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EP1648447A1 - Pyrazolines utilisees comme antagonistes par-1 pour traiter des maladies cardio-vasculaires - Google Patents

Pyrazolines utilisees comme antagonistes par-1 pour traiter des maladies cardio-vasculaires

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Publication number
EP1648447A1
EP1648447A1 EP04740582A EP04740582A EP1648447A1 EP 1648447 A1 EP1648447 A1 EP 1648447A1 EP 04740582 A EP04740582 A EP 04740582A EP 04740582 A EP04740582 A EP 04740582A EP 1648447 A1 EP1648447 A1 EP 1648447A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
cyano
cycloalkyl
aryl
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Withdrawn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
EP04740582A
Other languages
German (de)
English (en)
Inventor
Swen Allerheiligen
Dirk Brohm
Nicole Diedrichs
Britta-Nicole FRÖHLEN
Christoph Gerdes
Mark Jean Gnoth
Heike Heckroth
Walter Hübsch
Elisabeth Perzborn
Elke Stahl
Verena Vöhringer
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 AG
Original Assignee
Bayer Healthcare AG
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Filing date
Publication date
Priority claimed from DE102004010545A external-priority patent/DE102004010545A1/de
Application filed by Bayer Healthcare AG filed Critical Bayer Healthcare AG
Publication of EP1648447A1 publication Critical patent/EP1648447A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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
    • 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
    • C07D403/14—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 three or more hetero rings
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • PYRAZOLINE AS A PAR-1 ANTAGONIST FOR THE TREATMENT OF HEART CIRCULAR DISEASES
  • the present invention relates to the field of blood coagulation.
  • the present invention relates in particular to the use of pyrazolines as medicaments, new pyrazolines 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 thromboembolic diseases ,
  • Platelets are an important factor both in physiological hemostasis (hemostasis) and in thromboembolic disorders. In the arterial system in particular, platelets are of central importance in the complex interaction between 10 blood components and the wall of the vessel. Undesired thrombocyte activation can lead to thromboembolic disorders and thrombotic complications with life-threatening conditions through the formation of platelet-rich thrombi.
  • thrombocytes 15 endothelial cells and mesenchymal cells
  • Vu TKH Hung DT
  • Wheaton VI Coughlin SR
  • Thrombin inhibitors inhibit platelet aggregation or the formation of platelet-rich thrombi on platelets in vitro and in animal models.
  • arterial thrombosis can be successfully treated with inhibitors of platelet function as well as inhibitors of platinum (Bhatt DL, Topol EJ, Nat. Rev. Drug Discov. 2003, 20 2, 15-28).
  • thrombin effects on platelets reduce thrombus formation and the occurrence of clinical consequences such as heart attack and stroke.
  • Other cellular thrombin effects e.g. on vascular endothelial and smooth muscle cells, leukocytes and fibroblasts, may be responsible for inflammatory and proliferative diseases.
  • thrombin The cellular effects of thrombin are mediated, at least in part, by a family of G protein-coupled receptors (Protease Activated Receptors, PARs), the prototype of which is the PAR-1 Rezeppr.
  • PAR-1 is activated by binding thrombin and proteolytic cleavage of its extracellularly located N-terminus. Proteolysis exposes a new N-terrinin with the amino acid sequence SFLLR ... which, as an agonist ("tethered ligand”), leads to intramolecular receptor activation and transmission of intracellular signals.
  • Peptides derived from the tethered ligand sequence can act as agonists of the receptor and are used on platelets for activation and aggregation.
  • Antibodies and other selective PAR-1 antagonists inhibit thrombin-induced platelet aggregation in vitro at low to medium thrombin concentrations (Kahn ML, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR, J. Clin. Luvest. 1999, 103, 879-887).
  • Another thrombin receptor with possible significance for the pathophysiology of thrombotic processes, PAR-4 was identified on human and animal platelets.
  • PAR-1 antagonists reduce the formation of platelet-rich thrombi (Derian CK, Damiano BP, Addo MF, Darrow AL, D'Andrea MR, Nedelman M, Zhang HC, Maryanoff BE, Andrade-Gordon P, J. Pharmacol. Exp. Ther. 2003, 304, 855-861).
  • An object of the present invention is therefore to develop new PAR-1 antagonists for the treatment of cardiovascular diseases, such as e.g. to provide thromboembolic disorders in humans and animals.
  • EP-A 466 408, EP-A 438 690, EP-A 532 918 and WO 93/24463 describe structurally similar pyrazoline derivatives and their use as pesticides.
  • WO 02/00651 describes pyrazoline derivatives as factor Xa inhibitors for the treatment of thromboembolic disorders.
  • the present invention relates to compounds of the formula
  • E represents methylene, MI, an oxygen atom or a sulfur atom
  • n 0, 1, 2 or 3
  • n 1, 2 or 3
  • R 9 represents (QC -alkyl, (C 3 -C 7 ) -cycloalkyl, (C 6 -C ⁇ 0 ) -aryl, (C 3 -C 7 ) -cycloalkylmethyl or (C6-C 10 ) -arylmethyl,
  • X is the linkage site to the pyrazoline ring, for R 3, or (C 1 -C 8) alkylene-R 4, where alkylene having 1 to 4 fluorine atoms may be substituted, Y is R 3 or (C, -C 8 ) -Alkylene-R 4 , where alkylene can be substituted with 1 to 4 fluorine atoms,
  • R 5 represents optionally fluorine-substituted alkyl, (C 6 -C ⁇ 0) -aryl, benzyl, (C 3 -C 7) - cycloalkyl or alkylcarbonyl, where aryl, benzyl or cycloalkyl may be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, oxo, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, alkoxy, alkylamino, aryl, benzyl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylamino carbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl,
  • R 6 represents hydroxyl, amino, alkyl, alkylamino, alkoxy, (C 6 -C ⁇ 0 ) aryl, benzyloxy or 5- to 10-membered heterocyclyl, where aryl or benzyloxy can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, oxo, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, alkoxy, alkylamino , Aryl, benzyl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl,
  • R 7 represents hydrogen, alkyl or benzyl
  • R 8 represents hydrogen, alkyl, phenyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylcarbonyl optionally substituted by alkyl or arylsulfonyl optionally substituted by alkyl
  • cardiovascular diseases such as thromboembolic disorders.
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts; the compounds of formula (T) encompassed by the formulas mentioned below and their salts, solvates and solvates of the salts, and the compounds encompassed by formula (I) hereinafter referred to as exemplary embodiments and their salts, solvates and solvates of the salts, insofar as the Compounds of formula (I) mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore encompasses the enantiomers or diastereomers and their respective mixtures.
  • the stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and / or diastereomers.
  • the present invention encompasses all tautomeric forms.
  • preferred salts are physiologically acceptable salts of the compounds according to the invention. Also included are salts for pharmaceutical Applications themselves are not suitable 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, triftuoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzene acid.
  • Physiologically acceptable salts of the compounds according to the invention also include salts of conventional bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dime ylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • alkali metal salts for example sodium and potassium salts
  • alkaline earth metal salts for example calcium and magnesium salts
  • solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvate, in which coordination takes place with water.
  • Alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl represent a linear or branched alkyl radical having 1 to 8, usually 1 to 6, preferably 1 to 4, particularly preferably 1 to 3, carbon atoms, by way of example and preferably methyl, ethyl, propyl, isopropyl, "-Butyl, tert-butyl,” -pentyl and w-hexyl.
  • Alkylene stands for a straight-chain or branched alkylene radical with generally 1 to 8, preferably 1 to 6 carbon atoms, which optionally contains one or more double or triple bonds. Examples include and are preferably methylene, ethylene, propylene, propane-1,2-diyl, propane-2,2-diyl, butane-1,3-diyl, butane-2,4-diyl, pentane-2,4-diyl , 2-methyl-pentane-2,4-diyl.
  • Alkoxy is exemplary and preferably methoxy, ethoxy, ra-propoxy, isopropoxy, tert-butoxy,. z-pentoxy and n-hexoxy.
  • Alkylamino stands for an alkylamino radical with one or two (independently selected) alkyl substituents, for example and preferably for memylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, "-pentylamino, .z-hexylamino, NN-dimethylamino, NN-diethylamino , N-ethyl-N-methylamino, N-methyl-N -?
  • C 3 alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical each having 1 to 3 carbon atoms per alkyl substituent
  • Alkoxycarbonyl is exemplified and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and ra-hexoxycarbonyl.
  • Alkylaminocarbonyl stands for an alkylaminocarbonyl radical with one or two (independently selected) alkyl substituents, the alkyl substituents usually independently of one another generally having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, by way of example and preferably methylaminocarbonyl, ethylaminocarbonyl.
  • ylan__nocarbonyl stands for example for a monoalkylamino carbonyl radical with 1 to 3 carbon atoms or for a dialkylaminocarbonyl radical with 1 to 3 carbon atoms per alkyl substituent.
  • Alkylcarbonyl is exemplified and preferably methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylca bonyl, tert-butylcarbonyl, n-pentylcarbonyl and n-hexylcarbonyl.
  • Alkylcarbonyloxy is an example and preferably methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, w-pentylcarbonyloxy and n-hexylcarbonyloxy.
  • Alkylcarbonylamino is exemplary and preferably methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylamino and n-hexylcarbonylamino.
  • Alkylsulfonyl is exemplified and preferably methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.
  • Cycloalkyl stands for a mono- or bicyclic cycloalkyl group with usually 3 to 8, preferably 5 or 6 carbon atoms, examples and preferably for cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and norbornyl.
  • Aryl per se and "aryl” in aryloxy and arylcarbonylamino stands for a mono- to tricyclic aromatic radical with generally 6 to 14, preferably 6 to 10 carbon atoms, by way of example and preferably for phenyl, naphthyl and phenanthrenyl.
  • Aryloxy is exemplary and preferably phenyloxy and naphthyloxy.
  • Arylcarbonylamino is exemplary and preferably phenylcarbonylamino and naphthylcarbonylamino.
  • Heteroaryl stands for an aromatic mono- or bicyclic radical with generally 5 to 10, preferably 5 or 6 ring atoms and up to 5, preferably up to 4 heteroatoms from the series S, O and N, for example and preferably for thienyl, furyl, Pyrrolyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl.
  • Heterocyclyl stands for an optionally benzocondensed, mono- or bicyclic, heterocyclic radical with usually 3 to 10, preferably 5 to 10, in particular 5 or 6 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series N. , O, S, SO, SO 2 .
  • the heterocyclyl residues can be saturated or partially unsaturated.
  • 5- to 8-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the O, N and S series are preferred, for example and preferably for oxetan-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, Tetrahydrofuranyl, tetrahydro-thienyl, pyranyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, thiopyranyl, morpholin-1-yl, morpholin-2-yl, morpholin-3- yl, perhydroazepinyl, piperazin-1-yl, piperazin-2-yl.
  • Halogen represents fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
  • a symbol # on a carbon atom means that the compound is present in enantiomerically pure form with regard to the configuration on this carbon atom, which in the context of the present invention is understood to mean an enantiomeric excess of more than 90% (> 90% ee).
  • radicals in the compounds of the formula (I), their salts, their solvates or the solvates of their salts are substituted, the radicals can, unless otherwise specified, be substituted one or more times in the same or different ways. A substitution with up to three identical or different substituents is preferred. Substitution with a substituent is very particularly preferred.
  • the present invention furthermore relates to compounds of the formula (I)
  • E represents methylene, NH, an oxygen atom or a sulfur atom
  • n 0, 1, 2 or 3
  • n 1, 2 or 3
  • X represents R 3 or (CC 8 ) alkylene-R 4 , where alkylene can be substituted with 1 to 4 fluorine atoms,
  • Y represents (CC 8 ) alkylene-R 4 , where alkylene can be substituted by 1 to 4 fluorine atoms,
  • R 3 for 1,3-benzodioxol, 2,2-difluoro-l, 3-benzodioxol, 2,3-dihydro-l, 4-behzodioxin, 2,2,4,4-tetrafluoro-4H-l, 3-benzodioxin , Indanyl, 1,2,3,4-tetrahydronaphthyl, (C 6 -C ⁇ o) aryl, 5- to 10-membered heteroaryl, (C 3 -C 6 ) cycloalkyl or 5- to 10-membered heterocyclyl, where Aryl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 3 substituents, independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, Alkoxy, alkylamino,
  • R 5 represents alkyl which is optionally substituted by fluorine, (C 6 -C 0 ) aryl, benzyl, (C 3 -C 7 ) cycloalkyl or alkylcarbonyl, where aryl, benzyl or cycloalkyl can be substituted with 1 to 3 substituents, independently of one another selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, oxo, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, alkoxy , Alkylamino, aryl, benzyl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl,
  • R 6 represents hydroxy, amino, alkyl, alkylamino, alkoxy, (C 6 -C ⁇ 0 ) aryl, benzyloxy or 5- to 10-membered heterocyclyl, where aryl or benzyloxy can be substituted with 1 to 3 substituents, independently of one another from the group consisting of hydroxy, amino, halogen, cyano, nitro, oxo, monohalomethyl, dihalomethyl, trihalomethyl, monohalomethoxy, dihalomethoxy, trihalomethoxy, alkyl, alkoxy, alkylamino, aryl, benzyl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl , Alkylcarbonyloxy, alkylcarbonylamino and alkylsulfonyl,
  • R 7 represents hydrogen, alkyl or benzyl
  • R 8 represents hydrogen, alkyl, phenyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylcarbonyl optionally substituted by alkyl or arylsulfonyl optionally substituted by alkyl,
  • E represents methylene, NH or an oxygen atom
  • n 0, 1 or 2
  • n 1, 2 or 3
  • R 1 represents halogen, amino, cyano, nitro, trifluoromethyl, alkyl or alkoxy,
  • R 2 for a group of the formula -X -N- -YH
  • X represents R 3 or (CC 8 ) alkylene-R 4 ,
  • Y represents (C, -C 8 ) alkylene-R 4 ,
  • R 6 represents (dC 4 ) alkoxy
  • R 7 represents hydrogen or (CC 4 ) alkyl
  • R 8 represents (C 1 -C 4 ) alkyl or phenyl carbonyl optionally substituted with (C r C 4 ) alkyl,
  • E represents methylene, NH or an oxygen atom
  • n 0, 1 or 2
  • n 1, 2 or 3
  • R 1 represents halogen, amino, cyano, trifluoromethyl, (CC 4 ) alkyl or (CC 4 ) alkoxy,
  • X represents R 3 or (CC 6 ) alkylene-R 4 , R 3 for 1,3-benzodioxol, 2,2-difluoro-l, 3-benzodioxol, 2,3-dihydro-l, 4-benzodioxm, 2,2,4,4-tetrafluoro-4H-l, 3-benzodioxin , Phenyl, 5- or 6-membered heteroaryl or (C 3 -C 6 ) cycloalkyl, where phenyl, heteroaryl or cycloalkyl can be substituted with 1 or 2 substituents, independently selected from the group consisting of halogen, cyano, trichloromethyl , Trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, (C 1 -C 4 ) -alkyl and (dC 4 ) -alkoxy,
  • R 4 represents hydrogen, phenyl, 5- or 6-membered heteroaryl, (C 5 -C 6 ) cycloalkyl, 5- or 6-membered heterocyclyl, cyano, trifluoromethyl, -OR 5 or -NR 7 R 8 , where phenyl , Heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 2 substituents, independently of one another selected from the group consisting of halogen, cyano, oxo, trichloromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, (dC 4 ) -alkyl and (C ⁇ -C 4 ) alkoxy,
  • R 5 represents (dC 4 ) -alkyl optionally substituted with fluorine
  • R 7 represents hydrogen or (CC 4 ) alkyl
  • R 8 represents (CC 4 ) alkyl
  • n 1,
  • n 1
  • R 1 represents halogen
  • R 3 represents phenyl, 5- or 6-membered heteroaryl or (C 5 -C 6 ) cycloalkyl, where phenyl, heteroaryl or cycloalkyl can be substituted with 1 to 2 substituents, independently selected from the group consisting of halogen, cyano , Trichloromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, (C ⁇ -C) alkyl and (CC 4 ) alkoxy,
  • R 4 represents hydrogen, phenyl, 5- or 6-membered heteroaryl, (C 5 -C 6 ) cycloalkyl, 5- or 6-membered heterocyclyl, cyano, trifluoromethyl or -OR 5 , where phenyl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 2 substituents, independently selected from the group consisting of halogen, cyano, trichloromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, (CC 4 ) alkyl and (CC 4 ) alkoxy,
  • R 5 represents methyl or ethyl
  • the present invention furthermore relates to compounds of the formula (I)
  • E represents methylene, ⁇ H, an oxygen atom or a sulfur atom
  • n 0, 1, 2 or 3
  • n 1, 2 or 3
  • R 1 represents halogen, hydroxy, amino, cyano, nitro, alkyl, alkoxy, hydroxycarbonyl, aminocarbonyl, alkoxycarbonyl or alkylaminocarbonyl,
  • X represents R 3 or (CC 8 ) -alkylene-R 4
  • Y represents R 3 or (dC 8 ) -alkylene-R 4
  • R 4 is hydrogen, 1,3-benzodioxole, 2,2-difluoro-l, 3-benzodioxole, 2,3-dihydro-l, 4-benzodioxin, 2,2,4, 4-tetrafluoro-4H-l, 3 -benzodioxin, (C 6 -C ⁇ 0 ) aryl, (C 6 -C 10 ) - aryloxy, benzyloxy, 5- to 10-membered heteroaryl, (C 3 -C 7 ) cycloalkyl, 5- to 10-membered heterocyclyl , Hydroxy, amino, alkoxy, alkylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonylamino, optionally substituted with arylcarbonylamino or alkylcarbonyloxy, where aryl, heteroaryl, cycloalkyl or heterocycly
  • cardiovascular diseases such as thromboembolic diseases.
  • the present invention furthermore relates to compounds of the formula (I)
  • E represents methylene, NH, an oxygen atom or a sulfur atom
  • n 0, 1, 2 or 3
  • n 1, 2 or 3
  • R 1 represents halogen, hydroxy, amino, cyano, nitro, alkyl, alkoxy, hydroxycarbonyl, aminocarbonyl, alkoxycarbonyl or alkylaminocarbonyl,
  • Y represents (CC 8 ) alkylene-R 4 ,
  • E represents methylene, NH or an oxygen atom
  • n 0, 1 or 2
  • n 1, 2 or 3
  • R 1 represents halogen, cyano, nitro, alkyl or alkoxy
  • R 2 for a group of the formula O 1 -X -N- -YH
  • X represents R 3 or (CC 8 ) alkylene-R 4 ,
  • Y stands for (C ⁇ -Q) alkylene-R 4 ,
  • R 4 for hydrogen, 1,3-benzodioxole, 2,2-D_fluor-l, 3-benzodioxol, 2,3-dihydro-l, 4-benzodioxin, 2,2,4,4-tetrafluoro-4H-l, 3 -benzodioxin, phenyl, naphthyl, phenyloxy, benzyloxy, 5- or 6-membered heteroaryl, (C 5 -C 6 ) cycloalkyl, 5- or 6-membered heterocyclyl, (C ⁇ -C 4 ) alkoxy, (CC ) -Alkylamino, (-C-C 4 ) -alkoxy-carbonyl, optionally substituted with (-CC) -alkyl substituted phenylcarbonylamino or (-C-C) -alkylcarbonyloxy, where phenyl, naphthyl, heteroaryl, cycloalkyl or heterocyclyl can be
  • E represents methylene, NH or an oxygen atom
  • n 0 or 1
  • n 1, 2 or 3
  • R 1 represents halogen, cyano, (dC 4 ) -alkyl or (C_-C 4 ) -alkoxy,
  • X represents R 3 or (C r C 6 ) alkylene R 4 ,
  • R 3 for 1,3-benzodioxole, 2,2-difluoro-l, 3-benzodioxole, 2,3-dihydro-l, 4-benzodioxin, 2,2,4,4-tetrafluoro-4H-1,3-benzodioxin , Phenyl, 5- or 6-membered heteroaryl or (C 5 -C 6 ) cycloalkyl, where phenyl, heteroaryl or cycloalkyl can be substituted with 1 or 2 substituents, independently selected from the group consisting of halogen, cyano, trichloromethyl , Trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, (C ⁇ -C) alkyl and (C_-C 4 ) alkoxy, R 4 represents hydrogen, phenyl, 5- or 6-membered heteroaryl, (C 5 -C 6 ) cycloalkyl, 5- or 6-membered heterocycl
  • n 1,
  • n 1
  • R 1 represents halogen
  • X represents R 3 or (-CC 6 ) alkylene-R 4
  • R 3 represents phenyl, 5- or 6-membered heteroaryl or (C 5 -C 6 ) cycloalkyl
  • phenyl, heteroaryl or cycloalkyl being substituted can with 1 to 2 substituents, independently selected from the group consisting of halogen, cyano, trichloromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, (-C-C 4 ) alkyl and (CrC 4 ) alkoxy
  • R 4 represents hydrogen, phenyl, 5- or 6-membered heteroaryl, (C 5 -C 6 ) cycloalkyl or 5- or 6-membered heterocyclyl, where phenyl, heteroaryl, cycloalkyl or heterocyclyl can be substituted with 1 to 2 substituents , independently selected from the group consisting of halogen, cyano,
  • the present invention further provides a process for the preparation of the new compounds of the formula (I), compounds of the formula
  • R 1 , E, m and n have the meaning given above,
  • Z 1 represents halogen, preferably chlorine or bromine, or hydroxy
  • R 1 , E, X, m and n have the meaning given above,
  • R 1 , E, Y, m and n have the meaning given above,
  • R 1 , E, Y, m and n have the meaning given above,
  • R 1 , E, X, m and n have the meaning given above,
  • the general formula (I) comprises the compounds of the formulas (Ia), (Ib), (Ic), (Id) and (Ie).
  • Inert solvents are, for example, halogenated hydrocarbons 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, tetrahydrofuran or is preferred methylene chloride.
  • halogenated hydrocarbons 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, tetrahydrofuran or is preferred methylene chloride.
  • Bases are, for example, alkali carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethanol or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropyl amide, or others Bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, diisopropylethylamine or triethylamine is preferred.
  • alkali carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethanol or potassium tert-butoxide
  • amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropyl amide, or others
  • Bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, diisopropylethyl
  • Suitable dehydration reagents are, for example, carbodiimides such as N, N'-diethyl, N, N, -dipropyl, NN-diisopropyl, NN'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N - propyloxymethyl polystyrene (PS carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert-
  • carbodiimides such as N, N'-diethyl, N, N, -dipropyl, NN-diisopropyl, NN'-dicyclohexyl
  • Butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or Benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or 0- (benzotriazol-l -yl) -NNN ', N'-tetra-methyluromumhexa- fluorophosphate (HBTU), 2- (2-oxo-1 - (2H) -pyridyl) -l, 1,3,3 -tetramethyluronium tetrafluoroborate
  • TPTU 7-azabenzotriazole-l -y ⁇ -NNN'N'-tetramethyluronium hexafluorophosphate
  • HOBt 1-hydroxybenzotriazole
  • BOP benzotriazol-l-yloxytos (dimethylamino) - phosphoniumhexafluorophosphate
  • Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen bicarbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, or DBU, DB ⁇ , pyridine, or mixtures of the bases, a mixture of 4-dimethylaminopyridine and N-methylmorpholine is preferred.
  • alkali carbonates e.g. Sodium or potassium carbonate
  • hydrogen bicarbonate e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, or DBU, DB ⁇ , pyridine, or mixtures of the bases, a mixture of 4-dimethylaminopyridine and N-methylmorpholine is preferred.
  • the condensation is preferably carried out with N- (3-dimethylaminoisopropyl) -N-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt), 4-dimethylaminopyridine and N-methylmorpholine.
  • EDC N- (3-dimethylaminoisopropyl) -N-ethylcarbodiimide hydrochloride
  • HOBt 1-hydroxybenzotriazole
  • 4-dimethylaminopyridine N-methylmorpholine.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol ether dimethyl ether or diethylene dimethyl ether such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine, in the case of water-miscible solvents, mixtures of these with water are preferred,
  • reaction according to process [E] is preferably carried out in two stages:
  • the reaction in the first stage is generally carried out in inert solvents, preferably in a temperature range from 50 ° C. to the reflux of the solvent at normal pressure.
  • Inert solvents are, for example, alcohols such as methanol, ethanol, ra-propanol or isopropanol, preference is given to “O-propanol.
  • the reaction in the second stage is generally carried out in inert solvents, preferably in a temperature range from 50 ° C. to the reflux of the solvent at normal pressure.
  • Inert solvents are, for example, alcohols such as methanol, ethanol, propanol or isopropanol, ethanol being preferred.
  • R 1 , E, m and n have the meaning given above,
  • the reaction in the first stage is generally carried out in inert solvents, in the presence of a base, preferably in a temperature range from room temperature to the reflux of the solvent at atmospheric pressure.
  • Inert solvents are, for example, alcohols such as methanol, ethanol, n-propanol or isopropanol, ethanol is preferred.
  • Bases are, for example, organic bases such as amine bases, e.g. Piperidine, triethylamine, diisopropylethylamine or DBU, piperidine is preferred.
  • amine bases e.g. Piperidine, triethylamine, diisopropylethylamine or DBU, piperidine is preferred.
  • the reaction in the second stage is generally carried out in inert solvents, preferably in a temperature range from room temperature to the reflux of the solvent at normal pressure.
  • Inert solvents are, for example, alcohols such as methanol, ethanol, n-propanol or isopropanol, ethanol is preferred.
  • R 1 and m have the meaning given above,
  • reaction is generally carried out in inert solvents, if appropriate in the presence of a base, if appropriate with the addition of potassium iodide, preferably in a temperature range from room temperature to the reflux of the solvent at atmospheric pressure.
  • Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, hydrocarbons such as benzene, xylene, toluene, hexane or cyclohexane, or other solvents such as ethyl acetate, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, Acetonitrile or pyridine, dimethylformamide or tetrahydrofuran is preferred.
  • ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran
  • hydrocarbons such as benzene, xylene, toluene, hexane or cyclohexane
  • solvents such as ethyl acetate
  • Bases are, for example, alkali metal hydroxides such as sodium, potassium or lithium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methanolate, or sodium or potassium ethanolate or potassium tert-butoxide, or amides such as sodium amide, lithium bis- (trimethylsilyl) amide or lithium diisopropylamide, or other bases such as sodium hydride, pyridine or DBU, sodium hydride is preferred.
  • alkali metal hydroxides such as sodium, potassium or lithium hydroxide
  • alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methanolate, or sodium or potassium ethanolate or potassium tert-butoxide
  • amides such as sodium amide, lithium bis- (trimethylsilyl) amide or lithium diisopropylamide, or other bases such as sodium hydride, pyridine or DBU, sodium hydride is preferred.
  • the compounds according to the invention show an unforeseeable, valuable pharmacological and pharmacokinetic spectrum of action. These are PAR-1 antagonists.
  • the present invention furthermore relates to the use of the compounds according to the invention for the treatment and / or prophylaxis of diseases, preferably cardiac Circulatory diseases, for example thromboembolic diseases and / or thrombotic complications.
  • diseases preferably cardiac Circulatory diseases, for example thromboembolic diseases and / or thrombotic complications.
  • this includes in particular heart attack, stable angina pectoris, unstable angina pectoris, stroke, such as e.g. thrombotic stroke and thromboembolic stroke, transient ischemic attacks, reocclusion and restenosis after coronary interventions (reocclusion and restenosis after percutaneous coronary interventions, reocclusion and restenosis after coronary artery bypass surgery), disseminated intravascular coagulation and deep venous thrombosis, deep venom thrombosis,
  • stroke such as e.g. thrombotic stroke and thromboembolic stroke, transient ischemic attacks, reocclusion and restenosis after coronary interventions (reocclusion and restenosis after percutaneous coronary interventions, reocclusion and restenosis after coronary artery bypass surgery), disseminated intravascular coagulation and deep venous thrombosis, deep venom thrombosis,
  • the compounds according to the invention can be used to support thrombolytic therapy, to influence wound healing, in the prevention and treatment of atherosclerotic vascular diseases, such as e.g. Restenosis, coronary heart disease, cerebral ischemia and peripheral arterial disease, heart failure, hypertension, inflammatory diseases such as e.g. Asthma, inflammatory lung diseases, glomerulonephritis, inflammatory bowel diseases and rheumatic diseases of the musculoskeletal system, degenerative diseases such as e.g. neurodegenerative diseases and osteoporosis and neoplastic diseases such as Cancer.
  • atherosclerotic vascular diseases such as e.g. Restenosis, coronary heart disease, cerebral ischemia and peripheral arterial disease, heart failure, hypertension, inflammatory diseases such as e.g. Asthma, inflammatory lung diseases, glomerulonephritis, inflammatory bowel diseases and rheumatic diseases of the musculoskeletal system, degenerative diseases such as e.g.
  • the present invention furthermore relates to the use of the compounds according to the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • the present invention furthermore relates to the use of the compounds according to the invention for the manufacture of a medicament for the treatment and or prophylaxis of eradications, in particular the aforementioned diseases.
  • the present invention furthermore relates to a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using a therapeutically effective amount of a compound according to the invention.
  • the present invention further relates to medicaments containing a compound according to the invention and one or more further active substances.
  • the active ingredient can act systemically and / or locally.
  • it can be applied in a suitable manner, such as, for example, orally, parenterally, pulmonally, nasally, sublingually, lingually, buccally, rectally, transdermally, conjunctivally, otically or as an implant or stent.
  • the active ingredient can be administered in suitable administration forms for these administration routes.
  • state-of-the-art, fast and / or modified administration forms which give off the compounds according to the invention and contain the compounds according to the invention in crystalline and / or amorphized and or dissolved form, such as e.g. Tablets (non-coated or coated tablets, for example with gastric juice-resistant, delayed dissolving or insoluble coatings which control the release of the compounds according to the invention), rapidly disintegrating tablets or films / wafers, capsules, dragees, granules, pellets, powder, emulsified tablets in the oral cavity ions, suspensions, aerosols or solutions.
  • Tablets non-coated or coated tablets, for example with gastric juice-resistant, delayed dissolving or insoluble coatings which control the release of the compounds according to the invention
  • rapidly disintegrating tablets or films / wafers capsules, dragees, granules, pellets, powder, emulsified tablets in the oral cavity ions, suspensions, aerosols or solutions.
  • Parenteral administration can be done by bypassing a resorption step (intravenous, intraarterial, intracardial, intraspinal or intralumbal) or by switching on absorption (intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • Suitable forms of application for parenteral administration include: Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.
  • Oral application is preferred.
  • Inhaled drug forms including powder inhalers, nebulizers
  • nasal drops including powder inhalers, nebulizers
  • Z solutions including powder inhalers, nebulizers
  • sprays including tablets or capsules to be applied lingually, sublingually or buccally, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixes), lipophilic suspensions, ointments, creams, milk, pastes, powder, stents or implants.
  • the compounds according to the invention can be converted into the application forms mentioned in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable excipients.
  • Carriers e.g. microcrystalline cellulose
  • solvents e.g. liquid polyethylene glycols
  • emulsifiers e.g. sodium dodecyl sulfate
  • dispersants e.g. polyvinylpyrrolidone
  • synthetic and natural biopolymers e.g. albumin
  • stabilizers e.g. antioxidants such as ascorbic acid
  • dyes e.g. inorganic pigments
  • iron oxides e.g. inorganic pigments
  • the present invention furthermore relates to medicaments which contain at least one compound according to the invention, preferably together with one or more inert non- contain toxic, pharmaceutically suitable excipient, and their use for the aforementioned purposes.
  • Solvent ratios, dilution ratios and concentration details of liquid / liquid solutions each relate to the volume.
  • W / v means "weight / volume”.
  • 10% w / v means: 100 ml of solution or suspension contain 10 g of substance.
  • Method 1 Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60mm x 2mm, 3.5 ⁇ m; Eluent A: 5 ml HCIO 4 / I water, eluent B: acetonitrile; Gradient: 0min 2% B, 0.5min 2% B, 4.5min 90% B, 6.5min 90% B; Flow: 0.75ml / min, temp .: 30 ° C, UV detection: 210 n.
  • Method 2 Instrument: Micromass Quattro LCZ, with HPLC Agilent Series 1100; Column: Grom-S_L120 ODS-4 HE, 50 mm x 2.0 mm, 3 ⁇ m; Eluent A: 11 water + 1ml 50% formic acid, eluent B: 11 acetonitrile + 1ml 50% formic acid; Gradient: 0.0min 100% A -> 0.2min 100% A -> 2.9min 30% A ⁇ 3.1min 10% A - 4.5min 10% A; Oven: 55 ° C, flow: 0.8ml / min, UV detection: 208-400 nm.
  • Method 3 Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Grom-Sil 120 ODS-4 HE 50 mm x 2 mm, 3.0 ⁇ m; Eluent A: water + 500 ⁇ l 50% formic acid / 1, eluent B: acetonitrile + 500 ⁇ l 50% formic acid / 1; Gradient: 0.0min 0% B -> 2.9min 70% B - »3.1min 90% B - 4.5min 90% B; Oven: 50 ° C, flow: 0.8ml / min, UV detection: 210 nm.
  • Method 4 Instrument MS: Micromass TOF (LCT); HPLC instrument: 2-column circuit, Waters2690; Column: YMC-ODS-AQ, 50 mm x 4.6 mm, 3.0 ⁇ m; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0.0 min 100% A -> 0.2 min 95% A - »1.8 min 25% A -> 1.9 min 10% A - ⁇ 2.0 min 5% A -» 3.2 min 5% A; Oven: 40 ° C; Flow: 3.0 ml / min; UV detection: 210 nm.
  • Method 5 Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Grom-S1L120 ODS-4 HE, 50 mm x 2.0 mm, 3 ⁇ m; Eluent A: 11 water + 1ml 50% formic acid, eluent B: 11 acetonitrile + 1ml 50% formic acid; Gradient: 0.0min 100% A - 0.2min 100% A - »2.9min 30% A ⁇ » 3.1min 10% A - »4.5min 10% A; Oven: 55 ° C, flow: 0.8ml / min, UV detection: 210 nm.
  • Method 7 Instrument: Micromass GCT, GC6890; Column: Restek RTX-35MS, 30m x 250 ⁇ m x 0.25 ⁇ m; constant flow with helium: 0.88ml / min; Oven: 60 ° C; Inlet: 250 ° C; Gradient: 60 ° C (hold 0.30 min), 50 ° C / min - »120 ° C, 16 ° C / min ⁇ » 250 ° C, 30 ° C / min - »300 ° C (hold 1.7 min).
  • Method 8 (HPLC, enantiomer separation): Chiral silica gel selector KBD 6136 (10 ⁇ m, 350x30mm) based on the selector poly (N-methacryloyl-L-leucine-l-menthylamide); Eluent: tert-butyl methyl ether / ethyl acetate 90/10; Temperature: 24 ° C; Flow: 50 ml / min; TJV detection: 254 nm.
  • Method 10 (HPLC, enantiomer separation): Chiral silica gel selector KBD 8361A (250x20mm) based on the selector poly (N-methacryloyl-L-leucine-l-menthylamide); Iso-hexane / ethyl acetate 20/10; Temperature: 24 ° C; Flow: 25 ml / rnin; UV detection: 254 nm.
  • Method 13 Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 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: 210 nm.
  • Method 14 Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 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: 210 nm.
  • Method 15 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 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 16 Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 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: 210 nm.
  • Method 18 (HPLC, enantiomer separation): Chiral silica gel sector KBD 5326 (250 mm x 20 mm) based on the sector poly (N-methacryloyl-L-leucine-l-menthylamide); ethyl acetate; Temperature: 24 ° C; Flow: 25 ml / min; UV detection: 254 nm.
  • Method 19 (HPLC, enantiomer separation): Chiral silica gel selector KBD 5326 (250 mm x 20 mm) based on the selector poly (N-methacryloyl-L-leucine-dicyclopropylmethylamide); ethyl acetate; Temperature: 24 ° C; Flow: 25 ml / min; UV detection: 260 nm.
  • Method 20 (HPLC, enantiomer separation): Chiral silica gel selector KBD 5326 (250 mm x 20 mm) based on the selector poly (N-methacryloyl-L-leucine-dicyclopropylmethylamide); ethyl acetate; Temperature: 24 ° C; Flow: 25 nd / min; UV detection: 280 nm.
  • Method 21 (HPLC, enantiomer separation): Chiral selector Daicel Chiralcel OD-H (250 mm x 20 mm); wo-hexane / ethanol 40:60 (vol / vol); Temperature: 40 ° C; Flow: 15 ml / min; UV detection: 220 nm.
  • a suspension of 79 mg (2.0 mmol) sodium hydride in 3.6 ml THF is mixed with 157 mg (1.80 mmol) 1,3-oxazolidin-2-one and the mixture is stirred for 1 h at RT.
  • 60 mg (0.36 mmol) of potassium iodide and a solution of 500 mg (1.80 mmol) of 2-bromo-1- (4-bromophenyl) -2-ethanone in 3.6 ml of THF are added and the mixture is then stirred at 70 ° C. for 20 h. After cooling, 15 ml of water are carefully added and the mixture is extracted three times with dichloromethane.
  • Example 26 The compounds of Examples 2 to 25 are prepared analogously to Example 1. The raw products from the reactions are purified by stirring and / or by preparative HPLC. Example 26
  • Example 61 The compounds of Examples 27 to 60 are prepared analogously to Example 2.
  • Example 61 The compounds of Examples 27 to 60 are prepared analogously to Example 2.
  • Enantiomer separation from Example 80 by Method 10 gives the title compound as Enantiomer A (> 99% ee).
  • Example 120 is produced in analogy to Example 119.
  • Enantiomer separation from Example 122 by Method 12 gives the title compound as Enantiomer A (99.6% ee).
  • phenyl-3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.055 g (0.49 mmol) l-cyclohexylmethanamine are dissolved in 3 ml ethanol and heated to reflux overnight. After cooling to room temperature, the same volume of water is added to the reaction mixture, the product crystallizing out as a solid. The product is suctioned off and washed several times with diethyl ether. After drying under high vacuum, 0.057 g (60% of theory) of the product are obtained.
  • phenyl-3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidfn-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.048 g (0.49 mmol) of cyclohexylamine are dissolved in 3 ml of ethanol and heated to reflux overnight. After cooling to room temperature, the same volume of water is added to the reaction mixture, the product being removed as a solid. crystallized. The product is suctioned off and washed several times with diethyl ether. After drying in a high vacuum, 0.080 g (79% of theory) of the product are obtained.
  • phenyl-3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.064 g (0.49 mmol) of isopropyl beta-alaninate are dissolved in 3 ml of ethanol and heated to reflux overnight. After cooling to room temperature, the solvent is removed in vacuo and the product is purified by preparative HPLC. 0.1 g (92% of theory) of the product are obtained.
  • phenyl-3- (4-chl ⁇ henyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.055 g (0.49 mmol) of heptylamine are dissolved in 3 ml of ethanol and heated to reflux overnight. After cooling to room temperature, the same volume of water is added to the reaction mixture, the product crystallizing out as a solid. The product is suctioned off and washed several times with diethyl ether. After drying in a high vacuum, 0.09 g (85% of theory) of the product are obtained.
  • phenyl-3- (4-chloro-phenyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.066 g (0.49 mmol) 3-phenylpropan-l-amine are dissolved in 3 ml ethanol and heated to reflux overnight. After cooling to room temperature, the same volume of water is added to the reaction mixture, the product crystallizing out as a solid. The product is suctioned off and washed several times with diethyl ether. After drying under high vacuum, 0.094 g (85% of theory) of the product are obtained.
  • phenyl-3- (4-chloro-nyl) -N-cyano-4- (2-oxopyrrolidin-l-yl) -4,5-dihydro-lH-pyrazole-1-carboximidoate and 0.055 g ( 0.49 mmol) 3,3,3-trifluoropropane-l-amine are dissolved in 3 ml ethanol and heated to reflux overnight. After cooling to room temperature, the precipitate is filtered off and washed several times with diethyl ether. 0.089 g (85% of theory) of the product are obtained.
  • Enantiomer separation from Example 394 by Method 21 gives the title compound as enantiomer 1 (> 99.5% ee).
  • Enantiomer separation from Example 410 according to Method 22 gives the title compound as enantiomer 1 / diastereomer 1 (> 99.5% ee).
  • Example 410 Enantiomer separation of Example 410 according to Method 22 gives the title compound as enantiomer 1 / diastereomer 2 (> 99.5% ee).
  • the identification of agonists of the human protease activated receptor 1 (PARI) and the quantification of the effectiveness of the substances described here is carried out using a recombinant cell line.
  • the cell is originally derived from a human embryonic kidney cell (HEK293; ATCC: American Type Culture Collection, Manassas, VA 20108, USA).
  • the test cell line consumatively expresses a modified form of the calcium-sensitive photoprotein aequorin, which after reconstitution with the co-factor coelenterazine emits light when the free calcium concentration in the inner mitochondrial compartment increases (Rizzuto R, Simpson AW, Brini M, Pozzan T .; Nature 1992, 358, 325-327).
  • the cell stably expresses the endogenous human PARI receptor and the endogenous purinergic receptor P2Y2.
  • the resulting PARI test cell responds to stimulation of the endogenous PARI or P2Y2 receptor with an intracellular release of calcium ions, which can be quantified by the resulting aequorin luminescence with a suitable luminometer (Milligan G, Marshall F, Rees S, Trends in Pharmacological Sciences 1996, 17, 235-237).
  • Test procedure The cells are placed in culture medium (DMEM F12, supplemented with 10% FCS, 2 mM glutamine, 20 mM HEPES, 1,4mM pyruvate, 0, lmg / ml gentamycin, two days (48 hours) before the test.
  • test substances are pipetted onto the microtiter plate and 5 minutes after transfer of the test substances into the wells of the microtiter plate, the plate is transferred to the luminometer, a PARl agonist concentration corresponding to EC 50 is added and the resulting light signal is immediately measured in the luminometer.
  • the endogenous purinergic receptor is activated with an agonist (ATP, 10 ⁇ M final concentration) and the resulting light signal is measured.
  • ATP acetedoxifene
  • 10 ⁇ M final concentration a PARl agonist
  • SFLLRN thrombin receptor agonist
  • the increase in light transmission (amplitude of the aggregation curve in%) is determined 5 minutes after addition of the agonist in the presence and absence of test substance, and the inhibition is calculated.
  • the concentration that inhibits aggregation by 50% is calculated from the inhibition curves. The results are shown in Table B:
  • Human whole blood is obtained by venipuncture from voluntary donors and transferred to monovettes (Sarstedt, Nümbrecht, Germany) that contain sodium citrate as an anticoagulant (1 part sodium citrate 3.8% + 9 parts whole blood).
  • the monovettes are centrifuged at 900 revolutions per minute and 4 ° C over a period of 20 minutes (Heraeus Instruments, Germany; Megafuge 1.0RS).
  • the platelet-rich plasma is carefully removed and transferred to a 50 ml falcon tube.
  • ACD buffer 44 mM sodium citrate, 20.9 mM citric acid, 74.1 mM glucose
  • the volume of the ACD buffer corresponds to a quarter of the plasma volume.
  • the platelets are sedimented by centrifugation at 2500 revolutions and 4 ° C. for ten minutes. The supernatant is then carefully decanted off and discarded.
  • the precipitated platelets are first carefully washed with a milliliter of washing buffer (113 mM sodium chloride, 4 mM disodium hydrogen phosphate, 24 mM sodium dihydrogen phosphate, 4 mM potassium chloride, 0.2 mM ethylene glycol bis (2-aminoethyl) -N, N, NW tetraacetic acid, 0.1% glucose ) resuspended and then filled up with washing buffer to a volume which corresponds to that of the plasma amount. The washing process is carried out a second time.
  • washing buffer 113 mM sodium chloride, 4 mM disodium hydrogen phosphate, 24 mM sodium dihydrogen phosphate, 4 mM potassium chloride, 0.2 mM ethylene glycol bis (2-aminoethyl) -N,
  • incubation buffer 134 mM sodium chloride, 12 mM sodium hydrogen carbonate, 2.9 mM potassium chloride, 0.34 mM sodium dihydrogen carbonate, 5 mM HEPES, 5 mM glucose , 2 mM calcium chloride and 2 mM magnesium chloride
  • the platelet suspension is preincubated with the substance to be tested or the corresponding solvent for 10 minutes at 37 ° C (Eppendorf, Germany; Thermomixer Comfort).
  • the agonist 0.5 ⁇ M or 1 ⁇ M ⁇ -thrombin; Kordia, Netherlands, 3281 NIH Units / mg; or 30 ⁇ g / ml Thrombin receptor activating peptide (TRAP6); Bachern, Switzerland
  • a fluorescein-isothiocyanate-conjugated antibody is used which is directed against the human glycoprotein Ilb (CD41) (hnmunotech Coulter, France; Cat. No. 0649).
  • CD41 human glycoprotein Ilb
  • P-selectin human glycoprotein P-selectin
  • the activation state of the platelets can be determined.
  • P-selectin (CD62P) is localized in the ⁇ -granules of resting platelets. However, it is translocalized to the outer plasma membrane after in vitro or in vivo stimulation.
  • the samples are measured in the FACSCalibur TM Flow Cytometry System from Becton Dickinson nmunocytometry Systems, USA, and evaluated and graphically displayed using the CellQuest, Version 3.3 software (Becton Dickinson hnmunocytometry Systems, USA).
  • the degree of platelet activation is determined by the percentage of CD62P positive platelets (CD41 positive events). 10,000 CD41 positive events are counted from each sample.
  • the inhibitory effect of the substances to be tested is calculated on the basis of the reduction in platelet activation, which relates to the activation by the agonist.
  • Guinea pigs (strain: Dunkin Hartley) are treated orally, intravenously or intraperitoneally with test substances in a suitable formulation when awake or anesthetized. As a control, other guinea pigs are treated identically with the appropriate vehicle. Depending on the type of application, a different length of time is obtained from the deeply anesthetized animals by puncturing the heart or the aorta. The blood is collected in monovettes (Sarstedt, Nümbrecht, Germany) which are 3.8% anticoagulant sodium citrate (1st Part citrate solution + 9 parts blood) included. To obtain platelet-rich plasma, the citrate whole blood is centrifuged at 2500 rpm for 20 min at 4 ° C.
  • the aggregation is triggered by adding a thrombin receptor agonist (SFLLRN, 50 ⁇ g / ml) in an aggregometer and using the turbidimetric method according to Born (Born, GVR, Cross MJ, The Aggregation of Blood Platelets; J. Physiol. 1963, 168 , 178-195) at 37 ° C.
  • SFLLRN thrombin receptor agonist
  • the increase in light transmission (amplitude of the aggregation curve in%) is determined 5 minutes after adding the agonist.
  • the inhibitory effect of the administered test substances in the treated animals is calculated by reducing the aggregation, based on the mean value of the control animals.
  • the compounds according to the invention can be investigated in thrombosis models in suitable animal species in which thrombin-induced platelet aggregation is mediated via the PAR-1 receptor.
  • suitable animal species are guinea pigs and especially primates (compare: Kogushi M, Kobayashi H, Matsuoka T, Suzuki S, Kawahara T, Kajiwara A, Hishinuma I, Circulation 2003, 108 Suppl. 17, IV-280; Derian CK, Damiano BP, Addo MF, Darrow AL, D'Andrea MR, Nedelman M, Zhang HC, Maryanoff BE, Andrade-Gordon P, J. Pharmacol. Exp. Ther. 2003, 304, 855-861).
  • 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 lactose (monohydrate), 50 mg corn starch, 10 mg polyvinylpyrolidone (PVP 25) (from BASF, Germany) and 2 mg 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.
  • the granules are dried with the magnesium stearate for 5 min. mixed.
  • This mixture is ve ⁇ resst with a conventional tablet press (format of the tablet see above).
  • a single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension.
  • Rhodigel is suspended in ethanol, the compound of Example 1 is added to the suspension. The water is added with stirring. The mixture is stirred for about 6 hours until the swelling of the Rhodigel is complete.
  • 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 ⁇ m) and filled into heat-sterilized infusion bottles under aseptic conditions. These are closed with infusion stoppers and crimp caps.

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Abstract

L'invention concerne des pyrazolines de formule (I) dans laquelle E désigne méthylène, NH désigne un atome d'oxygène ou un atome de soufre, R2 désigne un groupe de formule (II). L'invention concerne également des procédé permettant de produire lesdites pyrazolines et leur utilisation pour préparer des médicaments utilisés dans le traitement et/ou la prophylaxie de pathologies, notamment de maladies cardio-vasculaires, comme par ex. des maladies thromboemboliques.
EP04740582A 2003-07-15 2004-07-02 Pyrazolines utilisees comme antagonistes par-1 pour traiter des maladies cardio-vasculaires Withdrawn EP1648447A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10331951 2003-07-15
DE102004010545A DE102004010545A1 (de) 2003-07-15 2004-03-04 Pyrazoline
PCT/EP2004/007227 WO2005007157A1 (fr) 2003-07-15 2004-07-02 Pyrazolines utilisees comme antagonistes par-1 pour traiter des maladies cardio-vasculaires

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EP1648447A1 true EP1648447A1 (fr) 2006-04-26

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EP (1) EP1648447A1 (fr)
AU (1) AU2004257406A1 (fr)
BR (1) BRPI0412554A (fr)
CA (1) CA2532316A1 (fr)
MA (1) MA27905A1 (fr)
MX (1) MXPA06000507A (fr)
NO (1) NO20060733L (fr)
WO (1) WO2005007157A1 (fr)

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DE102004061748A1 (de) * 2004-12-22 2006-07-06 Bayer Healthcare Ag Azetidin-substituierte Pyrazoline
DE102004061747A1 (de) * 2004-12-22 2006-07-06 Bayer Healthcare Ag Thiophen-substituierte Pyrazoline
DE102004061751A1 (de) * 2004-12-22 2006-07-06 Bayer Healthcare Ag Cyanoguanidin-substituierte Pyrazoline
US10023539B2 (en) 2014-12-08 2018-07-17 Bayer Pharma Aktiengesellschaft Aryl-cyanoguanidine compounds
WO2016166185A1 (fr) * 2015-04-17 2016-10-20 Bayer Pharma Aktiengesellschaft Nouveaux composés d'aryl-cyanoguanidine
US20180099937A1 (en) 2015-04-17 2018-04-12 Bayer Pharma Aktiengesellschaft Novel aryl-cyanoguanidine compounds
EP3109237A1 (fr) 2015-06-22 2016-12-28 AnaMar AB Nouveaux antagonistes de 5-ht2
CN111892585A (zh) * 2020-08-05 2020-11-06 杭州维坦医药科技有限公司 作为p2x3受体拮抗剂的n-甲酰胺基吡唑啉类衍生物及应用

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DE69131899T2 (de) * 1990-07-13 2000-08-17 Rohm And Haas Co., Philadelphia N-Aryl-3-aryl-4-substituierte-4,5-dihydro-1H-pyrazol-1-carboxamide und Verfahren zu deren Herstellung
DE4217862A1 (de) * 1991-08-28 1993-03-04 Bayer Ag Substituierte pyrazoline
DE4217863A1 (de) * 1991-08-28 1993-03-04 Bayer Ag Substituierte pyrazoline
DE4217864A1 (de) * 1992-05-29 1993-12-02 Bayer Ag Substituierte Pyrazoline
DE4233713A1 (de) * 1992-10-07 1994-04-14 Bayer Ag Substituierte 4,5-Dihydro-1-pyrazolcarbonsäureanilide

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Title
See references of WO2005007157A1 *

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CA2532316A1 (fr) 2005-01-27
WO2005007157A1 (fr) 2005-01-27
NO20060733L (no) 2006-04-10
MXPA06000507A (es) 2006-04-05
AU2004257406A1 (en) 2005-01-27
MA27905A1 (fr) 2006-05-02

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