, n-pentoxycarbonylamino and n-hexoxycarbonylamino.
  • Cycloalkyl represents a monocyclic cycloalkyl group having usually 3 to 6, preferably 3, 5 or 6 carbon atoms, by way of example and preferably cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Heterocyclyl is a monocyclic, heterocyclic radical having usually 5 to 7, preferably 5 or 6 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series ⁇ , O, S, SO, SO 2 , wherein a nitrogen atom can also form a ⁇ -oxide.
  • the heterocyclyl radicals may be saturated or partially unsaturated.
  • Heteroaryl is an aromatic, monocyclic radical having 5 or 6 ring atoms and up to 4, preferably up to 2 heteroatoms from the series S, O and N, where a nitrogen atom can also form an N-oxide, by way of example and preferably for thienyl, furyl , Pyrrolyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl.
  • Halogen is fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
  • radicals in the compounds of the formula (I), their salts, their solvates or the solvates of their salts are substituted
  • the radicals may, unless otherwise specified, be monosubstituted or polysubstituted or differently substituted. Substitution with up to three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.
  • X is NH or S
  • R 1 is phenyl, pyridyl or pyrimidyl
  • phenyl, pyridyl and pyrimidyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, Ci-Q-alkyl, C r C 4 alkoxy, C, -C 4 alkylamino, C r C 4 -alkylthio and C r C 4 alkylcarbonyl,
  • R 2 is phenyl, thienyl, furyl, thiazolyl, oxazolyl or imidazolyl,
  • phenyl, thienyl, furyl, thiazolyl, oxazolyl and imidazolyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, Ci-C 4 alkyl and Ci-C 4 alkoxy,
  • R 3 is hydrogen
  • R 4 is C r C 6 -alkyl or C 3 -C 6 -cycloalkyl, wherein alkyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, Ci-C 4 alkoxy, Ci-C 4 alkylamino and C 3 -C 6 cycloalkyl .
  • R 3 and R 4 are joined together and form a pyrrolidine ring with the atoms to which they are attached
  • pyrrolidine ring may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of C r C 4 alkyl and C r C 4 alkoxy,
  • R 5 is hydrogen, halogen, hydroxy, amino, C r C 6 alkyl, C, -C 6 alkoxy, C 1 -C 6 - alkylamino, Q-COE-alkylcarbonyloxy, Cj-C ⁇ alkylcarbonylamino, morpholinyl, thiomorpholinyl or 4- (C 1 -C 4 -alkyl) piperazinyl,
  • alkyl and alkylamino may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxy, amino, hydroxycarbonyl, C 1 -C 6 -alkylamino, CpC 4 -alkoxycarbonyl, pyrrolidinyl, piperidinyl,
  • pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl may in turn be substituted with 1 to 2 substituents where the substituents are independently selected from the group consisting of C r C 4 alkyl and C, -C 4 alkoxy,
  • R 4 and R 5 are joined together and form a pyrrolidinone ring with the atoms to which they are attached
  • pyrrolidinone ring may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of
  • R 6 is phenyl, tetrahydrofuranyl, pyranyl, piperidinyl or thiopyranyl,
  • phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, Hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, Ci-C 4 alkyl, C r C 4 - alkoxy, Ci-C4-alkylcarbonylamino, C) -C 4 -alkylaminocarbonyl and Ci-C 4 - alkoxycarbonylamino,
  • tetrahydrofuranyl, pyranyl, piperidinyl and thiopyranyl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, hydroxy, amino, cyano, oxo, hydroxycarbonyl, aminocarbonyl, C 1 -C 4 -alkyl, C] -C 4 alkoxy, Ci-C 4 alkyl carbonylamino, Ci-C4-alkylaminocarbonyl and Ci-C4-alkoxycarbonylamino,
  • R 5 and R 6 are joined together and together with the carbon atom to which they are attached form a group of the formula
  • R 7 and R 8 are joined together and together with the carbon atom to which they are attached form a cyclohexane ring
  • R 3 and R 5 are not both simultaneously attached to R 4 and
  • X is NH or S
  • R 1 is phenyl or pyridyl
  • phenyl and pyridyl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of halogen and methoxy,
  • R 2 is phenyl or thienyl
  • phenyl and thienyl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of fluorine, chlorine and bromine,
  • R 3 is hydrogen
  • R 4 is iso-propyl
  • R 3 and R 4 are joined together and form a pyrrolidine ring with the atoms to which they are attached
  • pyrrolidine ring may be substituted with 1 to 2 substituents methyl
  • R 5 is hydrogen, dQ-alkyl or C, -C 4 -alkoxy
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, hydroxycarbonyl and QC 4 - alkoxycarbonyl,
  • R 4 and R 5 are joined together and form a pyrrolidinone ring with the atoms to which they are attached
  • pyrrolidinone ring may be substituted with 1 to 2 substituents methyl
  • R 6 is phenyl or 4-pyranyl
  • phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen,
  • R 5 and R 6 are joined together and together with the carbon atom to which they are attached form a group of the formula
  • R 7 and R 8 are joined together and together with the carbon atom to which they are attached form a cyclohexane ring
  • R 3 and R 5 are not both simultaneously attached to R 4 and
  • R 2 is phenyl or thienyl, where phenyl and thienyl may be substituted by a substituent fluorine or chlorine.
  • R 5 is hydrogen or C 1 -C 4 -alkyl, where alkyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxy and hydroxycarbonyl.
  • R is phenyl, where phenyl may be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of halogen, hydroxy and C 1 -C 4 -alkoxy ,
  • R 6 is phenyl
  • phenyl may be substituted by 2 substituents methoxy or by a substituent methoxy and by a substituent chlorine.
  • the invention further provides a process for the preparation of the compounds of the formula (I), wherein the process
  • R 5 and R 6 have the abovementioned meaning
  • Y 1 is halogen, preferably chlorine, bromine or iodine, or hydroxy
  • R 3 , R 4 , R 5 and R 6 have the abovementioned meaning
  • Y 2 is halogen, preferably chlorine, bromine or iodine, or hydroxy
  • reaction according to process [A] and process [B] is carried out, if Y 1 or Y 2 is halogen, generally in inert solvents, in the presence of a base, preferably in a temperature range from 0 0 C to 40 0 C at atmospheric pressure.
  • Inert solvents are, for example, halohydrocarbons, such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents, such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile, preferably tetrahydrofuran or methylene chloride.
  • halohydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane
  • ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane
  • other solvents such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile, preferably tetrahydrofuran or methylene chloride.
  • bases are alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsiryl) amide or lithium diisopropylamide, or other bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, preferred is diisopropylethylamine.
  • alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butoxide
  • amides such as sodium amide, lithium bis (trimethylsiryl) amide or lithium diisopropylamide, or other bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, preferred is diisopropylethylamine.
  • reaction according to process [A] and process [B] is carried out, if Y 1 or Y 2 is hydroxy, generally in inert solvents, in the presence of dehydrating reagents, optionally in the presence of a base, preferably in a temperature range from 0 0 C to Room temperature at normal pressure.
  • Suitable dehydrating reagents for this purpose are, for example, carbodiimides, such as e.g. N, N-diethyl, N, N'-dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-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-1,2-oxazolium-3-sulfate or 2 tert-butyl 5-methylisoxazolium perchlorate, or acyla
  • 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.
  • the condensation is carried out with diisopropylethylamine.
  • Inert solvents are, for example, halohydrocarbons, such as dichloromethane or trichloromethane, hydrocarbons, such as benzene, nitromethane, dioxane, dimethylformamide, acetone and the like. nitrile or hexamethylphosphoric triamide. It is likewise possible to use mixtures of the solvents. Particularly preferred is dichloromethane or dimethylformamide.
  • the compounds of the formula (III) are known or can be synthesized by known methods from the corresponding starting compounds.
  • the compounds of formula (FV) are known or can be synthesized by known methods from the corresponding starting compounds.
  • the preparation of the aminoimidazoles is described, for example, by Cook, et al. J. Chem. Soc., 1949, 1074-1076 and Bador, et al. J. Chem. Soc., 1950, 2775-2780.
  • the compounds of formula (V) are known or can be synthesized by known methods from the corresponding starting compounds. Among others, peptide couplings and alkylations are used.
  • Y 3 is halogen, preferably iodine, bromine or chlorine,
  • R 4 has the meaning given above
  • reaction is generally carried out in inert solvents, in the presence of a base, preferably in a temperature range from 0 0 C to 40 0 C at atmospheric pressure.
  • Inert solvents are, for example, halohydrocarbons, such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents, such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile, preferably tetrahydrofuran or methylene chloride.
  • halohydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane
  • ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane
  • other solvents such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile, preferably tetrahydrofuran or methylene chloride.
  • bases are alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or other bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, preferred is diisopropylethylamine
  • the compounds of formula (VII) are known or can be synthesized by known methods from the corresponding starting compounds.
  • the compounds of the formula (VI) are known or can be prepared by combining compounds of the formula (IV) with compounds of the formula
  • R 3 has the meaning given above
  • Y 3 is halogen, preferably iodine, bromine or chlorine, and
  • Y 4 is halogen, preferably iodine or bromine, or hydroxy
  • the compounds of formula (VIII) are known or can be synthesized by known methods from the corresponding starting compounds.
  • the amines (II) can also be prepared by reductive amination of the primary amines with a suitable ketone or aldehyde.
  • the primary amines are thereby obtained by acylation of the aminoimidazoles (FV), the primary amine function being protected during the acylation with a suitable protecting group, such as a Boc group, which is cleaved after reaction according to the reaction conditions known to those skilled in the art.
  • Preferred acylating agents are the N-protected amino acids, which are activated using a coupling reagent.
  • the compounds of the invention show an unpredictable, valuable pharmacological and pharmacokinetic activity spectrum. These are compounds which influence the proteolytic activity of the serine protease thrombin.
  • the compounds of the invention inhibit the enzymatic cleavage of substrates that play an essential role in the activation of blood coagulation and aggregation of platelets. 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, preferably of thromboembolic diseases and / or thromboembolic complications.
  • thromboembolic disorders include in particular diseases such as acute coronary syndrome (ACS), heart attack with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI), stable angina pectoris, unstable Angina pectoris, reocclusions and restenoses after coronary interventions such as angioplasty, stent or aortocoronary bypass, peripheral arterial occlusive diseases, pulmonary embolism, venous thrombosis, especially in deep leg veins and renal veins, transient ischemic attacks, and thrombotic and thromboembolic stroke.
  • ACS acute coronary syndrome
  • STEMI heart attack with ST segment elevation
  • non-STEMI non-STEMI
  • stable angina pectoris unstable Angina pectoris
  • reocclusions reocclusions and restenoses after coronary interventions
  • peripheral arterial occlusive diseases such as angioplasty, stent or aortocoronary bypass, peripheral arterial occlusive diseases, pulmonary embolism,
  • the compounds according to the invention are therefore also suitable for the prevention and treatment of cardiogenic thromboembolisms, such as, for example, brain ischemia, stroke and systemic thromboembolisms and ischaemias, in patients with acute, intermittent or persistent cardiac arrhythmias, such as, for example, atrial fibrillation, and those who become one
  • cardiogenic thromboembolisms such as, for example, brain ischemia, stroke and systemic thromboembolisms and ischaemias
  • acute, intermittent or persistent cardiac arrhythmias such as, for example, atrial fibrillation
  • the compounds of the invention are suitable for the treatment of disseminated intravascular coagulation (DIC).
  • DIC disseminated intravascular coagulation
  • Thromboembolic complications also occur in microangiopathic hemolytic anemias, extracorporeal blood circuits such as hemodialysis, and heart valve prostheses.
  • the compounds according to the invention also have an influence on wound healing, for the prophylaxis and / or treatment of atherosclerotic vascular diseases and inflammatory diseases such as rheumatic diseases of the locomotor system, coronary heart diseases, cardiac insufficiency, hypertension, inflammatory diseases such as asthma, inflammatory lung diseases, Glomerulonephritis and inflammatory bowel diseases into consideration, moreover, also for the prophylaxis and / or treatment of Alzheimer's disease.
  • atherosclerotic vascular diseases and inflammatory diseases such as rheumatic diseases of the locomotor system, coronary heart diseases, cardiac insufficiency, hypertension, inflammatory diseases such as asthma, inflammatory lung diseases, Glomerulonephritis and inflammatory bowel diseases into consideration, moreover, also for the prophylaxis and / or treatment of Alzheimer's disease.
  • the compounds of the present invention can inhibit tumor growth and metastasis, in microangiopathies, age-related macular degeneration, diabetic retinopathy, diabetic nephropathy and other microvascular diseases and in the prevention and treatment of thromboembolic complications such as venous thromboembolism in tumor patients, especially those undergoing major surgery or chemo- or radiotherapy.
  • the compounds of the invention may also be used to prevent coagulation ex vivo, e.g. for the preservation of blood and plasma products, for the cleaning / pre-treatment of catheters and other medical aids and devices, for the coating of artificial surfaces of in vivo or ex vivo used medical aids and devices or for biological samples containing platelets.
  • Another object of the present invention is the use of the erf ⁇ ndungswashen compounds 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.
  • compositions containing a compound of the invention and one or more other active ingredients are pharmaceutical compositions containing a compound of the invention and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
  • suitable combination active ingredients may be mentioned by way of example and preferably:
  • lipid-lowering drugs in particular HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) - reductase inhibitors;
  • Coronary / vasodilators especially angiotensin converting enzyme (ACE) inhibitors; AII (angiotensin II) receptor antagonists; beta-adrenoceptor antagonists; alpha-1-adrenoceptor antagonists; diuretics; Calcium channel blockers; Substances that cause an increase in cyclic guanosine monophosphate (cGMP), such as soluble guanylate cyclase stimulators;
  • ACE angiotensin converting enzyme
  • AII angiotensin II receptor antagonists
  • beta-adrenoceptor antagonists beta-adrenoceptor antagonists
  • alpha-1-adrenoceptor antagonists diuretics
  • Calcium channel blockers Substances that cause an increase in cyclic guanosine monophosphate (cGMP), such as soluble guanylate cyclase stimulators;
  • Plasminogen activators thrombolytics / fibrinolytics
  • thrombolysis / fibrinolysis enhancing compounds such as plasminogen activator inhibitor (PAI inhibitor) inhibitors or thrombin-activated fibrinolysis inhibitor inhibitors (TAFI inhibitors); • anticoagulant substances (anticoagulants);
  • antiplatelet agents platelet aggregation inhibitors, platelet aggregation inhibitors
  • Fibrinogen receptor antagonists (glycoprotein IIb / IIIa antagonists);
  • Chemotherapeutic agents of malignant tumors such as anti-metabolites, alkylating cytostatic drugs, topoisomerase inhibitors, mitosis inhibitors and cytostatic antibiotics, hormones, hormone antagonists, other cytotoxic drugs (antibodies, kinase inhibitors, cytokines).
  • Another object of the present invention is a method for preventing blood coagulation in vitro, especially in blood or biological samples containing platelets, which is characterized in that an anticoagulatory effective amount of the compound of the invention is added.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivae otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • Tablets uncoated or coated tablets, for example, with enteric or delayed-dissolving or insoluble coatings containing the
  • Soft gelatin capsules Soft gelatin capsules
  • dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • the 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
  • involvement of resorption eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • parenteral administration are suitable as application forms, inter alia, 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 1 Instrument: HP 1100 with DAD Detection; Column: Kromasil RP-18, 60 mm ⁇ 2 mm, 3.5 ⁇ m; Eluent A: 5 ml perchloric acid / l water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B, 6.7 min 2% B, 7.5 min 2% B; Flow: 0.75 ml / min; Oven: 30 ° C; UV detection: 210 nm.
  • Method 2 Instrument: HP 1100 with DAD Detection; Column: Kromasil RP-18, 60 mm ⁇ 2 mm, 3.5 ⁇ m; Eluent A: 5 ml perchloric acid / l water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 9 min 90% B, 9.2 min 2% B, 10 min 2% B; Flow: 0.75 ml / min; Oven: 3O 0 C; UV detection: 210 nm.
  • Method 1 Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l 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 90% A ⁇ »2.5 min 30% A -> 3.0 min 5% A -» 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 5O 0 C; UV detection: 210 nm.
  • Method 2 Instrument: Micromass Platform LCZ with HPLC Agilent Series 1 100; Column: Thermo Hypersil GOLD 3 ⁇ 20mm x 4mm; 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 100% A -> 0.2 min 100% A - »2.9 min 30% A -> 3.1 min 10% A -» 5.5 min 10% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C .; UV detection: 208-400 nm.
  • Method 3 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Gemini 3 ⁇ 30 mm x 3.00 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 90% A -> 2.5 min 30% A - »3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 208-400 nm.
  • Method 1 Instrument: Micromass GCT, GC6890; Column: Restek RTX-35, 15 m ⁇ 200 ⁇ m ⁇ 0.33 ⁇ m; constant flow with helium: 0.88 ml / min; Oven: 7O 0 C; Inlet: 25O 0 C; Gradient: 70 0 C, 30 ° C / min ⁇ 310 0 C (3 min hold). starting compounds
  • Reaction solution is stirred for 2 h at room temperature and then acidified with aqueous hydrochloric acid and diluted with aqueous, saturated ammonium chloride solution.
  • the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are over
  • the suspension is stirred for 1 h at -78 0 C and then 2.89 ml (4:05 g, 33.44 mmol) are added dropwise 3-bromoprop-l-ene.
  • the reaction solution is stirred for 2 h at -20 0 C and then treated with aqueous saturated ammonium chloride solution, water and a hexane / diethyl ether mixture.
  • the aqueous phase is extracted twice with a hexane / diethyl ether mixture.
  • the combined organic phases are washed with water and aqueous, saturated sodium chloride solution. After drying, the solvent is removed on a rotary evaporator. Without further purification, 6.33 g (64% of theory) of the desired product are obtained.
  • the organic phase is separated and washed with 1N aqueous sodium hydroxide solution, aqueous 1N hydrochloric acid solution and water. After drying over magnesium sulfate, the solvent is removed and the residue is purified by flash chromatography. The product fractions are combined and concentrated to dryness. 5.18 g (58% of theory) of the desired product are obtained.
  • the reaction mixture is stirred for 1 h at -78 0 C and then is added 9.88 ml (13.05 g, 66.89 mmol) of bromoacetic acid tert-butyl ester added.
  • the solution is stirred for 2 h at -2O 0 C and then warmed to room temperature overnight.
  • the aqueous phase is extracted twice with 1: 1 hexane / diethyl ether.
  • the combined organic phases are washed successively with water and aqueous, saturated sodium chloride solution, dried, filtered and finally evaporated in vacuo to dryness.
  • the residue is separated by flash chromatography.
  • the product fractions are combined, the solvent removed and dried under high vacuum. 13.7 g (73% of theory) of the desired product are obtained.
  • reaction mixture is diluted with ethyl acetate and acidified with five percent potassium bisulfate solution until acidic.
  • the organic phase is washed twice more with this and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness in vacuo.
  • the residue is purified by preparative HPLC using a gradient of acetonitrile and water purified. The product fractions are combined and evaporated to dryness in vacuo to give 361 mg (40% of theory) of product.
  • Example 48A 28.7 g (92.0 mmol) of Example 48A is dissolved in 450 ml of toluene. Then 20.5 g (50.6 mmol) of Lawesson's reagent are added and the solution is stirred at 90 ° C. for 3 h. After two flashes column-chromatic purification on silica gel (cyclohexane / toluene 1: 1) to obtain 21.1 g (70% of theory) of the product.
  • the aminoimidazole of the following table is prepared analogously to Example 2A.
  • reaction solution is taken up in 500 ml of diethyl ether registered, wherein the conductive salt precipitates as oil and can be separated.
  • the organic phase is washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. This gives 9.00 g (97% of theory) of crude product, which is used without further purification in the next stage.
  • Example 52A A solution of 464 mg (1.68 mmol) of Example 52A in 8 ml of DMF is treated with 424 mg (1.85 mmol) of Example 55A, 704 mg (1.85 mmol) of HATU and 1.2 ml (6.73 mmol) of N, N-diisopropylethylamine. The mixture is then stirred overnight at room temperature. For workup, the reaction mixture is separated directly by preparative HPLC with a gradient of acetonitrile and water. The product-containing fractions are combined and after removal of the solvents in vacuo, they are further purified by preparative HPLC. After the solvents have been spun off from the product-containing fractions, 612 mg (75% of theory) of the product are obtained.
  • reaction mixture After cooling, the reaction mixture is concentrated by rotary evaporation, dissolved with water and acetonitrile and purified by preparative HPLC. The product fractions are combined and evaporated to dryness. For further purification, the product is purified a second time by preparative HPLC. 62 mg (33% of theory) of the desired product are obtained.
  • the solution is diluted with dichloromethane and washed twice with five percent potassium bisulfate solution, dried over sodium sulfate, filtered and concentrated in vacuo to 2 ml.
  • the residue is treated with 0.3 ml of trifluoroacetic acid and diluted after a further 5 min with dichloromethane.
  • the organic phase is washed with 1N sodium hydroxide solution and saturated sodium chloride solution, dried and evaporated to dryness in vacuo.
  • the reaction mixture is separated directly by preparative HPLC with a gradient of acetonitrile and water. The product-containing fractions are combined and evaporated to dryness in vacuo. This gives 12 mg (15% of theory) of the product.
  • Example 25 The examples in the following table are prepared analogously to Example 25 using the appropriate BOC-protected amine 56A and the appropriate carboxylic acid.
  • thrombin inhibition of the substances listed above a biochemical test system is used in which the reaction of a thrombin substrate is used to determine the enzymatic activity of human thrombin. Thrombin separates from the peptic substrate aminomethylcoumarin, which is measured fluorescently. The determinations are carried out in microtiter plates.
  • Substances to be tested are dissolved in various concentrations in dimethylsulfoxide and incubated for 15 min with human thrombin (0.06 nmol / l dissolved in 50 mmol / l Tris buffer [C, C, C-tris (hydroxymethyl) aminomethane], 100 mmol / l NaCl , 0.1% BSA [bovine serum albumin], pH 7.4) at 22 ° C. Subsequently, the substrate (5 .mu.mol / 1 Boc-Asp (OBzl) -Pro-Arg-AMC from Bachern) is added. After incubation for 30 min, the sample is excited at a wavelength of 360 nm and the emission is measured at 460 nm.
  • human thrombin 0.06 nmol / l dissolved in 50 mmol / l Tris buffer [C, C, C-tris (hydroxymethyl) aminomethane], 100 mmol / l NaCl , 0.1% BSA [bo
  • the test substances are tested for their inhibition of other human serine proteases, such as factor Xa, factor XIa, trypsin and plasmin.
  • factor Xa 1.3 nmol / l of Kordia
  • factor XIa 0.4 nmol / l of Kordia
  • trypsin 83 mU / ml of Sigma
  • plasmin 0.1 ⁇ g / ml of Kordia
  • these enzymes become dissolved (50 mmol / l Tris buffer [C, C, C-tris (hydroxymethyl) aminomethane], 100 mmol / l NaCl, 0.1% BSA [bovine serum albumin], 5 mmol / l calcium chloride, pH 7.4) and for 15 min with test substance in various concentrations in dimethyl sulfoxide and with dimethyl sulfoxide without test substance incubated.
  • the enzymatic reaction is then started by adding the appropriate substrates (5 ⁇ mol / 1 Boc-Ile-Glu-Gly-Arg-AMC from Bachern for factor Xa and trypsin, 5 ⁇ mol / 1 Boc-Glu (OBzl) -Ala-Arg).
  • the fluorescence is measured (excitation: 360 nm, emission: 460 nm).
  • the measured emissions of the test mixtures with test substance are compared with the test batches without test substance (excluding dimethylsulfoxide instead of test substance in dimethyl sulfoxide) and IC 50 values are calculated from the concentration-effect relationships.
  • Thrombogram thrombin generation assay according to Hemker
  • Octaplas® from Octapharma
  • the activity of thrombin in clotting plasma is determined by measuring the fluorescent cleavage products of substrate 1-1140 (Z-Gly-Gly-Arg). AMC, Bachern). The reactions are carried out in the presence of varying concentrations of test substance or the corresponding solvent.
  • Reagents from the company Thrombinoscope are used to start the reaction (PPP reagent: 30 pM recombinant tissue factor, 24 ⁇ M phospholipids in HEPES).
  • a Thrombin Calibrator from the company Thrombinoscope is used, whose amidolytic activity is required for calculating the thrombin activity in a sample with an unknown amount of thrombin.
  • the test is carried out according to the manufacturer (Thrombionsocpe BV): 4 .mu.l of the test substance or the solvent, 76 .mu.l of plasma and 20 .mu.l of PPP reagent or thrombin calibrator are incubated at 37 0 C for 5 min. After addition of 20 ⁇ l of 2.5 mM thrombin substrate in 20 mM Hepes, 60 mg / ml BSA, 102 mM CaCl 2 , the thrombin generation is measured for 120 min every 20 s. The measurement is carried out with a fluorometer (Fluoroskan Ascent) from Thermo Electron, which is equipped with a 390/460 nM filter pair and a dispenser.
  • a fluorometer Fluoroskan Ascent
  • the thrombogram is calculated and graphically displayed and the following parameters are calculated: lag time, time to peak, peak, ETP (endogenous thrombin potential) and start tail.
  • the anticoagulant activity of the test substances is determined in vitro in human, rabbit and rat plasma.
  • blood is removed using a 0.11 molar sodium citrate solution as a template in a mixing ratio of sodium citrate / blood 1/9.
  • the blood is mixed well immediately after collection and centrifuged for 15 minutes at approximately 4000 g. The supernatant is pipetted off.
  • the prothrombin time (PT, synonyms: thromboplastin time, quick test) is determined in the presence of varying concentrations of test substance or the corresponding solvent with a commercially available test kit (Neoplastin® from Boehringer Mannheim or Hemoliance® RecombiPlastin from Instrumentation Laboratory). The test compounds are incubated for 3 minutes at 37 ° C. with the plasma. Subsequently, coagulation is triggered by the addition of thromboplastin and the time of coagulation is determined. The concentration of test substance is determined which causes a doubling of the prothrombin time.
  • the thrombin time is determined in the presence of varying concentrations of test substance or the corresponding solvent with a commercially available test kit (Thrombin Reagent from Roche).
  • the test compounds are incubated for 3 minutes at 37 ° C with the plasma. Subsequently, coagulation is triggered by adding the thrombin reagent and determines the time of coagulation.
  • the concentration of test substance is determined which causes a doubling of the thrombin time.
  • the activated partial thromboplastin time is determined in the presence of varying concentrations of test substance or the corresponding solvent with a commercially available test kit (PTT Reagent from Roche).
  • the test compounds are incubated for 3 minutes at 37 ° C with the plasma and the PTT reagent (cephalin, kaolin). Subsequently, coagulation is triggered by addition of 25 mM CaCl 2 and the time of coagulation is determined.
  • the concentration of test substance is determined which causes a doubling of the APTT.
  • the thromboelastography is performed with the help of the thromboelastograph ROTEM from Pentapharm and the associated accessories cup and pin.
  • the measurement is in whole blood, which is previously taken in sodium citrate monovettes Sarstedt.
  • the blood is kept in the monovettes using a shaker in motion and at 37 0 C for 30 min. pre-incubated.
  • 20 ⁇ l of CaCl 2 solution from a 200 mM stock solution (diluted in 0.9% NaCl) are introduced into the cups (final concentration 12.5 mM).
  • Add 3.2 ⁇ l of substance or solvent The measurement is started by adding 300 ⁇ l of whole blood. After the addition, pipette up and down briefly with the pipette tip without creating any air bubbles.
  • CT clotting time / [sec.]
  • CFT clotting formation time / [sec.]
  • MCF maximum clot firmness / [mm]
  • alpha angle [ 0 J. Die Measurement points are collected every 3 seconds and displayed graphically over the y-axis as MCF [mm] and on the x-axis as time [sec].
  • the tail tip of the rats is catered for by 3 mm with a razor blade.
  • the tail is placed in 37 0 C tempered physiological saline and the bleeding from the incision wound observed over 15 minutes.
  • the time to stop the bleeding for at least 30 seconds initial bleeding time
  • the total bleeding time within 15 minutes cumulative bleeding time
  • the amount of blood loss via the photometric determination of the collected hemoglobin are determined.
  • test substances are administered either intravenously via the contralateral jugular vein as a single bolus or as a bolus followed by continuous infusion or orally by means of a gavage, prior to application of the extracorporeal circuit and tail tip incision.
  • the substances according to the invention can be converted into pharmaceutical preparations as follows:
  • Example 1 100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of corn starch, 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Germany) and 2 mg of magnesium stearate.
  • the mixture of the compound of Example 1, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.
  • Example 1 The compound of Example 1 is dissolved together with polyethylene glycol 400 in the water with stirring.
  • the solution is sterile filtered (pore diameter 0.22 microns) and filled under aseptic conditions in heat sterilized infusion bottles. These are closed with infusion stoppers and crimp caps.

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Abstract

L'invention concerne des acylaminoimidazoles et acylaminothiazoles et des procédés de production associés ainsi que leur utilisation pour produire des médicaments destinés au traitement thérapeutique et/ou prophylactique de maladies, notamment de maladies cardio-vasculaires, et de préférence de maladies thromboemboliques.
EP07818862A 2006-10-11 2007-10-10 Acylaminoimidazoles et acylaminothiazoles Withdrawn EP2079708A2 (fr)

Applications Claiming Priority (2)

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DE102006048042A DE102006048042A1 (de) 2006-10-11 2006-10-11 Acylaminoimidazole und Acylaminothiazole
PCT/EP2007/008789 WO2008043533A2 (fr) 2006-10-11 2007-10-10 Acylaminoimidazoles et acylaminothiazoles

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EP2350002A1 (fr) 2008-10-02 2011-08-03 Abbott Laboratories Nouveaux composés utilisés comme bloqueurs des canaux calciques
WO2011115813A1 (fr) 2010-03-18 2011-09-22 Abbott Laboratories Acétamides de lactame en tant que bloqueurs des canaux calciques
JP2015083542A (ja) * 2012-02-08 2015-04-30 大日本住友製薬株式会社 ３位置換プロリン誘導体
IN2014MU00072A (fr) * 2014-01-08 2015-08-21 Wockhardt Ltd
PT3762368T (pt) 2018-03-08 2022-05-06 Incyte Corp Compostos de aminopirazina diol como inibidores de pi3k-y
WO2020010003A1 (fr) 2018-07-02 2020-01-09 Incyte Corporation DÉRIVÉS D'AMINOPYRAZINE UTILISÉS EN TANT QU'INHIBITEURS DE PI3K-γ

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FR2842523A1 (fr) * 2002-07-17 2004-01-23 Sanofi Synthelabo Derives d'acylaminothiazole, leur preparation et leur application en therapeutique
EA011689B1 (ru) * 2004-03-23 2009-04-28 Пфайзер Продактс Инк. Имидазольные соединения для лечения нейродегенеративных расстройств
DE102006001574A1 (de) * 2006-01-12 2007-07-19 Bayer Healthcare Ag Acylaminoimidazole

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JP2010505896A (ja) 2010-02-25
WO2008043533A2 (fr) 2008-04-17
CA2666177A1 (fr) 2008-04-17
WO2008043533A3 (fr) 2008-07-03

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