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

Abstract

The invention relates to 3-cycloalkyl-1,2,4-triazin-5(2H)-ones, to a method for the production thereof, and to their use for producing medicaments for treating and/or preventing diseases, particularly chronic inflammatory diseases, for example, rheumatoid diseases and cardiovascular diseases, such as dyslipidaemias, arteriosclerosis, and coronary heart diseases.

Description

 3-cycloalkyl-l, 2,4-triazin-5 (2H) -ones

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. Diseases of the rheumatoid type, and cardiovascular diseases, such as Dyslipidaemias, arteriosclerosis 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 Sdentiarum Hungaricae, 1969, 61 (2), 181-196.

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. In particular, the formation of foam cells from the migrated monocytes by uptake of oxidized lipids plays a central role in plaque development and stability. To be recognized by monocytes, native lipoproteins must be modified to an atherogenic form. The enzyme 'Platelet-activating factor acetylhydrolase' (PAF-AH) plays a key role in this by forming the 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). This leads to the formation of the so-called 'fatty streaks', which represents the first visible arteriosclerotic Gefassveränderung. An inhibitor of PAF-AH would stop the formation of these macrophage-enriched lesions and would thus be useful for the treatment of arteriosclerosis.

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. Furthermore, their use would make sense - - in all diseases underlying endothelial dysfunction such as diabetes, hypertension and angina pectoris.

In addition, 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.

Surprisingly, it has been found that the 3-cycloalkyl-l, 2,4-triazine-5 (2H) -ones described in the present invention are inhibitors of PAF-AH.

The invention relates to compounds of the formula

in which

n is a number 1, 2, 3 or 4,

R ^{1 is} (C _r C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,

where 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,

where 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,

R ³ FLIR (C _{r C6)} -alkyl,

wherein 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,

wherein 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 .

(C ₁ -C ₆₎ alkylcarbonyl and (C _{r C6)} alkylcarbonylamino,

or

R ^{3 is} a 3- to 9-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, (Ci-C ₆₎ alkoxy, (Ci-C ₆₎ alkoxycarbonyl, and optionally (C _ö) -alkoxy-substituted (Ci-C ₆₎ alkyl,

R ^{4 is} 4- (phenyl) phenyl, 4- (pyridyl) phenyl, 6- (phenyl) pyridin-3-yl or 5- (phenyl) pyridin-2-yl,

whereby 4- (phenyl) phenyl, 4- (pyridyl) phenyl, 6- (phenyl) pyridin-3-yl and 5- (phenyl) pyridine

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₎ -

Alkoxycarbonyl, aminocarbonyl, (C ₁ -C ₆ ) -alkylaminocarbonyl, (C ₁ -C ₆ ) -alkylcarbonyl, - A -

_(Ci-C6) alkylcarbonylamino, (C _{r C6)} -Allcylaininosulfonyl and (Ci-C ₆₎ amino alkylsulfonyl,

R ^{5 is} hydrogen, (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 _{r C4)} alkyl and (C ₁ -Ca) -alkoxy,

and their salts, their solvates, and the solvates of their salts.

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.

Depending on their structure, 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.

If the compounds according to the invention can occur in tautomeric forms, 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.

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.

In the context of the invention, 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.

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 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-

Propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N, N-dimethylamino,

N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-iV-n-propylamino, N-isopropyl-N-propylamino, iV-tert-butyl-N-methylamino, N -emyl-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 1 to 3 carbon atoms each

Alkyl substituent. Alkylsulfonyl is, by way of example and by way of preference, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.

Alkoxycarbonyl is, by way of example and 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-methylaminocarbonyl, N-ethyl-Nn-pentylaminocarbonyl and Nn-hexyl-N-methylaminocarbonyl. 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-isopropyl-Nn-propylaminosulfonyl, N-tert-butyl-N-methyl-aminosulfonyl, N-emyl-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, 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. 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, pyrrolinyl, Tetrahydrofuranyl, tetrahydrothienyl, pyranyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, thiopyranyl, morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, Perhydroazazepinyl, piperazin-1-yl, piperazin-2-yl.

Halogen is fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

If 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,

where 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-Gύ-alkyl,

where 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,

wherein heterocyclyl and heteroaryl may in turn be substituted with 1 to 3 substituents, wherein the substituents are independently selected from

A 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 ) -alkyl animo,

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, (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,

wherein 4- (phenyl) ρhenyl 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 _r C ₄ ) alkyl, (C _r C ₄ ) - alkoxy and (C _{r C6)} alkylamino, R ⁵ is (C _{6 r} C) alkyl or hydrogen,

and their salts, their solvates, and the solvates of their salts.

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

n is the number 1,

R ^{1 is} methyl or ethyl,

R ^{2 is} phenyl,

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, (Ci-C ₆ ) alkylamino and pyrrolidinyl,

wherein pyrrolidinyl may in turn be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of

Oxo and (C _r C ₄ ) -alkyl,

or

R ^{3 is} piperidinyl or pyrrolidinyl,

where 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,

wherein 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,

and their salts, their solvates, and the solvates of their salts.

Preference is also given to those compounds of the formula (T) in which n is the number 1.

Preference is also given to those compounds of the formula (T) 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, (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.

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

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

The invention further provides a process for the preparation of the compounds of the formula (T), where compounds of the formula

in which

n, R ¹ , R ² and R ^{5 have} the abovementioned meaning,

with compounds of the formula

H ₄ R ^{3 /} ^ "^ (EQ),

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 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-1-ethoxycarbonyl-l, 2-dihydroquinoline, or propanephosphonic anhydride , or isobutyl chloroformate, or bis- (2-oxo-3-oxazolidinyl) -phosphoryl chloride or benzo-1-riazolyloxy-tri (dimethylamino) phosphomurrihexafluorophosphate, or O- (benzotriazol-1-yl) -NNN ', N'-tetra-methyluronium hexafluorophosphate (HBTU), 2- (2-oxo-l- (2H) -pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) or 0- (7-azabenzotriazole-1) yl) -N, N, N ', N'-tetramethyl-uronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or berizotoazol-1-yloxytris (drmemylarnmo) phosphonium hexafluorophosphate (BOP), or from these, with bases. Preferably, the condensation is carried out with HOBt and EDC.

Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines, e.g. Triethylamine, N-methylrnorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine. Preferably, 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.

The compounds of the formula (II) are known or can be prepared by reacting compounds of the formula

in which

n, R ¹ , R ² and R ^{5 have} the abovementioned meaning, 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 from 0 ^° C. to room temperature at atmospheric pressure.

In the case of reaction with bases, 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, or mixtures of solvents, as solvent are preferably tetrahydrofuran and / or methanol or dioxane.

In the case of reaction with acids, 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

in which

n, 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 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.

Examples of bases are 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.

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

in which

n and R ^{2 have} the abovementioned meaning,

with compounds of the formula

in which R ^{1 has} the meaning given above, and

R ^{7 is} hydrogen, methyl or ethyl,

be implemented.

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. Preferably, 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.

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

For example, 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 preparation of the compounds according to the invention can be illustrated by the following synthesis scheme.

Scheme 1:

i) hydrazine hydrate

Diisopropylethylamiπ

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

They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.

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. Arteriosclerosis, reperfusion tissue damage after stroke, myocardial infarction or peripheral arterial and venous vascular diseases and essential or pregnancy-induced hypertension.

Furthermore, 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.

Because of their pharmacological properties, 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. 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.

For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For the oral administration are according to the state of the art functioning fast and / or modified 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), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules) in the oral cavity , Dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). 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.

The oral application is preferred.

For the other routes of administration are suitable, for example 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. These excipients include, among others, excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyisocyanate). 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 ) and flavor and / or odor remedies.

Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.

In general, it has been found to be beneficial to administer amounts of about 5 to 250 mg / kg of body weight per 24 hours when administered parenterally to achieve effective results. When administered orally, the amount is about 5 to 100 mg / kg of body weight per 24 hours.

Nevertheless, it may be necessary to deviate from the stated amounts, 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 by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume. The term "w / v" means "weight / volume". Thus, for example, "10% w / v" means: 100 ml of solution or suspension contains 10 g of substance. A) Examples

Abbreviations:

Section. absolutely

Boc tert-butoxycarbonyl

CDCl ₃ deuterochloroform

CO ₂ carbon dioxide

TLC thin layer chromatography

DIEA N, N-diisopropylethylamine

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide d. Th. Of theory

EDC N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide eq. equivalent to

ESI electrospray ionization (in MS) sat. saturated

H hour

HOBt 1-hydroxy-1H-b enzotriazole

HPLC high pressure, high performance liquid chromatography conc. concentrated

LC-MS liquid chromatography-coupled mass spectroscopy min. minutes

MS mass spectroscopy

MW molecular weight [g / mol]

NMR nuclear magnetic resonance spectroscopy

Rf Retention Index (at DC)

RP-HPLC reverse phase HPLC

RT room temperature

Retention time (on HPLC)

TFA trifluoroacetic acid

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 /! 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.

starting compounds

Example IA

6-ethyl-3 - (trans-2-phenylcyclopropyl) -1,4,4-triazine-5 (2H) -one

A suspension of 2.96 g (55.3 mmol) of ammonium chloride in 50 ml of toluene is slowly added at ⁰ ° C. with 28 ml (56 mmol) of a 2M solution of trimethylaluminum in toluene. After completion of the gas evolution is stirred for 15 min at room temperature and then added 2.37 g (12.3 mmol) of trans-2-Prienylcyclopropancarbonsäureethylester and heated to 100 ⁰ C for 24 h. For workup, after cooling, the reaction solution with 13 g of silica gel is added (slightly exothermic) and filtered after stirring for 15 min. The residue is slurried once each with 580 ml of methanol / dichloromethane (1: 1) and once with 165 ml of methanol and filtered. The combined filtrates are concentrated in vacuo and the residue is stirred once with 190 ml of dichloromethane / methanol (10: 1) and filtered off. The filtrate is concentrated and 2.52 g (99% of theory) of 2-trans-phenylcyclopropanecarboximidamide hydrochloride are obtained.

A solution of 2.49 g (12.7 mmol) 2-trans-Phenylcyclopropancarboximidamid hydrochloride is dissolved in 24 ml of ethanol and treated at 0 ⁰ C with 15.2 ml (15.2 mmol) of an IM solution of hydrazine in THF. After 2 h, the ethanol is removed in vacuo and the residue taken up in 18 ml of DMF and treated with 1.39 g (13.2 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 0.568 g (19% of theory) of the product.

LC-MS (Method 1): R _t = 3.77 min

MS (ESIpos): m / z = 242 (M + H) ⁺

Example 2A

[6-ethyl-5-oxo-3- (trans-2-phenylcyclopropyl) -l, 2,4-triazrn-2 (5H) -yl] acetic acid tert-butyl ester

550 mg (2.3 mmol) of 6-ethyl-3- (trans-2-phenylcyclopropyl) -1,2,4-triazine-5 (2H) -one are dissolved in 15 ml of dichloromethane and treated with 0.6 ml (3.4 mmol) of N, N-Diisopropylemylamin and 578 mg (2.96 mmol) tert-butyl bromoacetate and then stirred overnight. After removal of the solvent in vacuo, the residue is purified by preparative HPLC. This gives 553 mg (68% of theory) of the product.

HPLC (Method 1): R _t = 4.70 min

MS (ESIpos): m / z = 356 (M + H) ⁺

Example 3A

[6-ethyl-5-oxo-3- (trans-2-phenylcyclopropyl) -l, 2,4-triazin-2 (5H) -yl] acetic acid

530 mg (1.5 mmol) of [6-ethyl-5-oxo-3- [trans-2-phenylcyclopropyl] -1,2,4-triazine-2 (5H) -yl] -acetic acid tert-butyl ester are dissolved in 12 Dissolved dichloromethane and treated with 12 ml (154 mmol) of trifluoroacetic acid and stirred overnight at RT. After removal of the solvent in vacuo, the residue is purified by preparative HPLC. 385 mg (86% of theory) of the product are obtained.

HPLC (Method 1): R _t = 3.74 min MS (ESIpos): m / z = 300 (M + H) ⁺

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 13.5 (s broad, IH), 7.35-7.15 (m, 5H) ₃ 5.2 (d, IH), 4.95 (d, IH), 2.6 (m , 3H), 2.4 (m, IH), 1.7 (m, IH), 1.5 (m, IH), 1.1 (t, 3H).

Example 4A

4 '- (Trifluoπnethyl) 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 ₁ = 4.99 min.

MS (EI): m / z = 285 (M + N ₂ H ₇ ) ⁺ .

Example 5A

N, N-diethyl-N '- {[4' - (trifluoromethyl) biphenyl-4-yl] methyl} ethane-l, 2-diamine

To a solution of 500 mg (2.00 mmol) 4 '- (trifluoromethyl) biphenyl-4-carbaldehyde and 280.8 μl

(2.00 mmol) of 1-amino-2-diethylaminoethane are added to 500 mg of 4X molecular sieve (powder, <5 micron). After 18 h at room temperature, the reaction mixture is filtered, washed with dichloromethane and concentrated in vacuo. The raw material is dissolved in 5 ml of absolute ethanol dissolved and mixed at 0 ° C with 90.7 mg (2.40 mmol) of sodium 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 6A

4 '- (trifluoromethyl) biphenyl-4-carbonitrile

is obtained analogously to the preparation of Example 4A.

Example 7A

l- [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 an IM 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 8A

1-Methyl-N- {[4 '- (trifluoromethyl) biphenyl-4-yl] ethyl} piperidine-4-aniine

A solution of 0.96 g (3.52 mmol) of 1- [4 '- (trifluoromethyl) -biphenyl-4-yl] -niethanamine 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 in vacuo 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 example of the following table is prepared analogously to Example 5A and 8A.

Ausführungsbeispiele

embodiments

example 1

N, 2- (diethylamino) ethyl] -2- [6-ethyl-5-oxo-3- (trans-2-phenylcyclopropyl) -1,2,4-triazine-2 (5H) -yl] - N- { [4 '- (trifluoromethyl) biphenyl-4-yl] methyl} acetamide Fungiat

To a solution of 85 mg (0.28 mmol) of [6-ethyl-5-oxo-3- (trans-2-phenylcyclopropyl) -l, 2,4-triazine-2 (5H) -yl] acetic acid in 6 ml of dichloromethane 99 mg (0.28 mmol) of N, N-diethyl-N '- {[4' - (trifluoromethyl) -biprienyl-4-yl] -methyl} -ethane-1,2-diamine, 4 mg (0.04 mmol) of HOBt and 56 mg ( 0.28 mmol) of EDC. For work-up, it is diluted with 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. 134 mg (69% of theory) of the product are obtained as the formic acid salt.

HPLC (Method 1): R _t = 4.77 min.

MS (ESIpos): m / z = 632 (M + H) ⁺

¹ H-NMR (400 MHz, TFA-dj): δ = 8.3 (s, IH), 7.9-7.7 (m, 6H), 7.55 (m, 3H), 7.3 (m, 4H), 5.95 (d, IH ), 5.8 (d, IH), 4.9 (s, 2H), 3.95 (m, 2H), 3.45 (m, 6H), 3.25 (m, IH), 3.1 (q, 2H), 2.55 (m, 2H) , 2.35 (m, IH), 1.45 (m, 9H). The examples of the following table are prepared analogously to Example 1.

Example 5

2- [6-ethyl-5-oxo-3- (trans-2-phenylcyclopropyl) -l, 2,4-triazine-2 (5H) -yl] -N - {[4 '- (trifluoromethyl) -biphenyl- 4-yl] methyl} acetamide formate

To a solution of 230 mg (0.32 mmol) 4 - ({[6-ethyl-5-oxo-3- (trans-2-phenylcyclopropyl) -l, 2,4-triazin-2 (5H) -yl] -acetyl} {[4 '- (trifluoromethyl) biphenyl-4-yl] methyl} amino) -piperidine-1-carboxylic acid tert-butyl ester in 5 ml of dichloromethane is added 0.25 ml (3.2 mmol) of trifluoroacetic acid. After 24 h at room temperature, the reaction mixture is concentrated and purified by preparative HPLC. After removal of the solvent in vacuo, the residue is purified by preparative HPLC, the aqueous phase containing 1% formic acid. This gives 181 mg (85% of theory) of product.

LC-MS (Method 1): R _t = 4.61 min.

MS (ESIpos): m / z = 616 (M + H) ⁺

B) Assessment of physiological efficacy

The suitability of the compounds according to the invention for the treatment of cardiovascular diseases can be demonstrated in the following assay systems:

In vitro assay of PAF-AH

Purification of 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 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). 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 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 μM substrate, 10 μM 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:

Table A:

In vivo Assay der PAF-AH

In vivo assay of PAF-AH

To determine the anti-atherosclerotic effect of PAF-AH inhibitors, 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.

C) Exemplary embodiments of pharmaceutical compositions

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

Tablet:

Composition:

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.

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 granulated with a 5% solution (m / m) of the PVP in water. The granules, after drying with the magnesium stearate for 5 min. mixed. This mixture is compressed with a conventional tablet press (for the tablet format see above).

Oral suspension:

Composition:

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

A single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension. HerstellmiR:

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.

Intravenous solution:

Composition:

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

production:

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 μm) and filled under aseptic conditions into heat-sterilized infusion bottles. These are closed with infusion stoppers and crimp caps.

Claims

claims 1. Compound of the formula

in which n is a number 1, 2, 3 or 4, R ^{1 is} (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl, wherein alkyl may be substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, oxo, phenyl, hydroxycarbonyl, (Ci-C ₆ ) alkoxycarbonyl, aminocarbonyl and (C _r C ₆ ) -alkylarninocarbonyl, R ^{2 is} phenyl or 5- or 6-membered heteroaryl, wherein phenyl and heteroaryl may be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of methoxy hydroxy, Arnino, halogen, cyano, trifluoromethyl, trifluoro (C _{r C6)} alkyl, (C _r C ₆ ) -alkoxy, (C _r C ₆ ) -alkylamino, (C _r 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 ) -alkylcarbonyl-amino, R ^{3 is} (C _r C ₆ ) -alkyl, wherein alkyl may be substituted with 1 to 3 substituents wherein the substituents are independently selected from the group consisting of hydroxy, amino, halogen, (C 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, (Ci-C ₆₎ alkoxycarbonyl, aminocarbonyl, (Ci-C ₆₎ alkylamino carbonyl, (C ₁ -C ₄ ) -alkylcarbonyl, (C ₁ -C ₆ ) -alkylcarbonylamino and (C ₁ -C ₆ ) -alkoxycarbonylamino, wherein heterocyclyl and heteroaryl may in turn be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of hydroxy, amino, oxo, halogen, cyano, Trifluoromethyl, trifluoromethoxy, (C _{r C6)} alkyl, (C ₁ -Ce) -alkoxy, (C ₁ -C ₆₎ alkyl amino, (Ci-C ₆₎ alkylthio, hydroxycarbonyl, (Ci-C ₆ ) alkoxycarbonyl, amino carbonyl, _(Ci-C6) alkylaminocarbonyl, (C _{r C6)} 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 with 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] _-C6) alkoxy substituted (C _{r C6)} 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 _{r C6)} alkoxy, (C _r C ₆₎ -Alkylammo, (C _{r C6)} alkylthio, (C _{r C6)} alkyl sulfonyl, hydroxycarbonyl, (C ₁ -C ₆₎ alkoxycarbonyl, aminocarbonyl, (C ₁ -C ₆₎ - alkylaminocarbonyl, ( C ₁ -C ₆₎ alkylcarbonyl, _(Ci-C6) alkylcarbonylamino, (C ₁ - C ₆ ) -alkylaminosulfonyl and (C ₁ -C ₆ ) -alkylsulfonylamino, R ^{5 is} hydrogen, (C _r C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl, where alkyl and cycloalkyl can be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, cyano, trifluoromethyl, (C ₁ -C ₄ ) -alkyl and (C ₁ -C ₃ ) - alkoxy, or one of its salts, its solvates or the solvates of its salts. 2. A compound according to claim 1, characterized in that n is the number 1, R ^{1 is} methyl, ethyl, n-propyl or isopropyl, R ^{2 is} phenyl, thienyl or pyridyl, wherein phenyl, thienyl and pyridyl 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 _r C ₄ ) alkyl, (C ₁ -Q) -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, wherein heterocyclyl and heteroaryl may in turn be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of hydroxy, amino, oxo, halogen, cyano, trifluoromethyl, trifluoromethoxy, (C _{r C4)} alkyl,

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, (Ci-C ₄ ) alkoxy, (Ci-C ₄ ) alkoxycarbonyl and optionally (C _r C ₄₎ alkoxy substituted (Ci-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} hydrogen or (C _r C ₆ ) alkyl. 3. A compound according to any one of claims 1 or 2, characterized in that n is the number 1, R ^{1 is} methyl or ethyl, R ^{2 is} phenyl, 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 _r C ₄ ) -alkyl, wherein alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of amino, (Ci-C ₆ ) alkylamino and pyrrolidinyl, wherein pyrrolidinyl may in turn be substituted with 1 to 3 substituents, wherein the substituents are independently selected from Group consisting of oxo and (C 1 -C ₄ ) -alkyl, or R ^{3 is} piperidinyl or pyrrolidinyl, where piperidinyl and pyrrolidinyl can be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of oxo, (C 1 -C ₄ ) -alkoxycarbonyl and optionally methoxy-substituted (C 1 -C ₄ ) -alkyl, R ^{4 is} 4- (phenyl) phenyl, where 4- (phenyl) phenyl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, difluoromethoxy and monofluoromethoxy, R ^{5 is} hydrogen. 4. A process for preparing a compound of formula (T) according to claim 1, characterized in that a compound of formula

in which n, R ¹ , R ² and R ^{5 have} the meaning given in claim 1, with a compound of the formula H _{4 3 /} -Nk JPC in which R ³ and R ^{4 have} the meaning given in claim 1, is implemented. 5. A compound according to any one of claims 1 to 3 for the treatment and / or prophylaxis of diseases. 6. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 3 in combination with at least one pharmaceutically acceptable, pharmaceutically acceptable carrier or other excipients. 7. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament. 8. Medicament according to claim 6 for the treatment and / or prophylaxis of chronic inflammatory diseases or cardiovascular diseases. 9. A method for combating arteriosclerosis in humans and animals by administering an effective amount of at least one compound according to any one of claims 1 to 3.