WO2006072351A1 - Pyrazolines a substitution heteroaryle en tant qu'antagonistes de par-1 - Google Patents

Pyrazolines a substitution heteroaryle en tant qu'antagonistes de par-1 Download PDF

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Publication number
WO2006072351A1
WO2006072351A1 PCT/EP2005/013221 EP2005013221W WO2006072351A1 WO 2006072351 A1 WO2006072351 A1 WO 2006072351A1 EP 2005013221 W EP2005013221 W EP 2005013221W WO 2006072351 A1 WO2006072351 A1 WO 2006072351A1
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group
formula
hydrogen
substituted
phenyl
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PCT/EP2005/013221
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German (de)
English (en)
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Dirk Brohm
Nicole Diedrichs
Walter Hübsch
Britta-Nicole FRÖHLEN
Christoph Gerdes
Mark Jean Gnoth
Elisabeth Perzborn
Verena Vöhringer
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Bayer Healthcare Ag
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    • 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
    • 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
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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

  • the present invention relates to the field of blood clotting.
  • the present invention relates to the use of heteroaryl-substituted pyrazolines as medicaments, to novel heteroaryl-substituted pyrazolines and to processes for their preparation and to their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular of cardiovascular diseases, preferably of thromboembolic disorders.
  • Platelets are a major factor in both hemostasis and thromboembolic disorders. Particularly in the arterial system, platelets are of central importance in the complex interaction between blood components and the vessel wall. Undesirable platelet activation can lead to thromboembolic diseases and thrombotic complications with life-threatening conditions by the formation of platelet-rich thrombi.
  • thrombin coagulation protease thrombin
  • Vu TKH Hung DT
  • Wheaton VI Coughlin SR 3 Cell 1991, 64, 1057-1068
  • thrombin inhibitors inhibit platelet aggregation or the formation of platelet-rich thrombi.
  • arterial thrombosis can be successfully treated with inhibitors of platelet function as well as thrombin inhibitors (Bhatt DL, Topol EJ, Nat., Rev. Drug Discov., 2003, 2, 15-28).
  • platelet thrombin antagonists are highly likely to reduce the formation of thrombi and the onset of clinical consequences such as myocardial infarction and stroke.
  • Other cellular thrombin effects for example 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, via a family of G protein-coupled receptors (PARs) whose prototype is the PAR-I receptor.
  • PAR-I is activated by binding of thrombin and proteolytic cleavage of its extracellular N-terminus. Proteolysis reveals a new N-terminus with the amino acid sequence SFLLRN ..., which acts as an agonist ("tethered ligand") for intramolecular receptor activation and transmission of intracellular signals.
  • Peptides derived from the tethered ligand sequence can be used as agonists of the receptor Be and lead to platelets for activation and aggregation.
  • Antibodies and other selective PAR-1 antagonists inhibit thrombin-induced aggregation of platelets in vitro at low to moderate thrombin concentrations (Kahn ML, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR, J. Clin. 103, 879-887).
  • Another thrombin receptor of potential importance for the pathophysiology of thrombotic processes, PAR-4 has been 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).
  • 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 diseases
  • WO 03/079973 describes pyrazoline derivatives for the treatment of cancer
  • WO 05/007157 describes pyrazoline derivatives as PAR-I antagonists for the treatment of heart -cycle-diseases.
  • the present invention relates to compounds of the formula
  • R 1 is a group of the formula
  • X is NH, an oxygen atom or a sulfur atom
  • R 7 is hydrogen, (C, -C 4) alkyl, cyclopropyl, (Ci-C 4) alkylcarbonyl, (Ci-C 6) -Alkylammocarbonyl, (C r C4) -alkoxycarbonyl or methylsulfonyl group,
  • alkyl may be substituted with 1 to 2 substituents independently selected from the group consisting of hydroxy, amino,
  • o 1, 2 or 3
  • p 1, 2 or 3
  • q 1, 2 or 3
  • R 4 is hydrogen, hydroxy, amino, 2-hydroxyeth-1-yl, (C 1 -C 3 ) -alkoxy or (C 1 -C 6 ) -alkylamino,
  • R 5 is hydrogen, methyl, ethyl, n-propyl, 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl or 2,3-dihydroxyprop -l-yl,
  • R 6 is hydrogen, methyl, ethyl, n-propyl, 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3
  • methylcarbonyl, ethylcarbonyl and n-propylcarbonyl may be substituted with 1 to 2 substituents independently selected from
  • alkyl may be substituted by 1 to 3 substituents independently selected from the group consisting of (C 3 -C 7 ) -cycloalkyl, phenyl, 1,3-benzodioxolyl,
  • phenyl and heteroaryl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, amino, cyano, nitro, (Ci-C 4 ) alkyl, (C r C 4 ) alkoxy, (C r C 6 ) -alkylamino, Trifluoromethyl, 2,2,2-trifluoroeth-l-yl, trifluoromethoxy, difluoromethoxy and (C r C 4) alkylsulfonyl,
  • R 2 is (C 3 -C 7 ) -cycloalkyl, phenyl, 1,3-benzodioxolyl, 2,2-difluoro-1,3-benzodioxolyl or 5- or 6-membered heteroaryl,
  • phenyl and heteroaryl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, amino, cyano, nitro, (CRQ) -alkyl, (C r C4) alkoxy, (C r C 6) Alkylamino, trifluoromethyl, 2,2,2-trifluoroeth-1-yl, trifluoromethoxy, difluoromethoxy and (C 1 -C 4 ) alkylsulfonyl,
  • O R is a group of the formula
  • R 8 represents halogen, cyano, trifluoromethyl, trifluoromethoxy or difluoromethoxy,
  • R 9 represents hydrogen, halogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy,
  • R is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy or difluoromethoxy,
  • R 11 is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy or
  • Compounds of the invention are the compounds of formula (I) and their salts, solvates and solvates of the salts; the compounds of formula (I) of the following five formulas and their salts, solvates and solvates of the salts and those of formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds 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 comprises 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, 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.
  • 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
  • solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
  • Alkylaminocarbonyl, alkylsulfonyl and alkoxycarbonyl are a linear or branched alkyl radical having .1 to 6, preferably having 1 to 4 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n Pentyl and n-hexyl.
  • 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 preferably methylamino, ethylamino, n-
  • C 1 -C 3 -alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having 1 to 3 carbon atoms each
  • Alkylcarbonyl is exemplified and preferably methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl and tert-butylcarbonyl.
  • 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 preferably methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-Nn-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-Nn pentylaminocarbonyl and Nn-hexyl-N-
  • C 1 -C 5 -alkylaminocarbonyl is, for example, a monoalkylaminocarbonyl 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 exemplary and preferably methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl and tert-butylsulfonyl.
  • Alkoxycarbonyl is, by way of example and by way of preference, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
  • Cycloalkyl represents a monocyclic or bicyclic cycloalkyl group having usually 3 to 7, preferably 5 or 6 carbon atoms, by way of example and cycloalkyl being preferably mentioned for cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohepryl.
  • Heteroaryl is an aromatic monocyclic radical having 5 or 6 ring atoms and up to 4, preferably up to 3 heteroatoms from the series S, O and N, by way of example and preferably for thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isooxazolyl, oxadiazolyl , Pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl.
  • Halogen is fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
  • a symbol # on a carbon atom means that the compound is in enantiomerically pure form with respect to the configuration at this carbon atom, which in the context of the present invention is understood to have 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 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.
  • A is a group of the formula
  • X is NH or an oxygen atom
  • R 7 is hydrogen, methyl, ethyl, cyclopropyl, methylcarbonyl or
  • ethyl may be substituted with 1 to 2 substituents independently selected from the group consisting of hydroxy, (Ci-C ß ) - alkylamino, methylcarbonyl and ethylcarbonyl,
  • methyl may be substituted with a substituent selected from the group consisting of methylcarbonyl and ethylcarbonyl,
  • o 1, 2 or 3
  • p is 1, 2 or 3
  • q is 1, 2 or 3
  • R 4 is hydrogen, hydroxy, amino, (C 1 -C 6 ) -alkylamino or 2-hydroxyeth-1-yl,
  • R 5 is hydrogen, methyl, ethyl, n-propyl, 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl or 2,3-dihydroxyprop -l-yl stands,
  • R 6 represents hydrogen, methyl, ethyl, n-propyl, 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl, 2,3-dihydroxyprop -l-yl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or methylsulfonyl,
  • methylcarbonyl, ethylcarbonyl and n-propylcarbonyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of hydroxy, amino, (C 1 -C 3 ) -alkoxy and (C 1 -C 3 ) -alkylcarbonyloxy,
  • R 2 is (C 1 -C 4 ) -alkyl
  • alkyl may be substituted by a substituent selected from the group consisting of (C 3 -C 7 ) -cycloalkyl, phenyl, 1,3-benzodioxolyl, 2,2-difluoro-1, 3-benzodioxolyl, thienyl, furyl, thiazolyl, Oxazolyl, isothiazolyl, isooxazolyl and pyridyl,
  • R 2 is (C 3 -C 7 ) -cycloalkyl, phenyl, 1,3-benzodioxolyl, 2,2-difluoro-1, 3-benzodioxolyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl, isooxazolyl or pyridyl,
  • phenyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl, isooxazolyl and pyridyl can be substituted by 1 to 3 substituents, independently selected from the group consisting of halogen, cyano, nitro, (Q-GO-alkoxy, trifluoromethyl, trifluoromethoxy and difluoromethoxy,
  • R 3 is a group of the formula
  • R 8 is halogen, cyano, trifluoromethyl, trifluoromethoxy or difluoromethoxy,
  • R is hydrogen or halogen
  • R, 1 1 0 U is hydrogen, fluorine, chlorine or trifluoromethyl
  • R > ⁇ is hydrogen, fluorine, chlorine or trifluoromethyl
  • R 1 is a group of the formula
  • X is NH or an oxygen atom
  • Y is NR 7 or an oxygen atom
  • R 7 is hydrogen, methyl, ethyl or cyclopropyl
  • o stands for 1 or 2
  • p stands for 1 or 2
  • R 4 is hydrogen, hydroxy, amino or (C 1 -C 6) -alkylamino
  • R 5 is hydrogen, methyl, ethyl, n-propyl, 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl or 2,3-dihydroxyprop -l-yl,
  • R 6 is hydrogen, methyl, ethyl, n-propyl, 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3
  • alkyl may be substituted with a substituent selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, phenyl, 1,3-benzodioxolyl and 2,2-difluoro-1,3-benzodioxolyl,
  • phenyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, nitro,
  • R 2 is cyclopentyl, cyclohexyl, cycloheptyl, phenyl, 1,3-benzodioxolyl, 2,2-difluoro-1,3-benzodioxolyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl, isooxazolyl or pyridyl,
  • phenyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl, isooxazolyl and pyridyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, nitro, (C r C 4 ) alkyl, (C r C 4 ) -alkoxy, trifluoromethyl, trifluoromethoxy and difluoromethoxy,
  • R 3 is a group of the formula
  • R 8 is halogen, cyano, trifluoromethyl, trifluoromethoxy or difluoromethoxy
  • R 9 is hydrogen or halogen
  • R 10 is hydrogen, fluorine or chlorine
  • R 11 is hydrogen, fluorine or chlorine
  • A is a group of the formula
  • ** represents the point of attachment to R 2 .
  • R 1 is a group of the formula
  • Y is NR 7 or an oxygen atom
  • R 7 is hydrogen, methyl, ethyl or cyclopropyl
  • p stands for 1 or 2
  • R 5 is hydrogen, methyl, ethyl or 2-hydroxyeth-1-yl
  • R 6 is 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoproprl-yl, 2,3-dihydroxyprop-1-yl or methylcarbonyl,
  • methylcarbonyl may be substituted with a substituent selected from the group consisting of hydroxy, methoxy and methylcarbonyloxy,
  • R 2 is methyl or ethyl
  • methyl and ethyl may be substituted by a substituent selected from the group consisting of cyclopentyl, phenyl, 1,3-benzodioxolyl and 2,2-difluoro-1,3-benzodioxolyl,
  • phenyl may in turn be substituted by 1 to 3 substituents, independently of one another, selected from the group consisting of halogen, cyano,
  • R 2 is cyclohexyl, cycloheptyl, phenyl, 1,3-benzodioxolyl, 2,2-difluoro-1,3-benzodioxolyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl, isooxazolyl or pyridyl,
  • phenyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl, isooxazolyl and pyridyl can be substituted by 1 to 3 substituents, independently selected from the group consisting of halogen, cyano, nitro, methyl, methoxy, trifluoromethyl, trifluoromethoxy and difluoromethoxy,
  • R 3 is a group of the formula
  • R 8 is halogen
  • A is a group of the formula
  • R 1 is a group of the formula
  • Y is NR 7 or an oxygen atom
  • R 7 is hydrogen or methyl
  • p stands for 1 or 2
  • R 5 is hydrogen, methyl or ethyl
  • R 6 is 2-hydroxyeth-1-yl, 2-aminoeth-1-yl, 3-hydroxyprop-1-yl, 3-aminoprop-1-yl, 2,3-dihydroxyprop-1-yl or methylcarbonyl,
  • methylcarbonyl may be substituted with a substituent selected from the group consisting of hydroxy, methoxy and methylcarbonyloxy,
  • R 2 is cyclohexyl, cycloheptyl, phenyl, 1,3-benzodioxolyl, 2,2-difluoro-1,3-benzodioxolyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl, isooxazolyl or pyridyl,
  • phenyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl, isooxazolyl and pyridyl can be substituted by 1 to 3 substituents, independently selected from the group consisting of halogen, cyano, nitro, methyl, methoxy, trifluoromethyl, trifluoromethoxy and difluoromethoxy,
  • R 3 is a group of the formula
  • R 8 is chlorine or fluorine
  • R 2 is (C 1 -C 6 ) -alkyl
  • alkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of (C 3 -C 7 ) cycloalkyl, phenyl, 1,3-benzodioxolyl, 2,2-difluoro-1,3-benzodioxolyl and 5 or 6-membered heteroaryl,
  • phenyl and heteroaryl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, amino, cyano, nitro, (C 1 -Q) -alkoxy, (C r C 4 ) -alkoxy, (C r C 6 ) -alkylamino, trifluoromethyl, trifluoromethoxy and difluoromethoxy,
  • R 2 is (C 3 -C 7 ) -cycloalkyl, phenyl, 1,3-benzodioxolyl, 2,2-difluoro-1,3-benzodioxolyl or 5- or 6-membered heteroaryl,
  • phenyl and heteroaryl may be substituted by 1 to 3 substituents independently selected from the group consisting of halogen, amino, cyano, nitro, (C 1 -Q) -alkyl, (C, -Q) -alkoxy, (C r C 6 ) -alkylamino, trifluoromethyl,
  • R 2 is phenyl, 1,3-benzodioxolyl or 2,2-difluoro-1,3-benzodioxolyl, where phenyl may be substituted by 1 to 3 substituents, independently of one another from the group consisting of halogen, trifluoromethoxy and difluoromethoxy.
  • Another object of the present invention is a process for the preparation of the novel compounds of formula (I), wherein either
  • R 1 and R 3 have the abovementioned meaning
  • R 2 has the meaning indicated above
  • R 1 and R 3 have the abovementioned meaning
  • R 2 has the meaning indicated above
  • R 1 and R 3 have the abovementioned meaning
  • reaction according to process [A] and the first step of process [C] is generally carried out in inert solvents, in the presence of dehydrating reagents, optionally in the presence of a base, optionally in the presence of tetra-n-butylammonium fluoride, preferably in a temperature range from O 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, NN'-dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylamino-isopropyl) -N-ethylcarbodiimide hydrochloride (EDC) (optionally in 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-
  • carbodiimides such as e.g. N, N'-diethyl, NN'-dipropyl, N, N'-diisopropyl, N
  • TPTU 1,1,3,3-tetramethyluronium tetrafluoroborate
  • HATU 1,1,3,3-tetramethyluronium tetrafluoroborate
  • HOBt 1-hydroxybenzotriazole
  • BOP Benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate
  • the coupling is performed with HOBt and EDC.
  • 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, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, or ⁇ itromethane, dioxane, dimethylformamide, acetonitrile or hexamethylphosphoric triamide. It is also possible to use mixtures of the solvents. Particularly preferred is dichloromethane or dimethylformamide.
  • the reaction according to process [B] is generally carried out in inert solvents, in the presence of ⁇ -bromo or ⁇ -chlorosuccinimide, in the presence of a base, preferably in a temperature range from 0 ° C. to reflux of the solvents under normal pressure.
  • a base preferably in a temperature range from 0 ° C. to reflux of the solvents under normal pressure.
  • the compound of the formula (V) is first reacted with N-bromo- or N-chlorosuccinimide and then the compound of the formula (IV) and the base are added.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, 1,2-dichloroethane or tetrachloromethane, or other solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide or N-methylpyrrolidone, methylene chloride being preferred.
  • halogenated hydrocarbons such as methylene chloride, trichloromethane, 1,2-dichloroethane or tetrachloromethane
  • other solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide or N-methylpyrrolidone, methylene chloride being preferred.
  • Bases include, for example, organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, or DBU, DB ⁇ , pyridine, or mixtures of bases, preferred is triethylamine.
  • organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, or DBU, DB ⁇ , pyridine, or mixtures of bases, preferred is triethylamine.
  • the reaction of the second stage of process [C] 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, hydrocarbons such as benzene, xylene or toluene, preference is given to toluene.
  • Acids are, for example, methanesulfonic acid, phosphoric acid or sulfuric acid, preference is given to methanesulfonic acid.
  • R 1 and R 3 have the abovementioned meaning
  • the reaction of the first stage is generally carried out in inert solvents, preferably in a temperature range from room temperature to the reflux of the solvent at atmospheric pressure.
  • Inert solvents are, for example, tetrahydrofuran, dioxane, dimethylformamide or acetonitrile, preference is given to dioxane.
  • the reaction of the second 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, or other solvents such as acetone, tetrahydrofuran, dioxane, dimethylformamide or acetonitrile, or mixtures of these solvents with water, preferably a mixture of methanol, acetone and water.
  • alcohols such as methanol, ethanol, n-propanol or isopropanol
  • other solvents such as acetone, tetrahydrofuran, dioxane, dimethylformamide or acetonitrile, or mixtures of these solvents with water, preferably a mixture of methanol, acetone and water.
  • Bases are, for example, alkali carbonates, e.g. Cesium carbonate, sodium or potassium carbonate, or bicarbonate, or alkali metal hydroxides, e.g. Lithium hydroxide, sodium or potassium hydroxide, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preferably sodium or potassium carbonate.
  • alkali carbonates e.g. Cesium carbonate, sodium or potassium carbonate, or bicarbonate
  • alkali metal hydroxides e.g. Lithium hydroxide, sodium or potassium hydroxide
  • organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preferably sodium or potassium carbonate.
  • the reaction of the third stage is generally carried out in inert solvents, 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, or other solvents such as dimethylformamide, acetonitrile, acetone, 2-butanone or N-methylpyrrolidone, preference is given to ethanol.
  • the fourth stage reaction is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from room temperature to reflux of the solvents under normal pressure.
  • Inert solvents are, for example, alcohols, such as methanol, ethanol, n-propanol or isopropanol, ethanol being preferred.
  • Bases are, for example, alkali hydroxides, e.g. Lithium hydroxide, sodium or potassium hydroxide, or alkali carbonates, e.g. Cesium carbonate, sodium or potassium carbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine,
  • 4-dimethylaminopyridine or diisopropylethylamine, or pyridine is preferably sodium hydroxide.
  • the compounds of formula (IV) are known or can be prepared by reacting compounds of formula (VII) with cyanogen bromide.
  • the reaction is generally carried out in inert solvents, in the presence of a base, preferably in a temperature range from room temperature to 5O 0 C at atmospheric pressure.
  • Inert solvents are, for example, alcohols, such as methanol, ethanol, n-propanol or isopropanol, preferably isopropanol.
  • Bases are, for example, alkali carbonates, e.g. Cesium carbonate, sodium or potassium carbonate, or bicarbonate, preferably sodium or potassium bicarbonate.
  • the compounds of the formula (VI) are known or can be prepared by reacting compounds of the formula (IV) in a two-stage process first with dimethyltrithio carbonate and then with hydrazine hydrate.
  • the reaction of 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 5O 0 C at atmospheric pressure.
  • Inert solvents are, for example, alcohols, such as methanol, ethanol, n-propanol or isopropanol, preferably isopropanol.
  • bases are alcoholates such as sodium or potassium methoxide or sodium or potassium ethoxide or potassium tert-butylate or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, potassium tert-butoxide being preferred.
  • the reaction of 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 atmospheric pressure.
  • Inert solvents are, for example, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone or acetonitrile, dimethyl sulfoxide being preferred.
  • R 1 and R 3 have the abovementioned meaning
  • 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, or other solvents such as tetrahydrofuran, or dimethylformamide, preferably ethanol.
  • Bases include, for example, organic bases such as amine bases, e.g. Piperidine, triethylamine, diisopropylethylamine or DBU, piperidine is preferred.
  • organic bases such as 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 atmospheric pressure.
  • Inert solvents are, for example, alcohols, such as methanol, ethanol, n-propanol or isopropanol, or other solvents, such as tetrahydrofuran or dimethylformamide, preference is given to ethanol.
  • R 3 has the meaning indicated above
  • R 1 has the meaning indicated 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 reflux of the solvent under 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 sulphoxide, acetonitrile or pyridine, preferred is dimethylformamide or tetrahydrofuran.
  • 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
  • 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 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, pyridine or DBU, preferred is sodium hydride.
  • the compounds of the formula (VIII) can be prepared by reacting compounds of the formula (XI)
  • R 1 and R 3 have the abovementioned meaning
  • the reaction is generally carried out in inert solvents, in the presence of an oxidizing agent, preferably in a temperature range from -78 ° C to 5O 0 C at atmospheric pressure.
  • Inert solvents are, for example, mixtures of water with dioxane, benzene or acetone, preferably a mixture of water and dioxane.
  • Oxidizing agents are, for example, ozone, potassium osmate, potassium permanganate or osmium tetroxide in the presence of sodium or potassium periodate, preferably potassium osmate with sodium periodate.
  • R 3 has the meaning indicated above
  • the compounds of the invention show an unpredictable, valuable pharmacological and pharmacokinetic activity spectrum.
  • These are selective antagonists of the PAR-I receptor, which act in particular as platelet aggregation inhibitors. 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 myocardial infarction with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI), stable angina pectoris, unstable angina pectoris, reocclusions and Restenosis following coronary interventions such as angioplasty, stent or aortocoronary bypass, peripheral arterial occlusive disease, pulmonary embolism, deep venous thrombosis and renal vein thrombosis, transient ischemic attacks, and thrombotic and thromboembolic stroke.
  • diseases such as myocardial infarction with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI)
  • stable angina pectoris such as myocardial infarction with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI)
  • unstable angina pectoris such as myocardial infarction with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI)
  • the substances are therefore also useful in the prevention and treatment of cardiogenic thromboembolism, such as brain ischemia, stroke and systemic thromboembolism and ischaemia, in patients with acute, intermittent or persistent cardiac arrhythmias, such as atrial fibrillation, and those undergoing cardioversion patients with valvular heart disease or with artificial heart valves.
  • cardiogenic thromboembolism such as brain ischemia, stroke and systemic thromboembolism and ischaemia
  • cardiac arrhythmias such as 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 come. compounds according to the invention also for influencing wound healing, for the prophylaxis and / or treatment of atherosclerotic vascular diseases and inflammatory diseases such as rheumatic diseases of the musculoskeletal system, coronary heart disease, heart failure, hypertension, inflammatory diseases such as asthma,. Inflammatory lung disease, glomerulonephritis and inflammatory bowel disease into consideration, as well as for the prophylaxis and / or treatment of Alzheimer's disease.
  • atherosclerotic vascular diseases and inflammatory diseases such as rheumatic diseases of the musculoskeletal system, coronary heart disease, heart failure, hypertension, inflammatory diseases such as asthma,. Inflammatory lung disease, glomerulonephritis and inflammatory bowel disease into consideration, as well as for the prophylaxis and / or treatment of Alzheimer's disease.
  • the compounds of the present invention can be used to inhibit tumor growth and metastasis, in microangiopathies, age-related macular degeneration, diabetic retinopathy, diabetic nephropathy and other microvascular diseases, and for the prevention and treatment of thromboembolic complications such as venous thromboembolism in tumors. 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 compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using a therapeutically effective amount of a compound of the invention.
  • Another object of the present invention are pharmaceutical compositions containing a compound of the invention and one or more other active ingredients.
  • 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, conjunctival, otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds of the invention in crystalline and / or amorphised and / or dissolved
  • Such as tablets uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings which control the release of the compound of the invention
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • the oral application is preferred.
  • Inhalation medicines including powder inhalants, 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
  • 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-toxic, pharmaceutically suitable excipients, and to their use for the abovementioned purposes.
  • medicaments which contain at least one compound according to the invention, preferably together with one or more inert non-toxic, pharmaceutically suitable excipients, and to their use for the abovementioned purposes.
  • it has been found to be beneficial to administer amounts of about 5 to 250 mg per 24 hours when administered parenterally to achieve effective results. When administered orally, the amount is about 5 to 100 mg per 24 hours.
  • Method 1 (HPLC, Enantiomer Separation): Chiral silica gel selector SYFO 7266 (250 mm x 30 mm) based on the selector poly (N-methacryloyl-D-leucine-dicyclopropylmethylamide); ethyl acetate; Temperature: 24 ° C; Flow: 50 ml / min; UV detection: 280 nm.
  • Method 5 (HPLC, separation of enantiomers): Chiral silica gel selector Chiralcel OD-H (250 mm ⁇ 20 mm); Daicel, Japan, iso-hexane / iso-propanol 1: 1; Temperature: 24 ° C; Flow: 15 ml / min; UV detection: 254 nm.
  • Method 6 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: 25O 0 C; Gradient: 6O 0 C (hold for 0.30 min), 50 ° C / min -> 12O 0 C, 16 ° C / min -> 250 0 C, 30 ° C / min -> 300 0 C (hold for 1.7 min).
  • Method 7 Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 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 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 8 Device Type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; 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.
  • the mixture is then added to a mixture of semisaturated ammonium chloride solution and ethyl acetate and the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated.
  • the solid is slurried with diethyl ether and separated on a glass frit. After drying in a high vacuum, 3.80 g (44% of theory) of the desired product are obtained as crystals.
  • the batch is then poured onto half-concentrated ammonium chloride solution and ethyl acetate.
  • the organic phase is separated, washed with water, saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated.
  • the residue is dissolved in 75 ml of tetrahydrofuran, 8.99 ml (8.99 mmol) of IN tetra-n-butylammonium fluoride solution are added dropwise and the mixture is stirred overnight.
  • the batch is then poured onto half-concentrated sodium bicarbonate solution and ethyl acetate.
  • the organic phase is separated, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated.
  • the solidifying from dichloromethane solid is filtered off with suction, washed with diethyl ether and dried. This results in 1.34 (39% of theory) of the product as crystals.
  • Example 28A Analogously to Example 28A, the compounds of Examples 29A to 34A are prepared.
  • the batch is then poured onto half-concentrated ammonium chloride solution and ethyl acetate.
  • the organic phase is separated, washed with water, saturated sodium carbonate solution, saturated sodium washed chloride solution, dried over magnesium sulfate, filtered and concentrated.
  • the residue is dissolved in 5 ml of tetrahydrofuran, added dropwise 0.34 ml (0.34 mmol) IN tetra-n-butyl-ammonium fluoride solution and stirred overnight.
  • the batch is then poured onto half-concentrated sodium bicarbonate solution and ethyl acetate.
  • the organic phase is separated, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated.
  • the crystallized from toluene solid is filtered off with suction, washed with diethyl ether and dried. This results in 97 mg (64% of theory) of the product as crystals.
  • Example 22 the compounds of Examples 23 to 43 are prepared.
  • Example 32 enantiomerically pure starting material is used.
  • Example 22 Analogously to the example described above (Example 22), the compounds of Examples 51 to 54 are prepared using N- [1 - [(E) -amino (hydroxyimino) methyl] -3- (4-chlorophenyl) -4, 5-dihydro-1H-pyrazol-4-yl] -N-ethyl-2-hydroxyacetamide (Example 18A) as starting material.
  • Example 51 is separated by method 3 into the enantiomers.
  • the active enantiomer elutes second.
  • Example 54 is separated into the enantiomers by Method 5. The active enantiomer elutes second.
  • the batch After cooling to room temperature, the batch is diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, water and with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC. This results in 52 mg (42% of theory) of the desired product.
  • the identification of agonists of the human Protease Activated Receptor 1 (PARI) as well as the quantification of the efficacy of the substances described here takes place with the aid of 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 constitutively expresses a modified form of the calcium-sensitive photoprotein aequorin, which emits light upon reconstitution with the co-factor coelenterazine with increases in the free calcium concentration in the inner mitochondrial compartment (Rizzuto R, Simpson AW, Brini M, Pozzan T Nature 1992, 358, 325-327).
  • the cell stably expresses the endogenous human PARI receptor as well as the endogenous purinergic receptor P2Y2.
  • the resulting PARI test cell responds to stimulation of the endogenous PARI or P2Y2 receptor with 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 Cells are cultured (DMEM F12 supplemented with 10% FCS, 2mM glutamine, 20mM HEPES, 1.4mM pyruvate, 0.1mg / ml gentamycin, 0.15mM) for 2 days (48 hrs.) Prior to assay % Na bicarbonate, BioWhittaker Cat # BE04-687Q, B-4800 Verviers, Belgium) in 384-well microtiter plates and maintained in a cell incubator (96% humidity, 5% v / v CO 2 , 37 0 C).
  • the culture medium is replaced by a Tyrodel solution (in mM: 140 NaCl, 5 KCl, 1 MgCl 2 , 2 CaCl 2 , 20 glucose, 20 HEPES), which additionally contains the co-factor coelenterazine (25 ⁇ M) and glutathione (4 mM), and then the microtiter plate is incubated for a further 3-4 hours. Then the 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 , and immediately measured the resulting light signal in the luminometer. To distinguish an antagonist substance effect from a toxic effect, the endogenous purinergic receptor with agonist is activated immediately afterwards (ATP, 10 ⁇ M final concentration) and the resulting light signal is measured.
  • Table A The results are shown in Table A:
  • Sex who had not received platelet aggregation medications within the past ten days.
  • the blood is used in monovettes (Sarstedt,
  • SFLLRN thrombin receptor agonist
  • Human whole blood is collected by venipuncture from volunteer donors and transferred to monovettes (Sarstedt, Nümbrecht, Germany) containing sodium citrate as anticoagulant (1 part sodium citrate 3.8% + 9 parts whole blood).
  • the monovettes are centrifuged at 900 rpm and 4 ° C for a period of 20 minutes (Heraeus Instruments, Germany, Megafuge 1.0RS).
  • the platelet rich plasma is gently removed and transferred to a 50 ml Falcon tube. Now the plasma is mixed with ACD buffer (44 fflM sodium citrate, 20.9 mM citric acid, 74.1 mM glucose).
  • the volume of the ACD buffer is one fourth of the plasma volume.
  • 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, N'N'-tetraacetic acid, 0.1% glucose
  • 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, N'N'-tetraacetic acid, 0.1% glucose
  • incubation buffer 134 mM sodium chloride, 12 mM sodium bicarbonate, 2.9 mM potassium chloride, 0.34 mM sodium dihydrogencarbonate, 5 mM HEPES, 5 mM glucose , 2 mM calcium chloride and 2 mM magnesium chloride
  • the platelet suspension is preincubated with the substance or the corresponding solvent for 10 minutes at 37 ° C. (Eppendorf, Germany, Thermomixer Comfort).
  • Addition of 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
  • TRIP6 thrombin receptor activating peptide
  • An aliquot of 50 ⁇ l is withdrawn at 0, 1, 2.5, 5, 10 and 15 minutes each time and transferred to one milliliter of single-concentrated CellFix TM solution (Becton Dickinson Immunocytometry Systems, USA).
  • a fluorescein-isothiocyanate-conjugated antibody directed against the human glycoprotein (CD41) is used (Immunotech Coulter, France, Cat. No. 0649).
  • the activation state of the platelets can be determined.
  • P-selectin (CD62P) is located in the ⁇ -granules of resting thrombocytes. However, it is translocated to the outer plasma membrane after in vitro or in vivo stimulation.
  • Samples are measured in the FACSCalibur TM Flow Cytometry System from Becton Dickinson Immunocytometry Systems, USA and evaluated and graphed using CellQuest, Version 3.3 (Becton Dickinson Immunocytometry Systems, USA) software.
  • the level of platelet activation is determined by the percentage of CD62P-positive platelets (CD41-positive events). From each sample 10,000 CD41 positive events are counted.
  • the inhibitory effect of the substances to be tested is calculated on the basis of the reduction of platelet activation, which relates to activation by the agonist.
  • Guinea pigs (strain: Dunkin Hartley) are treated in an active or anaesthetized state orally, intravenously or intraperitoneally with test substances in a suitable formulation. As a control, other guinea pigs are treated identically with the appropriate vehicle.
  • blood is obtained from deep anesthetized animals by puncturing the heart or the aorta. The blood is taken in monovettes (Sarstedt, Nümbrecht, Germany) containing as anticoagulant sodium citrate 3.8% (1 part citrate solution + 9 parts blood). To obtain platelet-rich plasma, the citrated whole blood is centrifuged at 2500 rpm for 20 minutes at 4 ° C.
  • the aggregation is triggered by the addition of a thrombin receptor agonist (SFLLRN, 50 ⁇ g / ml) in an aggregometer and determined by Born's turbidimetric method (Born, GVR, Cross MJ, The Aggregation of Blood Platelets, J. Physiol. 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 addition of the agonist.
  • the inhibitory effect of the administered test substances in the treated animals is calculated by reducing the aggregation, based on the mean 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-I receptor.
  • Guinea pigs and especially primates are suitable as animal species (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 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.
  • the rhodigel is suspended in ethanol, the compound of Example 1 is added to the suspension. While stirring, the addition of water. Until the swelling of the Rhodigels is complete, it is stirred for about 6 hours. Iatravenously administrable solution;
  • 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

La présente invention concerne le domaine de la coagulation sanguine, et en particulier l'utilisation de pyrazolines à substitution hétéroaryle en tant que médicaments. Elle concerne également de nouvelles pyrazolines à substitution hétéroaryle, des procédés de production desdites pyrazolines ainsi que leur utilisation pour la production de médicaments destinés à traiter et / ou à prévenir des maladies, en particulier des maladies cardio-vasculaires, de préférence des maladies thromboemboliques.
PCT/EP2005/013221 2004-12-22 2005-12-09 Pyrazolines a substitution heteroaryle en tant qu'antagonistes de par-1 WO2006072351A1 (fr)

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EP3109237A1 (fr) 2015-06-22 2016-12-28 AnaMar AB Nouveaux antagonistes de 5-ht2
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