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WO2006063791A1 - 3-benzylthio-1,2,4-triazin-5(2h)-ones constituant des inhibiteurs de paf-ah - Google Patents

3-benzylthio-1,2,4-triazin-5(2h)-ones constituant des inhibiteurs de paf-ah Download PDF

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Publication number
WO2006063791A1
WO2006063791A1 PCT/EP2005/013369 EP2005013369W WO2006063791A1 WO 2006063791 A1 WO2006063791 A1 WO 2006063791A1 EP 2005013369 W EP2005013369 W EP 2005013369W WO 2006063791 A1 WO2006063791 A1 WO 2006063791A1
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phenyl
substituents
alkyl
substituted
group
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PCT/EP2005/013369
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German (de)
English (en)
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Martin Hendrix
Katja Zimmermann
Timo Flessner
Claudia Hirth-Dietrich
Gunter Karig
Martin Raabe
Dagmar Karthaus
Martin Michels
Olaf Weber
Siegfried Zaiss
Franz Zumpe
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Bayer Healthcare Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D253/075—Two hetero atoms, in positions 3 and 5
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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

Definitions

  • the invention relates to 3-benzylthio-l, 2,4-triazine-5 (2H) -ones and processes for their preparation and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular of chronic inflammatory diseases, such. 5 diseases of the rheumatoid type, and cardiovascular diseases, such. Dyslipidaemias, arteriosclerosis and coronary heart disease.
  • WO 03/41712 relates inter alia to triazinones as Lp-PLA2 inhibitors for the treatment of arteriosclerosis.
  • ⁇ ⁇ migrating monocytes with pathogenic lipoproteins in the arterial wall plays a central role in terms of plaque development and stability.
  • 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 inflammatory mediators lysophosphatidylcholine and oxidized fatty acids from oxidized LDL (low-density lipoprotein).
  • Plasma PAF-AH is a monocyte and macrophage-secreted, calcium-independent member of the phospholipase A2 family.
  • the substrates of PAF-AH are the platelet-activating factor (PAF) and oxidized phospholipids in oxidized LDL (oxLDL). Cleavage of an acyl residue in the sn-2 position produces oxidized fatty acids and lysophosphatidylcholine (LysoPC).
  • the proinflammatory mediator LysoPC is responsible for the accumulation of cholesterol ester-5-loaded monocytes (foam cells) in the arteries (Quinn, et al., Proc Natl Acad., USA 1988, 85, 2805-2809).
  • PAF-AH inhibitors may find application in any disease involving activated monocytes, macrophages, or lymphocytes, since all of these cells express the enzyme.
  • An object of the present invention is therefore to provide new inhibitors of PAF-AH for the treatment of chronic inflammatory diseases and cardiovascular diseases in humans and animals.
  • the invention relates to compounds of the formula
  • R 1 is (C r C 4 ) -alkyl or (C 3 -C 7 ) -cycloalkyl
  • R 2 is phenyl
  • phenyl may be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, (C r C6) alkyl, (Ci-C 6) alkoxy, (C 1 -C 6) alkylamino, (C r C6) alkylthio, phenyl, phenoxy, hydroxycarbonyl, (C r C6) - alkoxycarbonyl, aminocarbonyl, (Ci-C6) alkylaminocarbonyl, (QC ⁇ ⁇ alkylcarbonyl and
  • R 3 is (C r C 6 ) -alkyl, wherein alkyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, halogen, (C r C 6 ) alkoxy, (C 1 -C 6 ) alkylamino, (Ci -C 6) alkylthio, 3- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl, hydroxycarbonyl, (Ci-C ⁇ ) - alkoxycarbonyl, aminocarbonyl, (C 1 -C 6) alkylaminocarbonyl, (C 1 -C 6 ) alkylcarbonyl,
  • heterocyclyl and heteroaryl may in turn be substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, oxo, halogen, cyano, trifluoromethyl, trifluoromethoxy, (C r C 6 ) alkyl , (C r C6) alkoxy, (Ci-C 6) alkylamino, (C r C6) alkylthio,
  • R 3 is a 3- to 9-membered heterocyclyl having 1 to 2 nitrogen atoms
  • heterocyclyl may be substituted with 1 to 5 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, oxo, formyl, (Ci-Co) -alkoxy, (Ci-C 6 ) -alkylamino, (C 1 -C 6) - alkoxycarbonyl, and optionally, (Ci-Ce) -alkoxy-substituted (Ci-C ⁇ ) alkyl,
  • R 4 is (phenyl) phenyl, (phenyl) pyridyl or (pyridyl) phenyl,
  • (phenyl) phenyl, (phenyl) pyridyl and (pyridyl) phenyl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of hydroxyl, amino, halogen, cyano, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, (C, -C 6) alkyl, (C r C6) alkoxy, (C r C6) alkylamino, (C, -C 6) alkylthio, (Ci-C 6) - alkylsulfonyl, hydroxycarbonyl, (Ci-C 6) alkoxycarbonyl, aminocarbonyl, (C r C6) alkyl aminocarbonyl, (Ci-C 6) alkylcarbonyl, (Ci-C ⁇ -alkylcarbonylamino, (C
  • R 4 is phenyl or pyridyl
  • phenyl and pyridyl may be substituted with 1 to 3 substituents, wherein the
  • R 5 is hydrogen or (C 1 -C 4 ) -alkyl
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, and the compounds of formula (I), hereinafter referred to as the exemplary embodiment (e) and their salts, solvates and solvates of the salts, insofar as the compounds of formula (I) mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore relates to 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 according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluorooic, propionic, lactic Malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • mineral acids for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluorooic, propionic, lactic Malic acid, citric acid, fumaric acid, maleic acid and benzoic 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 illustration, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • 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 salt
  • 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.
  • the free base of the salts of the compounds according to the invention can be obtained, for example, by addition of 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
  • Alkylaminosulfonyl and Alkylsulfonylamino stand for a linear or branched alkyl radical having usually 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl and n-hexyl.
  • Alkoxy is exemplified and preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • Alkylthio is exemplified and preferably methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.
  • Alkylamino is an alkylamino radical having one or two (independently selected) alkyl substituents, where a nitrogen atom can also form an N-oxide, by way of example and preferably methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N, N-dimethylamino, N, N-diethylamino, N -ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N-tert-butyl-N-methylamino, N Ethyln-pentylamino, Nn-hexyl-N-methylamino and diethylnitroryl.
  • C 1 -C 3 -alkylamino is, for example for a
  • Alkylsulfonyl is, by way of example and by way of preference, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.
  • Alkoxycarbonyl is by way of example and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
  • Alkylaminocarbonyl is an alkylaminocarbonyl radical having 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 -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-methylamin
  • C 1 -C 4 -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.
  • Alkylcarbonyl is by way of example and preferably methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl and n-hexylcarbonyl.
  • Alkylcarbonylamino is by way of example and preferably methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylamino and n-hexylcarbonylamino.
  • Alkoxycarbonylamino is by way of example and preferably methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, tert-butoxycarbonylamino, n-pentoxycarbonylamino and n-hexoxycarbonylamino.
  • Alkylaminosulfonyl represents an alkylaminosulfonyl radical having 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 methylaminosulfonyl, ethylaminosulfonyl, n -Propylamino-sulfonyl, isopropylaminosulfonyl, tert-butylaminosulfonyl, n-pentylaminosulfonyl, n-hexylaminosulfonyl, N, N-dimethylaminosulfonyl, N, N-diethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl, N-methyl-Nn-propylaminosulfonyl, N-isopropyl-N
  • QC 3 -alkylaminosulfonyl is, for example, a monoalkylaminosulfonyl radical having 1 to 3 carbon atoms or a dialkylaminosulfonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.
  • Alkylsulfonylamino is, by way of example and by way of preference, methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, n-pentylsulfonylamino and n-hexylsulfonylamino.
  • Cycloalkyl is a cycloalkyl group having usually 3 to 7, preferably 3 to 6 carbon atoms, by way of example and preferably cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Aryl is a mono- or bicyclic aromatic radical having usually 6 to 10 carbon atoms, by way of example and preferably aryl are called phenyl and ⁇ aphthyl.
  • Heteroaryl is an aromatic, mono- or bicyclic radical having usually 5 to 10, preferably 5 to 6 ring atoms and up to 5, preferably up to 4 heteroatoms from the series S, O and ⁇ , where a nitrogen atom is also a ⁇ - 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 is a mono- or bicyclic, heterocyclic radical having usually 3 to 9, 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, SO 2 , wherein a nitrogen atom can also form a ⁇ -oxide.
  • the heterocyclyl radicals may be saturated or partially unsaturated.
  • Halogen is fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be mono- or polysubstituted or differently substituted.
  • a sub Institution with up to three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.
  • R 1 is methyl or ethyl
  • R 2 is phenyl
  • phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, (Ci-C 4 ) alkyl, (Ci-GO-alkoxy and (C 1 -C 6 ) -alkylamino,
  • R 3 is (C r C 4 ) -alkyl
  • alkyl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, (Ci-C 4 ) alkoxy, (C r C6) alkylamino, 5- or 6-membered Heterocyclyl, 5- or 6-membered heteroaryl and
  • heterocyclyl and heteroaryl may in turn be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of hydroxy, amino, oxo, halogen, cyano, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 ) -alkoxy and (C 1 -C 6 ) -alkylamino,
  • R 3 is a 4- to 6-membered heterocyclyl having 1 to 2 nitrogen atoms
  • heterocyclyl may be substituted with 1 to 5 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, oxo, formyl, (Ci-C 4 ) alkoxy, (Ci-C 4 ) alkoxycarbonyl and optionally (C 1 -C 4 ) -alkoxy-substituted (C 1 -C 4 ) -alkyl,
  • R 4 is 4- (phenyl) phenyl, 4- (pyridin-2-yl) phenyl or 6- (phenyl) pyridin-3-yl,
  • 4- (phenyl) phenyl, 4- (pyridin-2-yl) phenyl and 6- (phenyl) pyridin-3-yl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of Hydroxy, amino, halogen, cyano, Trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, (C 1 -C 4 ) -alkyl, (C 4 -C 4 ) -alkoxy and (C 1 -C 6) -alkylamino,
  • R 5 is hydrogen or methyl
  • R 1 is methyl or ethyl
  • R 2 is phenyl
  • phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, trifluoromethyl and trifluoromethoxy,
  • R 3 is (C r C 4 ) -alkyl
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of amino, (QC ö ⁇ alkylamino and pyrrolidinyl,
  • pyrrolidinyl may in turn be substituted with 1 to 3 substituents, wherein the
  • Substituents are independently selected from the group consisting of oxo and (C r C4) alkyl,
  • R 3 is azetidinyl, piperidinyl or pyrrolidinyl
  • azetidinyl, piperidinyl or pyrrolidinyl may be substituted with 1 to 5
  • Substituents wherein the substituents are independently selected from the group consisting of oxo, formyl, (C 1 -C 4 ) -alkoxycarbonyl or optionally methoxy-substituted (C 1 -C 4 ) -alkyl,
  • R 4 is 4- (phenyl) phenyl, 4- (pyridin-2-yl) phenyl or 6- (phenyl) pyridin-3-yl,
  • 4- (phenyl) phenyl, 4- (pyridin-2-yl) phenyl and 6- (phenyl) pyridin-3-yl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of Fluorine, chlorine, trifluoromethyl and difluoromethyl, R 5 is hydrogen,
  • R 3 is diethylaminoethyl, diethylaminoethyl-N-oxide, N-methylpiperidin-4-yl, N-methylpiperidinyl-N-oxide, N-ethylpiperidin-4-yl or N- Ethylpiperidinyl-N-oxide.
  • R 3 is N, N-diethylcarbonylmethyl, (N-methylpyrrolidin-2-yl) methyl, (N-ethylpyrrolidin-2-yl) methyl, (pyrrolidin-2-yl ) methyl or (N-methyl-5-oxopyrrolidin-2-yl) methyl.
  • R 4 is 4- (4-trifluoromethylphenyl) phenyl, 4- (5-trifluoromethylpyridin-2-yl) phenyl or 6- (4-trifluoromethylphenyl) pyridine-3 -yl stands.
  • the invention further provides a process for the preparation of the compounds of the formula (I), where compounds of the formula
  • R 1 , R 2 and R 5 have the abovementioned meaning, with compounds of the formula
  • R 3 and R 4 have the abovementioned meaning
  • the reaction generally takes place in inert solvents, in the presence of dehydration reagents, if appropriate in the presence of a base, preferably in a temperature range from 0 ° C. to room temperature at normal pressure.
  • Suitable dehydrating reagents here are, for example, carbodiimides, such as, for example, N 3 N'-diethyl, N, N'-dipropyl, N 3 N -diisopropyl, N 1 N -dicyclohexylcarbodiimide, N- (3-dimethylamino-isopropyl) -N ' ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl 5-phenyl-1, 2-oxazolium-3-sulphate or 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamin
  • Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines, e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • the condensation is carried out with diisopropylethylamine.
  • Inert solvents are, for example, halohydrocarbons, such as dichloromethane or trichloromethane, hydrocarbons, such as benzene, nitromethane, dioxane, dimethylformamide, acetone and the like. nitrile or hexamethylphosphoric triamide. It is likewise possible to use mixtures of the solvents. Particularly preferred is dichloromethane or dimethylformamide.
  • the compounds of the formula (III) are known or can be synthesized by known processes from the corresponding starting materials.
  • R 1 , R 2 and R 5 have the meaning given above, and
  • R 6 is 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 atmospheric pressure.
  • suitable bases are, for example, alkali metal hydroxides such as sodium, lithium or potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, preference being given to sodium hydroxide.
  • Solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 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, dimethylsulfoxide, acetonitrile or pyridine, or mixture
  • suitable acids are, for example, hydrogen chloride or trifluoroacetic acid.
  • Solvents are, for example, halogenated hydrocarbons, such as dichloromethane. methane or trichloromethane, or ethers such as diethyl ether, tetrahydrofuran or dioxane, or other solvents such as dimethylformamide or acetonitrile. It is likewise possible to use mixtures of the solvents. Particularly preferred is the use of hydrogen chloride in dioxane or trifluoroacetic acid in dichloromethane.
  • the compounds of the formula (TV) are known or can be prepared by reacting compounds of the formula
  • R 1 , R 2 and R 5 have the abovementioned meaning
  • R 6 has the meaning given above, and
  • X 1 is 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. under atmospheric 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, preferably tetrahydrofuran or methylene chloride.
  • halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane
  • ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane
  • other solvents such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile, preferably tetrahydrofuran or methylene chloride.
  • bases examples include alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or 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, or others Bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, preferred is diisopropylethylamine.
  • alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butylate
  • amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or others
  • Bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, preferred is diisopropylethylamine.
  • the compounds of the formula (VI) are known or can be synthesized by known processes from the corresponding starting materials.
  • the compounds of the formula (V) are known or can be prepared by reacting compounds of the formula
  • R 1 has the meaning given above
  • R 2 and R 5 have the abovementioned meaning
  • X 2 is 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 4O 0 C at atmospheric 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, preferably water.
  • 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, preferably water.
  • bases examples include alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or other bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, preferred is potassium carbonate.
  • alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butoxide
  • amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or other bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, preferred is potassium carbonate.
  • the compounds of the invention show an unpredictable, valuable spectrum of pharmacological activity.
  • the pharmaceutical activity of the compounds according to the invention can be explained by their action as PAF-AH inhibitors.
  • Another object of the present invention is the use of the compounds according to the invention fertilize for the treatment and / or prophylaxis of diseases, preferably cardiovascular diseases, in particular atherosclerosis.
  • the compounds of the present invention can be used in the prevention and treatment of cardiovascular diseases such as atherosclerosis, reperfusion tissue damage after stroke, myocardial infarction or peripheral arterial and venous vascular diseases, and essential or pregnancy-induced hypertension.
  • cardiovascular diseases such as atherosclerosis, reperfusion tissue damage after stroke, myocardial infarction or peripheral arterial and venous vascular diseases, and essential or pregnancy-induced hypertension.
  • the compounds of the invention may be used in any type of disease involving lipid oxidation, inflammation and increased enzyme activity, such as arthritis, rheumatoid arthritis, diabetes mellitus, nephritis, osteoporosis, Crohn's disease, chronic inflammatory lung diseases such as adult respiratory distress syndrome (ARDS), inflammatory diseases of the brain such as Alzheimer's disease, sepsis and acute and chronic inflammation, restenosis after PTCA, graft rejection, chronic inflammatory fibrotic organ changes such as liver fibrosis, or the generalized autoimmune disease systemic lupus
  • the compounds according to the invention can be used alone and, if required, also in combination with other active substances, in particular with anti-hyperlipidemic, anti-arteriosclerotic, anti-diabetic, anti-inflammatory or anti-hypertensive agents.
  • active substances in particular with anti-hyperlipidemic, anti-arteriosclerotic, anti-diabetic, anti-inflammatory or anti-hypertensive agents.
  • examples are cholesterol synthesis inhibitors such as e.g. Statins, antioxidants such as e.g. Probucol, PPAR activators, insulin sensitizers, calcium channel antagonists, and non-steroidal anti-inflammatory drugs.
  • 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 the compounds of the invention.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivae otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the contain the compounds of the invention in crystalline and / or amorphous and / or dissolved form 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), rapidly disintegrating in the oral cavity Tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • 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 inhalers, nebulizers
  • nasal drops solutions, sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (such as patches)
  • milk Pastes, foams, scattering powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecylsulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odoriferous include, among others.
  • Excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl
  • compositions containing at least one compound of the invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • Example 24A is obtained analogously to the preparation of Example 21 A.
  • Example 24A is obtained analogously to the preparation of Example 21 A.
  • the solution is concentrated in vacuo, taken up in dichloromethane and washed with saturated sodium bicarbonate solution. After removal of the solvent in vacuo, the residue is purified by preparative HPLC, the aqueous phase containing 1% formic acid. The product-containing fractions were basified with sodium hydroxide solution and the product was extracted with methylene chloride and concentrated. 641 mg (39% of theory) of product are obtained.
  • 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 by means of a potassium bromide density gradient, solubilization is carried out with 0.1% Tween-20 (buffer: 20 mM K 2 HPO 4 ZBCH 2 PO 4 , pH 6.8). Then fractionation on a DEAE-Sepharose column (buffer: 20 mM K 2 HPO 4 ZKH 2 PO 4 , pH 6.8, 0.1% Tween-20, gradient: 0-300 mM KCl).
  • fractions with PAF-AH activity are pooled, dialysed (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 -600 mM 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 incubated in a buffer of 100 mM Tris-HCl, pH 8.2, 1 mM EGTA, 150 mM NaCl, 50 mM MgCl 2 with the addition of 25 ⁇ M substrate, 10 ⁇ M indicator and 0.1 ugZml PAF-AH at 37 0 C and the fluorescence (excitation 485 nm / emission 515 nm) was measured in the fluorescence reader Spectra Fluor (Tecan, Crailsheim, Germany). The results are shown in Table A:
  • the LDL receptor-deficient Watanabe rabbit (Buja, L.M., Arteriosclerosis 1983, 3, 87-101) is used. Either in short-term studies (1-2 months) the anti- atherosclerotic effect is indirectly determined by altered gene expression of relevant marker genes in atherosclerotic tissue, or in long-term studies (3-6 months) the formation of atherosclerotic plaques using histological techniques directly determined.
  • 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. production:
  • 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.
  • 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 under aseptic conditions into heat-sterilized infusion bottles. These are closed with infusion stoppers and crimp caps.

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Abstract

L'invention concerne des 3-benzylthio-1,2,4-triazin-5(2H)-ones représentées par la formule (I), des procédés de production de ces composés et l'utilisation desdits composés pour produire des médicaments destinés à traiter et/ou prévenir des maladies, en particulier des maladies inflammatoires chroniques, telles que des maladies rhumatismales, et des maladies cardio-vasculaires, telles que des dyslipidémies, l'artériosclérose et des maladies coronariennes.
PCT/EP2005/013369 2004-12-18 2005-12-13 3-benzylthio-1,2,4-triazin-5(2h)-ones constituant des inhibiteurs de paf-ah WO2006063791A1 (fr)

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DE102004061006A DE102004061006A1 (de) 2004-12-18 2004-12-18 3-Benzylthio-1,2,4-triazin-5(2H)-one

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008140449A1 (fr) 2007-05-11 2008-11-20 Thomas Jefferson University Méthodes de traitement et de prévention de maladies et de troubles neurodégénératifs
WO2012080497A2 (fr) 2010-12-17 2012-06-21 Glaxo Group Limited Procédés de traitement et de prévention de maladies oculaires
US8367679B2 (en) 2008-12-09 2013-02-05 Merck Sharp & Dohme Corp. Biaryl carboxamides
CN102924290A (zh) * 2012-09-25 2013-02-13 同济大学 一种darapladib中间体的合成方法
US9029383B2 (en) 2007-05-11 2015-05-12 The Trustees Of The University Of Pennsylvania Methods of treatment of skin ulcers
WO2017204316A1 (fr) * 2016-05-27 2017-11-30 塩野義製薬株式会社 Dérivé de 5-oxo-1,2,4-triazine et composition pharmaceutique correspondante
RU2686317C2 (ru) * 2015-04-24 2019-04-25 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фармакологии имени В.В. Закусова" Замещенные 1,2,5-триметил- и 2,2,6,6-тетраметил-4-аминопиперидины, обладающие антиишемическим действием
US10464896B2 (en) 2015-06-11 2019-11-05 Basilea Pharmaceutica International AG Efflux-pump inhibitors and therapeutic uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000066567A1 (fr) * 1999-05-01 2000-11-09 Smithkline Beecham Plc Composes pyrimidinones
WO2003041712A1 (fr) * 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Derives de pyridone, pyridazone et triazone en tant qu'inhibiteurs de lp-pla2
WO2005003118A1 (fr) * 2003-07-02 2005-01-13 Bayer Healthcare Ag 1,2,4-triazino-5(2h)-ones a substitution amide destinees au traitement de maladies inflammatoires chroniques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000066567A1 (fr) * 1999-05-01 2000-11-09 Smithkline Beecham Plc Composes pyrimidinones
WO2003041712A1 (fr) * 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Derives de pyridone, pyridazone et triazone en tant qu'inhibiteurs de lp-pla2
WO2005003118A1 (fr) * 2003-07-02 2005-01-13 Bayer Healthcare Ag 1,2,4-triazino-5(2h)-ones a substitution amide destinees au traitement de maladies inflammatoires chroniques

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008140449A1 (fr) 2007-05-11 2008-11-20 Thomas Jefferson University Méthodes de traitement et de prévention de maladies et de troubles neurodégénératifs
US9029383B2 (en) 2007-05-11 2015-05-12 The Trustees Of The University Of Pennsylvania Methods of treatment of skin ulcers
EP2977452A2 (fr) 2007-05-11 2016-01-27 Thomas Jefferson University Procédés de traitement et de prévention de maladies et de troubles neurodégénératifs
US8367679B2 (en) 2008-12-09 2013-02-05 Merck Sharp & Dohme Corp. Biaryl carboxamides
WO2012080497A2 (fr) 2010-12-17 2012-06-21 Glaxo Group Limited Procédés de traitement et de prévention de maladies oculaires
CN102924290A (zh) * 2012-09-25 2013-02-13 同济大学 一种darapladib中间体的合成方法
RU2686317C2 (ru) * 2015-04-24 2019-04-25 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фармакологии имени В.В. Закусова" Замещенные 1,2,5-триметил- и 2,2,6,6-тетраметил-4-аминопиперидины, обладающие антиишемическим действием
US10464896B2 (en) 2015-06-11 2019-11-05 Basilea Pharmaceutica International AG Efflux-pump inhibitors and therapeutic uses thereof
WO2017204316A1 (fr) * 2016-05-27 2017-11-30 塩野義製薬株式会社 Dérivé de 5-oxo-1,2,4-triazine et composition pharmaceutique correspondante

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