EP1644353A1 - 1,2,4-triazino-5(2h)-ones a substitution amide destinees au traitement de maladies inflammatoires chroniques - Google Patents

1,2,4-triazino-5(2h)-ones a substitution amide destinees au traitement de maladies inflammatoires chroniques

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Publication number
EP1644353A1
EP1644353A1 EP04737078A EP04737078A EP1644353A1 EP 1644353 A1 EP1644353 A1 EP 1644353A1 EP 04737078 A EP04737078 A EP 04737078A EP 04737078 A EP04737078 A EP 04737078A EP 1644353 A1 EP1644353 A1 EP 1644353A1
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EP
European Patent Office
Prior art keywords
substituents
alkyl
substituted
mmol
halogen
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.)
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Application number
EP04737078A
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German (de)
English (en)
Inventor
Timo Flessner
Kerstin Henninger
Martin Raabe
Elisabeth Woltering
Siegfried Zaiss
Katja Zimmermann
Franz Zumpe
Gunter Karig
Martin Hendrix
Olaf Weber
Dagmar Karthaus
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Bayer AG
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Bayer Healthcare AG
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Priority claimed from DE102004014061A external-priority patent/DE102004014061A1/de
Application filed by Bayer Healthcare AG filed Critical Bayer Healthcare AG
Publication of EP1644353A1 publication Critical patent/EP1644353A1/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Withdrawn legal-status Critical Current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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to id-substituted 1,2,4-triazin-5 (2H) -ones and processes for their preparation and their use for the manufacture of medicaments for the treatment and / or prophylaxis of diseases, in particular chronic inflammatory diseases, such as e.g. Diseases of the rheumatoid type, and cardiovascular diseases, such as Dyslipidemia, arteriosclerosis and coronary heart disease.
  • chronic inflammatory diseases such as e.g. Diseases of the rheumatoid type
  • cardiovascular diseases such as Dyslipidemia, arteriosclerosis and coronary heart disease.
  • WO 03/41712 relates inter alia to triazinones as Lp-PLA2 inhibitors for the treatment of arteriosclerosis.
  • the inflammatory component in the pathophysiology of arteriosclerosis is widely recognized today.
  • the inflammatory vascular changes result from the reaction of immigrating monocytes with pathogenic lipoproteins in the artery wall.
  • the formation of foam cells from the monocytes by immigrant Auf ⁇ ahme of oxidized 'lipids plays a central role in a plaque development and stability.
  • native lipoproteins In order to be recognized by monocytes, native lipoproteins must be modified to an atherogenic form.
  • the enzyme 'platelet-activating factor acetylhydrolase' (PAF-AH) plays a key role in this by forming the inflammation mediators lysophosphatidylcholine and oxidized fatty acids from oxidized LDL (low-density lipoprotein).
  • Plasma PAF-AH is a calcium-independent member of the phospholipase A2 family secreted by monocytes and macrophages.
  • the substrates of the PAF-AH are the platelet-activating factor (PAF) and oxidized phospholipids in the oxidized. LDL (oxLDL).
  • PAF platelet-activating factor
  • LDL oxLDL
  • LysoPC oxidized fatty acids and lysophosphatidylcholine
  • the pro-inflammatory mediator LysoPC is responsible for the accumulation of cholesterol ester-loaded monocytes (foam cells) in the arteries (Quinn, et al., Proc. Natl. Acad. Sei. USA 1988, 85, 2805-2809).
  • PAF-AH inhibitors could be used in any disease that has activated monocytes, macrophages or lymphocytes, since all of these cells express the enzyme.
  • the amide-substituted 1,2,4-triazin-5 (2H) -one inhibitors described in the present invention are PAF-AH inhibitors.
  • the invention relates to compounds of the formula
  • Y represents an oxygen atom or a sulfur atom
  • n a number 1, 2 or 3
  • n stands for a number 1, 2, 3 or 4,
  • R 1 stands for CC 6 alkyl or C 3 -C 7 cycloalkyl, where alkyl can be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, cyano, oxo, phenyl, hydroxycarbonyl, Alkoxycarbonyl, A inocarbonyl and alkylaminocarbonyl,
  • R 2 represents 5- to 10-membered heteroaryl, where heteroaryl can be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of hydroxyl, arnino, halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylamino, alkylthio, aryl, aryloxy, hydroxycarbonyl, alkoxycarbonyl , Aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl and alkylcarbonylamino,
  • R 3 represents hydrogen or C, -C 6 alkyl, where alkyl can be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of hydroxyl, amino, halogen, alkoxy, alkylamino, hydroxyalkylamino, alkylthio , Heterocyclyl, heteroaryl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylammocarbonyl, alkylcarbonyl and alkylcarbonylamino,. ...
  • heterocyclyl and heteroaryl can in turn be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of hydroxyl, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylamino, alkylthio, Hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylammocarbonyl, alkylcarbonyl and alkylcarbonylamino,
  • R 3 represents a 3- to 8-membered heterocyclyl having 1 to 2 nitrogen atoms, where heterocyclyl can be substituted by 1 to 2 substituents, the substituents being selected independently of one another from the group consisting of, optionally with hydroxyl, amino or Alkoxy substituted alkyl,
  • R 4 stands for aryl or heteroaryl, where aryl and heteroaryl can be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylamino , Alkylthio, alkylsulfonyl, aryl, aryloxy, heteroaryl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylammocarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylaminosulfonyl and alkylsulfonylamino, in which alkyl, alkoxy, alkylthio and alkylsulfonyl can be substituted with 1 to 3 substituents halogen, and in which aryl and heteroaryl can in turn be substituted with 1 to 3 substituents, the substituents being selected
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, and also the compounds encompassed by the formula (I) hereinafter referred to as exemplary embodiment (e) and their salts, solvates and solvates of the salts, to the extent the compounds mentioned below of formula (I) are not already salts, solvates or solvates of the salts.
  • the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore relates to 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.
  • preferred salts are physiologically acceptable salts of the compounds according to the invention. Also included, however, are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • Physiologically acceptable salts of the compounds of the invention also include salts of conventional bases such as for example and preferably alkali metal salts (eg sodium and potassium 5 salts), alkaline earth metal salts (such as "., Calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines of 1 up to 16 carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and ethylenediamine.
  • alkali metal salts eg sodium and potassium 5 salts
  • alkaline earth metal salts such as "., Calcium and magnesium salts
  • Solvates in the context of the invention are those forms of the compounds of the invention - -. Denotes that "in solid or liquid state by coordination with Lnmrs ⁇ s- agent molecules forming a complex Hydrates are a specific form of solvates where the coordination is with water he follows.
  • the free base of the salts of the compounds according to the invention can be obtained, for example, by adding an aqueous base, for example dilute sodium hydroxide solution, and subsequent extraction with a solvent by methods known to the person skilled in the art.
  • an aqueous base for example dilute sodium hydroxide solution
  • Alkoxy exemplifies and preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-5 butoxy, n-pentoxy and n-hexoxy.
  • Alkylthio is exemplary and preferably methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.
  • Alkylamino stands for an alkylamino radical with one or two (independently selected) alkyl substituents, for example and preferably for methylarnino, ethylamino, n-0 propylamino, isopropylamino, tert-butylamino, n-pentylamino, ' n-hexylamino, NN-dimethylamino, NN -Diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn- propylamino, N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.
  • C 1 -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.
  • Alkylsulfonyl is exemplified and preferably methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl ' and n-hexylsulfonyl.
  • Alkoxycarbonyl exemplifies and preferably represents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
  • Alkylammocarbonyl stands for an alkylaminocarbonyl radical with one or two (independently selected) alkyl substituents, the alkyl substituents 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, n-propylamino-carbonyl, isopropylaminocarbonyl, tert.-butylaminocarbonyl, n-pentylarninocarbonyl, n-hexylaminocarbonyl, NN-dimethylamrnocarbonyl, NN-diethylaminocarbonyl, N-ethyl-N-methyl-arninocarbonyl, N-methyl-Nn-propyl N-isopropyl-Nn-propylarninocarbonyl, N-tert-butyl-N-methylaminocarbony
  • C 1 -C 3 alkylaminocarbonyl represents, for example, a monoalkylaminocarbonyl radical having 1 to 3 carbon atoms or a dialkylaminocarbonyl radical each having 1 to 3 carbon atoms per alkyl substituent.
  • Alkylcarbonyl is an example and preferably methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl and n-hexylcarbonyl.
  • Alkylcarbonylamino is exemplary and preferably methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylamino and n-hexylcarbonylamino.
  • Allc laminosulfonyl represents an alkylaminosulfonyl radical with one or two (independently selected) alkyl substituents, the alkyl substituents independently of one another generally having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, for example and preferably methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl, tert-butylaminosulfonyl, n-pentylaminosulfonyl, n-hexylamino sulfonyl, NN-dimethylaminosulfonyl, NN-diethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl, N-methyl-Nn-propylaminosulfonyl, N-isopropyl-Nn-propyl
  • C 1 -C 3 alkylaminosulfonyl is, for example, a monoalkylaminosulfonyl radical having 1 to 3 carbon atoms or a dialkylaminosulfonyl radical each having 1 to 3 carbon atoms per alkyl substituent.
  • Alkylsulfonylamino is exemplary and preferably methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, n-pentylsulfonylamino and n-hexylsulfonylamino.
  • Cycloalkyl stands for a cycloalkyl group with usually 3 to 8, preferably 5 to 7 carbon atoms, examples and preferably for cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Aryl stands for a mono- to tricyclic aromatic radical with generally 6 to 14, preferably 6 to 10 carbon atoms, examples and preferably for aryl are phenyl, antaphthyl and phenanthrenyl.
  • Aryloxy stands for a mono- to tricyclic aromatic radical with generally 6 to 14, preferably 6 to 10 carbon atoms, which is bonded via an oxygen atom, for example and preferably for aryloxy, phenoxy, ⁇ aphthyloxy and phenanthrenyloxy are mentioned.
  • Heteroaryl stands for an aromatic, mono- or bicyclic radical with generally 5 to 10, preferably 5 to 6 ring atoms and up to 5, preferably up to 4 heteroatoms from the series S, O and ⁇ , a nitrogen atom also being a ⁇ - Can form oxide, by way of example and preferably for thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,. Indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzimidazolyl.
  • Heterocyclyl stands for a mono- or bicyclic, heterocyclic radical with generally 4 to 10, preferably 5 to 8 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series ⁇ , O, S, SO, S0 2 , whereby a nitrogen atom can also form a ⁇ -oxide.
  • 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, ⁇ and S series are preferred, for example and preferably for oxetan-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, Tetrahydrofuranyl, tetrahydrothienyl, 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 bond means the point of attachment in the molecule. If radicals in the compounds according to the invention are substituted, the radicals, unless otherwise specified, can be substituted one or more times in the same or different manner. A substitution with up to three identical or different substituents is preferred. Substitution with a substituent is very particularly preferred.
  • Preferred compounds of the formula (I) are those in which Y represents an oxygen atom or a sulfur atom, m represents a number 1 or 2, n represents a number 1, 2 or 3,
  • R 1 represents C 1 -C 6 -alkyl or C 3 -C 6 -cycloalkyl, where alkyl can be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, cyano, oxo, Phenyl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl and alkylammocarbonyl,
  • R 2 stands for 5- to 10-membered heteroaryl, where heteroaryl can be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy , Alkylamino, alkylthio, aryl, aryloxy, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylammocarbonyl, alkylcarbonyl and alkylcarbonylamino,
  • R 3 stands for hydrogen or CC 6 alkyl, where alkyl can be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of hydroxy, amino, alkoxy, alkylamino and hydroxyalkylamino, or R 3 represents a 5- to 7-membered heterocyclyl having 1 to 2 nitrogen atoms, it being possible for heterocyclyl to be substituted with 1 to 2 substituents, the substituents being selected independently of one another from the group consisting of optionally substituted with hydroxyl, amino or alkoxy alkyl,
  • R 4 represents aryl or heteroaryl, where aryl and heteroaryl can be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylamino, aryl, aryloxy , Heteroaryl, alkylammocarbonyl and alkylcarbonylamino, in which ⁇ lkylTrr ⁇ d alkoxy can be substituted with 1 to 3 substituents halogen, and in which aryl and heteroaryl can in turn be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, cyano , Trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylamino, alkylammocarbonyl and alkylcarbonylamino, in which alkyl and alkoxy can in turn be substitute
  • Y represents a sulfur atom
  • n 1
  • n stands for the number 1
  • R 1 stands for C 1 -C 4 -alkyl, cyclopentyl or cyclohexyl, where alkyl can be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of fluorine, cyano, oxo, phenyl, alkoxycarbonyl, aminocarbonyl and Alkylammocarbonyl
  • R 2 stands for pyridyl, thienyl, furyl, thiazolyl, oxadiazolyl, benzimidazolyl or benzoxazolyl, it being possible for pyridyl, thienyl, furyl, thiazolyl, oxadiazolyl, benzimidazolyl and benzoxazolyl to be substituted with 1 to 3 substituents, the substituents being selected independently from one another Group consisting of halogen, trifluoromethyl, trifluoromethoxy and methyl,
  • R 3 represents hydrogen or -CC alkyl, where alkyl can be substituted with a substituent, the substituent being selected from the group consisting of amino and C 1 -C 4 -alkylamino,
  • R 3 represents piperidinyl or pyrrolidinyl, it being possible for piperidinyl and pyrrolidinyl to be substituted by a C 4 alkyl substituent,
  • R 4 represents phenyl, where phenyl may be substituted with a substituent, whereby the substituent is selected from the group consisting of trifluoromethyl, trifluoromethoxy, C ⁇ -C 4 - alkyl, C ⁇ -C 4 -alkoxy and phenyl, which phenyl in turn be substituted can with a substituent, the substituent being selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C r C 3 alkyl and CC 3 alkoxy,
  • Preferred compounds of the formula (I) are also those in which
  • Y represents a sulfur atom
  • n 1
  • n stands for the number 1
  • R 1 represents -Gralkyl, where alkyl can be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of fluorine, cyano, oxo, phenyl and alkoxycarbonyl,
  • R 2 represents pyridyl, thienyl, furyl or thiazolyl, where pyridyl, thienyl, furyl and thiazolyl can be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, trifluoromethyl, trifluoromethoxy and methyl,
  • R 3 represents hydrogen or C r C 4 alkyl, where alkyl can be substituted with a substituent, the substituent being selected from the group consisting of amino and C 4 alkylamino,
  • R 3 represents piperidinyl or pyrrolidinyl, where piperidinyl and pyrrolidinyl can be substituted by a substituent C1-C-alkyl,
  • R 4 stands for phenyl, where phenyl can be substituted with a substituent, the substituent being selected from the group consisting of CC 4 alkyl, C 1 -C 4 alkoxy and phenyl, in which phenyl can in turn be substituted with a substituent, the substituent being selected from the group consisting of halogen, trifluoromethyl, C1-C 3 -alkyl and C ⁇ -C 3 -alkoxy,
  • Preferred compounds of the formula (I) are also those in which
  • Y represents an oxygen atom or a sulfur atom
  • n a number 1, 2 or 3
  • n stands for a number 1, 2, 3 or 4,
  • R 1 represents C r C 6 ⁇ alkyl or C 3 -C 7 cycloalkyl, where alkyl can be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, oxo, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl and alkylammocarbonyl,
  • R represents 5- to 10-membered heteroaryl, where heteroaryl can be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of hydroxyl, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, Alkylamino, alkylthio, aryl, aryloxy, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylammocarbonyl, alkylcarbonyl and alkylcarbonylamino,
  • R J represents hydrogen or CC 6 alkyl, where alkyl can be substituted with 1 to 3 substituents, where the substituents. are independently selected from the group consisting of hydroxy, amino, halogen, alkoxy, alkylamino, hydroxyalkylamino, alkylthio, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylammocarbonyl, alkylcarbonyl and alkylcarbonylamino,
  • R 4 stands for aryl or heteroaryl, where aryl and heteroaryl can be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of hydroxyl, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylamino , Alkylthio, alkylsulfonyl, aryl, aryloxy, heteroaryl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylammocarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylaminosulfonyl and alkylsulfonylamino, in which aryl and heteroaryl can in turn be substituted with 1 to 3 substituents, the substituents being selected independently of one another, the substituents being selected independently of one another, the substituents being selected independently of one another Group consisting of hydroxy, amino, halogen,
  • Preferred compounds of the formula (I) are those in which Y represents an oxygen atom or a sulfur atom,
  • n a number 1 or 2
  • n stands for a number - 1, 2 or 3
  • R 1 represents C-C ⁇ -alkyl or C 3 -C 6 cycloalkyl, where alkyl can be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, oxo, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl and alkylammocarbonyl,
  • R 2 stands for 5- to 10-membered heteroaryl, where heteroaryl can be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy , Alkylamino, alkylthio, aryl, aryloxy, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl and alkylcarbonylamino,
  • R 3 represents hydrogen or -CC 6 -alkyl, where alkyl can be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of hydroxy, amino, alkoxy, alkylamino and hydroxyalkylamino,
  • R 4 represents aryl or heteroaryl, where aryl and heteroaryl can be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylamino, aryl, aryloxy , Heteroaryl, alkylammocarbonyl and alkylcarbonylamino, in which aryl and heteroaryl may in turn be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylamino, alkylammocarbonyl and alkylcarbonylamino .
  • Preferred compounds of the formula (I) are also those in which Y represents a sulfur atom
  • n 1
  • R 1 stands for C r C 4 alkyl or cyclohexyl, where alkyl can be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of fluorine, oxo and alkoxycarbonyl,
  • R 2 represents pyridyl, thienyl, furyl or benzoxazolyl, where pyridyl, thienyl, furyl and benzoxazolyl can be substituted with 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, trifluoromethyl and trifluoromethoxy,
  • R 3 represents hydrogen or diethylaminoethyl
  • R 4 represents phenyl, where phenyl can be substituted with a phenyl, in which phenyl can in turn be substituted with a substituent, the substituent being selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, CC 3 alkyl and CC 3 alkoxy , -
  • Preferred compounds of the formula (I) are those in which Y represents a sulfur atom.
  • R 1 represents ethyl, ethoxycarbonylethyl, 3-oxobut-l-yl, trifluoromethyl or cyclohexyl.
  • Preferred compounds of the formula (I) are those in which R 4 is a substituent of the formula
  • R 5 stands for hydrogen, halogen, trifluoromethyl or trifluoromethoxy.
  • the invention further relates to a process for the preparation of the compounds of the formula (I), wherein compounds of the formula
  • R 3 and R 4 have the meaning given above
  • reaction is generally carried out in inert solvents, in the presence of dehydrating reagents, if appropriate in the presence of a base, preferably in a temperature range from 0 ° C. to room temperature at atmospheric pressure.
  • Suitable dehydration reagents are, for example, carbodiimides such as N, N-diethyl, NN'-dipropyl, NN'-diisopropyl, NN'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of penta- fluorophenol (PFP)), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-lj2-oxazolium-3-sulfate or 2 -tert.-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as
  • 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.
  • the condensation is preferably carried out with diisopropylethylamine.
  • Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, nitromethane, dioxane, dimethylformamide, acetonitrile or hexamethylphosphoric triamide. It is also possible to use mixtures of the solvents. Dichloromethane or dimethylformamide is particularly preferred.
  • the compounds of the formula (JE) are known or can be synthesized from the corresponding starting materials by known processes.
  • R 6 ÜR alkyl preferably methyl, ethyl or tert-butyl,,,,.
  • the reaction is generally carried out in inert solvents, preferably in a temperature range from 0 ° C. to room temperature at normal pressure.
  • alkali metal hydroxides as bases such as sodium, lithium or potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or Kahumcarbonat, is preferably sodium hydroxide.
  • solvents are halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloromethane - Chloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, dioxane or tetrahydrofuran, alcohols such as methanol, ethanol, n-propanol or iso-propanol, or other solvents such as Dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile or pyridine,
  • suitable acids are, for example, hydrogen chloride or trifluoroacetic acid.
  • Solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, or ethers such as diethyl ether, tetrahydrofuran or dioxane, or other solvents such as dimethylformamide or acetonitrile. It is also possible to use mixtures of the solvents.
  • the use of hydrogen chloride in dioxane or trifluoroacetic acid in dichloromethane is particularly preferred.
  • the compounds of formula (JE) are known or can be prepared by compounds of formula
  • n and R 6 have the meaning given above, and
  • X 1 represents halogen, preferably iodine or bromine
  • the reaction is generally carried out in inert solvents, in the presence of a base, preferably in a temperature range from 0 ° C. to 40 ° C. at normal pressure.
  • 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 methylene chloride is preferred.
  • 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 methylene chloride is preferred.
  • 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 other bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, diisopropylethylamine is preferred.
  • the compounds of the formula (V) are known or can be synthesized from the corresponding starting materials by known processes.
  • Y and R 1 have the meaning given above, with compounds of the formula - (CH 2 ) - x 2 (v ⁇ ), in which m and R 2 have the meaning given above, and
  • X 2 represents halogen, preferably iodine or bromine.
  • the reaction is generally carried out in a solvent, in the presence of a base, preferably in a temperature range from 0 ° C. to 40 ° C. at normal pressure.
  • 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, or water or mixtures of the solvents with Water, water is preferred.
  • 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, or water or mixtures of the solvents with Water, water is preferred.
  • 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, preference is given to potassium carbonate.
  • 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, preference is given to potassium carbonate.
  • One equivalent of the compounds of the formula (VE)
  • the compounds according to the invention show an unforeseeable, valuable pharmacological spectrum of action.
  • the pharmaceutical activity of the compounds according to the invention can be explained by their action as PAF-AH inhibitors.
  • the present invention furthermore relates to the use of the compounds according to the invention for the treatment and / or prophylaxis of diseases, preferably cardiovascular diseases, in particular arteriosclerosis.
  • the compounds according to the invention can be used in the prevention and treatment of cardiovascular diseases, such as e.g. Atherosclerosis, reperfusion tissue damage after stroke, heart attack or peripheral arterial and venous vascular diseases and essential or pregnancy-induced high blood pressure.
  • cardiovascular diseases such as e.g. Atherosclerosis, reperfusion tissue damage after stroke, heart attack or peripheral arterial and venous vascular diseases and essential or pregnancy-induced high blood pressure.
  • the compounds according to the invention can be used in all types of diseases which include lipid oxidation, inflammation and increased enzyme activity, such as, for example, arthritis, rheumatoid arthritis, diabetes mellitus, kidney inflammation, osteoporosis, Crohn's disease, chronic inflammatory lung diseases such as adult respiratory distress syndromes (AJRDS), inflammatory diseases of the brain such as Alzheimer's disease, sepsis, and acute and chronic inflammation, restenosis after 'PTCA, transplant rejection, inflammatory fibrotic organ changes such as liver fibrosis, or generalized autoimmune disease systemic lupus erythematosus or other forms of lupus erythematosus or dermal inflammatory diseases like psoriasis.
  • diseases which include lipid oxidation, inflammation and increased enzyme activity, such as, for example, arthritis, rheumatoid arthritis, diabetes mellitus, kidney inflammation, osteoporosis, Crohn's disease, chronic inflammatory lung diseases such as adult respiratory distress syndromes (AJ
  • the compounds according to the invention can be used alone and, if necessary, in combination with other active ingredients, in particular with anti-hyperlipidemic, anti-arteriosclerotic, anti-diabetic, anti-inflammatory or anti-hypertensive active ingredients.
  • active ingredients in particular with anti-hyperlipidemic, anti-arteriosclerotic, anti-diabetic, anti-inflammatory or anti-hypertensive active ingredients.
  • examples of these are cholesterol synthesis inhibitors such as e.g. Statins, antioxidants such as Probucol, PPAR activators, irisulin sensitizers, calcium channel antagonists, and non-steroidal anti-inflammatory drugs.
  • the present invention further relates to the use of the compounds 1 of the invention for the treatment and / or prophylaxis of diseases, especially of 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 diseases, 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 the compounds according to the invention.
  • the compounds according to the invention can act systemically and / or locally. For this purpose, they can be applied in a suitable manner, such as, for example, orally, parenterally, pulmonally, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • state-of-the-art, fast and / or modified application forms which release 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 or delayed dissolving or insoluble coatings, control the release of the compound according to the invention), tablets or films / wafers which disintegrate rapidly in the oral cavity, films / lyophilisates, capsules (for example Hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols. or solutions.
  • Tablets non-coated or coated tablets, for example • with gastric juice-resistant or delayed dissolving or insoluble coatings, control the release of the compound according to the invention
  • tablets or films / wafers which disintegrate rapidly in the oral cavity, films / lyophilisates, capsules (for example Hard or soft ge
  • Parenteral administration can be done by bypassing an absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbal) or by switching on absorption (e.g. intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • absorption step e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbal
  • absorption e.g. intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal.
  • Suitable forms of application for parenteral administration include: Injection and irifusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Oral application is preferred.
  • Inhalation medication forms including powder inhalers, nebulizers
  • nasal drops, solutions, sprays including tablets, films / wafers or capsules to be applied lingually, sublingually or buccally, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixes), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as plasters), Milk, pastes, foams, scattering powder, implants or stents.
  • the compounds according to the invention can be converted into the administration forms mentioned. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries.
  • auxiliaries include, inter alia, carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polymer ethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (for example antioxidants such as ascorbic acid), dyes (for example inorganic pigments such as iron oxides ) and taste and / or smell.
  • carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polymer ethylene glycols
  • emulsifiers and dispersing or wetting agents for example sodium dodecyl s
  • the present invention further relates to medicaments which contain at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable auxiliaries, and to their use for the purposes mentioned above.
  • 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: Micromass Quattro LCZ, with HPLC Agilent Series 1100; Column: Grom-SIL120 ODS-4 HE, 50 mm x 2.0 mm, 3 ⁇ m; Eluent A: 1 1 water + 1 ml 50% formic acid, eluent B: 1 1 acetonitrile + 1 ml 50% formic acid; Gradient: 0.0 min 100% A - »0.2 min 100% A -» 2.9 min 30% A -> 3.1 min 10% A -> 4.5 min 10% A; Oven: 55 ° C; Flow: 0.8 ml / min; UV detection: 208-400 nm.
  • Method 2 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 + 5 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 3 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 10 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min - -. 90% A- ⁇ -3. ⁇ 'EHn_30% A - 3.0 min 5% A - 4.5 min- 5% A ;. Flow: 0.0 min l " ml / min, 2.5 rnra / 3.Q min / 4.5 min 2 ml / min; oven: 50 ° C; UV detection: 210 nm.
  • Method 5 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 20 min 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 208-400 nm.
  • Method 8 (preparative HPLC): column: GromSil C18, 250 mm x 30 mm; Flow: 40 ml / min; 30 running time: 40 min; Detection: 210 nm; Eluent A: water with 0.05% formic acid, eluent B: acetonitrile, gradient: 5 min 10% B - »35 min 95% B - 37 min 95% B -> 40.01 min 10% B.
  • Starting compounds Example 1A
  • the reaction mixture is taken up in 25 ml of ethyl acetate, filtered through kieselguhr, once with 20 ml of 1N hydrochloric acid and sat. Washed sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. After chromatography on silica gel (cyclohexane / ethyl acetate: 10/1 -> 3/1), the product fractions are concentrated and dried in a high vacuum. 1.01 g (91% of theory) of the title compound are obtained.
  • the production is carried out analogously to the production of Example 51A.
  • Example 33 A and Example 51A analogously to the procedure of Example 4, using TBTU as coupling reagent.
  • the purification via HPLC is carried out in the presence of formic acid in the eluent A.
  • the product is isolated as a formate salt.
  • the preparation takes place starting from example 33A and example 52A analogously to the instruction of example 4 using TBTU as coupling reagent.
  • the purification via HPLC is carried out in the presence of formic acid in the eluent A.
  • the product is isolated as a formate salt.
  • PAF-AH activity is isolated from the LDL fraction of human plasma. This is done according to a protocol by Stafforini et al. (J. Biol. Chem. 1987, 262: 4223-4230). After isolation of the LDL fraction via a potassium bromide density gradient, solubilization is carried out with 0.1% Tween-20 (buffer: 20 mM K 2 HP0 4 fK. 2 P0 4 , pH 6.8). Then fractionation on a DEAE-Sepharose column (buffer: 20 mM K 2 HPO 4 / KH 2 PO 4 , pH 6.8, 0.1% Tween-20, gradient: 0-300 mM KCl).
  • fractions with PAF-AH activity are pooled, dialyzed (50 mM Tris pH 7.5; 0.1% Tween-20) and then purified on a MonoQ column (buffer: 50 mM Tris pH 7.5; 0.1% Tween-20, gradient: 0 -600mM KCl).
  • 2-Thio-PAF (Cayman Chemicals, Ann Arbor, MI, USA) is used as a substrate for the PAF-AH.
  • BODIPY FL L-cysteine (Molecular Probes, Eugene, OR, USA) serves as an indicator of the free thiol group of the resulting product.
  • the reaction is carried out in a buffer of 100 mM Tris-HC1, pH 8.2, 1 mM EGTA, 150 mM NaCl, 50 mM MgCl 2 with the addition of 25 ⁇ M substrate, 10 ⁇ M indicator and 0!
  • the LDL-, receptor-deficient. Watanabe rabbit (Buja, L.M., ärteriosclerosis .1983, 3, 87-101) was used. Either in short-term examinations (1-2 months) the anti- atherosclerotic effect is determined indirectly by a change in gene expression, of relevant marker genes in tissue susceptible to atherosclerosis, or. Long-term studies (3-6 months) directly determined the formation of atherosclerotic plaques using histological techniques.
  • the substances according to the invention can be converted into pharmaceutical preparations as follows:
  • Composition 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.
  • 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 1,2,4-triazino-5(2H)-ones à substitution amide et des procédés de fabrication de ces composés, ainsi que leur utilisation dans la fabrication de médicaments destinés au traitement et/ou à la prophylaxie de maladies, notamment de maladies inflammatoires chroniques telles que par ex. des maladies rhumatoïdes, et de maladies cardiovasculaires telles que par ex. des dyslipidémies, l'artériosclérose et des maladies cardiaques coronariennes Formule (I).
EP04737078A 2003-07-02 2004-06-21 1,2,4-triazino-5(2h)-ones a substitution amide destinees au traitement de maladies inflammatoires chroniques Withdrawn EP1644353A1 (fr)

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DE10329713 2003-07-02
DE102004014061A DE102004014061A1 (de) 2003-07-02 2004-03-23 Amid-substituierte 1,2,4-Triazin-5(2H)-one
PCT/EP2004/006682 WO2005003118A1 (fr) 2003-07-02 2004-06-21 1,2,4-triazino-5(2h)-ones a substitution amide destinees au traitement de maladies inflammatoires chroniques

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DE102004061005A1 (de) * 2004-12-18 2006-06-22 Bayer Healthcare Ag 3-Cycloalkyl-1,2,4-triazin-5(2H)-one
DE102004061006A1 (de) * 2004-12-18 2006-06-22 Bayer Healthcare Ag 3-Benzylthio-1,2,4-triazin-5(2H)-one
DE102004061009A1 (de) * 2004-12-18 2006-06-22 Bayer Healthcare Ag Substituierte 1,2,4-Triazin-5(2H)-one
DE102004061008A1 (de) * 2004-12-18 2006-06-22 Bayer Healthcare Ag 3-Arylalkyl- und 3-Heteroarylalkyl-substituierte 1,2,4-Triazin-5(2H)-one
US8637536B2 (en) 2010-12-06 2014-01-28 Glaxo Group Limited Pyrimidinone compounds for use in the treatment of diseases or conditions mediated by Lp-PLA2
ES2847883T3 (es) 2010-12-17 2021-08-04 Glaxo Group Ltd Uso de inhibidores de LP-PLA2 en el tratamiento y prevención de enfermedades oculares
US8975400B2 (en) 2011-07-27 2015-03-10 Glaxo Group Limited 2,3-dihydroimidazo[1, 2-c] pyrimidin-5(1 H)-one compounds use as LP-PLA2 inhibitors
AR087309A1 (es) 2011-07-27 2014-03-12 Glaxo Group Ltd Compuesto heterociclico de anillos condensados sustituido, composicion farmaceutica que lo comprende y su uso para la fabricacion de un medicamento para el tratamiento de enfermedades neurogenerativas y aterosclerosis
EP2948457A4 (fr) 2013-01-25 2016-09-07 Glaxosmithkline Ip Dev Ltd Composés
UY35276A (es) 2013-01-25 2014-08-29 Glaxosmithkline Ip Dev Ltd Nuevos compuestos que inhiben la actividad de Lp-PLA2
CA2899143A1 (fr) 2013-01-25 2014-07-31 Glaxosmithkline Intellectual Property Development Limited Composes de pyrimidone bicycliques utilises en tant qu'inhibiteurs de lp-pla2
WO2016012917A1 (fr) 2014-07-22 2016-01-28 Glaxosmithkline Intellectual Property Development Limited Dérivés 1,2,3,5-tétrahydro-imidazo [1,2-c]pyrimidine utiles pour le traitement de maladies et de troubles médiés par la lp-pla2
WO2016012916A1 (fr) 2014-07-22 2016-01-28 Glaxosmithkline Intellectual Property Development Limited Dérivés 1,2,3,5-tétrahydro-imidazo [1,2-c]pyrimidine utiles pour le traitement de maladies et de troubles médiés par la lp-pla2
JP2018521021A (ja) 2015-06-11 2018-08-02 バジリア・ファルマスーチカ・インターナショナル・アーゲーＢａｓｉｌｅａ Ｐｈａｒｍａｃｅｕｔｉｃａ Ｉｎｔｅｒｎａｔｉｏｎａｌ Ａｇ 排出ポンプ阻害剤及びその治療的使用
US20230044787A1 (en) 2019-11-09 2023-02-09 Shanghai SIMR Biotechnology Co., Ltd Tricycle dihydroimidazopyrimidone derivative, preparation method thereof, pharmaceutical composition and use thereof
CN115304620A (zh) 2021-05-07 2022-11-08 上海赛默罗生物科技有限公司 嘧啶酮衍生物、其制备方法、药物组合物和用途

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IL146210A0 (en) * 1999-05-01 2002-07-25 Smithkline Beecham Plc Pyrimidinone compounds
GB0127143D0 (en) * 2001-11-10 2002-01-02 Smithkline Beecham Novel compounds
GB0209988D0 (en) * 2002-05-01 2002-06-12 Bayer Ag Novel Heterocycles

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