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WO2006063812A1 - 3-cycloalkyl-1,2,4-triazin-5(2h)-ones - Google Patents

3-cycloalkyl-1,2,4-triazin-5(2h)-ones Download PDF

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Publication number
WO2006063812A1
WO2006063812A1 PCT/EP2005/013432 EP2005013432W WO2006063812A1 WO 2006063812 A1 WO2006063812 A1 WO 2006063812A1 EP 2005013432 W EP2005013432 W EP 2005013432W WO 2006063812 A1 WO2006063812 A1 WO 2006063812A1
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substituents
phenyl
alkyl
substituted
group
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German (de)
English (en)
Inventor
Martin Hendrix
Katja Zimmermann
Claudia Hirth-Dietrich
Gunter Karig
Dagmar Karthaus
Martin Raabe
Olaf Weber
Siegfried Zaiss
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Bayer AG
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Bayer Healthcare AG
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    • 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]
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • 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
    • 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

Definitions

  • the invention relates to 3-cycloalkyl-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.
  • 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 now widely recognized.
  • the inflammatory vascular changes are caused by the reaction of migrating monocytes with pathogenic lipoproteins in the arterial wall.
  • the formation of foam cells from the migrated monocytes by uptake of oxidized lipids plays a central role in 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-loaded monocytes (foam cells) in the arteries (Quinn, et al., Proc Natl Acad., USA, 1988, 55, 2805-2809).
  • the increased LysoPC content of oxLDL also appears to be responsible for the endothelial dysfunction seen in patients with atherosclerosis.
  • PAF-AH inhibitors are therefore also suitable for the treatment of this phenomenon.
  • their use would make sense - - in all diseases underlying endothelial dysfunction such as diabetes, hypertension and angina pectoris.
  • PAP-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 novel inhibitors of PAP-AH for the treatment of chronic inflammatory diseases and cardiovascular diseases in humans and animals.
  • the invention relates to compounds of the formula
  • n is a number 1, 2, 3 or 4,
  • R 1 is (C r C 4 ) -alkyl or (C 3 -C 7 ) -cycloalkyl
  • alkyl may be substituted by 1 to 3 substituents, the substituents being independently selected from the group consisting of halogen, cyano, oxo, phenyl, hydroxycarbonyl, (C 1 -C 6 ) -alkoxycarbonyl, aminocarbonyl and (Q-C 6 ) alkylaminocarbonyl,
  • R 2 is phenyl or 5- or 6-membered heteroaryl
  • phenyl and heteroaryl 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, trifluoromethoxy, (C 1 -C 6 ) -alkyl, (C 1 -) C 6) alkoxy, (Ci-C 6) alkylamino, (Ci-C 6) alkylthio, phenyl, phenoxy, hydroxycarbonyl, (C 1 -C 6) alkoxycarbonyl, aminocarbonyl, (C r C6) alkylaminocarbonyl , (C 1 -C 6 ) -alkylcarbonyl and (C 1 -C 4 -alkylcarbonylarnino,
  • alkyl may be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of hydroxy, amino, halo, (C r C6) alkoxy, (C r C6) alkylamino, (Ci- C 6) alkylthio, 3- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl, hydroxycarbonyl, (C r C6) - alkoxycarbonyl, aminocarbonyl, (Ci-C6) alkylaminocarbonyl, (C r C 6) Alkylcarbonyl, (C 1 -C 6 ) -alkylcarbonylamino and (C 1 -C 6 ) -alkoxycarbonylamino,
  • 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, (Ci-C 6 ) alkyl , (C r C6) alkoxy, (C r C6) alkylamino, (C 1 -C 6) alkylthio, hydroxycarbonyl, (Ci-C 6) alkoxycarbonyl, aminocarbonyl, (Ci-C6) alkylaminocarbonyl .
  • 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
  • R 4 is 4- (phenyl) phenyl, 4- (pyridyl) phenyl, 6- (phenyl) pyridin-3-yl or 5- (phenyl) pyridin-2-yl,
  • 2-yl may be substituted by 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, (Ci-C 6 ) alkyl, (Ci-C 6) alkoxy, (C r C6) alkylamino, (CrC 6) alkylthio, (C r C6) alkylsulfonyl, hydroxycarbonyl, (C 1 -C 6) -
  • R 5 is hydrogen, (C 1 -C 6 ) -alkyl or (C 3 -C 7 ) -cycloalkyl,
  • alkyl and cycloalkyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of
  • 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 which are preferred in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included are salts which are not suitable for pharmaceutical applications themselves but can be used, for example, for the isolation or purification of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid acetic acid, trifluoroacetic acid, propionic acid
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts). salts), alkaline earth salts (eg calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as by way of example and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, Prokain, 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). salts), alkaline earth salts (eg calcium and magnesium
  • 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
  • Alkylcarbonylamino, alkoxycarbonylamino, 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-penryl and n-hexyl.
  • Alkoxy is, by way of example and by way of preference, 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, by way of example and preferably methylamino, ethylamino, n-
  • C 1 -C 3 -alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having 1 to 3 carbon atoms each
  • Alkyl substituent 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 by way of preference, 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, wherein the alkyl substituents independently of one another generally have 1 to 6, preferably 1 to 4, more 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-
  • C 1 -C 5 -alkylaminocarbonyl is, for example, a monoalkylaminocarbonyl radical having 1 to 3 carbon atoms or a dialkylaminocarbonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.
  • 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-dimethylamino-sulfonyl, N, N-diethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl, N-methyl-Nn-propylaminosulfonyl, N-isopropy
  • C 1 -C 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 naphthyl.
  • 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 N, where a nitrogen atom is also an N- 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 N, O, S, SO, SO 2 , wherein a nitrogen atom can also form an N-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 may, unless otherwise specified, be mono- or polysubstituted or differently substituted. Substitution with up to three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent. Preference is given to those compounds of the formula (I) in which
  • n is the number 1
  • R 1 is methyl, ethyl, n-propyl or isopropyl
  • R 2 is phenyl, thienyl or pyridyl
  • phenyl, thienyl and pyridyl can 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, trifluoromethoxy, (C 1 -C 4 ) -alkyl, ( C r C 4 ) -alkoxy and (C r C 6 ) -alkylamino,
  • R 3 is (Ci-G ⁇ -alkyl
  • alkyl may be substituted with 1 to 2 substituents where the substituents are independently selected from the group consisting of hydroxy, amino, (Ci-C 4) -alkoxy, (C r C6) alkylamino, 5- or 6- heterocyclyl, 5- or 6-membered heteroaryl and (C 1 -C 6 ) -alkoxycarbonylamino,
  • heterocyclyl and heteroaryl may in turn be substituted with 1 to 3 substituents, wherein the substituents are independently selected from
  • 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 (Ci-C 4) alkoxy substituted (C r C4) alkyl,
  • R 4 is 4- (phenyl) phenyl or 4- (pyridin-2-yl) phenyl,
  • Substituents wherein the substituents are independently selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, (C r C 4 ) alkyl, (C r C 4 ) - alkoxy and (C r C6) alkylamino, R 5 is (C 6 r C) alkyl or hydrogen,
  • n is the number 1
  • 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 1 -C 4 ) -alkyl
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of amino, (Ci-C 6 ) 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
  • R 3 is piperidinyl or pyrrolidinyl
  • piperidinyl and pyrrolidinyl may be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of oxo, (C] -C 4 ) -alkoxycarbonyl and optionally methoxy-substituted (QC 4 ) -alkyl,
  • R 4 is 4- (phenyl) phenyl
  • 4- (phenyl) phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of
  • Halogen, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, difluoromethoxy and monofluoromethoxy, R 5 is hydrogen
  • R 2 is phenyl, where phenyl may be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of fluorine, chlorine and trifluoromethyl.
  • R 2 is a 5- or 6-membered heteroaryl, where heteroaryl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of hydroxyl, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, (Ci ⁇ C6) alkyl, (Ci-C 6) alkoxy, (C 1 - C 6) alkylamino, (Ci-C 6) alkylthio, phenyl, phenoxy , Hydroxycarbonyl, (C 1 -C 6 ) -alkoxycarbonyl, aminocarbonyl, (C 1 -C 6 ) -alkylaminocarbonyl, (C 1 -C 6 ) -alkylcarbonyl and (C 1 -C 6 ) -alkylcarbonylamino.
  • R 3 is diethylaminoethyl, N-methylpiperidin-4-yl, N-ethylpiperidin-4-yl or 1,2,2,6,6-pentamethylpiperidin-4-yl ,
  • R 4 is 4- (phenyl) phenyl, where 4- (phenyl) phenyl may be substituted in the para position to the point of attachment of the phenyl rings with a substituent, where the substituent is selected is selected from the group consisting of fluorine, chlorine and trifluoromethyl.
  • the invention further provides a process for the preparation of the compounds of the formula (T), where compounds of the formula
  • R 1 , R 2 and R 5 have the abovementioned meaning
  • R 3 and R 4 have the abovementioned meaning
  • the reaction is generally carried out in inert solvents, in the presence of approximately reagents Dehydratisie-, optionally in the presence of a base, preferably in a temperature range of 0 0 C to room temperature under normal pressure.
  • Suitable dehydrating here for example, carbodiimides such as N 1 N-diethyl-, N, N'-dipropyl-, N, N'-diisopropyl-, N, N'-dicyclohexylcarbodiimide, N- suitable (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-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy
  • 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-methylrnorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • the condensation is carried out with diisopropylethylamine.
  • Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane or t-chloromethane, hydrocarbons, such as benzene, etromonethane, dioxane, dimethylformamide, acetonitrile or hexamethylphosphoric triamide. It is likewise possible to use mixtures of the solvents. Particularly preferred is dichloromethane or dimethylformamide.
  • the compounds of formula (HI) are known or can be synthesized by known methods from the corresponding starting materials.
  • R 1 , R 2 and R 5 have the abovementioned meaning
  • 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.
  • bases which are suitable, for example, are alkali metal hydroxides such as sodium, lithium or potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, preferred is 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,
  • 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 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 (IV) are known or can be prepared by reacting compounds of the formula
  • R 1 and R 2 have the abovementioned meaning
  • R 5 and R 6 have the abovementioned meaning, 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, chloromethane 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, chloromethane 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 for compounds in which R 5 is hydrogen, and sodium hydride for compounds in which R 5 is an alkyl radical.
  • 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
  • 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
  • n and R 2 have the abovementioned meaning
  • R 7 is hydrogen, methyl or ethyl
  • the reaction is generally carried out in a solvent, in the presence of a base, preferably in a temperature range from 2O 0 C to 200 0 C at atmospheric pressure.
  • a base preferably in a temperature range from 2O 0 C to 200 0 C at atmospheric pressure.
  • the reaction is carried out by first stirring at room temperature for 5 to 45 minutes and then heating to the reflux temperature of the solvent.
  • Solvents are, for example, dimethylformamide or dimethylacetamide.
  • compounds of formula (VE) may be prepared from the corresponding amidines by reaction with an ethereal hydrazine solution or hydrazine hydrate in ethanol. Purification of the compounds of the formula (IV) thus prepared is generally not necessary for the further conversion to compounds of the formula (V).
  • the compounds of the invention show an unpredictable, valuable pharmacological spectrum of 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 of the invention 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 cardiovascular disorders.
  • cardiovascular diseases such as cardiovascular disorders.
  • the compounds of the invention may be used in any type of disease involving lipid oxidation, inflammation and increased enzyme activity, such as e.g. Arthritis, rheumatoid arthritis, diabetes mellitus, nephritis, osteoporosis, Crohn's disease, chronic inflammatory lung diseases such as adult respiratory distress syndrome (ARDS), brain inflammatory diseases such as Alzheimer's disease, sepsis and acute and chronic inflammation, restenosis after PTCA, transplantation Rejections, chronic 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 such as psoriasis.
  • ARDS adult respiratory distress syndrome
  • brain inflammatory diseases such as Alzheimer's disease, sepsis and acute and chronic inflammation
  • restenosis after PTCA transplantation Rejections
  • chronic inflammatory fibrotic organ changes such as liver fibrosis
  • 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 antihypertensive agents.
  • active substances in particular with anti-hyperlipidemic, anti-arteriosclerotic, anti-diabetic, anti-inflammatory or antihypertensive 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. For this purpose, they may be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, 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.
  • the compound of the invention donating application forms containing the inventive compounds in crystalline and / or amorphized and / or dissolved form, such as.
  • Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • the oral application is preferred.
  • Inhalation medicines including powder inhalers, nebulizers
  • nasal drops solutions, sprays
  • lingual, sublingual or buccal tablets to be applied, 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 include, among others, excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyisocyanate).
  • ethylene glycols ethylene glycols
  • emulsifiers and dispersing or wetting agents for example sodium dodecylsulfate, 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, for example, iron oxides
  • flavor and / or odor remedies for example sodium dodecylsulfate, 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, for example, iron oxides
  • flavor and / or odor remedies for example sodium dodecylsulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • 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.
  • Method 1 Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm ⁇ 2 mm, 3.5 ⁇ m; Eluent A: 5 ml HClO 4 /! Water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 9 min 90% B, 9.2 min 2% B, 10 min 2% B; Flow: 0.75 ml / min; Oven: 3O 0 C; UV detection: 210 nm.
  • reaction mixture is taken up in 25 ml of ethyl acetate, filtered through diatomaceous earth, washed once each with 20 ml of 1 N hydrochloric acid and saturated 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 under high vacuum. This gives 1.01 g (91% of theory) of the title compound.
  • 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 ZKH 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 nmZ 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., Arteriosis osis 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 atherosclerosis-susceptible 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.
  • 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

La présente invention concerne des 3-cycloalkyl-1,2,4-triazin-5(2H)-ones et un procédé de production desdites substances, ainsi que leur utilisation pour produire des médicaments destinés à traiter et / ou à prévenir des maladies, en particulier des maladies inflammatoires chroniques, telles que par ex. des maladies rhumatoïdes, et des maladies cardio-vasculaires, telles que par ex. les dyslipidémies, l'artériosclérose et les coronaropathies.
PCT/EP2005/013432 2004-12-18 2005-12-14 3-cycloalkyl-1,2,4-triazin-5(2h)-ones Ceased WO2006063812A1 (fr)

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DE102004061005.3 2004-12-18
DE102004061005A DE102004061005A1 (de) 2004-12-18 2004-12-18 3-Cycloalkyl-1,2,4-triazin-5(2H)-one

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Cited By (4)

* 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
US9029383B2 (en) 2007-05-11 2015-05-12 The Trustees Of The University Of Pennsylvania Methods of treatment of skin ulcers
US9988373B2 (en) 2013-12-26 2018-06-05 Shionogi & Co., Ltd. Nitrogen-containing six-membered cyclic derivatives and pharmaceutical composition comprising the same

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001060805A1 (fr) * 2000-02-16 2001-08-23 Smithkline Beecham P.L.C. Derives de pyrimidine-4-one utilises comme inhibiteurs de ldl-pla¿2?
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
WO2001060805A1 (fr) * 2000-02-16 2001-08-23 Smithkline Beecham P.L.C. Derives de pyrimidine-4-one utilises comme inhibiteurs de ldl-pla¿2?
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 (5)

* 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
WO2012080497A2 (fr) 2010-12-17 2012-06-21 Glaxo Group Limited Procédés de traitement et de prévention de maladies oculaires
US9988373B2 (en) 2013-12-26 2018-06-05 Shionogi & Co., Ltd. Nitrogen-containing six-membered cyclic derivatives and pharmaceutical composition comprising the same

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