DE102007061756A1 - Substituted 4-aminopyrimidine-5-carboxylic acids and their use - Google Patents

Abstract

The present application relates to novel substituted 4-aminopyrimidine-5-carboxylic acid derivatives, processes for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, preferably for treatment and / or prophylaxis of cardiovascular diseases, especially dyslipidaemias, atherosclerosis and cardiac insufficiency.

Description

The present application relates to novel substituted 4-aminopyrimidine-5-carboxylic acid derivatives, Process for their preparation, their use for treatment and / or Prophylaxis of diseases and their use for the production of medicaments for the treatment and / or prophylaxis of diseases, preferably for the treatment and / or prophylaxis of cardiovascular Diseases, in particular of dyslipidaemias, arteriosclerosis and heart failure.

In spite of Multiple therapy successes remain cardiovascular diseases a serious public health problem. While the treatment with statins by inhibition of HMG-CoA reductase very successful both the plasma concentrations of LDL cholesterol (LDL-C) as well as reducing the mortality of high-risk patients, so today there are no convincing treatment strategies for Therapy of patients with unfavorable HDL-C / LDL-C ratio or hypertriglyceridemia.

fibrates In addition to niacin, they are the only treatment option for Patients of these risk groups. They lower elevated Triglycerides by 20-50%, LDL-C lower by 10-15%, alter the LDL particle size of atherogenic Low density LDL to normal dense and less atherogenic LDL and increase the HDL concentration by 10-15%.

Fibrates act as weak agonists of the peroxisome proliferator-activated receptor (PPAR) -alpha ( Nature 1990, 347, 645-50 ). PPAR-alpha is a nuclear receptor that regulates the expression of target genes by binding to DNA sequences in the promoter region of these genes [also called PPAR response elements (PPRE)]. PPREs have been identified in a number of genes that encode proteins that regulate lipid metabolism. PPAR-alpha is highly expressed in the liver and its activation leads inter alia to decreased VLDL production / secretion and reduced apolipoprotein CIII (ApoCIII) synthesis. In contrast, the synthesis of apolipoprotein A1 (ApoA1) is increased.

A disadvantage of previously approved fibrates is their weak interaction with the receptor (EC ₅₀ in the μM range), which in turn leads to the relatively low pharmacological effects described above.

WO 99/41253 discloses substituted pyrimidines for the treatment of viral infections. JP 2001-89452 describes substituted pyrimidines for the treatment of autoimmune diseases. In WO 03/045941 Pyrimidines are disclosed for the treatment of immunological and inflammatory diseases. In WO 2004/111014 substituted pyrimidines are claimed for the treatment of cystic fibrosis. 4-aminopyrimidines are used in WO 2005/003099 described as ion channel modulators for the treatment of pain, arthritis, migraine, epilepsy and incontinence. WO 2005/040133 claims aminopyrimidines for the treatment of inflammatory disorders. WO 2005/1104 16 discloses 4,5-disubstituted 2-arylpyrimidines as C5a receptor ligands for the treatment of inflammatory, immunological and cardiovascular diseases. In WO 2006/124874 Inter alia, substituted pyrimidines for the treatment of cancer are described. In WO 2006/097220 4-phenoxy-2-phenylpyrimidinecarboxylic acids are claimed as PPAR-alpha modulators for the treatment of dyslipidaemias and arteriosclerosis.

task The present invention was the provision of new compounds, as PPAR alpha modulators for treatment and / or prophylaxis especially cardiovascular diseases can and improved metabolic stability compared with prior art compounds.

in welcher
R¹ für Wasserstoff oder (C₁-C₃)-Alkyl steht,
R² für (C₁-C₆)-Alkyl, (C₃-C₆)-Alkenyl oder (C₃-C₇)-Cycloalkyl steht,
wobei (C₁-C₆)-Alkyl mit 1 oder 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Trifluormethyl, Hydroxy, (C₁-C₄)-Alkoxy, Trifluormethoxy und (C₃-C₇)-Cycloalkyl substituiert sein kann,
worin (C₃-C₇)-Cycloalkyl seinerseits mit 1 oder 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Hydroxy, Oxo, (C₁-C₄)-Alkyl, Trifluormethyl, 2,2,2-Trifluorethyl, (C₁-C₄)-Alkoxy und Trifluormethoxy substitutiert sein kann,
und
wobei (C₃-C₇)-Cycloalkyl mit 1 oder 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Hydroxy, Oxo, (C₁-C₄)-Alkyl, Trifluormethyl, 2,2,2-Trifluorethyl, (C₁-C₄)-Alkoxy und Trifluormethoxy substitutiert sein kann,
und
wobei in allen genannten Cycloalkyl-Gruppen eine CH₂-Einheit gegen Sauerstoff ausgetauscht sein kann,
oder
R¹ und R² zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Pyrrolidin- oder Piperidin-Ring bilden, welcher seinerseits mit 1 oder 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Trifluormethyl, (C₁-C₄)-Alkyl, Hydroxy, (C₁-C₄)-Alkoxy und Trifluormethoxy substituiert sein kann,
R³ für (C₁-C₄)-Alkyl oder Cyclopropyl steht,
wobei (C₁-C₄)-Alkyl mit 1 bis 3 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor und (C₁-C₄)-Alkoxy substituiert sein kann,
R⁴ für Wasserstoff oder Fluor steht,
R⁵ für Wasserstoff, Fluor, Chlor oder Methyl steht,
R⁶ für Wasserstoff, Halogen, Nitro, Cyano, Trifluormethyl, Methyl, Ethyl, Trifluormethoxy oder Methoxy steht,
R⁷ für Wasserstoff, Fluor, Chlor oder Methyl steht,
wobei mindestens einer der Reste R⁴, R⁵, R⁶ und R⁷ von Wasserstoff verschieden ist,
sowie ihre Salze, Solvate und Solvate der Salze.The present invention relates to compounds of the general formula (I)

in which
R ^{1 is} hydrogen or (C ₁ -C ₃ ) -alkyl,
R ^{2 is} (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -alkenyl or (C ₃ -C ₇ ) -cycloalkyl,
where (C ₁ -C ₆ ) -alkyl having 1 or 2 substituents independently of one another is selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy and (C ₃ -C ₇ ) -cycloalkyl can
in which (C ₃ -C ₇ ) -cycloalkyl in turn having 1 or 2 substituents selected independently from the group fluorine, hydroxy, oxo, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C ₁ -C ₄ ) -alkoxy and trifluoromethoxy can be substituted,
and
where (C ₃ -C ₇ ) -cycloalkyl having 1 or 2 substituents independently of one another is selected from the group consisting of fluorine, hydroxyl, oxo, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C ₁ -C ₄ ) alkoxy and trifluoromethoxy can be substituted,
and
wherein in all said cycloalkyl groups a CH ₂ unit may be exchanged for oxygen,
or
R ¹ and R ² together with the nitrogen atom to which they are attached form a pyrrolidine or piperidine ring, which in turn is independently selected from the group of fluorine, trifluoromethyl, (C ₁ -C ₄ ) with 1 or 2 substituents Alkyl, hydroxy, (C ₁ -C ₄ ) -alkoxy and trifluoromethoxy may be substituted,
R ^{3 is} (C ₁ -C ₄ ) -alkyl or cyclopropyl,
where (C ₁ -C ₄ ) -alkyl having 1 to 3 substituents independently of one another can be substituted by the group fluorine and (C ₁ -C ₄ ) -alkoxy,
R ^{4 is} hydrogen or fluorine,
R ^{5 is} hydrogen, fluorine, chlorine or methyl,
R ^{6 is} hydrogen, halogen, nitro, cyano, trifluoromethyl, methyl, ethyl, trifluoromethoxy or methoxy,
R ^{7 is} hydrogen, fluorine, chlorine or methyl,
wherein at least one of R ⁴ , R ⁵ , R ⁶ and R ^{7 is} different from hydrogen,
and their salts, solvates and solvates of the salts.

invention Compounds are the compounds of the formula (I) and their salts, Solvates and solvates of the salts, the compounds encompassed by formula (I) the following formulas and their salts, solvates and solvates the salts as well as those of formula (I), hereinafter referred to as exemplary embodiments 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.

The Compounds according to the invention can depending on their structure in stereoisomeric forms (Enantiomers, diastereomers) exist. The invention therefore comprises the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers can the stereoisomerically uniform constituents in known Isolate way.

Provided the compounds of the invention in tautomers Forms may include the present invention all tautomeric forms.

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

physiological acceptable salts of the compounds of the invention include acid addition salts of mineral acids, Carboxylic acids and sulfonic acids, e.g. B. 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.

physiological acceptable salts of the compounds of the invention Also include salts of conventional bases, such as by way of example and preferably alkali metal salts (eg sodium and potassium salts), Alkaline earth salts (eg calcium and magnesium salts) and ammonium salts, derived from ammonia or organic amines having 1 to 16 C atoms, as exemplified and preferably ethylamine, diethylamine, triethylamine, Ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, Dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, Arginine, lysine, ethylenediamine and N-methylpiperidine.

When Solvates are in the context of the invention, such forms of the invention Compounds referred to in solid or liquid Condition through coordination with solvent molecules to form a complex. Hydrates are a special form of solvates, where coordination takes place with water. As solvates are in the context of the present invention, hydrates are preferred.

Furthermore For example, the present invention also encompasses prodrugs of the invention Links. The term "prodrugs" includes compounds, which may themselves be biologically active or inactive, however, during their residence time in the body too be implemented according to the invention compounds (for example metabolically or hydrolytically).

In particular, the present invention also includes hydrolyzable ester derivatives of the carboxylic acids of the formula (I). These are understood as esters which can be hydrolyzed in physiological media and in particular in vivo enzymatically or chemically to the free carboxylic acids. As such esters are straight-chain or branched (C ₁ -C ₆ ) alkyl esters in which the alkyl group with hydroxy, (C ₁ -C ₄ ) alkoxy, amino, mono (C ₁ -C ₄ ) alkylamino and / or Di (C ₁ -C ₄ ) alkylamino may be substituted, preferably. Particularly preferred are the methyl or ethyl esters of the compounds of formula (I).

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
In the context of the invention, alkyl is a linear or branched alkyl radical having in each case the number of carbon atoms specified. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, 2 Methylbutyl, 3-methylbutyl, n -hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,4-dimethylpentyl, 4.4 Dimethylpentyl and 1,4,4-trimethylpentyl.
Alkenyl in the context of the invention is a straight-chain or branched alkenyl radical having 3 to 6 carbon atoms and one or two double bonds. Preference is given to a straight-chain or branched alkenyl radical having 3 or 4 carbon atoms and one double bond. By way of example and by way of preference: allyl, isopropenyl and n-but-2-en-1-yl.
Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy and tert-butoxy.
Cycloalkyl in the context of the invention is a monocyclic, saturated alkyl radical having 3 to 7 carbon atoms. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.

If Residues substituted in the compounds of the invention Unless otherwise specified, the radicals may be be mono- or polysubstituted. In the context of the present Inven tion holds that for all residues that occur repeatedly, whose meaning is independent of each other. A substitution with one, two or three identical or different substituents is preferred. Most preferably, the substitution with a substituent.

Preferred in the context of the present invention are compounds of the formula (I) in which
R ^{1 is} hydrogen, methyl or ethyl
R ^{2 is} (C ₁ -C ₆ ) -alkyl, cyclopropyl, cyclopentyl or cyclohexyl,
where (C ₁ -C ₆ ) -alkyl can be substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl, cyclopropyl, cyclopentyl and cyclohexyl,
in which cyclopropyl, cyclopentyl and cyclohexyl may themselves be substituted by a substituent selected from the group consisting of fluorine, methyl, ethyl and trifluoromethyl,
and
where cyclopropyl, cyclopentyl and cyclohexyl can be substituted by a substituent selected from the group consisting of fluorine, methyl, ethyl and trifluoromethyl,
or
R ¹ and R ² together with the nitrogen atom to which they are attached form a pyrrolidine or piperidine ring, which in turn may be substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl, methyl and ethyl,
R ^{3 is} (C ₁ -C ₄ ) -alkyl or trifluoromethyl,
R ^{4 is} hydrogen,
R ^{5 is} hydrogen or fluorine,
R ^{6 is} hydrogen, fluorine, chlorine, trifluoromethyl or methyl,
R ^{7 is} hydrogen or methyl,
wherein at least one of R ⁵ , R ⁶ and R ^{7 is} different from hydrogen,
and their salts, solvates and solvates of the salts.

Particular preference is given to compounds of the formula (I) in which
R ^{1 is} hydrogen or ethyl,
R ^{2 is} ethyl, iso-propyl, cyclopropyl or cyclopropylmethyl,
R ^{3 is} methyl, ethyl or iso-propyl,
R ^{4 is} hydrogen,
R ^{5 is} hydrogen,
R ^{6 is} hydrogen, chlorine or methyl,
R ^{7 is} hydrogen or methyl,
wherein at least one of R ⁶ and R ^{7 is} different from hydrogen,
and their salts, solvates and solvates of the salts.

Particular preference is also given to compounds of the formula (I) in which
R ^{1 is} hydrogen or ethyl,
R ^{2 is} ethyl, iso-propyl, iso-butyl or cyclopropylmethyl,
R ^{3 is} iso-butyl,
R ^{4 is} hydrogen,
R ^{5 is} hydrogen,
R ^{6 is} hydrogen, chlorine or methyl,
R ^{7 is} hydrogen or methyl,
wherein at least one of R ⁶ and R ^{7 is} different from hydrogen,
and their salts, solvates and solvates of the salts.

The in the respective combinations or preferred combinations of Residues in the specified radical definitions become independent of the respective specified combinations of the radicals as desired also replaced by residue definitions of other combinations.

All Particularly preferred are combinations of two or more of above preferred ranges.

in welcher R³, R⁴, R⁵, R⁶ und R⁷ jeweils die oben angegebenen Bedeutungen haben,
und
R⁸ für (C₁-C₄)-Alkyl steht,
mit Hilfe eines geeigneten Chlorierungsmittels, wie beispielsweise Phosphoroxychlorid, in eine Verbindung der Formel (III)

in welcher R³, R⁴, R⁵, R⁶, R⁷ und R⁸ jeweils die oben angegebenen Bedeutungen haben, überführt
und diese anschliessend in einem inerten Lösungsmittel in Gegenwart einer Base mit einer Verbindung der Formel (IV)

in welcher R¹ und R² jeweils die oben angegebenen Bedeutungen haben,
zu Verbindungen der Formel (V)

in welcher R¹, R², R³, R⁴, R⁵, R⁶, R⁷ und R⁸ jeweils die oben angegebenen Bedeutungen haben,
umsetzt und diese durch basische oder saure Hydrolyse in die Carbonsäuren der Formel (I)

in welcher R¹, R², R³, R⁴, R⁵, R⁶ und R⁷ jeweils die oben angegebenen Bedeutungen haben,
überführt
und die Verbindungen der Formel (I) gegebenenfalls mit den entsprechenden (i) Lösungsmitteln und/oder (ii) Basen oder Säuren zu ihren Solvaten, Salzen und/oder Solvaten der Salze umsetzt.The invention further provides a process for the preparation of the compounds of the formula (I) according to the invention, which comprises reacting a compound of the formula (II)

in which R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ each have the meanings given above,
and
R ^{8 is} (C ₁ -C ₄ ) -alkyl,
with the aid of a suitable chlorinating agent, such as, for example, phosphorus oxychloride, into a compound of the formula (III)

in which R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ each have the meanings given above, transferred
and this then in an inert solvent in the presence of a base with a compound of formula (IV)

in which R ¹ and R ² each have the meanings given above,
to compounds of the formula (V)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ each have the meanings given above,
and these by basic or acidic hydrolysis into the carboxylic acids of the formula (I)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ each have the meanings given above,
transferred
and optionally reacting the compounds of the formula (I) with the corresponding (i) solvents and / or (ii) bases or acids to their solvates, salts and / or solvates of the salts.

The compounds of the formula (IV) are commercially available, known from the literature or can be prepared in Analo be produced to literature methods.

in welcher R³ und R⁸ die oben angegebenen Bedeutungen haben,
zunächst in einem inerten Lösungsmittel in Gegenwart einer Base mit einer Verbindung der Formel (VII)

in welcher R⁴, R⁵, R⁶ und R⁷ die oben angegebenen Bedeutungen haben,
zu einer Verbindung der Formel (VIII)

in welcher R³, R⁴, R⁵, R⁶, R⁷ und R⁸ jeweils die oben angegebenen Bedeutungen haben,
umsetzt und diese anschliessend in einem inerten Lösungsmittel in Gegenwart einer Base und einer Bromquelle, wie beispielsweise N-Bromsuccinimid, sowie eines geeigneten Radikalstarters, wie beispielsweise Dibenzoylperoxid, zu einer Verbindung der Formel (IX)

in welcher R³, R⁴, R⁵, R⁶, R⁷ und R⁸ jeweils die oben angegebenen Bedeutungen haben,
oxidiert [vgl. z. B. Veale C. A. et al., J. Org. Chem. 1993, 58, 4490–4493 ].The compounds of the formula (II) can be prepared by reacting compounds of the formula (VI)

in which R ³ and R ^{8 have} the meanings given above,
first in an inert solvent in the presence of a base with a compound of the formula (VII)

in which R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meanings given above,
to a compound of formula (VIII)

in which R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ each have the meanings given above,
and then these in an inert solvent in the presence of a base and a bromine source, such as N-bromosuccinimide, and a suitable radical initiator, such as dibenzoyl peroxide, to give a compound of formula (IX)

in which R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ each have the meanings given above,
oxidized [cf. z. B. Veal CA et al., J. Org. Chem. 1993, 58, 4490-4493 ].

The Compounds of the formulas (VI) and (VII) are commercially available, known from the literature or can be analogous to those known from the literature Process are produced.

The reaction (II) → (III) is carried out without solvent or optionally in an inert solvent suitable under the reaction conditions, for example hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone (NMP) or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. The reaction preferably takes place without solvent.

The Reaction (II) → (III) generally takes place in one Temperature range from 0 ° C to + 160 ° C, preferably at + 20 ° C to + 120 ° C, optionally in one Microwave. The reaction can be normal, elevated or at low pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.

inert Solvent for process step (III) + (IV) → (V) are, for example, ethers, such as diethyl ether, Dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, Hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylsulfoxide, N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (NMP), pyridine, acetone, 2-butanone or Acetonitrile. It is also possible mixtures of the above Use solvent. Preference is given to dimethylformamide or tetrahydrofuran.

When Base for process step (III) + (IV) → (V) Usual inorganic and organic bases are suitable. These include in particular alkali metal hydroxides such as Lithium, sodium or potassium hydroxide, alkali or alkaline earth carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, Alkali hydrides such as sodium or potassium hydride, organometallic bases such as n-butyl lithium or tert. organic amines such as diisopropylethylamine or triethylamine. Preferred is triethylamine. The base is here in an amount of 1 to 5 mol, preferably in an amount of 1.2 to 3 mol, based on 1 mol of the compound of formula (IV) used.

The Reaction (III) + (IV) → (V) is generally carried out in a temperature range from 0 ° C to + 150 ° C, preferably at + 20 ° C to + 120 ° C. The reaction can occur at normal, increased or carried out at reduced pressure be (eg from 0.5 to 5 bar). In general, one works at Normal pressure.

The Hydrolysis of the carboxylic acid esters in the process steps (V) → (I) is carried out by customary methods, if appropriate in a microwave, adding the esters in inert solvents treated with acids or bases, with the latter initially formed salts by subsequent treatment converted into the free carboxylic acids with acid become. In the case of the tert-butyl ester, the ester cleavage takes place preferably with acids.

When inert solvents are suitable for hydrolysis the carboxylic ester water or the usual for ester cleavage organic solvents. These include in particular Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as Acetone, acetonitrile, dichloromethane, dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the abovementioned solvents use. In the case of basic ester hydrolysis are preferred Mixtures of water with dioxane, tetrahydrofuran, methanol and / or Ethanol used. In the case of the reaction with trifluoroacetic acid is preferred dichloromethane and in the case of the reaction with hydrogen chloride preferably tetrahydrofuran, diethyl ether, dioxane or water used.

When Bases are suitable for ester hydrolysis the usual inorganic bases. These include, in particular, alkali metal or alkaline earth hydroxides such as sodium, lithium, potassium or barium hydroxide, or alkali or alkaline earth carbonates such as sodium, Potassium or calcium carbonate. Preference is given to sodium hydroxide or Potassium hydroxide used.

When Acids are generally suitable for ester cleavage Sulfuric acid, hydrochloric acid / hydrochloric acid, hydrogen bromide / hydrobromic acid, Phosphoric acid, acetic acid, trifluoroacetic acid, Toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof optionally with the addition of water. Prefers are hydrogen chloride or trifluoroacetic acid in the case the tert-butyl ester and hydrochloric acid in the case of the methyl esters.

The Ester cleavage generally occurs in a temperature range from 0 ° C to + 100 ° C, preferably at 0 ° C up to + 50 ° C. The reaction can be normal, elevated or at a reduced pressure (e.g. from 0.5 to 5 bar).

[a): Natriumethanolat, Ethanol, Rückflußtemperatur; b): N-Bromsuccinimid, K₂CO₃, kat. Dibenzoylperoxid, Rückflußtemperatur; c): POCl₃, Rückflußtemperatur; d): Triethylamin, Tetrahydrofuran, Rückflußtemperatur; e): NaOH:, Ethanol/Wasser, Rückflußtemperatur oder Mikrowelle, 140°C].The preparation of the compounds according to the invention can be illustrated by the following synthesis scheme: Scheme 1

[a): sodium ethoxide, ethanol, reflux temperature; b): N-bromosuccinimide, K ₂ CO ₃ , cat. Dibenzoyl peroxide, reflux temperature; c): POCl ₃ , reflux temperature; d): triethylamine, tetrahydrofuran, reflux temperature; e): NaOH :, ethanol / water, reflux temperature or microwave, 140 ° C].

The Compounds of the invention have valuable pharmacological properties and can help prevent and treatment of diseases used in humans and animals become.

The Compounds of the invention are highly effective PPAR alpha modulators and also have an elevated metabolic Stability on. They are particularly suitable for primary and / or secondary prevention as well as treatment of cardiovascular diseases caused by disorders in fatty acid and glucose metabolism. Such disorders include dyslipidaemias (hypercholesterolemia, Hypertriglyceridemia, increased concentrations postprandial plasma triglycerides, hypoalphalipoproteinemia, combined hyperlipidemia), arteriosclerosis and metabolic Diseases (metabolic syndrome, hyperglycemia, insulin-dependent Diabetes, non-insulin-dependent diabetes, gestational diabetes, Hyperinsulinemia, insulin resistance, glucose intolerance, Obesity (obesity) and diabetic sequelae such as retinopathy, Nephropathy and neuropathy).

When highly effective PPAR-alpha modulators are the erindeungsgemäßen Compounds in particular also to the primary and / or secondary Prevention and treatment of heart failure.

For the purposes of the present invention, the term cardiac failure also includes more specific or related forms of disease such as right heart failure, left heart failure, global insufficiency, by hyper tonus induced heart failure, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, heart valve failure, heart failure in heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valvular insufficiency, combined heart valve defects, myocarditis, chronic myocarditis, acute myocarditis, viral Myocarditis, diabetic cardiac insufficiency, alcoholic cardiomyopathy, cardiac storage disorders, diastolic heart failure and systolic heart failure.

Further independent risk factors for cardiovascular Diseases which are affected by the inventive Are treated with hypertension, ischemia, Myocardial infarction, angina pectoris, myocardial insufficiency, restenosis, pulmonary hypertension, increased levels of fibrinogen and low density LDL and elevated levels of Plasminogen activator inhibitor 1 (PAI-1).

About that In addition, the compounds of the invention also for the treatment and / or prevention of micro- and macrovascular damage (vasculitis), reperfusion damage, arterial and venous thrombosis, edema, Cancer (skin cancer, liposarcoma, carcinoma of the gastrointestinal tract, the liver, pancreas, lung, kidney, ureter, Prostate and the genital tract), diseases of the central Nervous system and neurodegenerative disorders (stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, Depression, multiple sclerosis), inflammatory diseases, Immune diseases (Crohn's disease, ulcerative colitis, lupus erythematosus, rheumatoid arthritis, asthma), chronic obstructive pulmonary disease (chronic bronchitis, COPD), kidney disease (glomerulonephritis), Thyroid disorders (hyperthyroidism), diseases the pancreas (pancreatitis), liver fibrosis, skin diseases (Psoriasis, acne, eczema, atopic dermatitis, dermatitis, keratitis, Scarring, warts, chilblains), sepsis, viral diseases (HPV, HCMV, HIV), cachexia, osteoporosis, gout, incontinence as well used for wound healing and angiogenesis.

The Effectiveness of the compounds of the invention can be z. B. in vitro by that described in the examples section Check transactivation assay.

The Effectiveness of the compounds of the invention in vivo can be z. B. by those described in the example section Check examinations.

Another The present invention is the use of the invention Compounds for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another The present invention is the use of the invention Compounds for the manufacture of a medicament for treatment and / or disease prevention, in particular the aforementioned diseases.

Another The subject of the present invention is a method of treatment and / or disease prevention, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.

The Compounds according to the invention can Used alone or as needed in combination with other drugs become. Another object of the present invention are pharmaceuticals, containing at least one of the invention Compounds and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned Diseases.

Examples of suitable combination active ingredients are lipid metabolism-altering active ingredients, antidiabetic agents, hypotensive agents, circulation-promoting and / or antithrombotic agents and also antioxidants, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists. Anorectics, PAF-AH inhibitors, anti-inflammatory drugs (COX inhibitors, LTB ₄ receptor antagonists), analgesics (aspirin), antidepressants and other psychotropic drugs.

object In particular, combinations of the present invention are at least one of the compounds of the invention with at least a fat metabolism-altering agent, an antidiabetic, a hypotensive agent and / or an antithrombotic acting means.

• • den Fettstoffwechsel verändernden Wirkstoffen, beispielhaft und vorzugsweise aus der Gruppe der HMG-CoA-Reduktase-Inhibitoren, Inhibitoren der HMG-CoA-Reduktase-Expression, Squalensynthese-Inhibitoren, ACHT-Inhibitoren, LDL-Rezeptor-Induktoren, Cholesterin-Absorptionshemmer, polymeren Gallensäureadsorber, Gallensäure-Reabsorptionshemmer, MTP-Inhibitoren, Lipase-Inhibitoren, LpL-Aktivatoren, Fibrate, Niacin, CETP-Inhibitoren, PPAR-γ- und/oder PPAR-δ-Agonisten, RXR-Modulatoren, FXR-Modulatoren, LXR-Modulatoren, Thyroidhormone und/oder Thyroidmimetika, ATP-Citrat-Lyase-Inhibitoren, Lp(a)-Antagonisten, Cannabinoid-Rezeptor 1-Antagonisten, Leptin-Rezeptor-Agonisten, Bombesin-Rezeptor-Agonisten, Histamin-Rezeptor-Agonisten sowie der Antioxidantien/Radikalfänger;
• • Antidiabetika, die in der Roten Liste 2004/II, Kapitel 12 genannt sind, sowie beispielhaft und vorzugsweise jenen aus der Gruppe der Sulphonylharnstoffe, Biguanide, Meglitinid-Derivate, Glukosidase-Inhibitoren, Oxadiazolidinone, Thiazolidindione, GLP 1-Rezeptor-Agonisten, Glukagon-Antagonisten, Insulin-Sensitizer, CCK 1-Rezeptor-Agonisten, Leptin-Rezeptor-Agonisten, Inhibitoren von Leberenzymen, die an der Stimulation der Glukoneogenese und/oder Glykogenolyse beteiligt sind, Modulatoren der Glukoseaufnahme sowie der Kaliumkanalöffner, wie z. B. denjenigen, die in WO 97/26265 und WO 99/03861 offenbart sind;
• • den Blutdruck senkenden Wirkstoffen, beispielhaft und vorzugsweise aus der Gruppe der Calcium-Antagonisten, Angiotensin AII-Antagonisten, ACE-Inhibitoren, beta-Rezeptoren-Blocker, alpha-Rezeptoren-Blocker, ECE-Inhibitoren und der Vasopeptidase-Inhibitoren;
• • antithrombotisch wirkenden Mitteln, beispielhaft und vorzugsweise aus der Gruppe der Thrombozytenaggregationshemmer oder der Antikoagulantien;
• • Diuretika;
• • Aldosteron- und Mineralokorticoid-Rezeptor-Antagonisten;
• • Vasopressin-Rezeptor-Antagonisten;
• • organischen Nitraten und NO-Donatoren;
• • positiv-inotrop wirksamen Verbindungen;
• • Verbindungen, die den Abbau von cyclischem Guanosinmonophosphat (cGMP) und/oder cyclischem Adenosinmonophosphat (CAMP) inhibieren, wie beispielsweise Inhibitoren der Phosphodiesterasen (PDE) 1, 2, 3, 4 und/oder 5, insbesondere PDE 5-Inhibitoren wie Sildenafil, Vardenafil und Tadalafil sowie PDE 3-Inhibitoren wie Milrinone;
• • natriuretischen Peptiden, wie z. B. "atrial natriuretic peptide" (ANP, Anaritide), "B-type natriuretic peptide" oder "brain natriuretic peptide" (BNP, Nesiritide), "C-type natriuretic peptide" (CNP) sowie Urodilatin;
• • Calcium-Sensitizern, wie beispielhaft und vorzugsweise Levosimendan;
• • Kalium-Supplements;
• • NO-unabhängigen, jedoch Häm-abhängigen Stimulatoren der Guanylatcyclase, wie insbesondere den in WO 00/06568 , WO 00/06569 , WO 02/42301 und WO 03/095451 beschriebenen Verbindungen;
• • NO- und Häm-unabhängigen Aktivatoren der Guanylatcyclase, wie insbesondere den in WO 01/19355 , WO 01/19776 , WO 01/19778 , WO 01/19780 , WO 02/070462 und WO 02/070510 beschriebenen Verbindungen;
• • Inhibitoren der humanen neutrophilen Elastase (HNE), wie beispielsweise Sivelestat und DX-890 (Reltran);
• • die Signaltransduktionskaskade inhibierenden Verbindungen, wie beispielsweise Tyrosinkinase-Inhibitoren, insbesondere Sorafenib, Imatinib, Gefitinib und Erlotinib; und/oder
• • den Energiestoffwechsel des Herzens beeinflussenden Verbindungen, wie beispielweise Etomoxir, Dichloracetat, Ranolazine und Trimetazidine

kombiniert werden.The compounds of the invention may preferably be with one or more

• Fat metabolism-altering agents, by way of example and preferably from the group of HMG-CoA reductase inhibitors, inhibitors of HMG-CoA reductase expression, squalene synthesis inhibitors, ECHT inhibitors, LDL receptor inducers, cholesterol absorption inhibitors, polymeric Bile acid adsorbents, bile acid reabsorption inhibitors, MTP inhibitors, lipase inhibitors, LpL activators, fibrates, niacin, CETP inhibitors, PPAR-γ and / or PPAR-δ agonists, RXR modulators, FXR modulators, LXR modulators , Thyroid hormones and / or thyroid mimetics, ATP citrate lyase inhibitors, Lp (a) antagonists, cannabinoid receptor 1 antagonists, leptin receptor agonists, bombesin receptor agonists, histamine receptor agonists and antioxidants / radical scavengers;
• • Antidiabetics used in the Red List 2004 / II, Chapter 12 as well as exemplarily and preferably those from the group of sulfonylureas, biguanides, meglitinide derivatives, glucosidase inhibitors, oxadiazolidinones, thiazolidinediones, GLP 1 receptor agonists, glucagon antagonists, insulin sensitizers, CCK 1 receptor agonists, Leptin receptor agonists, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of glucose uptake and potassium channel openers, such as. B. those in WO 97/26265 and WO 99/03861 are disclosed;
• The hypotensive agents, by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, beta-receptor blockers, alpha-receptor blockers, ECE inhibitors and the vasopeptidase inhibitors;
• Antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors or anticoagulants;
• • diuretics;
• • aldosterone and mineralocorticoid receptor antagonists;
• Vasopressin receptor antagonists;
• • organic nitrates and NO donors;
• • positive inotropic compounds;
• Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (CAMP), such as inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors such as sildenafil, Vardenafil and tadalafil and PDE 3 inhibitors such as milrinone;
• Natriuretic peptides, such as Atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, Nesiritide), C-type natriuretic peptide (CNP) and urodilatin;
• Calcium sensitizers, such as by way of example and preferably levosimendan;
• • potassium supplements;
• • NO-independent, but heme-dependent guanylate cyclase stimulators, such as those in WO 00/06568 . WO 00/06569 . WO 02/42301 and WO 03/095451 described compounds;
• • NO- and heme-independent activators of guanylate cyclase, in particular the in WO 01/19355 . WO 01/19776 . WO 01/19778 . WO 01/19780 . WO 02/070462 and WO 02/070510 described compounds;
• Inhibitors of human neutrophil elastase (HNE), such as Sivelestat and DX-890 (Reltran);
• The signal transduction cascade inhibiting compounds, such as tyrosine kinase inhibitors, in particular sorafenib, imatinib, gefitinib and erlotinib; and or
• • the energy metabolism of the heart affecting compounds such as etomoxir, dichloroacetate, ranolazines and trimetazidines

be combined.

Under the fat metabolism changing active ingredients are preferably Compounds from the group of HMG-CoA reductase inhibitors, squalene synthesis inhibitors, ECHT inhibitors, cholesterol absorption inhibitors, MTP inhibitors, Lipase inhibitors, thyroid hormones and / or thyroid mimetics, niacin receptor agonists, CETP inhibitors, PPAR gamma agonists, PPAR delta agonists, polymeric bile acid adsorbers, Bile acid reabsorption inhibitors, antioxidants / radical scavengers and the cannabinoid receptor 1 antagonists.

at a preferred embodiment of the invention the compounds of the invention in combination with a HMG-CoA reductase inhibitor from the class of statins, as exemplary and preferably lovastatin, simvastatin, pravastatin, Fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin, administered.

In a preferred embodiment of the invention, the compounds of the invention in combination with a squalene synthesis inhibitor, as exemplified and preferably BMS-188494 or TAK-475.

at a preferred embodiment of the invention the compounds of the invention in combination with an EIGHT inhibitor, such as by way of example and preferably melinamides, Pactimibe, eflucimibe or SMP-797.

at a preferred embodiment of the invention the compounds of the invention in combination with a cholesterol absorption inhibitor, as exemplified and preferably Ezetimibe, Tiqueside or Pamaqueside administered.

at a preferred embodiment of the invention the compounds of the invention in combination with an MTP inhibitor, such as by way of example and preferably implitapide or JTT-130.

at a preferred embodiment of the invention the compounds of the invention in combination with a lipase inhibitor, such as by way of example and preferably orlistat, administered.

at a preferred embodiment of the invention the compounds of the invention in combination with a thyroid hormone and / or thyroid mimetic, as exemplified and preferably D-thyroxine or 3,5,3'-triiodothyronine (T3).

at a preferred embodiment of the invention the compounds of the invention in combination with an agonist of the niacin receptor, as exemplified and preferably Niacin, Acipimox, Acifran or Radecol.

at a preferred embodiment of the invention the compounds of the invention in combination with a CETP inhibitor, such as by way of example and preferably torcetrapib, JTT-705 or CETP vaccine (Avant).

at a preferred embodiment of the invention the compounds of the invention in combination with a PPAR gamma agonist, as exemplified and preferably Pioglitazone or rosiglitazone.

at a preferred embodiment of the invention the compounds of the invention in combination with a PPAR delta agonist, as exemplified and preferably GW-501516 administered.

at a preferred embodiment of the invention the compounds of the invention in combination with a polymeric bile acid adsorbent, as exemplified and preferably cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.

at a preferred embodiment of the invention the compounds of the invention in combination with a bile acid reabsorption inhibitor, as exemplified and preferably ASST (= IBAT) inhibitors such as e.g. Eg AZD-7806, S-8921, AK-105, BART-1741, SC-435 or SC-635.

at a preferred embodiment of the invention the compounds of the invention in combination with an antioxidant / free radical scavenger, as exemplified and preferably probucol, AGI-1067, BO-653 or AEOL-10150.

at a preferred embodiment of the invention the compounds of the invention in combination with a cannabinoid receptor 1 antagonist, as exemplified and preferably rimonabant or SR-147778.

Under Antidiabetics are preferably insulin and insulin derivatives as well understood oral effective hypoglycemic agents. insulin and insulin derivatives include both insulins animal, human or biotechnological origin as well as mixtures thereof. The orally active hypoglycemic agents preferably include sulphonylureas, biguanides, meglitinide derivatives, Glucosidase inhibitors and PPAR-gamma agonists.

In a preferred embodiment of the invention, the compounds of the invention administered in combination with insulin.

at a preferred embodiment of the invention the compounds of the invention in combination with a sulphonylurea, as exemplified and preferably Tolbutamide, glibenclamide, glimepiride, glipizide or gliclazide.

at a preferred embodiment of the invention the compounds of the invention in combination with a biguanide, such as by way of example and preferably metformin, administered.

at a preferred embodiment of the invention the compounds of the invention in combination with a meglitinide derivative, as exemplified and preferably Repaglinide or nateglinide.

at a preferred embodiment of the invention the compounds of the invention in combination with a glucosidase inhibitor, as exemplified and preferably Miglitol or acarbose, administered.

at a preferred embodiment of the invention the compounds of the invention in combination with a PPAR gamma agonist, for example, from the class of Thiazolidinediones exemplified and preferably pioglitazones or rosiglitazone.

Under the blood pressure lowering agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, beta-receptor blockers, alpha-receptor blockers and diuretics.

at a preferred embodiment of the invention the compounds of the invention in combination with a diuretic, such as by way of example and preferably a loop diuretic such as furosemide, bumetanide or torsemide, or a thiazide or Thiazide-like diuretic such as chlorothiazide or hydrochlorothiazide, administered.

at a preferred embodiment of the invention the compounds of the invention in combination with an aldosterone or mineralocorticoid receptor antagonist, as exemplified and preferably spironolactone or eplerenone, administered.

at a preferred embodiment of the invention the compounds of the invention in combination with a vasopressin receptor antagonist, as exemplified and preferably Conivaptan, Tolvaptan, Lixivaptan or SR-121463.

at a preferred embodiment of the invention the compounds of the invention in combination with an organic nitrate or NO donor, as exemplified and preferably sodium nitroprusside, nitroglycerin, isosorbide mononitrate, Isosorbide dinitrate, molsidomine or SIN-1, or in combination with administered by inhaled NO.

at a preferred embodiment of the invention the compounds of the invention in combination with a positive inotropic effective compound as exemplified and preferably cardiac glycosides (digoxin), beta-adrenergic and dopaminergic Agonists such as isoproterenol, epinephrine, norepinephrine, dopamine or Dobutamine, administered.

at a preferred embodiment of the invention the compounds of the invention in combination with a calcium antagonist, as exemplified and preferably Nifedipine, amlodipine, verapamil or diltiazem.

at a preferred embodiment of the invention the compounds of the invention in combination with an angiotensin AII antagonist, as exemplified and preferably Losartan, valsartan, candesartan, embusartan or telmisartan.

at a preferred embodiment of the invention the compounds of the invention in combination with an ACE inhibitor, such as by way of example and preferably enalapril, Captopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

at a preferred embodiment of the invention the compounds of the invention in combination with a beta-receptor blocker, as exemplified and preferably Propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, Penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, Metoprolol, Betaxolol, Celiprolol, Bisoprolol, Carteolol, Esmolol, Labetalol, Carvedilol, Adaprolol, Landiolol, Nebivolol, Epanolol or bucindolol.

at a preferred embodiment of the invention the compounds of the invention in combination with an alpha-receptor blocker, as exemplified and preferably Prazosin, administered.

at a preferred embodiment of the invention the compounds of the invention in combination with an antisympathotonic, as exemplified and preferably Reserpine, clonidine or alpha-methyl-dopa, or in combination with a potassium channel agonist, such as by way of example and preferably minoxidil, Diazoxide, dihydralazine or hydralazine.

Under antithrombotic agents are preferably compounds from the group of platelet aggregation inhibitors or anticoagulants Understood.

at a preferred embodiment of the invention the compounds of the invention in combination with a platelet aggregation inhibitor, as exemplified and preferably Aspirin, clopidogrel, ticlopidine or dipyridamole.

at a preferred embodiment of the invention the compounds of the invention in combination with a thrombin inhibitor, as exemplified and preferably Ximelagatran, melagatran, bivalirudin or Clexane.

at a preferred embodiment of the invention the compounds of the invention in combination with a GPIIb / IIIa antagonist, as exemplified and preferably Tirofiban or abciximab.

at a preferred embodiment of the invention the compounds of the invention in combination with a factor Xa inhibitor, as exemplified and preferably Rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, Razaxaban, Fondaparinux, Idraparinux, PMD-3112, YM-150, KFA-1982, EMID-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

at a preferred embodiment of the invention the compounds of the invention in combination with heparin or a low molecular weight (LMW) heparin derivative administered.

at a preferred embodiment of the invention the compounds of the invention in combination with a vitamin K antagonist, as exemplified and preferably Coumarin, administered.

Especially preferred in the context of the present invention are combinations containing at least one of the invention Compounds and one or more other active ingredients selected from the group consisting of HMG-CoA reductase inhibitors (statins), Diuretics, beta-receptor blockers, organic nitrates and NO donors, ACE inhibitors, angiotensin AII antagonists, aldosterone and mineralocorticoid receptor antagonists, Vasopressin receptor antagonists, antiplatelet agents and anticoagulants, and their use for treatment and / or Prevention of the aforementioned diseases.

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.

The Compounds according to the invention can act systemically and / or locally. For this purpose can they are applied in a suitable manner, such as. Oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

For These routes of administration can be the inventive Compounds are administered in suitable administration forms.

For the oral administration are functional according to the prior art, the compounds of the invention quickly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphised and / or dissolved Contain form such. As tablets (uncoated or coated Tablets, for example, with enteric or delayed dissolving or insoluble coatings that release control the compound of the invention), rapidly disintegrating tablets or films / wafers in the oral cavity, Films / lyophilisates, capsules (for example hard or soft gelatin capsules), Dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

The Parenteral administration can bypass a resorption step happen (eg intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with involvement of absorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Suitable for parenteral administration themselves as application forms u. a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are suitable for. B. Inhalation medicines (including powder inhalers, nebulizers), nasal drops, solutions or -sprays, lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or eye preparations, Vaginal capsules, aqueous suspensions (lotions, Shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg pilasters), milk, pastes, Foams, scattering powders, implants or stents.

Prefers are the oral or parenteral administration, especially oral and intravenous administration.

The Compounds according to the invention can converted into the mentioned application forms become. This can be done in a conventional manner by mixing with inert, Non-toxic, pharmaceutically suitable excipients happen. These adjuvants include u. a. excipients (for example, microcrystalline cellulose, lactose, mannitol), Solvents (eg liquid polyethylene glycols), Emulsifiers and dispersing or wetting agents (for example sodium dodecylsulphate, Polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), Stabilizers (eg antioxidants such as ascorbic acid), Dyes (eg inorganic pigments such as iron oxides) and flavor and / or scent remedies.

in the In general, it has proven to be beneficial in parenteral Application amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight to achieve effective results administer. For oral administration, the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg body weight.

Nevertheless it may be necessary, if necessary, of the quantities mentioned to deviate, depending on body weight, Application route, individual behavior towards the Active substance, method of preparation and time or interval, too which the application takes place. So it can in some cases be sufficient, with less than the aforementioned minimum quantity while in other cases the said upper limit must be exceeded. In case of application larger quantities may be recommended, this one in several single doses to distribute over the day.

The The following embodiments illustrate the Invention. The invention is not limited to the examples.

abs.

absolut

Ac₂O

Acetanhydrid

AcOH

Essigsäure

aq.

wässrig

d

Tage

DC

Dünnschichtchromatographie

DCI

direkte chemische Ionisation (bei MS)

dd

Dublett von Dublett (bei NMR)

DDQ

2,3-Dichlor-5,6-dicyano-1,4-benzochinon

DIAD

Diisopropylazodicarboxylat

DMF

Dimethylformamid

DMSO

Dimethylsulfoxid

dt

Dublett von Triplett (bei NMR)

d. Th.

der Theorie (bei Ausbeute)

eq.

Äquivalent(e)

ESI

Elektrospray-Ionisation (bei MS)

h

Stunde(n)

HPLC

Hochdruck-, Hochleistungsflüssigchromatographie

LHMDS

Lithium-N,N-bistrimethylsilylamid

LC-MS

Flüssigchromatographie-gekoppelte Massenspektrometrie

min

Minute(n)

MPLC

Mitteldruckchromatographie

MS

Massenspektrometrie

mz

Multiplett, zentriert (bei NMR)

n-Bu

n-Butyl

NMR

Kernresonanzspektrometrie

o-Tol

ortho-Tolyl

Ph

Phenyl

RP

reverse Phase (bei HPLC)

RT

Raumtemperatur

R_t

Retentionszeit (bei HPLC)

sbr

Singulett, breit (bei NMR)

sept

Septett (bei NMR)

t-Bu

tert.-Butyl

THF

Tetrahydrofuran

tt

Triplett von Triplett (bei NMR)

UV

Ultraviolett-Spektrometrie

v/v

Volumen-zu-Volumen-Verhältnis (einer Mischung)

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.

Section.

absolutely

Ac ₂ O

acetic anhydride

AcOH

acetic acid

aq.

aqueous

d

days

DC

TLC

DCI

direct chemical ionization (in MS)

dd

Doublet of doublet (by NMR)

DDQ

2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DIAD

diisopropylazodicarboxylate

DMF

dimethylformamide

DMSO

dimethyl sulfoxide

dt

Doublet of triplet (by NMR)

d. Th.

the theory (at yield)

eq.

Equivalent (s)

IT I

Electrospray ionization (in MS)

H

Hour (s)

HPLC

High pressure, high performance liquid chromatography

LHMDS

Lithium N, N-bistrimethylsilylamide

LC-MS

Liquid chromatography-coupled mass spectrometry

min

Minute (s)

MPLC

medium pressure

MS

Mass spectrometry

mz

Multiplet, centered (by NMR)

n-Bu

n-butyl

NMR

nuclear magnetic resonance spectrometry

o-Tol

ortho-tolyl

Ph

phenyl

RP

reverse phase (on HPLC)

RT

room temperature

R _t

Retention time (by HPLC)

sbr

Singlet, broad (by NMR)

sept

Septet (by NMR)

t-Bu

tert-butyl

THF

tetrahydrofuran

tt

Triplet of triplet (by NMR)

UV

Ultraviolet spectrometry

v / v

Volume-to-volume ratio (of a mixture)

LC-MS and HPLC methods:

method 1 (LC-MS): Device type MS: Micromass ZQ; device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Gemini 3 μ 30 mm × 3.00 mm; Eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 11 acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; River: 0.0 min 1 ml / min → 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.

method 2 (LC-MS): Device type MS: Micromass ZQ; device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2.5 μ MAX-RP 100A Mercury 20 mm × 4 mm; Eluent A: 11 water + 0.5 ml 50% formic acid, eluent B: 11 acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A → 0.1 min 90% A → 3.0 min 5% A → 4.0 min 5% A → 4.01 min 90% A; Flow: 2 ml / min ;; Oven: 50 ° C; UV detection: 210 nm.

Method 3 (LC-MS): Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Merck Chromolith SpeedROD RP-18e 100 × 4.6 mm; Eluent A: 11 water + 0.5 ml 50% formic acid; Eluent B: 11 acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 10% B → 7.0 min 95% B → 9.0 min 95% B; Oven: 35 ° C; Flow: 0.0 min 1.0 ml / min → 7.0 min 2.0 ml / min → 9.0 min 2.0 ml / min; UV detection: 210 nm Starting Compounds and Intermediates: Example 1A Ethyl 2- (4-chlorophenyl) -4-methyl-6-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylate

To a solution of 3.66 g (53.703 mmol) of sodium ethylate and 5.00 g (29.537 mmol) of 4-chlorobenzamidine hydrochloride in 50 ml of ethanol are added under argon atmosphere 5.00 g (26.851 mmol) Ethylidenmalonsäurediethylester. The reaction mixture is stirred for 1.5 hours at reflux temperature. After cooling, the mixture is concentrated, taken up in dichloromethane and then washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. This gives 6.86 g (75% of theory) of crude product in 86% purity (LC-MS), which is reacted without further purification operation.
LC-MS (Method 1): R _t = 0.87 min; MS (ESIpos): m / z = 295 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.20 (t, 3H), 1.28 (d, 3H), 3.40 (d, 1H), 3.97-4.03 (m, 1H), 4.16 (q, 2H), 7.52 (d, 2H), 7.85 (d, 2H), 9.53 (sbr, 1H). Example 2A Ethyl 2- (4-chlorophenyl) -4-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate

A solution of 3.00 g (about 8.753 mmol) of Example 1A, 1.56 g (8.753 mmol) of N-bromosuccinimide, 212 mg (0.875 mmol) of dibenzoyl peroxide and 1.81 g (13.130 mmol) of potassium carbonate ground in a mortar in 150 ml of dioxane is refluxed for 1 h stirred under an argon atmosphere. After cooling, the mixture is treated with water and then extracted with dichloromethane and ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. This gives 2.5 g (66% of theory) of crude product in 71% purity (LC-MS), which is reacted without further purification operation.
LC-MS (Method 1): R _t = 1.04 min; MS (ESIpos): m / z = 293 [M + H] ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.28 (t, 3H), 2.32 (s, 3H), 4.28 (q, 2H), 7.62 (d, 2H), 8.13 (i.e. , 2H), 13.11 (sbr, 1H). Example 3A Ethyl 2- (4-chlorophenyl) -4- (1-methylethyl) -6-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylate

To a solution of 1.59 g (23.336 mmol) of sodium ethylate and 2.45 g (12.835 mmol) of 4-chlorobenzamidine hydrochloride in 10 ml of ethanol under an argon atmosphere, 2.5 g (11.668 mmol) of (2-methylpropylidene) malonate are added. The reaction mixture is stirred for 6.5 h at reflux temperature. After cooling, the mixture is concentrated, taken up in dichloromethane and then washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. This gives 3.03 g (60% of theory) of crude product (75% purity (LC-MS)), which is reacted without further purification operation.
LC-MS (Method 3): R _t = 2.23 min; MS (ESIpos): m / z = 323 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.87 (d, 3H), 1.07 (d, 3H), 1.20 (t, 3H), 1.70-1.80 (m, 1H), 3.50 (d, 1H), 3.76 (dd, 1H), 4.16 (q, 2H), 7.53 (d, 2H), 7.88 (d, 2H), 11.01 (sbr, 1H). Example 4A Ethyl 2- (4-chlorophenyl) -4- (1-methylethyl) -6-oxo-1,6-dihydropyrimidine-5-carboxylate

A solution of 3.00 g (about 6.970 mmol) of Example 3A, 1.24 g (6.970 mmol) of N-bromosuccinimide, 0.34 mg (1.394 mmol) of dibenzoyl peroxide and 1.44 g (10.456 mmol) ground in a mortar potassium carbonate in 100 ml of dioxane is overnight Argon atmosphere stirred at reflux temperature. After cooling, the mixture is mixed with a saturated aqueous sodium thiosulfate solution and then the volatile components are separated on a rotary evaporator. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over sodium sulfate and then concentrated. This gives 2.46 g (51% of theory) of crude product in 46% purity (LC-MS), which is reacted without further purification operation.
LC-MS (Method 3): R _t = 2.50 min; MS (ESIpos): m / z = 321 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.18 (d, 6H), 1.26 (t, 3H), 4.23 (q, 2H), 7.54 (d, 2H), 8.20 (i.e. , 2H). Example 5A 4-Chloro-2- (4-chlorophenyl) -6-methylpyrimidine-5-carboxylic acid ethyl ester

1.5 g (5.124 mmol) of Example 2A in 19.1 ml (204.971 mmol) of phosphorus oxychloride are stirred for 2 hours at reflux temperature. The reaction mixture is evaporated. The residue is treated with a 25% aqueous ammonium hydroxide solution, adjusted to pH 7 with 1N hydrochloric acid and then extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated. This gives 1.38 g (87% of theory) of the target compound.
LC-MS (Method 3): R _t = 3.10 min; MS (ESIpos): m / z = 311 [M + H] ⁺ . Example 6A Ethyl 2- (4-chlorophenyl) -4-methyl-6 - [(1-methylethyl) amino] pyrimidine-5-carboxylate

To a solution of 250 mg (0.803 mmol) of Example 5A in 4 ml of tetrahydrofuran is added 203 mg (2.01 mmol) of triethylamine and 71 mg (1.205 mmol) of isopropylamine. The reaction mixture is stirred overnight at 80.degree. The mixture is doped and used without further workup. This gives 250 mg (91% of theory) of the target compound LC-MS (Method 3): R _t = 3.29 min; MS (ESIpos): m / z = 334 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.26 (d, 6H), 1.34 (t, 3H), 2.60 (t, 3H), 3.23-3.30 (m, 1H), 4.32 (q, 2H), 7.56 (d, 2H), 7.90 (sbr, 1H), 8.36 (d, 2H). Example 7A Ethyl 2- (4-chlorophenyl) -4 - [(cyclopropylmethyl) amino] -6-methylpyrimidine-5-carboxylate

To a solution of 100 mg (0.321 mmol) of Example 5A in 1.6 ml of tetrahydrofuran is added 81 mg (0.803 mmol) of triethylamine and 34 mg (0.482 mmol) of cyclopropylmethylamine. The reaction mixture is stirred overnight at 80.degree. The mixture is concentrated by rotary evaporation and used without further workup. This gives 100 mg (97% of theory) of the target compound
LC-MS (Method 3): R _t = 3.28 min; MS (ESIpos): m / z = 346 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.29-0.32 (m, 2H), 0.46-0.50 (m, 2H), 1.35 (t, 3H), 2.60 (s, 3H) , 3.45 (dd, 2H), 4.36 (q, 2H), 7.57 (d, 2H), 8.22 (sbr, 1H), 8.37 (d, 2H). Example 8A Ethyl 4-chloro-2- (4-chlorophenyl) -6- (1-methylethyl) pyrimidine-5-carboxylate

1.5 g (about 2151 mmol) of Example 4A in 8 ml (86.041 mmol) of phosphorus oxychloride are stirred for 2 h at reflux temperature. The reaction mixture is evaporated. The residue is treated with a 25% aqueous ammonium hydroxide solution, adjusted to pH 7 with 1N hydrochloric acid and then extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated. The residue is subjected to column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 50/1 → 20/1) to give 540 mg (55% of theory) of crude product in 74% purity (LC-MS), which without further cleaning operation is implemented.
LC-MS (Method 3): R _t = 3.32 min; MS (ESIpos): m / z = 339 [M + H] ⁺ . Example 9A Ethyl 2- (4-chlorophenyl) -4- (diethylamino) -6-methylpyrimidine-5-carboxylate

To a solution of 100 mg (0.321 mmol) of Example 5A in 2 ml of tetrahydrofuran, 1.8 ml (13,498 mmol) of triethylamine and 35 mg (0.482 mmol) of diethylamine are added. The reaction mixture is stirred overnight at 80.degree. The mixture is concentrated by rotary evaporation and used without further workup. This gives 100 mg (90% of theory) of the target compound
LC-MS (Method 3): R _t = 2.95 min; MS (ESIpos): m / z = 348 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.17 (t, 6H), 1.32 (t, 3H), 2.34 (s, 3H), 3.50 (q, 4H), 4.33 (q , 2H), 7.56 (d, 2H), 8.32 (d, 2H), 8.59 (sbr, 1H). Example 10A Ethyl 2- (4-chlorophenyl) -4- (ethylamino) -6- (1-methylethyl) pyrimidine-5-carboxylate

To a solution of 60 mg (about 0.131 mmol) of Example 8A in 0.8 ml of THF are added 9 mg (0.196 mmol) Ethylamine and 0.8 ml (5.498 mmol) of triethylamine added. The reaction mixture is stirred overnight at 80.degree. The reaction mixture is concentrated by rotary evaporation and the residue is reacted without further work-up. This gives 55 mg (100% Th.) Of the target compound in 90% purity (LC-MS).
LC-MS (Method 3): R _t = 3.51 min; MS (ESIpos): m / z = 348 [M + H] ⁺ . Example 11A Ethyl 2- (4-chlorophenyl) -4- (cyclopropylamino) -6- (1-methylethyl) pyrimidine-5-carboxylate

To a solution of 60 mg (about 0.131 mmol) of Example 8A in 0.8 ml of THF are added 11 mg (0.196 mmol) of cyclopropanamine and 556 mg (5.498 mmol) of triethylamine. The reaction mixture is stirred overnight at 80.degree. The mixture is purified by preparative HPLC without elution (eluent: acetonitrile / water, gradient 10/90 → 90/10). This gives 40 mg (85% Th.) Of the target compound.
LC-MS (Method 1): R _t = 1.90 min; MS (ESIpos): m / z = 360 [M + H] ⁺ . Example 12A Ethyl 2- (4-chlorophenyl) -4- (methylamino) -6- (1-methylethyl) pyrimidine-5-carboxylate

To a solution of 60 mg (about 0.131 mmol) of Example 8A in 0.8 ml of THF are added 0.09 ml (0.196 mmol) of methanamine solution (2M in THF) and 556 mg (5.498 mmol) of triethylamine. The reaction mixture is stirred overnight at 80.degree. The mixture is purified by preparative HPLC without elution (eluent: acetonitrile / water, gradient 10:90 → 90:10). This gives 60 mg (100% Th.) Of the target compound.
LC-MS (Method 1): R _t = 1.82 min; MS (ESIpos): m / z = 334 [M + H] ⁺ . Example 13A Ethyl 2- (4-chlorophenyl) -4-ethyl-6-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylate

7.09 ml (18.98 mmol) of sodium ethylate solution (21% by weight in ethanol) are initially charged. Then 2.10 g (10.43 mmol) of 4-chlorobenzamidine hydrochloride are dissolved in 50 ml of ethanol and 1.90 g (9.49 mmol) of propylidenemalonic acid diester [ BC Ranu, R. Jana, Eur. J. Org. Chem. (2006) 3767-3770 ] was added under argon atmosphere. The reaction mixture is stirred for 2 h at reflux temperature. After cooling, the mixture is concentrated, taken up in water, adjusted to pH 4-5 with 1N hydrochloric acid and then extracted with ethyl acetate (3x). The combined organic phases are dried with magnesium sulfate and the solvent is removed on a rotary evaporator. The residue is purified by preparative MPLC (Biotage 40M cartridge, eluent: isohexane / ethyl acetate = 1/1). This gives 1.37 g (35% of theory) of crude product (82% purity (LC-MS)), which is reacted without further purification operation.
LC-MS (Method 3): R _t = 1.92 min; MS (ESIpos): m / z = 309 [M + H] ⁺ . Example 14A Ethyl 2- (4-chlorophenyl) -4-ethyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate

1.38 g (4.47 mmol) of Example 13A is dissolved in 40 ml of tetrachloromethane and treated under argon atmosphere with 0.835 g (4.69 mmol) of N-bromosuccinimide, 0.054 mg (0.223 mmol) of dibenzoyl peroxide and 6.18 g (44.69 mmol) of potassium carbonate. The mixture is then stirred at reflux temperature for 30 min. After cooling, the batch is mixed with 100 ml of water and extracted with dichloromethane (3x). The combined organic phases are dried with magnesium sulfate. Then, the volatile components are separated by distillation under reduced pressure. This gives 1.25 g (73% of theory) of crude product in 80% purity (LC-MS), which is reacted without further purification operation.
LC-MS (Method 1): R _t = 1.17 min; MS (ESIpos): m / z = 307 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.34 (t, 3H), 1.42 (t, 3H), 2.83 (mz, 2H), 4.45 (q, 2H), 7.48 (i.e. , 2H), 8.27 (d, 2H), 12.78 (sbr, 1H). Example 15A Ethyl 4-chloro-2- (4-chlorophenyl) -6-ethylpyrimidine-5-carboxylate

1.25 g (3.26 mmol) Example 14A and 12.2 ml of phosphoxyl chloride are stirred for 2 hours at reflux temperature. Then, the volatile components are separated on a rotary evaporator and the residue was added carefully and under ice cooling in water. Then it is mixed with 25% aqueous ammonia solution, then neutralized with 1N hydrochloric acid and extracted with dichloromethane (3x). The combined organic phases are dried with magnesium sulfate. Then the batch is concentrated on a rotary evaporator. The residue is purified by preparative MPLC (Biotage 40M cartridge, eluent: isohexane / ethyl acetate = 7/3). This gives 560 mg (52% of theory) of the target compound.
LC-MS (Method 3): R _t = 3.32 min; MS (ESIpos): m / z = 325 [M] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.31 (t, 3H), 1.35 (t, 3H), 2.84 (q, 2H), 4.45 (q, 2H), 7.64 (i.e. , 2H), 8.37 (d, 2H). Example 16A Ethyl 2- (4-chlorophenyl) -4-ethyl-6 - [(1-methylethyl) amino] pyrimidine-5-carboxylate

100 mg (0.31 mmol) of Example 15A, 39 .mu.l (0.46 mmol) of isopropylamine and 107 .mu.l (0.77 mmol) of triethylamine are dissolved in 3 ml of tetrahydrofuran and then reacted at 80.degree. C. overnight. Then the volatile components are separated on a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). This gives 42 mg (39% of theory) of the target compound.
LC-MS (Method 1): R _t = 1.83 min; MS (ESIpos): m / z = 348 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (t, 3H), 1.26 (d, 6H), 1.34 (t, 3H), 2.89 (q, 2H), 4.34 (q , 2H), 4.45 (mz, 1H), 7.58 (d, 2H), 7.75 (d, 1H), 8.38 (d, 2H). Example 17A Ethyl 2- (4-chlorophenyl) -4-ethyl-6- (prop-2-en-1-ylamino) pyrimidine-5-carboxylate

100 mg (0.31 mmol) of Example 15A, 35 μl (0.46 mmol) of allylamine and 107 μl (0.77 mmol) of triethylamine are dissolved in 3 ml of tetrahydrofuran and then reacted at 80 ° C. overnight. Then the volatile components are separated on a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). This gives 70 mg (66% of theory) of the target compound.
LC-MS (Method 1): R _t = 1.77 min; MS (ESIpos): m / z = 346 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.25 (t, 3H), 1.34 (t, 3H), 2.87 (q, 2H), 4.20 (mz, 2H), 4.35 (q , 2H), 5.12 (dd, 1H), 5.23 (dd, 1H), 5.99 (mz, 1H), 7.57 (d, 2H), 8.02 (t, 1H), 8.37 (d, 2H). Example 18A Ethyl 2- (4-chlorophenyl) -4- (diethylamino) -6-ethylpyrimidine-5-carboxylate

100 mg (0.31 mmol) of Example 15A, 48 .mu.l (0.46 mmol) of diethylamine and 107 .mu.l (0.77 mmol) of triethylamine are dissolved in 3 ml of tetrahydrofuran and then reacted at 80.degree. C. overnight. Then the volatile components are separated on a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). This gives 90 mg (81% of theory) of the target compound.
LC-MS (method 1): R _t = 1.71 min; MS (ESIpos): m / z = 362 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.17 (t, 6H), 1.22 (t, 3H), 1.32 (t, 3H), 2.59 (q, 2H), 3.51 (q , 4H), 4.33 (q, 2H), 7.57 (d, 2H), 8.33 (d, 2H). Example 19A Ethyl 2- (4-chlorophenyl) -4- (cyclohexylamino) -6-ethylpyrimidine-5-carboxylate

100 mg (0.31 mmol) of Example 15A, 53 μl (0.46 mmol) of cyclohexylamine and 107 μl (0.77 mmol) of triethylamine are dissolved in 3 ml of tetrahydrofuran and then reacted at 80 ° C. overnight. Then the volatile components are separated on a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). This gives 43 mg (36% of theory) of the target compound.
LC-MS (Method 1): R _t = 2.01 min; MS (ESIpos): m / z = 388 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.18-1.51 (m, 11H), 1.61 (m, 1H), 1.72 (m, 2H), 1.96 (mz, 2H), 2.91 (q, 2H), 4.17 (mz, 1H), 4.34 (q, 2H), 7.58 (d, 2H), 7.89 (d, 1H), 8.36 (d, 2H). Example 20A Ethyl 2- (4-chlorophenyl) -4-ethyl-6-piperidin-1-yl-pyrimidine-5-carboxylate

100 mg (0.31 mmol) of Example 15A, 46 .mu.l (0.46 mmol) of piperidine and 107 .mu.l (0.77 mmol) of triethylamine are dissolved in 3 ml of tetrahydrofuran and then reacted at 80.degree. C. overnight. Then the volatile components are separated on a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). This gives 123 mg (98% of theory) of the target compound.
LC-MS (Method 3): R _t = 3.36 min; MS (ESIpos): m / z = 374 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 1.31 (t, 3H), 1.58 (m, 4H), 1.64 (m, 2H), 2.66 (q , 2H), 3.58 (mz, 4H), 4.32 (q, 2H), 7.56 (d, 2H), 8.34 (d, 2H). Example 21A Ethyl 4-ethyl-2- (4-methylphenyl) -6-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylate

7.46 ml (19.98 mmol) of sodium ethylate solution (21% by weight in ethanol) is initially charged. Then 1.47 g (10.99 mmol) of 4-methylbenzamidine in 50 ml of ethanol and 2.00 g (9.99 mmol) of propylidenemalonic acid diester [ BC Ranu, R. Jana, Eur. J. Org. Chem. (2006) 3767-3770 ] was added under argon atmosphere. The reaction mixture is stirred for 2 h at reflux temperature. After cooling, the mixture is concentrated, taken up in water, adjusted to pH 4-5 with 1N hydrochloric acid and then extracted with ethyl acetate (3x). The combined organic phases are dried with magnesium sulfate and the solvent is removed on a rotary evaporator. The residue is purified by preparative MPLC (Biotage 40M cartridge, eluent: isohexane / ethyl acetate = 1/1). This gives 1.32 g (37% of theory) of crude product (88% purity (LC-MS)), which is reacted without further purification operations.
LC-MS (Method 3): R _t = 1.44 min; MS (ESIpos): m / z = 289 [M + H] ⁺ . Example 22A Ethyl 4-ethyl-2- (4-methylphenyl) -6-oxo-1,6-dihydropyrimidine-5-carboxylate

1.32 g (4.58 mmol) of Example 21A are dissolved in 40 ml of tetrachloromethane and treated under argon with 0.856 g (4.81 mmol) of N-bromosuccinimide, 0.055 mg (0.229 mmol) of dibenzoyl peroxide and 6.32 g (45.78 mmol) of potassium carbonate. The mixture is then stirred at reflux temperature for 30 minutes. After cooling, the batch is mixed with 100 ml of water and extracted with dichloromethane (3x). The combined organic phases are dried with magnesium sulfate. Then, the volatile components are separated by distillation under reduced pressure. This gives 1.31 g of crude product which consists of ethyl 2- [4- (bromomethyl) phenyl] -4-ethyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate and the target substance in a ratio of 1.5: 1. The crude material thus obtained is taken up in 40 ml of ethanol and placed under argon with 26 mg (0.247 mmol) of palladium on carbon (10 w / w), as well as with 779 mg (12.35 mmol) of ammonium formate. The mixture is then stirred at reflux temperature for 30 minutes. After cooling, it is filtered through Celite. The crude material thus obtained is finally purified by preparative MPLC (Biotage 40M cartridge, eluent: isohexane / ethyl acetate = 1/1). This gives 450 mg (35% of theory) of the target compound.
LC-MS (Method 3): R _t = 2.18 min; MS (ESIpos): m / z = 287 [M + H] ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.21 (t, 3H), 1.28 (t, 3H), 2.39 (s, 3H), 4.28 (q, 2H), 7.35 (i.e. , 2H), 8.04 (d, 2H), 12.97 (sbr, 1H). Example 23A Ethyl 4-chloro-6-ethyl-2- (4-methylphenyl) pyrimidine-5-carboxylate

450 mg (1.60 mmol) of Example 22A and 5.96 ml of phosphoxyl chloride are stirred for 2 hours at reflux temperature. The batch is concentrated on a rotary evaporator and the residue is taken up in water while being cautiously cooled. It is then treated with 25% aqueous ammonia solution, then neutralized with 1N hydrochloric acid and extracted with dichloromethane (3x). The combined organic phases are dried with magnesium sulfate. Then, the volatile components are separated by distillation under reduced pressure. The residue is purified by preparative MPLC (Biotage 40M cartridge, eluent: isohexane / ethyl acetate = 7/3). This gives 421 mg (85% of theory) of the target compound.
LC-MS (Method 3): R _t = 3.22 min; MS (ESIpos): m / z = 305 [M] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.30 (t, 3H), 1.35 (t, 3H), 2.40 (s, 3H), 2.82 (q, 2H), 4.44 (q , 2H), 7.38 (d, 2H), 8.27 (d, 2H). Example 24A Ethyl 4- (diethylammno) -6-ethyl-2- (4-methylphenyl) pyrimidine-5-carboxylate

100 mg (0.328 mmol) of Example 23A, 51 μl (0.492 mmol) of diethylamine and 114 μl (0.820 mmol) of triethylamine are dissolved in 3 ml of tetrahydrofuran and then reacted at 80 ° C. for 3 h. Then the volatile components are separated on a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). This gives 78 mg (66% of theory) of the target compound.
LC-MS (Method 2): R _t = 2.32 min; MS (ESIpos): m / z = 342 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.17 (t, 6H), 1.22 (t, 3H), 1.32 (t, 3H), 2.37 (s, 3H), 2.58 (q , 2H), 3.50 (q, 4H), 4.32 (q, 2H), 7.30 (d, 2H), 8.23 (d, 2H). Example 25A Ethyl 4-ethyl-6 - [(1-methylethyl) amino] -2- (4-methylphenyl) pyrimidine-5-carboxylate

100 mg (0.328 mmol) of Example 23A, 42 .mu.l (0.492 mmol) of diethylamine and 114 .mu.l (0.820 mmol) of triethylamine are dissolved in 3 ml of tetrahydrofuran and then reacted at 80.degree. C. for 2 h. Then the volatile components are separated on a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 90:10). This gives 68 mg (62% of theory) of the target compound.
LC-MS (Method 2): R _t = 2.66 min; MS (ESIpos): m / z = 328 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (t, 3H), 1.26 (d, 6H), 1.34 (t, 3H), 2.38 (s, 3H), 2.90 (q , 2H), 4.34 (q, 2H), 4.45 (mz, 1H), 7.31 (d, 2H), 7.75 (d, 1H), 8.28 (d, 2H). Example 26A 2- (4-Chloro-phenyl) -4- (2-methyl-propyl) -6-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylic acid, methyl ester

Eine Mischung aus 5.02 g (10.27 mmol) Beispiel 26A, 1.83 g (10.27 mmol) N-Bromsuccinimid, 497 mg (2.05 mmol) Dibenzoylperoxid und 2.13 g (15.40 mmol) gemahlenes Kaliumcarbonat in 120 ml Dioxan wird unter Argonatmosphäre 3 h bei Rückflußtemperatur gerührt. Nach dem Abkühlen wird der Ansatz mit einer gesättigten wässrigen Natriumthiosulfat-Lösung versetzt und anschließend eingeengt. Die wässrige Phase wird mit Dichlormethan extrahiert und die organische Phase wird erst mit Wasser und dann mit einer gesättigten wässrigen Natriumchlorid-Lösung gewaschen. Es wird mit Natriumsulfat getrocknet: und eingeengt. Das Rohmaterial wird mit Acetonitril versetzt und die entstandenen Kristalle werden abgesaugt. Dann wird im Hochvakuum bis zur Gewichtskonstanz getrocknet. Man erhält 1.47 g (40% d. Tb.) der Zielverbindung in 88%-iger Reinheit (LC-MS), welche ohne weitere Reinigungsschritte umgesetzt wird.
LC-MS (Methode 2): R_t = 2.02 min; MS (EIpos): m/z = 321 [M + H]⁺.
¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.92 (d, 6H), 2.11–2.21 (m, 1H), 2.41 (d, 2H), 3.80 (s, 3H), 7.61 (d, 2H), 8.14 (d, 2H), 13.13 (sbr, 1H). Beispiel 28A 4-Chlor-2-(4-chlorphenyl)-6-(2-methylpropyl)pyrimidine-5-carbonsäuremethylester

3.0 g (22.71 mmol) of dimethyl malonate, 2.15 g (24.98 mmol) of 3-methylbutanal, 0.22 ml (2.27 mmol) of piperidine and 0.13 ml (2.27 mmol) of acetic acid are dissolved in 40 ml of dichloromethane and reacted overnight at the inverse water at reflux temperature. The volatile components are separated on a rotary evaporator. This gives (3-methylbutylidene) -propansäuredimethylester, which is reacted without further purification operations. To a mixture of 3.52 g (51.78 mmol) of sodium ethylate and 5.44 g (24.48 mmol) of 4-chlorobenzamidine hydrochloride in 50 ml of methanol are added under argon atmosphere 5.18 g (~ 25.89 mmol) of the crude material thus obtained. The reaction mixture is stirred overnight at reflux temperature. After cooling, the mixture is concentrated and treated with water. The aqueous phase is extracted with ethyl acetate and dichloromethane. The organic phase is then washed with water and with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. This gives 5.02 g (40% of theory) of crude product in 66% purity (LC-MS), which is reacted without further purification steps.
LC-MS (method 2): R _t = 1.83 min; MS (EIpos): m / z = 323 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.93 (dd, 6H), 1.15-1.23 (dd, 1H), 1.46-1.53 (dd, 1H), 2.06 (sbr, 1H) , 3.44 (d, 1H), 3.69 (s, 3H), 3.93-4.00 (dd, 1H), 7.52 (d, 1H), 7.86 (d, 1H), 11.15 (sbr, 1H). Example 27A 2- (4-Chloro-phenyl) -4- (2-methyl-propyl) -6-oxo-1,6-dihydropyrimidine-5-carboxylic acid, methyl ester

A mixture of 5.02 g (10.27 mmol) of Example 26A, 1.83 g (10.27 mmol) of N-bromosuccinimide, 497 mg (2.05 mmol) of dibenzoyl peroxide and 2.13 g (15.40 mmol) of ground potassium carbonate in 120 ml of dioxane is stirred under argon atmosphere for 3 hours at reflux temperature , After cooling, the mixture is treated with a saturated aqueous sodium thiosulfate solution and then concentrated. The aqueous phase is extracted with dichloromethane and the organic phase is washed first with water and then with a saturated aqueous sodium chloride solution. It is dried with sodium sulfate: and concentrated. The crude material is mixed with acetonitrile and the resulting crystals are filtered off with suction. Then it is dried under high vacuum to constant weight. This gives 1.47 g (40% of theory) of the target compound in 88% purity (LC-MS), which is reacted without further purification steps.
LC-MS (method 2): R _t = 2.02 min; MS (EIpos): m / z = 321 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.92 (d, 6H), 2.11-2.21 (m, 1H), 2.41 (d, 2H), 3.80 (s, 3H), 7.61 (d, 2H), 8.14 (d, 2H), 13.13 (sbr, 1H). Example 28A 4-Chloro-2- (4-chlorophenyl) -6- (2-methylpropyl) pyrimidines-5-carboxylic acid, methyl ester

400 mg (~ 1.10 mmol) of Example 27A and 4.09 ml (43.89 mmol) of phosphoxyl chloride are stirred for 1 h at reflux temperature. The reaction mixture is evaporated. The residue is mixed with an ammonium hydroxide solution (25% in water), adjusted to pH 7 with 1 N hydrochloric acid and then extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated. This gives 416 mg (98% of theory) of crude product in 88% purity (LC-MS), which is reacted without further purification operation.
LC-MS (Method 1): R _t = 1.76 min; MS (EIpos): m / z = 339 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.93 (d, 6H), 2.20-2.29 (m, 1H), 2.68 (d, 2H), 3.97 (s, 3H), 7.64 (d, 2H), 8.36 (d, 2H). Example 29A Methyl 2- (4-chlorophenyl) -4- (diethylamine) -6- (2-methylpropyl) pyrimidine-5-carboxylate

19 mg (0.265 mmol) of diethylamine and 45 mg (0.442 mmol) of triethylamine are added to a solution of 60 mg (0.177 mmol) of Example 28A in 1.2 ml of THF. The mixture is stirred overnight at 80.degree. The reaction mixture is concentrated by rotary evaporation and used further without further work-up. This gives 36 mg (54% of theory) of the target compound.
LC-MS (Method 1): R _t = 1.79 min; MS (EIpos): m / z = 376 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.89 (d, 6H), 1.17 (t, 6H), 2.15-2.23 (m, 1H), 2.44 (d, 2H), 3.49 (q, 4H), 3.85 (s, 3H), 7.56 (d, 2H), 8.32 (d, 2H). Example 30A 2- (4-Chloro-phenyl) -4- (2-methyl-propyl) -6 - [(2-methyl-propyl) -amino] -pyrimidine-5-carboxylic acid, methyl ester

19 mg (0.265 mmol) of isobutylamine and 45 mg (0.442 mmol) of triethylamine are added to a solution of 60 mg (0.177 mmol) of Example 28A in 1.2 ml of THF. The mixture is stirred overnight at 80.degree. The reaction mixture is concentrated by rotary evaporation and used further without further work-up. This gives 41 mg (62% of theory) of the target compound.
LC-MS (Method 1): R _t = 1.94 min; MS (EIpos): m / z = 376 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.91 (d, 6H), 0.93 (d, 2H), 1.93-2.00 (m, 1H), 2.10-2.19 (m, 1H) , 2.73 (d, 2H), 3.39 (t, 2H), 3.87 (s, 3H), 7.57 (d, 2H), 7.85 (t, 1H), 8.35 (d, 2H). Example 31A 2- (4-Chloro-phenyl) -4- (cyclopentylamino) -6- (2-methyl-propyl) -pyrimidine-5-carboxylic acid, methyl ester

23 mg (0.265 mmol) of cyclopentylamine and 45 mg (0.442 mmol) of triethylamine are added to a solution of 60 mg (0.177 mmol) of Example 28A in 1.2 ml of THF. The mixture is stirred overnight at 80.degree. The reaction mixture is concentrated by rotary evaporation and used further without further work-up. This gives 43 mg (63% of theory) of the target compound.
LC-MS (Method 1): R _t = 1.99 min; MS (EIpos): m / z = 388 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.91 (d, 6H), 1.48-1.76 (6H), 2.03-2.18 (3H), 2.74 (d, 2H), 3.86 (s , 3H), 4.48-4.56 (m, 1H), 7.58 (d, 2H), 7.73 (d, 1H), 8.36 (d, 2H). Example 32A 2- (4-Chloro-phenyl) -4- (ethylamino) -6- (2-methyl-propyl) -pyrimidine-5-carboxylic acid, methyl ester

12 mg (0.265 mmol) of ethylamine and 45 mg (0.442 mmol) of triethylamine are added to a solution of 60 mg (0.177 mmol) of Example 28A in 1.2 ml of THF. The mixture is stirred at 80 ° C overnight. The reaction mixture is concentrated by rotary evaporation and used further without further work-up. This gives 32 mg (53% of theory) of the target compound.
LC-MS (Method 1): R _t = 1.79 min; MS (EIpos): m / z = 348 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.91 (d, 6H), 1.21 (t, 3H), 2.08-2.19 (m, 1H), 2.70 (d, 2H) , 2.54-3.60 (m, 2H), 3.86 (s, 3H), 7.58 (d, 2H), 7.74 (t, 1H), 8.36 (d, 2H). Example 33A 2- (4-Chlorophenyl) -4 - [(cyclopropylmethyl) amino] -6- (2-methylpropyl) pyrimidine-5-carboxylic acid, methyl ester

19 mg (0.265 mmol) of cyclopropanemethylamine and 45 mg (0.442 mmol) of triethylamine are added to a solution of 60 mg (0.177 mmol) of Example 28A in 1.2 ml of THF. The mixture is stirred overnight at 80.degree. The reaction mixture is concentrated by rotary evaporation and used further without further work-up. This gives 31 mg (47% of theory) of the target compound.
LC-MS (Method 1): R _t = 1.88 min; MS (EIpos): m / z = 374 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.28-0.32 (m, 2H), 0.43-0.49 (m, 2H), 0.91 (d, 6H), 1.13-1.17 (m, 1H), 2.09-2.19 (m, 1H), 2.73 (d, 2H), 3.42 (dd, 2H), 3.87 (s, 3H), 7.57 (d, 2H), 7.90 (t, 1H), 8.36 (i.e. , 2H). Example 34A 2- (4-Chloro-phenyl) -4 - [(1-methyl-ethyl) -amine] -6- (2-methyl-propyl) -pyrimidine-5-carboxylic acid, methyl ester

To a solution of 60 mg (0.177 mmol) of Example 28A in 1.2 ml of THF are added 16 mg (0.265 mmol) of isopropylamine and 45 mg (0.442 mmol) of triethylamine. The mixture is stirred at 80 ° C for 30 h. Then the volatile components are separated on a rotary evaporator. The residue is taken up in ethyl acetate and washed several times with water. The organic phase is dried but magnesium sulfate, the solvent evaporated in vacuo and the crude product purified by chromatography on silica gel (eluent: dichloromethane). This gives 35 mg (49% of theory) of the target compound.
LC-MS (Method 3): R _t = 3.49 min; MS (EIpos): m / z = 362 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.91 (d, 6H), 1.25 (d, 6H), 2.10-2.18 (m, 1H), 2.73 (d, 2H), 3.86 (s, 3H), 4.23-4.51 (m, 1H), 7.57 (d, 2H), 8.35 (d, 2H). Exemplary embodiments: Example 1 2- (4-Chlorophenyl) -4-methyl-6 - [(1-methylethyl) amino] pyrimidine-5-carboxylic acid hydrochloride

To a solution of 250 mg (0.749 mmol) of Example 6A in 15.6 ml of ethanol is added 7.5 ml (14.978 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture is stirred at 80 ° C for 6 h. For workup, the reaction mixture is adjusted to pH 1 with 1N hydrochloric acid and the volatile components are distilled off in vacuo. The resulting crystals are filtered off and dried under high vacuum. This gives 195 mg (74% of theory) of the target compound.
LC-MS (Method 1): R _t = 1.01 min; MS (ESIpos): m / z = 306 [M + H-HCl] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.27 (d, 6H), 2.68 (s, 3H), 4.45-4.52 (m, 1H), 7.58 (d, 2H) , 8.35 (d, 2H), 8.63 (sbr). Example 2 2- (4-Chlorophenyl) -4 - [(cyclopropylmethyl) amino] -6-methylpyrimidine-5-carboxylic acid hydrochloride

To a solution of 100 mg (0.289 mmol) of Example 7A in 6 ml of ethanol is added 2.9 ml (5.783 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture is stirred at 80 ° C for 6 h. For workup, the reaction mixture is adjusted to pH 1 with 1N hydrochloric acid and the volatile components are distilled off in vacuo. The resulting crystals are filtered off and dried under high vacuum. This gives 83 mg (79% of theory) of the target compound.
LC-MS (Method 1): R _t = 1.05 min; MS (ESIpos): m / z = 318 [M + H-HCl] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.29-0.33 (m, 2H), 0.46-0.51 (m, 2H), 1.14-1.19 (m, 1H), 2.65 (s, 3H), 3.48 (dd, 2H), 7.61 (d, 2H), 8.34 (d, 2H), 8.75 (sbr). Example 3 2- (4-Chlorophenyl) -4- (diethylamino) -6-methylpyrimidine-5-carboxylic acid hydrochloride

100 mg (0.287 mmol) Example 9A are taken up in 6 ml of ethanol and with 2.8 mL (5.75 mmol) of a 2M aqueous sodium hydroxide solution added. Subsequently, 40 min at 140 ° C in implemented a single-mode microwave (Emrys Optimizer). The approach is concentrated to pH 1 with 1N hydrochloric acid and the Residue by preparative HPLC (eluent: acetonitrile / water, Gradient 90:10). This gives 15 mg (28% d. Th.) Of the target compound.

The resulting crystals are filtered off and dried under high vacuum. This gives 25 mg (24% of theory) of the target compound.
LC-MS (Method 3): R _t = 1.62 min; MS (ESIpos): m / z = 320 [M + H] ⁺ -HCl.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.19 (t, 6H), 2.38 (s, 3H), 3.57 (q, 4H), 7.55 (d, 2H), 8.31 (i.e. , 2H), 13:58 (sbr, 1H). Example 4 2- (4-Chlorophenyl) -4- (ethylamino) -6- (1-methylethyl) pyrimidine-5-carboxylic acid hydrochloride

55 mg (about 0.142 mmol) of Example 10A are taken up in 2 ml of ethanol and admixed with 1.4 ml (2,846 mmol) of a 2M aqueous sodium hydroxide solution. The mixture is then reacted at 140 ° C. for 20 minutes and then at 150 ° C. for 20 minutes in a single-mode microwave (Emrys Optimizer). The mixture is concentrated and the aqueous residue is taken up and adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals are filtered off and dried under high vacuum. This gives 15 mg (27% of theory) of the target compound.
LC-MS (Method 1): R _t = 1.46 min; MS (ESIpos): m / z = 319 [M + H-HCl] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.20 (t, 3H), 1.22 (d, 6H), 3.51-3.59 (m, 2H), 3.65-3.72 (m, 1H) , 7.57 (d, 2H), 7.97 (sbr, 1H), 8.38 (d, 2H), 13.59 (sbr, 1H). Example 5 2- (4-Chlorophenyl) -4- (cyclopropylamino) -6- (1-methylethyl) pyrimidine-5-carboxylic acid hydrochloride

80 mg (0.222 mmol) of Example 11A are taken up in 3 ml of ethanol and admixed with 2.2 ml (4.446 mmol) of a 2M aqueous sodium hydroxide solution. It is then reacted for 20 minutes at 140 ° C in a single-mode microwave (Emrys Optimizer). The mixture is concentrated and the aqueous residue is taken up and adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals are filtered off and dried under high vacuum. This gives 82 mg (91% of theory) of the target compound.
LC-MS (Method 3): R _t = 2.89 min; MS (ESIpos): m / z = 332 [M + H-HCl] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.56-0.60 (m, 2H), 0.80-0.85 (m, 211), 1.22 (d, 6H), 2.98-3.03 (m, 1H), 3.61-3.66 (m, 1H), 7.58 (d, 2H), 7.86 (sbr, 1H), 8.43 (d, 2H). Example 6 2- (4-Chlorophenyl) -4- (methylamino) -6- (1-methylethyl) pyrimidine-5-carboxylic acid hydrochloride

60 mg (0.180 mmol) of Example 12A are taken up in 2 ml of ethanol and admixed with 1.8 ml (3.595 mmol) of a 2M aqueous sodium hydroxide solution. It is then reacted for 20 minutes at 140 ° C in a single-mode microwave (Emrys Optimizer). The mixture is concentrated and the aqueous residue is taken up and adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals are filtered off and dried under high vacuum. This gives 60 mg (97% of theory) of the target compound.
LC-MS (Method 3): R _t = 2.46 min; MS (ESIpos): m / z = 306 [M + H-HCl] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (d, 6H), 3.02 (d, 3H), 7.57 (d, 2H), 7.82 (sbr, 1H), 8.40 (i.e. , 2H). Example 7 2- (4-Chlorophenyl) -4-ethyl-6 - [(1-methylethyl) amino] pyrimidine-5-carboxylic acid

42 mg (0.121 mmol) of Example 16A are taken up in 5 ml of ethanol and admixed with 193 mg (4.83 mmol) of sodium hydroxide. After addition of a few drops of water is reacted for 2 h at reflux temperature. The mixture is concentrated, taken up with water and adjusted to pH 1 with 1N hydrochloric acid. Then it is extracted with Essigsäureethyester (3x). Then the combined organic phases are dried with magnesium sulfate. The solvent is removed on a rotary evaporator and the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 90:10). This gives 8 mg (21% of theory) of the target compound.
LC-MS (Method 3): R _t = 2.12 min; MS (ESIpos): m / z = 320 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.17-1.31 (m, 9H), 2.97 (q, 2H), 4.44 (mz, 1H), 7.58 (d, 2H), 8.13 (d, 1H), 8.38 (d, 2H), 13.57 (sbr, 1H). Example 8 2- (4-Chlorophenyl) -4-ethyl-6- (prop-2-en-1-ylamino) pyrimidine-5-carboxylic acid

70 mg (0.202 mmol) of Example 17A are taken up in 5 ml of ethanol and admixed with 323 mg (8.10 mmol) of sodium hydroxide. After addition of a few drops of water is reacted for 2 h at reflux temperature. The mixture is concentrated, taken up with water and adjusted to pH 1 with 1N hydrochloric acid. Then it is extracted with Essigsäureethyester (3x). Then the combined organic phases are dried with magnesium sulfate. The solvent is separated on a rotary evaporator. This gives 55 mg (86% of theory) of the target compound.
LC-MS (Method 2): R _t = 1.71 min; MS (ESIpos): m / z = 318 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.25 (t, 3H), 2.97 (q, 2H), 4.22 (mz, 2H), 5.12 (dd, 1H), 5.23 (dd , 1H), 6.00 (mz, 1H), 7.57 (d, 2H), 8.32-8.42 (m, 3H), 13.60 (sbr, 1H). Example 9 2- (4-Chlorophenyl) -4- (diethylamino) -6-ethylpyrimidine-5-carboxylic acid

90 mg (0.249 mmol) of Example 18A are taken up in 5 ml of ethanol and admixed with 398 mg (9.95 mmol) of sodium hydroxide. After addition of a few drops of water is reacted overnight at reflux temperature. The mixture is concentrated, taken up with water and adjusted to pH 1 with 1N hydrochloric acid. Then it is extracted with Essigsäureethyester (3x). The combined organic phases are dried with magnesium sulfate and the solvent is removed on a rotary evaporator. The residue is finally purified by preparative HPLC (eluent: acetonitrile / water, gradient 90:10). This gives 54 mg (65% of theory) of the target compound.
LC-MS (Method 1): R _t = 0.94 min; MS (ESIpos): m / z = 334 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.16-1.26 (m, 9H), 2.65 (q, 2H), 3.57 (q, 4H), 7.56 (d, 2H), 8.33 (d, 2H), 13.59 (sbr, 1H). Example 10 2- (4-Chlorophenyl) -4- (cyclohexylamino) -6-ethylpyrimidine-5-carboxylic acid

43 mg (0.111 mmol) of Example 19A are taken up in 5 ml of ethanol and admixed with 177 mg (4.43 mmol) of sodium hydroxide. After addition of a few drops of water is reacted overnight at reflux temperature. The mixture is concentrated, taken up in water and adjusted to pH 1 with 1N hydrochloric acid. The mixture is then extracted with Essigsäureethyester (3x): Then the combined organic phases are dried with magnesium sulfate and the solvent is removed on a rotary evaporator. The residue was purified by preparative HPLC (eluent: acetonitrile / water, gradient 90:10). This gives 7 mg (18% of theory) of the target compound.
LC-MS (Method 3): R _t = 2.53 min; MS (ESIpos): m / z = 360 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.20-1.51 (m, 9H), 1.60 (m, 1H), 1.71 (m, 2H), 1.96 (mz, 2H), 2.98 (q, 2H), 7.58 (d, 2H), 8.30 (mz, 1H), 8.36 (d, 2H), 13.59 (sbr, 1H). Example 11 2- (4-Chloro-phenyl) -4-ethyl-6-piperidin-1-yl-pyrimidine-5-carboxylic acid

126 mg (0.337 mmol) of Example 20A are taken up in 5 ml of ethanol and admixed with 539 mg (13.48 mmol) of sodium hydroxide. After addition of a few drops of water is reacted overnight at reflux temperature. The mixture is concentrated, taken up with water and adjusted to pH 1 with 1N hydrochloric acid. It is then extracted with Essigsäureethyester (3x) and the combined organic phases are dried with magnesium sulfate. Then the solvent is separated on a rotary evaporator. This gives 104 mg (87% of theory) of the target compound.
LC-MS (Method 3): R _t = 1.82 min; MS (ESIpos): m / z = 346 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.53-1.73 (m, 6H), 2.73 (q, 2H), 3.65 (mz, 4H), 7.57 (d, 2H), 8.34 (d, 2H), 13.51 (sbr, 1H). Example 12 4- (Diethylamino) -6-ethyl-2- (4-methylphenyl) pyrimidine-5-carboxylic acid

78 mg (0.228 mmol) of Example 24A are taken up in 3 ml of ethanol and admixed with 365 mg (9.14 mmol) of sodium hydroxide. It is then reacted overnight at reflux temperature. Since the conversion remains incomplete, 15 min at 140 ° C in a single-mode microwave (Emrys Optimizer) tempered. The mixture is concentrated, taken up with water and adjusted to pH 1 with 1N hydrochloric acid. Then it is extracted with Essigsäureethyester (3x). Then the combined organic phases are dried with: magnesium sulfate. The solvent is separated on a rotary evaporator. Finally, it is dried in a high vacuum. This gives 60 mg (80% of theory) of the target compound.
LC-MS (Method 3): R _t = 1.60 min; MS (ESIpos): m / z = 314 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.14-1.27 (m, 9H), 2.37 (s, 3H), 2.66 (q, 2H), 3.58 (q, 4H), 7.30 (d, 2H), 8.22 (d, 2H), 13.53 (sbr, 1H). Example 13 4-Ethyl-6 - [(1-methylethyl) amino] -2- (4-methylphenyl) pyrimidine-5-carboxylic acid

68 mg (0.208 mmol) of Example 25A are taken up in 3 ml of ethanol and admixed with 332 mg (8.31 mmol) of sodium hydroxide. After addition of a few drops of water is reacted overnight at reflux temperature. The mixture is concentrated, taken up with water and adjusted to pH 1 with 1N hydrochloric acid. It is then extracted with Essigsäureethyester (3x), the combined organic phases are dried with magnesium sulfate. Then the solvent is separated on a rotary evaporator. This gives 54 mg (87% of theory) of the target compound.
LC-MS (Method 3): R _t = 1.82 min; MS (ESIpos): m / z = 300 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.26 (d, 6H), 2.38 (s, 3H), 2.97 (q, 2H), 4.44 (m.p. , 1H), 7.31 (d, 2H), 8.17 (sbr, 1H), 8.28 (d, 2H), 13.47 (sbr, 1H). Example 14 2- (4-Chlorophenyl) -4- (2-methylpropyl) -6 - [(2-methylpropyl) amino] pyrimidine-5-carboxylic acid hydrochloride

41 mg (0.109 mmol) of Example 30A are taken up in 1.2 ml of dioxane and admixed with 2.2 ml (4.64 mmol) of a 2M aqueous sodium hydroxide solution. It is then 40 min at 150 ° C in a single-mode microwave (Emrys Optimizer) implemented. The mixture is concentrated and the residue taken up in water. Then it is adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals are filtered off, re-absorbed with water and extracted with Essigsäureethyester (3x). The organic phase is concentrated. This gives 16 mg (36% of theory) of the target compound.
LC-MS (Method 1): R _t = 1.40 min; MS (EIpos): m / z = 362 [M + H-HCl] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.91 (d, 6H), 0.94 (d, 6H), 1.89-2.03 (m, 1H), 2.13-2.23 (m, 1H) , 2.86 (d, 2H), 3.42 (dd, 2H), 7.57 (d, 2H), 8.26 (sbr, 1H), 8.36 (d, 2H). Example 15 2- (4-Chlorophenyl) -4- (cyclopentylamino) -6- (2-methylpropyl) pyrimidine-5-carboxylic acid hydrochloride

41 mg (0.106 mmol) of Example 31A are taken up in 1.2 ml of dioxane and admixed with 2.1 ml (4.23 mmol) of a 2M aqueous sodium hydroxide solution. It is then 40 min at 150 ° C in a single-mode microwave (Emrys Optimizer) implemented. The mixture is concentrated and the residue taken up in water. Then it is adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals are filtered off, re-absorbed with water and extracted with Essigsäureethyester (3x). The organic phase is concentrated. This gives 21 mg (47% of theory) of the target compound.
LC-MS (Method 3): R _t = 2.64 min; MS (EIpos): m / z = 374 [M + H-HCl] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.91 (d, 6H), 1.48-1.73 (m, 6H), 2.05-2.12 (m, 2H), 2.13-2.22 (m, 1H), 2.88 (d, 2H), 4.47-4.55 (m, 1H), 7.57 (d, 2H), 8.18 (d, 1H), 8.37 (d, 2H), 13.63 (sbr, 1H). Example 16 2- (4-Chlorophenyl) -4- (ethylamino) -6- (2-methylpropyl) pyrimidine-5-carboxylic acid hydrochloride

31 mg (0.089 mmol) of Example 32A are taken up in 1.0 ml of dioxane and admixed with 1.8 ml (3.565 mmol) of a 2M aqueous sodium hydroxide solution. It is then 40 min at 150 ° C in a single-mode microwave (Emrys Optimizer) implemented. The mixture is concentrated and the residue taken up in water. Then it is adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals are filtered off, re-absorbed with water and extracted with Essigsäureethyester (3x). The organic phase is concentrated. This gives 15 mg (45% of theory) of the target compound.
LC-MS (Method 3): R _t = 2.14 min; MS (EIpos): m / z = 324 [M + H-HCl] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.91 (d, 6H), 1.21 (t, 3H), 2.12-2.28 (m, 1 ¹ 1), 2.85 (d, 2H) , 3.55-3.66 (m, 1H), 7.57 (d, 2H), 8.09 (sbr, 1H), 8.36 (d, 2H), 13.52 (sbr, 1H). Example 17 2- (4-Chlorophenyl) -4 - [(cyclopropylmethyl) amino] -6- (2-methylpropyl) pyrimidine-5-carboxylic acid hydrochloride

30 mg (0.080 mmol) of Example 33A are taken up in 0.9 ml of dioxane and admixed with 1.6 ml (3.210 mmol) of a 2M aqueous sodium hydroxide solution. It is then 40 min at 150 ° C in a single-mode microwave (Emrys Optimizer) implemented. The mixture is concentrated and the residue taken up in water. Then it is adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals are filtered off, re-absorbed with water and extracted with Essigsäureethyester (3x). The organic phase is concentrated. This gives 16 mg (50% of theory) of the target compound.
LC-MS (Method 3): R _t = 2.48 min; MS (EIpos): m / z = 360 [M + H-HCl] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.25-0.30 (m, 2H), 0.41-0.48 (m, 2H), 0.91 (d, 6H), 1.06-1.15 (m, 1H), 2.13-2.23 (m, 1H), 2.87 (d, 2H), 3.43 (dd, 2H), 7.57 (d, 2H), 8.23 (sbr, 1H), 8.36 (d, 2H), 13.55 (sbr , 1H). Example 18 2- (4-Chlorophenyl) -4 - [(1-methylethyl) amine] -6- (2-methylpropyl) pyrimidine-5-carboxylic acid hydrochloride

33 mg (0.091 mmol) of Example 34A are taken up in 1.0 ml of dioxane and admixed with 1.8 ml (3.648 mmol) of a 2M aqueous sodium hydroxide solution. It is then 40 min at 150 ° C in a single-mode microwave (Emrys Optimizer) implemented. The mixture is concentrated and the residue taken up in water. Then it is adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals are filtered off with suction. This gives 24 mg (68% of theory) of the target compound.
LC-MS (Method 3): R _t = 2.38 min; MS (EIpos): m / z = 348 [M + H-HCl] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.91 (d, 6H), 1.26 (d, 6H), 2.13-2.23 (m, 1H), 2.87 (d, 2H), 4.37 -4.47 (m, 1H), 7.57 (d, 2H), 8.00 (sbr, 1H), 8.36 (d, 2H), 13.57 (sbr, 1H). Example 19 2- (4-Chlorophenyl) -4- (diethylamino) -6- (2-methylpropyl) pyrimidine-5-carboxylic acid

36 mg (0.091 mmol) of Example 29A are taken up in 1.0 ml of dioxane and admixed with 1.9 ml (3.83 mmol) of a 2M aqueous sodium hydroxide solution. It is then reacted at 150 ° C for 40 minutes and at 170 ° C for 40 minutes in a single-mode microwave (Emrys Optimizer). The mixture is concentrated and residue is taken up in water. Then it is adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals are filtered off with suction and purified by HPLC (Sunfire C 1, eluent acetonitrile / 0.2% aqueous TFA). This gives 0.6 mg (2% of theory) of the target compound.
LC-MS (Method 2): R _t = 2.20 min; MS (EIpos): m / z = 362 [M + H-HCl] ⁺ .

B. Evaluation of Pharmacological Activity

The Pharmacological action of the invention Compounds can be shown in the following assays:

B-1: Cellular Transactivation Assay:

• a) Test principle: A cellular assay is used to identify activators of the peroxisome proliferator-activated receptor alpha (PPAR-alpha). Because mammalian cells contain various endogenous nuclear receptors that provide a unique interpreta An established chimera system, in which the ligand-binding domain of the human PPARα receptor is fused to the DNA binding domain of the yeast transcription factor GAL4, is used to complicate the results. The resulting GAL4-PPARα chimera is co-transfected into CHO cells with a reporter construct and stably expressed.
• b) Cloning: The GAL4-PPARα expression construct contains the ligand binding domain of PPARα (amino acids 167-468) which is PCR amplified and into the vector pcDNA3.1 is cloned into it. This vector already contains the GAL4 DNA binding domain (amino acids 1-147) of the vector pFC2-dbd (Stratagene). The reporter construct, which five copies of the GAL4 binding site upstream of one Contains thymidine kinase promoter leads to expression the firefly luciferase (Photinus pyralis) after activation and binding of GAL4-PPARα.
• c) Test Procedure: CHO (Chinese hamster ovary) cells stably expressing the above-described GAL4-PPARα chimera and the luciferase reporter gene construct are in the medium (Optimem, GIBCO), 2% charcoal-purified fetal on the day before the test Calf serum (Hyclone), 1.35 mM sodium pyruvate (GIBCO), 0.2% sodium bicarbonate (GIBCO) with 1 x 10 ³ cells plated in 96-well microtiter plates and in a cell incubator (96% humidity, 5% v / v CO ₂ , 37 ° C) held. On the test day, the substances to be tested are taken up in the above-mentioned medium, but without the addition of calf serum, and added to the cells. After a stimulation time of 6 h, the luciferase activity is measured using a video camera. The measured relative light units result in a sigmoidal stimulation curve as a function of the substance concentration. The EC ₅₀ values are calculated using the computer program GraphPad PRISM (version 3.02).

The following table lists the EC ₅₀ values of representative example compounds: Table Example no. EC ₅₀ [nM] 1 79 9 138 11 167 13 238 19 174

B-2: fibrinogen determination:

To determine the effect on the plasma fibrinogen concentration male Wistar rats or NMRI mice are treated for a period of 4-9 days by gavage or via feed admixture with the substance to be examined. Subsequently, in terminal anesthesia citrated blood is obtained by cardiac puncture. The plasma fibrinogen levels are calculated according to the Clauss method [ A. Clauss, Acta Haematol. 17, 237-46 (1957) ] by measuring the thrombin time with human fibrinogen as a standard.

B-3: Test description for finding pharmacologically active substances containing the apoprotein A1 (ApoA1) and HDL cholesterol (HDL-C) in the serum of transgenic mice, which are transfected with the human ApoA1 gene (hApoA1) increase or serum triglycerides (TG) lower:

The Substances that affect their HDL-C increasing activity in vivo are to be examined male transgenic hApoA1 mice administered orally. The animals will become one Day before the start of the trial randomized groups with the same number of animals, usually n = 7-10, assigned. During the Throughout the experiment the animals have drinking water and food ad libitum to disposal. The substances are taken once a day Orally administered for 7 days. For this purpose, the test substances in a solution of Solutol HS 15 + ethanol + saline (0.9%) in the ratio 1 + 1 + 8 or in a solution from Solutol HS 15 + saline (0.9%) in the ratio 2 + 8 solved. The application of dissolved substances takes place in a volume of 10 ml / kg of body weight a gavage. As a control group, animals serve the same be treated, but only the solvent (10 ml / kg Body weight) without test substance.

Before the first substance application, each mouse is used to determine ApoA1, serum cholesterol, HDL-C and serum triglycerides (TG) are drawn from blood by puncture of the retroorbital venous plexus (initial value). Subsequently, the animals are given the test substance for the first time with a gavage. 24 hours after the last substance application (on the 8th day after the start of treatment), each animal is again drawn by puncture of the retroorbital venous plexus to determine the same parameters. The blood samples are centrifuged and, after recovery of the serum, TG, cholesterol, HDL-C and human ApoA1 are incubated with a Cobas Integra 400 plus instrument (Cobas Integra, Roche Diagnostics GmbH, Mannheim) using the respective cassettes (TRIGL, CHOL2, HDL-C and APOAT). HDL-C is purified by gel filtration and post-column derivatization with MEGA cholesterol reagent (Merck KGaA) analogous to Method of Garber et al. [J. Lipid Res. 41, 1020-1026 (2000)] certainly.

The Effect of the test substances on HDL-C, hApoA1 or TG concentrations is determined by subtracting the measured value of the 1st blood sample (pre-value) determined from the reading of the second blood sample (after treatment). The differences of all HDL-C, hApoA1 and TG values become one Group averaged and with the mean of the differences of the control group compared. Statistical evaluation is done with Student's t-test after checking the variances Homogeneity.

substances the HDL-C of the treated animals, compared to that of the control group, statistically significant (p <0.05) increase by at least 20% or the TG statistically significant (p <0.05) by at least 25% are considered pharmacologically effective.

B-4: DOCA / salt model:

The Administration of desoxycorticosterone acetate (DOCH) in combination with a high salt diet and unilateral kidney removal induces a hypertension in the rat which is characterized by relatively low Renin level is characterized. As a result of this endocrine hypertension (BUT is a direct precursor of aldosterone) it comes in dependence from the selected DOCH concentration to hypertrophy of the heart and other end organ damage, e.g. The kidney, the u. a. characterized by proteinuria and glomerulosclerosis. In this rat model, test substances can be applied to existing ones examine antihypertrophic and end organ protective effects.

About 8 weeks old (body weight between 250 and 300 grams), male Sprague Dawley (SD) rats are left uninephrectomized. For this purpose, the rats are anesthetized with 1.5-2% isoflurane in a mixture of 66% N ₂ O and 33% O ₂ and the kidney is removed via a flank incision. As a later control animals serve so-called sham-operated animals, which no kidney is removed.

Uninephrectomized SD rats receive 1% sodium chloride in drinking water and once weekly Subcutaneous injection of desoxycorticosterone acetate (dissolved in sesame oil; Fa. Sigma) between the shoulder blades injected (high dose: 100 mg / kg / week, etc.), normal dose: 30 mg / kg / week s. c.).

The Substances that are being tested for their protective effect in vivo should be, by gavage or on the food (Ssniff) or drinking water. The animals are randomized one day before the start of the experiment and groups with the same number of animals, as a rule n = 10. Throughout the experiment, the animals have drinking water and feed ad libitum available. The substances will be Once a day for 4-6 weeks by gavage, food or drinking water. The placebo group used are animals that treated the same way, but only the solvent or the feed or drinking water obtained without test substance.

The Effect of the test substances is hemodynamic by measuring Parameters [blood pressure, heart rate, inotropy (dp / dt), relaxation time (tau), maximal left ventricular pressure, left ventricular enddiastolic pressure (LVEDP)], weight determination of heart, kidney and lung, measurement of protein excretion and by measuring the Gene expression of biomarkers, (eg ANP, atrial natriuretic peptides, and BNP, Brain Natriuretic Peptide) by RT / TaqMan PCR after RNA isolation determined from cardiac tissue.

The Statistical evaluation is done with Student's t-test after prior checking the variances on homogeneity.

B-5: Determination of metabolic stability

To determine the metabolic stability of test compounds, these are used in vitro with liver microsomes or, preferably, with primary fresh hepatocytes of various animal species (eg from rat and Dog) as well as of human origin to obtain and compare metabolite profiles of as complete a hepatic phase I and phase II metabolism as possible.

The test compounds are incubated at a concentration of 10-20 μM. For this purpose, stock solutions of the substances are prepared in a concentration of 1-2 mM in acetonitrile and then pipetted with a 1: 100 dilution in the incubation. Liver microsomes are incubated in 50 mM potassium phosphate buffer (pH 7.4) with and without NADPH-generating system consisting of 1 mM NADP ⁺ , 10 mM glucose-6-phosphate and 1 unit of glucose-6-phosphate dehydrogenase at 37 ° C incubated. Primary hepatocytes are also incubated in suspension in Williams E medium at 37 ° C. After an incubation period of 0-4 hours, the incubation approaches are stopped with acetonitrile (final concentration about 30%) and the protein is centrifuged off at about 15,000 × g. The thus stopped samples are either analyzed directly or stored at -20 ° C until analysis.

The Analysis is performed by high performance liquid chromatography with ultraviolet and mass spectrometric detection (HPLC-UV-MS / MS). To do this, the supernatants of the incubation samples with suitable C18 reversed-phase columns and variable Eluent mixtures of acetonitrile and 10 mM aqueous Ammonium formate solution chromatographed. The UV chromatograms in conjunction with mass spectrometric MS / MS data are used for Identification and structure elucidation of the metabolites.

C. Embodiments for pharmaceutical compositions

The Compounds according to the invention can converted into pharmaceutical preparations as follows become:

Tablet:

Composition:

100 mg of the compound according to the invention, 50 mg lactose (Monohydrate), 50 mg corn starch (native), 10 mg polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

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

production:

The Mixture of compound of the invention, lactose and starch is mixed with a 5% solution (m / m) of the PVP in water granulated. The granules will dry after drying mixed with the magnesium stearate for 5 minutes. This mixture will compressed with a standard tablet press (format of Tablet see above). As a guide for the compression a pressing force of 15 kN is used.

Orally administrable suspension:

Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water.

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

production:

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

Orally administrable solution:

Composition:

500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the Compound of the invention correspond to 20 g oral solution.

production:

The Compound of the invention is in the mixture of polyethylene glycol and polysorbate suspended with stirring. The stirring process is until complete dissolution continued the compound of the invention.

iv solution:

The Compound of the invention is in a concentration below the saturation solubility in a physiological compatible solvents (eg isotonic Saline, glucose solution 5% and / or PEG 400 solution 30%). The solution will be filtered sterile and into sterile and pyrogen-free injection containers bottled.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• WO 99/41253 [0006]
• - JP 2001-89452 [0006]
• WO 03/045941 [0006]
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• WO 2005/003099 [0006]
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Cited non-patent literature

• - Nature 1990, 347, 645-50 [0004]
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Claims (11)

Compound of the formula (I)

in which R ^{1 is} hydrogen or (C ₁ -C ₃ ) -alkyl, R ^{2 is} (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -alkenyl or (C ₃ -C ₇ ) -cycloalkyl wherein (C ₁ -C ₆ ) -alkyl having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) alkoxy, trifluoromethoxy and (C ₃ -C ₇ ) cycloalkyl substituted in which (C ₃ -C ₇ ) -cycloalkyl in turn having 1 or 2 substituents independently selected from the group fluorine, hydroxy, oxo, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, 2,2,2-trifluoroethyl , (C ₁ -C ₄ ) -alkoxy and trifluoromethoxy, and wherein (C ₃ -C ₇ ) -cycloalkyl having 1 or 2 substituents independently selected from the group fluorine, hydroxy, oxo, (C ₁ -C ₄ ) Alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C ₁ -C ₄ ) alkoxy and trifluoromethoxy, and wherein in each of said cycloalkyl groups a CH ₂ unit may be replaced by oxygen, or R ¹ and R ² together with the nitrogen atom to which they are attached form a pyrrolidine or piperidine ring, which in turn has 1 or 2 substituents independently selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, hydroxy, (C ₁ -C ₄ ) -alkoxy and trifluoromethoxy, R ^{3 is} (C ₁ -C ₄ ) -alkyl or cyclopropyl, where (C ₁ -C ₄ ) -alkyl having 1 to 3 substituents selected independently of one another may be substituted the group of fluorine and (C ₁ -C ₄₎ -alkoxy, R ⁴ stands for hydrogen or fluorine, R ⁵ represents hydrogen, fluorine, chlorine or methyl, R ⁶ is hydrogen, halogen, nitro, cyano, trifluoromethyl, R ^{7 is} hydrogen, fluorine, chlorine or methyl, wherein at least one of R ⁴ , R ⁵ , R ⁶ and R ^{7 is} different from hydrogen, and their salts, solvates and solvates of salts. A compound of the formula (I) according to Claim 1, in which R ^{1 is} hydrogen, methyl or ethyl R ^{2 is} (C ₁ -C ₆ ) -alkyl, cyclopropyl, cyclopentyl or cyclohexyl, where (C ₁ -C ₆ ) - Alkyl having a substituent selected from the group consisting of fluorine, trifluoromethyl, cyclopropyl, cyclopentyl and cyclohexyl, in which cyclopropyl, cyclopentyl and cyclohexyl may in turn be substituted by a substituent selected from among fluorine, methyl, ethyl and trifluoromethyl, and where cyclopropyl, Cyclopentyl and cyclohexyl may be substituted with one substituent selected from the group fluorine, methyl, ethyl and trifluoromethyl, or R ¹ and R ² together with the nitrogen atom to which they are attached form a pyrrolidine or piperidine ring, which in turn with can be a substituent selected from the group of fluorine, trifluoromethyl, methyl and ethyl substituted, R ³ stands for (C ₁ -C ₄₎ -alkyl or trifluoromethyl, R ⁴ f r is hydrogen, R ⁵ is hydrogen or fluorine, R ^{6 is} hydrogen, fluorine, chlorine, trifluoromethyl or methyl, R ^{7 is} hydrogen or methyl, wherein at least one of R ⁵ , R ⁶ and R ^{7 is} different from hydrogen, and their salts, solvates and solvates of the salts. A compound of formula (I) according to claim 1 or 2 wherein R ^{1 is} hydrogen or ethyl, R ^{2 is} ethyl, iso-propyl, cyclopropyl or cyclopropylmethyl, R ^{3 is} methyl, ethyl or iso -propyl, R ⁴ is hydrogen, R ^{5 is} hydrogen, R ^{6 is} hydrogen, chlorine or methyl, R ^{7 is} hydrogen or methyl, wherein at least one of R ⁶ and R ^{7 is} different from hydrogen, and their salts, solvates and solvates salts. A compound of the formula (I) according to claim 1 or 2, in which R ^{1 is} hydrogen or ethyl, R ^{2 is} ethyl, iso-propyl, iso-butyl or cyclopropylmethyl, R ^{3 is} iso-butyl, R ^{4 is} hydrogen R ^{5 is} hydrogen, R ^{6 is} hydrogen, chlorine or methyl, R ^{7 is} hydrogen or methyl, wherein at least one of R ⁶ and R ^{7 is} different from hydrogen, and their salts, solvates and solvates of the salts , Process for the preparation of compounds of the formula (I) as defined in claims 1 to 4, characterized in that a compound of the formula (II)

in which R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ each have the meanings given in claims 1 to 4, and R ^{8 is} (C ₁ -C ₄ ) -alkyl, with the aid of a suitable chlorinating agent, such as For example, phosphorus oxychloride, in a compound of formula (III)

in which R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ each have the meanings given above, and then these in an inert solvent in the presence of a base with a compound of formula (N)

in which R ¹ and R ² each have the meanings given in claims 1 to 4, to give compounds of the formula (V)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ each have the meanings given above, and reacting these by basic or acidic hydrolysis into the carboxylic acids of the formula (I)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ each have the meanings given in claims 1 to 4, and the compounds of the formula (I) are optionally converted with the corresponding (i) Solvents and / or (ii) bases or acids to their solvates, salts and / or solvates of the salts. A compound of the formula (I) as claimed in any one of the claims 1 to 4, for the treatment and / or prophylaxis of diseases. Use of a compound of formula (I) as in one of claims 1 to 4 defined for the production a medicament for the treatment and / or prophylaxis of dyslipidaemias, Atherosclerosis and heart failure. Medicament containing a compound of the formula (I) as defined in any one of claims 1 to 4, in combination with an inert, non-toxic, pharmaceutically acceptable excipient. Medicament containing a compound of the formula (I) as defined in any one of claims 1 to 4, in combination selected with one or more further active ingredients from the group consisting of HMG-CoA reductase inhibitors, diuretics, beta-receptor blockers, organic nitrates and NO donors, ACE inhibitors, Angiotensin AII antagonists, aldosterone and mineralocorticoid receptor antagonists, Vasopressin receptor antagonists, antiplatelet agents as well as anticoagulants. Medicament according to claim 8 or 9 for the treatment and / or prophylaxis of dyslipidaemias, arteriosclerosis and heart failure. Method for the treatment and / or prophylaxis of Dyslipidaemias, arteriosclerosis and heart failure in Humans and animals using an effective amount at least a compound of formula (I) as in any one of the claims 1 to 4, or a drug as in any of the claims 8 to 10 defined.