DE102004061009A1 - Substituted 1,2,4-triazine-5 (2H) -ones - Google Patents

Abstract

The invention relates to substituted 1,2,4-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, especially of chronic inflammatory diseases such. B. diseases of the rheumatoid type, and cardiovascular diseases such. As dyslipidaemias, arteriosclerosis and coronary heart disease.

Description

The This invention relates to substituted 1,2,4-triazine-5 (2H) -ones and methods for their manufacture and their use for the manufacture of medicaments for the treatment and / or prophylaxis of diseases, in particular of chronic inflammatory diseases, e.g. diseases of the rheumatoid group, and cardiovascular diseases, such as. dyslipidemias, Atherosclerosis and coronary heart disease.

The Synthesis of amide-substituted 1,2,4-triazine-5 (2H) -ones is described in G. Hornyak, et al., Acta Chimica Academiae Scientiarum Hungaricae, 1969, 61 (2), 181-196.

WHERE No. 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 today generally accepted. The inflammatory vascular changes caused by the reaction of immigrant monocytes with pathogenic Lipoproteins in the arterial wall. Especially the emergence of Foam cells from the immigrated monocytes by uptake of oxidizing lipids occupies a central role in terms of plaque development and stability one. To be recognized by monocytes, native lipoproteins must become one modified atherogenic form. The enzyme 'platelet-activating factor acetylhydrolase (PAF-AH) is significantly involved in this by being oxidized LDL (low-density lipoprotein) the inflammatory mediators lysophosphatidylcholine as well as oxidized fatty acids forms.

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 for the accumulation of cholesterol ester-loaded monocytes (foam cells) responsible in the arteries (Quinn, et al., Proc. Natl. Acad. Sci. LISA 1988, 85, 2805-2809). this leads to for the formation of the so-called 'fatty streaks', which represents the first visible arteriosclerotic vessel change. An inhibitor the PAF-AH would be the Stopping and formation of these macrophage-enriched lesions useful for the Treatment of arteriosclerosis.

Of the Increased LysoPC content of oxLDL also seems to be endothelial Dysfunction attributable to patients with atherosclerosis observed. PAF-AH inhibitors are therefore also suitable for treatment this phenomenon. Further would be their use makes sense in all diseases involving endothelial Underlying dysfunction, such as Diabetes, hypertension and Angina pectoris.

In addition, PAF-AH Inhibitors in any disease, the activated monocytes, macrophages or Lymphocytes have their application, since all these cells express the enzyme.

A The object of the present invention is therefore new inhibitors PAF-AH for the treatment of chronic inflammatory diseases and cardiovascular diseases in humans and animals put.

Surprisingly was found to be those described in the present invention substituted 1,2,4-triazine-5 (2H) -one inhibitors of PAF-AH are.

in welcher
A für ein Schwefelatom oder Methylen steht,
R¹ für (C₁-C₄)-Alkyl oder (C₃-C₇)-Cycloalkyl steht, wobei Alkyl substituiert sein kann mit 1 bis 3 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Halogen, Cyano, Oxo, Phenyl, Hydroxycarbonyl, (C₁-C₆)-Alkoxycarbonyl, Aminocarbonyl und (C₁-C₆)-Alkylaminocarbonyl,
R² für Phenyl oder 5- oder 6-gliedriges Heteroaryl steht,
wobei Phenyl und Heteroaryl substituiert sein können mit 1 bis 3 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Hydroxy, Amino, Halogen, Cyano, Trifluormethyl, Trifluormethoxy, (C₁-C₆)-Alkyl, (C₁- C₆)-Alkoxy, (C₁-C₆)-Alkylamino, (C₁-C₆)-Alkylthio, Phenyl, Phenoxy, Hydroxycarbonyl, (C₁-C₆)-Alkoxycarbonyl, Aminocarbonyl, (C₁-C₆)-Alkylaminocarbonyl, (C₁-C₆)-Alkylcarbonyl und (C₁-C₆)-Alkylcarbonylamino,
R³ für (C₁-C₆)-Alkyl steht,
wobei Alkyl substituiert sein kann mit 1 bis 3 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Hydroxy, Amino, Halogen, (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkylamino, (C₁-C₆)-Alkylthio, 3- bis 7-gliedriges Heterocyclyl, 5- oder 6-gliedriges Heteroaryl, Hydroxycarbonyl, (C₁-C₆)-Alkoxycarbonyl, Aminocarbonyl, (C₁-C₆)-Alkylaminocarbonyl, (C₁-C₆)-Alkylcarbonyl, (C₁-C₆)-Alkylcarbonylamino und (C₁-C₆)-Alkoxycarbonylamino,
worin Heterocyclyl und Heteroaryl wiederum substituiert sein können mit 1 bis 3 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Hydroxy, Amino, Oxo, Halogen, Cyano, Trifluormethyl, Trifluormethoxy, (C₁-C₆)-Alkyl, (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkylamino, (C₁-C₆)-Alkylthio, Hydroxycarbonyl, (C₁-C₆)-Alkoxycarbonyl, Aminocarbonyl, (C₁-C₆)-Alkylaminocarbonyl, (C₁-C₆)-Alkylcarbonyl und (C₁-C₆)-Alkylcarbonylamino,
oder
R³ für ein 3- bis 9-gliedriges Heterocyclyl mit 1 bis 2 Stickstoffatomen steht, wobei Heterocyclyl substituiert sein kann mit 1 bis 5 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Hydroxy, Amino, Oxo, Formyl, (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkoxycarbonyl und gegebenenfalls (C₁-C₆)-Alkoxy substituiertes (C₁-C₆)-Alkyl,
R⁴ für 4-(Phenyl)phenyl, 4-(Pyridyl)phenyl, 6-(Phenyl)pyridin-3-yl oder 5-(Phenyl)pyridin-2-yl steht,
wobei 4-(Phenyl)phenyl, 4-(Pyridyl)phenyl, 6-(Phenyl)pyridin-3-yl und 5-(Phenyl)pyridin-2-yl substituiert sein können mit 1 bis 3 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Hydroxy, Amino, Halogen, Cyano, Trifluormethyl, Difluormethyl, Monofluormethyl, Trifluormethoxy, Difluormethoxy, Monofluormethoxy, (C₁-C₆)-Alkyl, (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkylamino, (C₁-C₆)-Alkylthio, (C₁-C₆)-Alkylsulfonyl, Hydroxycarbonyl, (C₁-C₆)-Alkoxycarbonyl, Aminocarbonyl, (C₁-C₆)-Alkylaminocarbonyl, (C₁-C₆)-Alkylcarbonyl, (C₁-C₆)-Alkylcarbonylamino, (C₁-C₆)-Alkylaminosulfonyl und (C₁-C₆)-Alkylsulfonylamino,
R⁵ für (C₁-C₆)-Alkyl oder (C₃-C₇)-Cycloalkyl steht,
wobei Alkyl und Cycloalkyl substituiert sein können mit 1 bis 3 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Halogen, Cyano, Trifluormethyl, (C₁-C₄)-Alkyl und (C₁-C₃)-Alkoxy,
und ihre Salze, ihre Solvate und die Solvate ihrer Salze.The invention relates to compounds of the formula

in which
A is a sulfur atom or methylene,
R ^{1 is} (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl, wherein alkyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano , Oxo, phenyl, hydroxycarbonyl, (C ₁ -C ₆ ) -alkoxycarbonyl, aminocarbonyl and (C ₁ -C ₆ ) -alkylaminocarbonyl,
R ^{2 is} phenyl or 5- or 6-membered heteroaryl,
wherein phenyl and heteroaryl 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, (C ₁ -C ₆ ) alkyl, (C ₁ - C ₆ ) -Alkoxy, (C ₁ -C ₆ ) -alkylamino, (C ₁ -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} (C ₁ -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 ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylamino, ( C ₁ -C ₆ ) -alkylthio, 3- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl, hydroxycarbonyl, (C ₁ -C ₆ ) -alkoxycarbonyl, aminocarbonyl, (C ₁ -C ₆ ) -alkylaminocarbonyl, ( C ₁ -C ₆ ) -alkylcarbonyl, (C ₁ -C ₆ ) -alkylcarbonylamino and (C ₁ -C ₆ ) -alkoxycarbonylamino,
in which heterocyclyl and heteroaryl may in turn be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of hydroxyl, amino, oxo, halogen, cyano, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy, (C ₁ -C ₆ ) -alkylamino, (C ₁ -C ₆ ) -alkylthio, hydroxycarbonyl, (C ₁ -C ₆ ) -alkoxycarbonyl, aminocarbonyl, (C ₁ -C ₆ ) -Alkylaminocarbonyl, (C ₁ -C ₆ ) -alkylcarbonyl and (C ₁ -C ₆ ) -alkylcarbonylamino,
or
R ^{3 is} a 3- to 9-membered heterocyclyl having 1 to 2 nitrogen atoms, wherein heterocyclyl may be substituted by 1 to 5 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, oxo, formyl, ( C ₁ -C ₆ ) -alkoxy, (C ₁ -C ₆ ) -alkoxycarbonyl and optionally (C ₁ -C ₆ ) -alkoxy-substituted (C ₁ -C ₆ ) -alkyl,
R ^{4 is} 4- (phenyl) phenyl, 4- (pyridyl) phenyl, 6- (phenyl) pyridin-3-yl or 5- (phenyl) pyridin-2-yl,
wherein 4- (phenyl) phenyl, 4- (pyridyl) phenyl, 6- (phenyl) pyridin-3-yl and 5- (phenyl) pyridin-2-yl may be substituted with 1 to 3 substituents, wherein the substituents are independently are selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy, (C ₁ -C ₆ ) -alkylamino, (C ₁ -C ₆ ) -alkylthio, (C ₁ -C ₆ ) -alkylsulfonyl, hydroxycarbonyl, (C ₁ -C ₆ ) -alkoxycarbonyl, aminocarbonyl, (C ₁ -C ₆ ) -alkylaminocarbonyl , (C ₁ -C ₆ ) -alkylcarbonyl, (C ₁ -C ₆ ) -alkylcarbonylamino, (C ₁ -C ₆ ) -alkylaminosulfonyl and (C ₁ -C ₆ ) -alkylsulfonylamino,
R ^{5 is} (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,
wherein alkyl and cycloalkyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, (C ₁ -C ₄ ) alkyl and (C ₁ -C ₃ ) alkoxy .
and their salts, their solvates, and the solvates of their salts.

Compounds of the invention are the compounds of formula (I) and their salts, solvates and solvates the salts as well as those of formula (I), hereinafter referred to as embodiment (e) mentioned compounds and their salts, solvates and solvates of Salts, as far as those of formula (I), hereinafter not already mentioned salts, solvates and solvates salts.

Depending on their structure, the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore relates to the enantiomers or diastes and their respective mixtures. From such mixtures of enantiomers. and / or diastereomers, the stereoisomerically uniform constituents can be isolated in a known manner.

Provided the compounds of the invention can occur in tautomeric forms, For example, the present invention encompasses all tautomeric forms.

When Salts are physiologically acceptable in the context of the present invention Salts of the compounds of the invention prefers. Also included are salts that are suitable for pharmaceutical applications themselves are not suitable but for example for insulation or cleaning the compounds of the invention can be used.

physiological Safe 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, Sulfuric acid, Phosphoric acid, methane, ethanesulfonic, toluene sulfonic acid, benzenesulfonic, naphthalenedisulfonic, Acetic acid, trifluoroacetic, propionic acid, Lactic acid, Tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and Benzoic acid.

physiological acceptable salts of the compounds of the invention also include Salts more usual Bases, such as by way of example and preferably alkali metal salts (e.g. Sodium and potassium salts), alkaline earth salts (e.g., calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 carbon atoms, such as by way of example and preferably ethylamine, Diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, Diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, Dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

When In the context of the invention, solvates are those forms of the compounds according to the invention, which in solid or liquid Condition by coordination with solvent molecules a complex form. Hydrates are a special form of solvates in which the coordination with water takes place.

The free base of the salts of the compounds of the invention may, for example by adding an aqueous Base, for example, diluted Caustic soda, and subsequent Extraction with a solvent obtained by methods known to those skilled in the art.

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
Alkyl per se and "alk" and "alkyl" in alkoxy, alkylthio, alkylamino, alkylsulfonyl, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonylamino, alkoxycarbonylamino, alkylaminosulfonyl and alkylsulfonylamino represent a linear or branched alkyl radical with generally 1 to 6, preferably 1 to 4, more 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 exemplary and preferably methoxy, ethoxy, n-propoxy, Isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

alkylthio is exemplary and preferably methylthio, ethylthio, n-propylthio, Isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.

Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents, by way of example and by way of preference 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-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 having in each case 1 to 3 carbon atoms per alkyl substituent.

alkylsulfonyl is exemplary and preferably methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, tert -butylsulfonyl, n -pentylsulfonyl and n-hexylsulfonyl.

alkoxycarbonyl is exemplary 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-methylaminocarbonyl, N-ethyl-Nn-pentylaminocarbonyl and Nn-hexyl-N-methylaminocarbonyl. C ₁ -C ₃ -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 exemplary 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.

alkoxycarbonylamino is exemplary 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 Propylaminosulfonyl, isopropylaminosulfonyl, tert -butylaminosulfonyl, n -pentylaminosulfonyl, n-hexylaminosulfonyl, N, N-dimethylaminosulfonyl, N, N -diethylaminosulfonyl, N -ethyl-N-methylaminosulfonyl, N -methyl-Nn-propylaminosulfonyl, N-isopropyl Nn-propylaminosulfonyl, N-tert-butyl-N-methylaminosulfonyl, N-ethyl-Nn-pentylaminosulfonyl and Nn-hexyl-N-methylaminosulfonyl. 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 exemplary and preferably methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, Isopropylsulfonylamino, tert-butylsulfonylamino, n-pentylsulfonylamino and n-hexylsulfonylamino.

cycloalkyl stands for a cycloalkyl group of usually 3 to 7, preferably 3 to 6 carbon atoms, by way of example and preferably for cycloalkyl are called cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and Cycloheptyl.

aryl stands for a mono- or bicyclic aromatic radical, as a rule 6 to 10 carbon atoms, by way of example and preferably aryl called phenyl and naphthyl.

heteroaryl stands for an aromatic, mono- or bicyclic radical as a rule 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 one nitrogen atom can also form 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. Preference is given to 5- to 8-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S, by way of example and preferably for oxetan-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pynolinyl, 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 stands for Fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

If Residues in the compounds of the invention may be substituted the radicals, unless otherwise specified, one or more times be substituted identically or differently. A substitution with up to three identical or different substituents are preferred. Very particular preference is given to the substitution with a substituent.

Preference is given to those compounds of the formula (I) in which
A is a sulfur atom or methylene,
R ^{1 is} methyl, ethyl, n-propyl or isopropyl,
R ^{2 is} phenyl, thienyl or pyridyl,
where phenyl, thienyl and pyridyl can 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, (C ₁ -C ₄ ) -alkyl, ( C ₁ -C ₄ ) -alkoxy and (C ₁ -C ₆ ) -alkylamino,
R ^{3 is} (C ₁ -C ₄ ) -alkyl,
wherein alkyl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) alkylamino, 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl and (C ₁ -C ₆ ) -alkoxycarbonylamino,
in which heterocyclyl and heteroaryl may in turn be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of hydroxyl, amino, oxo, halogen, cyano, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy and (C ₁ -C ₆ ) -alkylamino,
or
R ^{3 is} a 4- to 6-membered heterocyclyl having 1 to 2 nitrogen atoms,
wherein heterocyclyl may be substituted with 1 to 5 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, oxo, formyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl and optionally (C ₁ -C ₄ ) -alkoxy-substituted (C ₁ -C ₄ ) -alkyl,
R ^{4 is} 4- (phenyl) phenyl or 4- (pyridin-2-yl) phenyl,
wherein 4- (phenyl) phenyl and 4- (pyridin-2-yl) 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, difluoromethyl , Monofluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy and (C ₁ -C ₆ ) -alkylamino,
R ^{5 is} (C ₁ -C ₆ ) -alkyl,
and their salts, their solvates, and the solvates of their salts.

Preference is also given to those compounds of the formula (I) in which
A is a sulfur atom or methylene,
R ^{1 is} methyl or ethyl,
R ^{2 is} phenyl, thienyl or pyridyl,
wherein 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,
wherein alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of amino, (C ₁ -C ₆ ) -alkylamino and pyrrolidinyl,
in which pyrrolidinyl can in turn be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of oxo and (C ₁ -C ₄ ) -alkyl,
or
R ^{3 is} azetidinyl, piperidinyl or pyrrolidinyl,
wherein azetidinyl, piperidinyl and 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 and optionally methoxy-substituted (C ₁ -C ₄ ) alkyl,
R ^{4 is} 4- (phenyl) phenyl or 4- (pyridin-2-yl) phenyl,
wherein 4- (phenyl) phenyl and 4- (pyridin-2-yl) 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} (C ₁ -C ₆ ) -alkyl,
and their salts, their solvates, and the solvates of their salts.

Preference is also given to those compounds of the formula (I) in which R ^{1 is} methyl or ethyl.

Preference is also given to those compounds of the formula (I) in which 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.

Preference is also given to those compounds of the formula (I) in which 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, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy, (C ₁ -C ₆ ) -alkylamino, (C ₁ -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.

Preference is also given to those compounds of the formula (I) in which R ^{2 is} pyridyl or thienyl.

Preference is also given to those compounds of the formula (I) in which R ^{3 is} diethylaminoethyl, N-methylpiperidin-4-yl, N-ethylpiperidin-4-yl or 1,2,2,6,6-pentamethylpiperidin-4-yl ,

Preference is also given to those compounds of the formula (I) in which 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.

Preference is also given to those compounds of the formula (I) in which R ^{5 is} methyl.

in welcher
A, R¹, R² und R⁵ die oben angegebene Bedeutung haben,
mit Verbindungen der Formel

in welcher
R³ und R⁴ die oben angegebene Bedeutung haben,
umgesetzt werden.The invention further provides a process for the preparation of the compounds of the formula (I), where compounds of the formula

in which
A, R ¹ , R ² and R ^{5 have} the abovementioned meaning,
with compounds of the formula

in which
R ³ and R ^{4 have} the abovementioned meaning,
be implemented.

The Reaction is generally carried out in inert solvents, in the presence of dehydrating reagents, optionally in the presence of a Base, preferably in a temperature range from 0 ° C to room temperature at atmospheric pressure.

When Dehydrating reagents are suitable here, for example, carbodiimides such as. N, N'-diethyl, N, N'-dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -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-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotriazol-1-yl) -N, N, N ', N'-tetra-methyluronium hexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) -pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) or O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyl-uronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), or mixtures thereof, with bases. Preferably the condensation was carried out with HOBt and EDC.

bases For example, alkali metal carbonates, e.g. Sodium or potassium carbonate, or bicarbonate, or organic bases such as trialkylamines, e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine. Preferably, the condensation with Diisopropylethylamine performed.

inert solvent For example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbon, such as benzene, nitromethane, Dioxane, dimethylformamide, acetonitrile or hexamethylphosphoric triamide. It is also possible Mixtures of solvents use. Particularly preferred is dichloromethane or dimethylformamide.

The Compounds of formula (III) are known or can be after synthesize known methods from the corresponding starting materials.

in welcher
A, R¹, R² und R⁵ die oben angegebene Bedeutung haben, und
R⁶ für Alkyl, bevorzugt Methyl, Ethyl oder tert.-Butyl, steht,
mit Basen (Methyl, Ethyl) oder mit Säuren (tert.-Butyl) umgesetzt werden.The compounds of the formula (II) are known or can be prepared by reacting compounds of the formula

in which
A, R ¹ , R ² and R ^{5 have} the meaning given above, and
R ^{6 is} alkyl, preferably methyl, ethyl or tert-butyl,
with bases (methyl, ethyl) or with acids (tert-butyl).

The Reaction is generally carried out in inert solvents, preferably in a temperature range of 0 ° C to room temperature at normal pressure.

in the Case of the reaction with bases are suitable as bases, for example Alkali hydroxides such as sodium, lithium or potassium hydroxide, or Alkali carbonates such as cesium carbonate, Sodium or potassium carbonate, preferred is sodium hydroxide. solvent 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, dimethyl sulfoxide, acetonitrile or pyridine, or mixtures of solvents, as a solvent are preferably tetrahydrofuran and / or methanol or dioxane.

in the Case of reaction with acids are suitable as acids for example, hydrogen chloride or trifluoroacetic acid. solvent 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 mix the solvent use. Particularly preferred is the use of hydrogen chloride in dioxane or trifluoroacetic acid in dichloromethane.

in welcher
A, R¹ und R² die oben angegebene Bedeutung haben,
mit Verbindungen der Formel

in welcher
R⁵ und R⁶ die oben angegebene Bedeutung haben, und
X¹ für Halogen, bevorzugt Iod oder Brom, steht,
umgesetzt werden.The compounds of the formula (IV) are known or can be prepared by reacting compounds of the formula

in which
A, R ¹ and R ^{2 have} the abovementioned meaning,
with compounds of the formula

in which
R ⁵ and R ^{6 have} the abovementioned meaning, and
X ^{1 is} halogen, preferably iodine or bromine,
be implemented.

The Reaction is generally carried out in inert solvents, in the presence a base, preferably in a temperature range from 0 ° C to 40 ° C at atmospheric pressure.

inert solvent 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.

bases For example, 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 sodium hydride.

The Compounds of formula (VI) are known or can be after synthesize known methods from the corresponding starting materials.

in welcher
R² die oben angegebene Bedeutung hat,
mit Verbindungen der Formel

in welcher
R¹ die oben angegebene Bedeutung hat, und
R¹ für Wasserstoff, Methyl oder Ethyl steht,
umgesetzt werden.The compounds of the formula (V) in which A represents a methylene group are known or can be prepared by reacting compounds of the formula

in which
R ^{2 has} the meaning given above,
with compounds of the formula

in which
R ^{1 has} the meaning given above, and
R ^{1 is} hydrogen, methyl or ethyl,
be implemented.

The Reaction generally takes place in a solvent, in the presence of a solvent Base, preferably in a temperature range from 20 ° C to 200 ° C at atmospheric pressure. Preferably, the reaction is carried out so that first 5 to 45 minutes at room temperature touched and then to the reflux temperature of the solvent is heated.

solvent For example, dimethylformamide or dimethylacetamide.

The compounds of the formulas (VII) and (VIII) are known or can be prepared by known processes synthesize from the corresponding starting materials.

For example can Compounds of formula (VII) can 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 thus prepared (VII) is generally for the further conversion to compounds of the formula (V) is not necessary.

in welcher
R¹ die oben angegebene Bedeutung hat,
mit Verbindungen der Formel

in welcher
R² die oben angegebene Bedeutung hat, und
X² für Halogen, bevorzugt Iod oder Brom, steht,
umgesetzt werden.The compounds of the formula (V) in which A represents a sulfur atom are known or can be prepared by reacting compounds of the formula

in which
R ^{1 has} the meaning given above,
with compounds of the formula

in which
R ^{2 has} the meaning given above, and
X ^{2 is} halogen, preferably iodine or bromine,
be implemented.

The Reaction generally takes place in a solvent, in the presence of a solvent Base, preferably in a temperature range from 0 ° C to 40 ° C at atmospheric pressure.

solvent 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 solvent with water, water is preferred.

bases For example, 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.

From The compounds of formula (X) is an equivalent used to the compounds of the formula (IX).

The Compounds of formulas (IX) and (X) are known or can be Synthesize by known methods from the corresponding starting materials.

The Preparation of the compounds of the invention can be illustrated by the following synthesis scheme.

Scheme 1:

The Compounds of the invention show an unpredictable, valuable pharmacological activity spectrum.

she are therefore suitable for use as a medicament for treatment and / or prophylaxis of diseases in humans and animals.

The pharmaceutical effectiveness of the compounds of the invention can be explain by their action as PAF-AH inhibitors.

Another The present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, preferably of cardiovascular diseases, especially arteriosclerosis.

The Compounds of the invention can used in the prevention and treatment of cardiovascular diseases, such as. Atherosclerosis, reperfusion tissue damage after stroke, heart attack or peripheral arterial and venous vascular diseases and essential or pregnancy-induced hypertension.

Farther can the compounds of the invention in any kind of disorders, which include lipid oxidation, inflammation and an increased enzyme activity includes, used as e.g. Arthritis, rheumatoid arthritis, Diabetes mellitus, nephritis, Osteoporosis, Crohn's disease, chronic inflammatory lung diseases such as Adult Respiratory Distress Syndrome (ARDS), inflammatory brain diseases such as Alzheimer's disease, sepsis and acute as well as chronic inflammation, Restenosis after PTCA, graft rejection, chronic inflammatory fibrotic organ changes such as liver fibrosis, or the more generalized autoimmune systemic disease Lupus erythematosus or other forms of lupus erythematosus or dermal inflammatory diseases like psoriasis.

The Compounds of the invention can due to their pharmacological properties alone and when needed also in combination with other active substances, in particular with anti-hyperlipidemic, anti-arteriosclerotic, anti-diabetic, anti-inflammatory or anti-hypertensive Active ingredients are used. 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 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 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 The subject of the present invention is a method of treatment and / or prophylaxis of diseases, in particular those mentioned above Diseases using a therapeutically effective amount the compounds of the invention.

The Compounds of the invention can act systemically and / or locally. For this purpose they can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

For this Application routes can the compounds of the invention be administered in suitable administration forms.

For the oral Application are functioning according to the prior art rapidly and / or modifies the compounds according to the invention donating Application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, e.g. Tablets (uncoated or coated Tablets, for example, with enteric or delayed dissolving or insoluble coatings that control the release of the compound of the invention), in the oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, Capsules (for example hard or soft gelatine capsules), dragees, Granules, pellets, powders, emulsions, suspensions, aerosols or Solutions.

The Parenteral administration can bypass a resorption step happen (e.g., intravenously, intraarterial, intracardiac, intraspinal or intralumbar) or involving absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, Suspensions, emulsions, lyophilisates or sterile powders.

Prefers is the oral application.

For the others Application routes are suitable, e.g. Inhalation medicines (i.a. Powder inhalers, nebulizers), nasal drops, solutions, sprays; lingual, sublingual or buccally applied tablets, films / wafers or capsules, Suppositories, ear or eye preparations, vaginal capsules, aqueous Suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic Systems (such as patches), milk, pastes, foams, Implants or stents.

The Compounds of the invention can in the cited Application forms are transferred. This can be done in a conventional manner by mixing with inert, Non-toxic, pharmaceutically suitable excipients happen. Among these adjuvants include et al excipients (for example, microcrystalline cellulose, lactose, mannitol), solvent (e.g., liquid Polyethylene glycols), emulsifiers and dispersing or wetting agents (For example, sodium dodecyl sulfate, Polyoxysorbitanoleat), binder (For example, polyvinylpyrrolidone), synthetic and natural polymers (for example, albumin), stabilizers (e.g., antioxidants such as for example ascorbic acid), Dyes (e.g., inorganic pigments such as iron oxides) and flavor and / or scent remedies.

Another The present invention relates to medicaments which are at least a compound of the invention, usually together with one or more inert, non-toxic, pharmaceutical contain suitable excipients, as well as their use to the previously mentioned purposes.

in the In general, it has proven to be beneficial in parenteral Application amounts of about 5 to 250 mg / kg body weight per 24 hours to Achieving effective results. For oral administration is the amount about 5 to 100 mg / kg of body weight every 24 hours.

Nevertheless, it may be necessary to deviate from the quantities mentioned, and Although depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The Percentages in the following tests and examples are provided not stated otherwise, weight percentages; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions each on the volume. The term "w / v" means "weight / volume". For example, "10% means w / v ": 100 ml solution or Suspension contain 10 g of substance.

A) Examples

Abbreviations:

Section.

absolutely

Boc

tert-butoxycarbonyl

CDCl ₃

deuterochloroform

CO ₂

carbon dioxide

DC

TLC

DIEA

N, N-diisopropylethylamine

DMF

N, N-dimethylformamide

DMSO

dimethyl sulfoxide

d. Th.

the theory

EDC

N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide

eq.

equivalent to

IT I

Electrospray ionization (in MS)

ges.

saturated

H

hour

HOBt

1-hydroxy-1H-benzotriazole

HPLC

High pressure, high performance liquid chromatography

conc.

concentrated

LC-MS

Liquid chromatography-coupled mass spectroscopy

minute

minutes

MS

mass spectroscopy

MW

Molecular weight [g / mol]

NMR

Nuclear Magnetic Resonance Spectroscopy

R _f

Retention index (at DC)

RP-HPLC

Reverse phase HPLC

RT

room temperature

R _t

Retention time (at HPLC)

TFA

trifluoroacetic

THF

tetrahydrofuran

HPLC method:

• Method 1 (HPLC): Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm × 2 mm, 3.5 μm; Eluent A: 5 ml HClO ₄ / l 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: 30 ° C; UV detection: 210 nm.

Starting Compounds: Example 1A 6-Ethyl-3- (2-phenylethyl) -1,2,4-triazine-5 (2H) -one

A solution of 5 g (21.8 mmol) of 3-phenylpropanimidamide hydrobromide is dissolved in 50 ml of ethanol and treated at 0 ° C with 26.2 ml (26.2 mmol) of a 1M solution of hydrazine in THF. After 2 h, the ethanol is removed in vacuo and the residue is taken up in 40 ml of DMF and admixed with 3.22 g (30.6 mmol) of 2-oxobutanoic acid. The reaction mixture is first stirred for 30 minutes at room temperature and then for 3 hours at reflux temperature. The solvent is removed in vacuo and the residue is purified by preparative HPLC. This gives 2.14 g (40% of theory) of the product.
LC-MS (Method 1): R _t = 3.58 min
MS (ESIpos): m / z = 230 (M + H) ⁺

Example 2A 2- [6-Ethyl-5-oxo-3- (2-phenylethyl) -1,2,4-triazin-2 (5H) -yl] -propanoic acid tert -butyl ester

1.50 g (6.54 mmol) of 6-ethyl-3- (2-phenylethyl) -1,2,4-triazine-5 (2H) -one are dissolved in 50 ml of N, N-dimethylformamide and initially with cooling in portions with a suspension of 0.29 g (7.20 mmol) of 60% sodium hydride in mineral oil. After completion of the evolution of hydrogen, the mixture is stirred for 15 min and then 1.64 g (7.85 mmol) of tert-butyl 2-bromopropanoic acid added and stirred for 2 h at room temperature. For workup, the reaction solution is diluted with sodium bicarbonate solution and extracted with methylene chloride. The combined organic phases are dried over sodium sulfate and after removal of the solvent in vacuo, the residue is purified by preparative HPLC. This gives 1.06 g (45% of theory) of the product.
HPLC (Method 1): R _t = 4.76 min
MS (ESIpos): m / z = 358 (M + H) ⁺

Example 3A 2- [6-Ethyl-5-oxo-3- (2-phenylethyl) -1,2,4-triazine-2 (5H) -yl] -propanoic acid

1.05 g (2.9 mmol) of tert-butyl 2- [6-ethyl-5-oxo-3- (2-phenylethyl) -1,2,4-triazine-2 (5H) -yl] propanoate are dissolved in 12 ml of dichloromethane dissolved and mixed with 3.4 ml (44 mmol) of trifluoroacetic acid and stirred at 40 ° C overnight. After removal of the solvent in vacuo, the residue is purified by preparative HPLC. This gives 0.45 g (51% of theory) of the product.
HPLC (Method 1): R _t = 3.84 min
MS (ESIpos): m / z = 302 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 13 (s broad, 1H), 7.35-7.15 (m, 5H), 4.9 (q, 1H), 3.2-2.9 (m, 4H), 2.55 (q, 2H), 1.55 (d, 3H), 1.1 (t, 3H).

The Examples of the following table are analogous to the examples 1A to 3A produced.

Example 13A 3 - [(2,3-Difluorobenzyl) thio] -6-ethyl-1,2,4-triazine-5 (2H) -one

A solution of 5.0 g (32 mmol) of 6-ethyl-3-mercapto-1,2,4-triazine-5 (2H) -one and 4.4 g (32 mmol) of potassium carbonate in 80 ml of water is treated with 6.65 g (32 mmol ) 2,3-Difluorbenzylbromid and stirred overnight. For workup, the mixture is adjusted to pH 1 with 1N hydrochloric acid solution and the precipitated solid is filtered off with suction. The solid is then taken up in methylene chloride and washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. This gives 7.98 g (88% of theory) of the product.
LC-MS (Method 1): R _t = 4.06 min
MS (ESIpos): m / z = 284 (M + H) ⁺

Example 14A 2- [3 - [(2,3-Difluorobenzyl) thio] -6-ethyl-5-oxo-1,2,4-triazin-2 (5H) -yl] -propanoic acid tert -butyl ester

1.50 g (5.3 mmol) of 3 - [(2,3-difluorobenzyl) thio] -6-ethyl-1,2,4-triazine-5 (2H) -one are dissolved in 20 ml of N, N-dimethylformamide and initially taken under Cooling added in portions with a suspension of 0.23 g (5.8 mmol) of 60% sodium hydride in mineral oil. After completion of the evolution of hydrogen, the mixture is stirred for 15 min and then 2.21 g (10.6 mmol) of tert-butyl 2-bromopropanoic acid added and stirred for 2 h at room temperature temperature. For workup, the reaction solution is diluted with sodium bicarbonate solution and extracted with methylene chloride. The combined organic phases are dried over sodium sulfate and after removal of the solvent in vacuo, the residue is purified by preparative HPLC. This gives 0.84 g (38% of theory) of the product.
HPLC (Method 1): R _t = 5.15 min
MS (ESIpos): m / z = 412 (M + H) ⁺

Example 15A 2- [3 - [(2,3-Difluorobenzyl) thio] -6-ethyl-5-oxo-1,2,4-triazin-2 (5H) -yl] propanoic acid

2.39 g (5.8 mmol) of tert-butyl 2- [3 - [(2,3-difluorobenzyl) thio] -6-ethyl-5-oxo-1,2,4-triazine-2 (5H) -yl] propanoate are dissolved in 10 ml of dichloromethane and treated with 6.7 ml (87 mmol) of trifluoroacetic acid and stirred overnight at 40 ° C. After removal of the solvent in vacuo, the residue is purified by preparative HPLC. This gives 1.9 g (90% of theory) of the product.
HPLC (Method 1): R _t = 4.2 min
MS (ESIpos): m / z = 356 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 13.5 (s broad, 1H), 7.35 (m, 2H), 7.2 (m, 1H), 5.2 (q, 1H), 4.5 (s, 2H ), 2.55 (q, 2H), 1.6 (d, 3H), 1.1 (t, 3H).

The Examples of the following table are analogous to Example 13A to 15A produced.

Example 21A 4 '- (trifluoromethyl) biphenyl-4-carbaldehyde

1.0 g (4.44 mmol) of 1-bromo-4- (trifluoromethyl) benzene, 1.13 g (7.56 mmol) of 4-formylphenylboronic acid and 0.94 g (8.89 mmol) of sodium carbonate are initially charged in 7.5 ml of water and 20.0 ml of dimethoxyethane. It is passed through the mixture for 1 h of argon. Then, 0.26 g (0.22 mmol) of tetrakis (triphenylphosphine) palladium (0) (Pd (PPh ₃ ) ₄ ) is added and the mixture is stirred for 18 h at reflux. The 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.
HPLC (Method 1): R _t = 4.99 min.
MS (EI): m / z = 285 (M + N ₂ H ₇ ) ⁺ .

Example 22A N, N-diethyl-N '- {[4' - (trifluoromethyl) biphenyl-4-yl] methyl} ethane-1,2-diamine

To a solution of 500 mg (2.00 mmol) of 4 '- (trifluoromethyl) biphenyl-4-carbaldehyde and 280.8 μl (2.00 mmol) of 1-amino-2-diethylaminoethane is added 500 mg 4Å molecular sieve (<5 micron powder). After 18 h at room temperature, the reaction mixture is filtered, washed with dichloromethane and concentrated in vacuo. The crude material is dissolved in 5 ml of absolute ethanol and at 0 ° C with 90.7 mg (2.40 mmol) of sodium added borohydride. After 1 h at room temperature, the reaction mixture is mixed with water and extracted with dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. After chromatography on silica gel (cyclohexane / ethyl acetate: 3/1), the product fractions are combined, concentrated in vacuo and dried under high vacuum. 585 mg (75% of theory) of the title compound are obtained.
HPLC (Method 1): R _t = 4.10 min.
MS (EIpos): m / z = 351 (M + H) ⁺ .

Example 23A

wird analog zur Herstellung von Beispiel 21A erhalten.4 '- (trifluoromethyl) biphenyl-4-carbonitrile

is obtained analogously to the preparation of Example 21A.

Example 24A 1- [4 '- (trifluoromethyl) biphenyl-4-yl] methanamine

A solution of 6.2 g (22.7 mmol) of 4 '- (trifluoromethyl) biphenyl-4-carbonitrile in 70 ml of dry THF is slowly added at 0 ° C with 32.6 ml (32.6 mmol) of a 1M solution of lithium aluminum hydride in THF. After 3 h, 100 ml of water are slowly added and then filtered with suction from the precipitate formed. The precipitate is washed several times with methyl tert-butyl ether and the washings combined with the filtrate and placed in a separatory funnel. The aqueous phase is separated and washed with methyl tert-butyl ether. The combined organic phases are dried over sodium sulfate, concentrated in vacuo and then purified on silica gel. This gives 3.2 g (54% of theory) of the product.
HPLC (Method 1): R _t = 4.18 min.
MS (ESIpos): m / z = 252 (M + H) ⁺ .

Example 25A 1-Methyl-N - {[4 '- (trifluoromethyl) biphenyl-4-yl] methyl} piperidin-4-amine

A solution of 0.96 g (3.52 mmol) of 1- [4 '- (trifluoromethyl) biphenyl-4-yl] methanamine in a mixture of 10 ml of methanol and 0.6 ml of acetic acid is mixed with 0.45 g (3.87 mmol) of 1-methyl-4- piperidone and 0.28 g (4.22 mmol) of sodium cyanoborohydride and stirred overnight at room temperature. For working up, the reaction is mixed with 20 ml of 1N sodium hydroxide solution, the methanol is largely removed under reduced pressure and the residual aqueous reaction mixture is extracted several times with dichloromethane. The organic phase is concentrated in vacuo and purified by preparative HPLC. This gives 0.86 g (70% of theory) of the product.
HPLC (Method 1): R _t = 4.10 min.
MS (ESIpos): m / z = 349 (M + H) ⁺ .

The Examples of the following table are analogous to Example 22A and 25A produced.

EXAMPLES Example 1 N- [2- (Diethylamino) ethyl] -2- [6-ethyl-3 - [(4-fluorobenzyl) thio] -5-oxo-1,2,4-triazine-2 (5H) - yl] -N - {[4 '- (trifluoromethyl) -biphenyl-4-yl] methyl} propanamide

To a solution of 100 mg (0.30 mmol) of 2- [6-ethyl-3 - [(4-fluorobenzyl) thio] -5-oxo-1,2,4-triazine-2 (5H) -yl] propanoic acid in 2 100 ml of N, N-diethyl-N '- {[4' - (trifluoromethyl) -biphenyl-4-yl] -methyl} -ethan-1,2-diamine, 171 mg (0.53 mmol) (benzotriazole -1-yloxy) bis-dimethylaminomethyliumte trafluoroborate and 0.1 ml of diisopropylethylamine and stirred overnight. For workup, 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. 105 mg (53% of theory) of product are obtained.
HPLC (Method 1): R _t = 4.86 min.
MS (ESIpos): m / z = 670 (M + H) ^+
1 H-NMR (400 MHz, TFA-d ₁ ): δ = 7.8 (d, 2H), 7.7 (d, 2H), 7.6 (d, 2H), 7.35 (m, 2H), 7.25 (d, 2H) , 7.1 (m, 2H), 5.9 (q, 1H), 5.05 (d, 1H), 4.9 (d, 1H), 4.75-4.55 (m, 2H), 4.3-3.8 (m, 6H), 3.5. (m, 6H), 3.05 (m, 2H), 2.0 (d, 3H), 1.55-1.35 (m, 9H).

The Examples of the following table are prepared analogously to Example 1. In the cases where formate salts are shown, the basic extraction is dispensed with. In the cases of hydrochlorides, these are from the free bases by putting with hydrochloric acid recovered in diethyl ether.

B) Assessment of physiological effectiveness

The Suitability of the compounds of the invention for the treatment of cardiovascular disease can be used in the following assay systems to be shown:

In vitro assay the PAF-AH

purification the PAF-AH from human plasma

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 with 0.1% Tween-20 (buffer: 20 mM K ₂ HPO ₄ / KH ₂ PO 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). The 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).

Thio-PAF assay

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-HCl, pH 8.2, 1 mM EGTA, 150 mM NaCl, 50 mM MgCl ₂ with addition of 25 μM substrate, 10 μM indicator and 0.1 μg / ml PAF-AH at 37 ° C incubated and the fluorescence (excitation 485 nm / emission 515 nm) in the fluorescence reader Spectra Fluor (Tecan, Crailsheim, Germany) measured. The results are shown in Table A:

Table A:

In vivo assay the PAF-AH

to Determination of the anti-atherosclerotic effect of PAF-AH inhibitors becomes the LDL receptor deficient Watanabe rabbit (Buja, L.M., Arteriosclerosis 1983, 3, 87-141). This is either in short-term studies (1-2 months), the anti-atherosclerotic Effect by a changed Gene expression of relevant marker genes in atherosclerosis-susceptible tissue Indirectly determined or in long-term studies (3-6 months) the emergence of atherosclerotic plaques with the help of histological Techniques determined directly.

C) exemplary embodiments for pharmaceutical compositions

The substances according to the invention can as follows be converted into pharmaceutical preparations:

Tablet:

Composition:

100 mg of the compound of Example 1, 50 mg lactose (monohydrate), 50 mg cornstarch, 10 mg polyvinylpyrolidone (PVP 25) (BASF, Germany) and 2 mg of magnesium stearate.

tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

The Mixture of the compound of Example 1, lactose and starch is with a 5% solution (m / m) of the PVP in water granulated. The granules will dry after drying with the magnesium stearate for 5 minute mixed. This mixture is compressed with a conventional tablet press (Format of the tablet see above).

Oral suspension:

Composition:

1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg Rhodigel (xanthan gum) (FMC, USA) and 99 g of water.

one Single dose of 100 mg of the compound of the invention correspond 10 ml oral suspension.

production:

The Rhodigel is suspended in ethanol, the compound of the example 1 is added to the suspension. While stirring the addition of the water takes place. Until the completion of the swelling of the Rhodigels is stirred for about 6h.

Intravenously administrable Solution:

Composition:

1 mg of the compound of Example 1, 15 g of polyethylene glycol 400 and 250 g of water for Injections.

production:

The Compound of Example 1 is used together with polyethylene glycol 400 dissolved in the water with stirring. The solution is sterilized by filtration (pore diameter 0.22 μm) and under aseptic conditions filled into heat-sterilized infusion bottles. These are with infusion stoppers and crimp caps locked.

Claims (9)

Compound of the formula

in which A is a sulfur atom or methylene, R ^{1 is} (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl, where alkyl may be substituted by 1 to 3 substituents, wherein the substituents are independently are selected from the group consisting of halogen, cyano, oxo, phenyl, hydroxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonyl, aminocarbonyl and (C ₁ -C ₆ ) alkylaminocarbonyl, R ^{2 is} phenyl or 5- or 6-membered Heteroaryl, where phenyl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy, (C ₁ -C ₆ ) -alkylamino, (C ₁ -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} (C ₁ -C ₆ ) -alkyl, where A is Alkyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, halogen, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₆ ) -alkylthio, 3- to 7-membered heterocyclyl, 5- or 6-membered heteroaryl, hydroxycarbonyl, (C ₁ -C ₆ ) -alkoxycarbonyl, aminocarbonyl, (C ₁ -C ₆ ) -alkylamino carbonyl, ( C ₁ -C ₆ ) -alkylcarbonyl, (C ₁ -C ₆ ) -alkylcarbonylamino and (C ₁ -C ₆ ) -alkoxycarbonylamino, in which heterocyclyl and heteroaryl may in turn be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of hydroxyl, amino, oxo, halogen, cyano, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy, (C ₁ -C ₆ ) -alkylamino, (C ₁ -C ₆ ) -alkylthio, hydroxycarbonyl, (C ₁ -C ₆ ) -alkoxycarbonyl, aminocarbonyl, (C ₁ -C ₆ ) -Alkylaminocarbonyl, (C ₁ -C ₆ ) -alkylcarbonyl and (C ₁ -C ₆ ) -alkylcarbonylamino, or R ^{3 is} a 3- to 9-membered heterocyclyl having 1 to 2 nitrogen atoms, where heterocyclyl may be substituted by 1 to 5 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, oxo, formyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxycarbonyl and optionally (C ₁ -C ₆ ) -alkoxy-substituted (C ₁ -C ₆ ) -alkyl, R ^{4 is} 4- (phenyl) -phenyl, 4- (pyridyl) -phenyl, 6- (phenyl) -pyridin-3-yl or 5- (phenyl) -pyridine 2-yl s wherein 4- (phenyl) phenyl, 4- (pyridyl) phenyl, 6- (phenyl) pyridin-3-yl and 5- (phenyl) pyridin-2-yl may be substituted with from 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 ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy, ( C ₁ -C ₆ ) -alkylamino, (C ₁ -C ₆ ) -alkylthio, (C ₁ -C ₆ ) -alkylsulfonyl, hydroxycarbonyl, (C ₁ -C ₆ ) -alkoxycarbonyl, aminocarbonyl, (C ₁ -C ₆ ) Alkylaminocarbonyl, (C ₁ -C ₆ ) -alkylcarbonyl, (C ₁ -C ₆ ) -alkylcarbonylamino, (C ₁ -C ₆ ) -alkylaminosulphonyl and (C ₁ -C ₆ ) -alkylsulphonylamino, R ^{5 represents} (C ₁ -) C ₆ ) alkyl or (C ₃ -C ₇ ) cycloalkyl, wherein alkyl and cycloalkyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, (C ₁ -C ₄ ) -alkyl un d (C ₁ -C ₃ ) -alkoxy, or one of its salts, its solvates or the solvates of its salts. A compound according to claim 1, characterized in that A is a sulfur atom or methylene, R ^{1 is} methyl, ethyl, n-propyl or isopropyl, R ^{2 is} phenyl, thienyl or pyridyl, wherein phenyl, thienyl and pyridyl may be substituted having 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy; (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy and (C ₁ -C ₆ ) -alkylamino, R ^{3 is} (C ₁ -C ₄ ) -alkyl, where alkyl may be substituted by 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) alkylamino, 5- or 6-membered heterocyclyl, 5 or 6-membered heteroaryl and (C ₁ -C ₆ ) alkoxycarbonylamino, wherein heterocyclyl and heteroaryl may in turn be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, oxo, halogen , Cyano, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy and (C ₁ -C ₆ ) -alkylamino, or R ³ for a 4- to 6-membered heterocyclyl having 1 to 2 nitrogen atoms, wherein heterocyclyl may be substituted with 1 to 5 substituents, wherein the substituents are independently selected from the group consisting of s is hydroxy, amino, oxo, formyl, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) -alkoxycarbonyl and optionally (C ₁ -C ₄ ) -alkoxy-substituted (C ₁ -C ₄ ) -alkyl, R ^{4 is} 4- (phenyl) phenyl or 4- (pyridin-2-yl) phenyl, wherein 4- (phenyl) phenyl and 4- (pyridin-2-yl) phenyl may be substituted with 1 to 3 substituents, wherein the substituents independently of one another are selected from the group consisting of hydroxy, amino, halogen, cyano, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy and (C ₁ -C ₆ ) -alkylamino, R ^{5 is} (C ₁ -C ₆ ) -alkyl. A compound according to any one of claims 1 or 2, characterized in that A is a sulfur atom or methylene, R ^{1 is} methyl or ethyl, R ^{2 is} phenyl, thienyl or pyridyl, where phenyl may be substituted by 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, wherein alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting from amino, (C ₁ -C ₆ ) -alkylamino and pyrrolidinyl, in which pyrrolidinyl may in turn be substituted by 1 to 3 substituents, where the substituents are independent g each other are selected from the group consisting of oxo and (C ₁ -C ₄ ) alkyl, or R ^{3 is} azetidinyl, piperidinyl or pyrrolidinyl, wherein azetidinyl, piperidinyl and 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 and optionally methoxy substituted (C ₁ -C ₄ ) alkyl, R ^{4 is} 4- (phenyl) phenyl or 4- (pyridine 2-yl) phenyl, wherein 4- (phenyl) phenyl and 4- (pyridin-2-yl) 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} (C ₁ -C ₆ ) -alkyl. Process for the preparation of a compound of formula (I) according to claim 1, characterized in that a compound of formula

in which A, R ¹ , R ² and R ^{5 have} the meaning given in claim 1, with a compound of the formula

in which R ³ and R ^{4 have} the meaning given in claim 1, is reacted. A compound according to any one of claims 1 to 3 for the treatment and / or prophylaxis of diseases. Medicaments containing at least one compound according to one of the claims 1 to 3 in combination with at least one pharmaceutically acceptable, pharmaceutically acceptable carrier or other excipients. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament. Medicament according to claim 6 for the treatment and / or Prophylaxis of chronic inflammatory diseases or cardiovascular diseases. Method of control of arteriosclerosis in humans and animals by administration of a effective amount of at least one compound according to any one of claims 1 to Third