WO2009080242A1

WO2009080242A1 - Substituted 4-aminopyrimidine-5-carboxylic acid and use thereof

Info

Publication number: WO2009080242A1
Application number: PCT/EP2008/010691
Authority: WO
Inventors: Lars BÄRFACKER; Barbara ALBRECHT-KÜPPER; Peter Kolkhof; Yolanda Cancho Grande; Klemens Lustig
Original assignee: Bayer Schering Pharma Aktiengesellschaft
Priority date: 2007-12-20
Filing date: 2008-12-16
Publication date: 2009-07-02
Also published as: DE102007061756A1

Abstract

The present invention relates to novel substituted 4-aminopyrimidine-5-carboxylic acid derivatives, method for the production thereof, use thereof for treating and/or preventing illnesses, and use for producing pharmaceuticals for treating and/or preventing illnesses, preferably for treating and/or preventing cardiovascular diseases, particularly dyslipidemias, atherosclerosis, and heart failure.

Description

Substituted 4-aminopyrimidine-5-carboxylic acids and their use

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.

Despite multiple therapeutic successes, cardiovascular disease remains a serious public health problem. While treatment with statins by inhibition of HMG-CoA reductase very successfully reduces both the plasma concentrations of LDL-cholesterol (LDL-C) and the mortality of high-risk patients, today there are no convincing treatment strategies for the treatment of patients with unfavorable HDL-C / LDL-C ratio or hyper-triglyceridemia.

In addition to niacin, fibrates are currently the only treatment option for patients in these risk groups. They lower elevated triglycerides by 20-50%, lower LDL-C by 10-15%, change the LDL particle size from low density atherogenic 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) -αα (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 CHI (ApoCIII) synthesis. In contrast, the synthesis of apolipoprotein Al (ApoAl) 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. WO 03/045941 discloses pyrimidines for the treatment of immunological and inflammatory diseases. WO 2004/111014 claims substituted pyrimidines for the treatment of cystic fibrosis. 4-aminopyrimidines are described in WO 2005/003099 as ion channel modulators for the treatment of pain, arthritis, migraine, epilepsy and incontinence described. WO 2005/040133 claims aminopyrimidines for the treatment of inflammatory disorders. WO 2005/110416 discloses 4,5-disubstituted 2-arylpyrimidines as C5a receptor ligands for the treatment of inflammatory, immunological and cardiovascular diseases. Inter alia, substituted pyrimidines for the treatment of cancer are described in WO 2006/124874. WO 2006/097220 claims 4-phenoxy-2-phenylpyrimidinecarboxylic acids and, in WO 2008/031500 and WO 2008/031501, 4-phenoxy- or 2-phenoxynicotinic acids as PPAR-alpha modulators for the treatment of dyslipidemias and arteriosclerosis.

It is an object of the present invention to provide novel compounds which can be used as PPAR-alpha modulators for the treatment and / or prophylaxis of, in particular, cardiovascular diseases and have improved metabolic stability compared to compounds of the prior art.

The present invention relates to compounds of the general formula (I)

in which

R ^{1 is} hydrogen or (C _r C ₃ ) -alkyl,

R ² is (C _r _C6) alkyl, (C ₃ -C ₆₎ alkenyl or (C ₃ -C ₇₎ cycloalkyl,

where (C ₁ -C ₄ ) -alkyl having 1 or 2 substituents independently of one another can be substituted from the group of fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy and (C ₃ -C ₇ ) -cycloalkyl,

wherein (C ₃ -C ₇ ) -cycloalkyl in turn having 1 or 2 substituents independently selected from the group fluorine, hydroxy, oxo, (C _r C ₄ ) alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C _r C ₄ ) alkoxy and trifluoromethoxy can be substituted, and

where (C ₃ -C ₇ ) -cycloalkyl having 1 or 2 substituents selected independently of one another from the group fluorine, hydroxyl, oxo, (Ci-C ₄ ) alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, (Ci-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 ) -alkyl by 1 or 2 substituents , Hydroxy, (C 1 -C ₄ ) -alkoxy and trifluoromethoxy may be substituted,

R ³ is (C _r C ₄₎ -alkyl or cyclopropyl,

wherein (C] _-C4) alkyl having 1 to 3 substituents independently selected from the group of fluorine and (Ci-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.

Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts. Depending on their structure, the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.

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

Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms. Atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.

In addition, the present invention also includes prodrugs of the compounds of the invention. The term "prodrugs" includes compounds which themselves are biologically active or inactive may, however, be converted into compounds of the invention during their residence time in the body (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 to mean esters which can be hydrolyzed in physiological media and in particular in vivo enzymatically or chemically to the free carboxylic acids. As such esters, straight-chain or branched (C 1 -C ₆ ) -alkyl esters in which the alkyl group is hydroxyl,

Amino, mono- (Ci-C ₄ ) -alkylamino and / or di- (C iC ₄ ) -alkylamino may be substituted. 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. By way of example and preferably mention may be made of: 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 radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. Within the scope of the present invention It holds true that for all radicals which occur several times, their meaning is independent of one another. Substitution with one, two or three identical or different substituents is preferred. Very particular preference is given to 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 may 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 -O-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 residue definitions given in detail in the respective combinations or preferred combinations of residues are also replaced by residue definitions of other combinations, regardless of the particular combinations of the residues indicated.

Very particular preference is given to combinations of two or more of the abovementioned preferred ranges. 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, R, R, R and R 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 phosphorus oxychloride, into a compound of formula (IH)

in which R, R, R, R, R and R each have the meanings given above, überfuhrt

and this then in an inert solvent in the presence of a base with a compound of formula (IV)

K

\

N-H y (IV),

in which R ¹ and R ² each have the meanings given above,

to compounds of the formula (V)

in which R>, D R ^, T Rt I, Rτ4, R 5, Rτ6, R R7 and R 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 analogy to processes known from the literature.

The compounds of the formula (II) can be prepared by reacting compounds of the formula (VI)

(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 (VΗ)

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, R, R ₁ R, R and R 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, R, R, R, R and R each have the meanings given above,

oxidized [cf. eg, Veale 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 prepared in analogy to processes known from the literature.

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

The reaction (II) -> (IH) is generally carried out in a temperature range from 0 ⁰ C to +160 ⁰ C, preferably at +20 ⁰ C to +120 ⁰ C, optionally in a microwave. The reaction can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.

Inert solvents for process step (IE) + (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 , Dimethyl sulfoxide, N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (ΝMP), pyridine, acetone, 2-butanone or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using dimethylformamide or tetrahydrofuran.

Suitable bases for process step (HT) + (IV) -> • (V) are customary inorganic and organic bases. These include in particular alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal 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 used 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).

The reaction (IH) + (FV) -> (V) is generally carried out in a temperature range from 0 ⁰ C to +150 ⁰ C, preferably at +20 ⁰ C to +120 ⁰ C. The reaction can be at normal, elevated or be carried out at reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure. The hydrolysis of the carboxylic acid esters in process steps (V) -> (I) by conventional methods, optionally in a microwave, by treating the esters in inert solvents with acids or bases, wherein the salts initially formed in the latter by subsequent treatment with acid be converted into the free carboxylic acids. In the case of the tert-butyl ester ester cleavage is preferably carried out with acids.

Suitable inert solvents for the hydrolysis of the carboxylic acid esters are water or the organic solvents customary for ester cleavage. 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 solvents mentioned. In the case of basic ester hydrolysis, preference is given to using mixtures of water with dioxane, tetrahydrofuran, methanol and / or ethanol. In the case of the reaction with trifluoroacetic acid, preference is given to using dichloromethane and, in the case of the reaction with hydrogen chloride, preferably tetrahydrofuran, diethyl ether, dioxane or water.

Suitable bases for the ester hydrolysis are the customary inorganic bases. These include in particular alkali metal or alkaline earth metal hydroxides such as sodium, lithium, potassium or barium hydroxide, or alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate. Preference is given to using sodium hydroxide or potassium hydroxide.

Suitable acids for the ester cleavage are generally sulfuric acid, hydrochloric acid / hydrochloric acid, hydrobromic / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with the addition of water. Hydrogen chloride or trifluoroacetic acid are preferred in the case of the tert-butyl esters and hydrochloric acid in the case of the methyl esters.

The Esterspaltung is generally carried out in a temperature range of 0 ⁰ C to +100 ⁰ C, preferably from 0 ⁰ C to +50 ⁰ C. The reaction may be at atmospheric, elevated or reduced pressure is performed (for example from 0.5 to 5 bar) ,

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 ⁰ C].

The compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.

The compounds according to the invention are highly effective PPAR-alpha modulators and moreover have increased metabolic stability. They are particularly suitable for primary and / or secondary prevention and treatment of cardiovascular diseases caused by Disturbances in fatty acid and glucose metabolism are caused. Such disorders include dyslipidaemias (hypercholesterolemia, hypertriglyceridemia, elevated levels of postprandial plasma triglycerides, hypoalphalipoproteinemia, combined hyperlipidemias), arteriosclerosis, and metabolic disorders (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).

As a highly effective PPAR-alpha modulators, the compounds according to the invention are also particularly suitable for primary and / or secondary prevention and treatment of cardiac insufficiency.

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

Other independent cardiovascular disease risk factors that can be treated by the compounds of the present invention are hypertension, ischemia, myocardial infarction, angina pectoris, cardiac insufficiency, restenosis, pulmonary hypertension, increased levels of fibrinogen and low density LDL, and elevated levels of plasminogen activator. Inhibitor 1 (PAI-I).

In addition, the compounds of the invention may also be used for the treatment and / or prevention of cancers such as skin cancer, breast cancer, brain tumors, head and neck cancer, liposarcoma, carcinoma of the eye, gastrointestinal tract, thyroid, liver, pancreas of the respiratory organs, the kidney, the ureter, the prostate, the genital tract and their distant metastases as well as lyphomas, sarcomas and leukemias.

In addition, the compounds according to the invention can also be used for the treatment and / or prevention of micro- and macrovascular damage (vasculitis), reperfusion damage, arterial as well as venous thromboses, edema, 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 diseases (chronic bronchitis, COPD), kidney disease (glomerulonephritis), thyroid disease (hyperthyroidism), diseases of the pancreas (pancreatitis), liver fibrosis, skin diseases (psoriasis, acne, eczema, atopic dermatitis, dermatitis, Keratitis, scarring, wart formation, chilblains), sepsis, viral diseases (HPV, HCMV, HTV), cachexia, osteoporosis, gout, incontinence as well as wound healing, angiogenesis and anti-aging.

The effectiveness of the compounds of the invention can be e.g. in vitro by the transactivation assay described in the Examples section.

The efficacy of the compounds of the invention in vivo can be e.g. Check by the tests described in the example section.

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

Another object of the present invention is the use of the erfϊndungsgemäßen compounds for the manufacture of a medicament for the treatment and / or prevention of Erkran- kungen, in particular the aforementioned diseases.

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

Another object of the present invention are the compounds of the invention for use in a method for the treatment and / or prophylaxis of dyslipidaemias, arteriosclerosis and heart failure.

The compounds of the invention may be used alone or as needed in combination with other agents. Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases. AIs suitable combination active ingredients are exemplary and preferably mentioned: fat metabolism-altering agents, antidiabetics, blood pressure lowering agents, circulation-promoting and / or antithrombotic agents and 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.

The present invention relates, in particular, to combinations of at least one of the compounds according to the invention with at least one lipid metabolism-altering active ingredient, an antidiabetic agent, a hypotensive agent and / or an antithrombotic agent.

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

The substances which modify the lipid metabolism, by way of example and preferably from the group of HMG-CoA reductase inhibitors, inhibitors of HMG-CoA reductase expression, squalene synthesis inhibitors, ACAT inhibitors, LDL receptor inducers, cholesterol Absorption inhibitors, polymeric bile acid adsorbers, 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 the antioxidants / free radical scavengers;

• Antidiabetics listed in the Red List 2004 / Η, Chapter 12, and by way of example and preferably those of 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 those disclosed in WO 97/26265 and WO 99/03861;

The hypotensive agents, by way of example and preferably from the group of calcium antagonists, angiotensin Aue 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, e.g. 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, in particular the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;

Guanylate cyclase NO- and heme-independent activators, in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;

• inhibitors of human neutrophil elastase (HNE), such as Sivelestat and DX-890 (Reltran);

The signal transduction cascade inhibiting compounds, such as tyrosine kinase inhibitors, especially sorafenib, imatinib, Gefϊtinib and erlotinib; and or

• compounds affecting the energy metabolism of the heart, such as estimoxir, dichloroacetate, ranolazines and trimetazidines

be combined. Among the lipid metabolism-changing active compounds are preferably compounds from the group of HMG-CoA reductase inhibitors, squalene synthesis inhibitors, ACAT inhibitors, cholesterol Absoφtionhemmer, 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.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin ,

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably melinamide, pactimibe, eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thyroid hormone and / or thyroid mimetic, such as by way of example and preferably D-thyroxine or 3,5,3'-triiodothyronine (T3).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an agonist of the niacin receptor, such as by way of example and preferably niacin, Acipimox, Acifran or Radecol. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as, by way of example and by way of preference, torcetrapib, JTT-705 or CETP vaccine (Avant).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-gamma agonist, such as by way of example and preferably pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR delta agonist such as, for example and preferably, GW-501516.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.

In a preferred embodiment of the invention, the compounds of the invention are used in combination with a bile acid reabsorption inhibitor such as, for example, and preferably ASBT (= L3AT) inhibitors such as e.g. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an antioxidant / radical catalyst such as, by way of example and by way of preference, probucol, AGI-1067, BO-653 or AEOL-10150.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a cannabinoid receptor 1 antagonist, such as by way of example and preferably rimonabant or SR-147778.

Antidiabetic agents are preferably understood as meaning insulin and insulin derivatives as well as orally active hypoglycemic agents. Insulin and insulin derivatives here include both insulins of 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 according to the invention are administered in combination with insulin. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a sulphonylurea, such as, by way of example and by way of preference, tolbutamide, glibenclamide, glimepiride, glipizide or gliclazide.

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

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a meglitinide derivative, such as by way of example and preferably repaglinide or nateglinide.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a glucosidase inhibitor, such as by way of example and preferably miglitol or acarbose.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-gamma agonist, for example from the class of thiazolidinediones, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.

The blood pressure lowering agents are preferably understood as meaning compounds from the group of calcium antagonists, angiotensin AQ antagonists, ACE inhibitors, beta-receptor blockers, alpha-receptor blockers and diuretics.

In a preferred embodiment of the invention, the compounds of the invention are administered 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.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an aldosterone or mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vasopressin receptor antagonist, such as by way of example and preferably Conivaptan, tolvaptan, lixivaptan or SR-121463.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with an organic nitrate or NO donor, such as by way of example and by way of example. Sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-I, or administered in combination with inhaled NO.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a positive inotropically active compound, such as by way of example and preferably cardiac glycosides (digoxin), beta-adrenergic and dopaminergic agonists such as isoproterenol, adrenaline, norepinephrine, dopamine or dobutamine, administered.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin Aü antagonist, such as by way of example and preferably losartan, valsartan, candesartan, embusartan or telmisartan.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACE inhibitor such as, for example and preferably, enalapril, captopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a beta-receptor blocker, such as by way of example 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 bucine dolol administered.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-receptor blocker, such as by way of example and preferably prazosin.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with an antisympathotonicum, such as by way of example and preferably reserpine, clonidine or alpha-methyl-dopa, or in combination with a potassium channel agonist such as, for example and preferably, minoxidil, diazoxide, dihydralazine or hydralazine.

Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors or anticoagulants. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombin inhibitor, such as by way of example and preferably ximelagarran, melagatran, bivalirudin or Clexane.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPUb / IIIa antagonist, such as by way of example and preferably tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD No. 3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.

Particularly preferred in the context of the present invention are combinations containing at least one of the compounds according to the invention and one or more further active compounds selected from the group consisting of HMG-CoA reductase inhibitors (statins), diuretics, beta-receptor blockers, organic nitrates and NO Donors, ACE inhibitors, angiotensin Aü antagonists, aldosterone and mineralocorticoid receptor antagonists, vasopressin receptor antagonists, platelet aggregation inhibitors and anticoagulants, and their use for the treatment and / or prevention of the aforementioned diseases.

The compounds according to the invention can be used for the treatment and / or prophylaxis of cancers alone or as needed in combination with other anti-tumor agents. The present invention particularly relates to combinations of at least one of the compounds according to the invention with at least one other anti-tumor active ingredient selected from the group consisting of alkylating agents, antimetabolites, of Plant derived anti-tumor agents, hormone therapy agents, topoisomerase inhibitors, camptothecin derivatives, kinase inhibitors, targeted drugs, antibodies, immunoconjugates, interferon and / or immunomodulators, antiangiogenic compounds, antisense RNA and RNA interference, and others Tumor medication.

As suitable combination active ingredients may be mentioned by way of example and preferably:

Alkylating agents such as chloromethine N-oxide, cyclophosphamide, ifosfamide, thiotepa, ranimustine, Νimustin, temozolomide, altretamine, apaciquin, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, mafosfamide and mitolactol; Platinum-coordinated alkylating agents such as, for example, cisplatin, carboplatin, eptaplatin, lobaplatin, Νedaplatin, oxaliplatin and satraplatin;

Antimetabolites such as methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil alone or in combination with leucovorin, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, gemcitabine, fludarabine, 5-azacitidine, capecitabine, cladribine, clofarabine, Decitabine, eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, melphalan, Νelarabine, Νolatrexed, ocfosfit, disodium

Premetrexed, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, vincristine, and vinorelbine;

• hormonal agents such as exemestane, lupron, anastrozole, doxercalciferol, fadrozole, formestan, 11-beta hydroxysteroid dehydrogenase-1 inhibitors, 17-alpha hydroxylase / 17,20 lyase inhibitors such as abiraterone acetate, 5-alpha reductase

Inhibitors such as finasteride and epristeride, anti-estrogens such as tamoxifen citrate and fulvestrant, trelstar, toremifene, raloxifene, lasofoxifene, letrozole, anti-androgens such as bicalutamide, flutamide, mifepristone, ilutamide, Casodex and anti-progesterone, and combinations thereof;

• plant-derived antitumor agents such as mitotic inhibitors such as epothilones (sagopilone, ixabepilone and epothilone B), vinblastine, vinflunine, docetaxel, and paclitaxel;

Cytotoxic topoisomerase inhibitors such as aclarubicin, doxorubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan, topotecan, edotecarin, epimbicin, etoposide, exatecan, germantcan, lurtotecan, mitoxantrone, pirambicin, pixantrone, Rubitecan, Sobuzoxan, Tafluposide, and combinations thereof; • Immunological agents exemplified and preferably from the group of interferons such. Interferon alpha, Interferon alpha-2a, Interferon alpha-2b, Interferon beta, Interferon gamma- Ia and interferon gamma-nl, and other immune stimulants such. B. L19-IL2 and other IL2 Derivatives, Filgrastim, Lentinan, Sizofilan, TheraCys, Ubenimex, Aldesleukin, Alemtuzumab, BAM-002, Dacarbazine, Daclizumab, Denileukin, Gemtuzumab, Ozogamicin,

Ibritumomab, Imiquimod, Lenograstim, Lentinan, Melanoma Vaccine (Corixa), Molgramostim, Sargramostim, Tasonermin, Tecleukin, Thymalasin, Tositumomab, Vimlizine, Epratuzumab, Mitumomab, Oregovomab, Pemtumomab and Proveng;

Immunomodulators such as Krestin, Lentinan, Sizofiran, Picibanil, ProMun and Ubenimex;

Antiangiogenic compounds such as, for example, acitretin, aflibercept, angiostatin, aplidine, asentar, axitinib, recentin, bevacizumab, brivanib alaninate, cilengtide, combretastatin, DAST, endostatin, fenretinide, halofuginone, pazopanib, ranibizumab, rebarastat, Removab, Revlimid , Sorafenib, vatalanib, squalamine, sunitinib, telatinib, thalidomide, Ukrain and vitaxin;

VEGF inhibitors such as sorafenib, DAST, bevacizumab, sunitinib, recentin, axitinib, aflibercept, telatinib, brivanib alaninate, vatalanib, pazopanib, and ranibizumab;

• antibodies such as trastuzumab, cetuximab, bevacizumab, rituximab, ticilimumab, ipilimumab, lumiliximab, catumaxomab, atacicept, orregovomab and alemtumab;

EGFR (HERI) inhibitors such as cetuximab, panitumumab, vectibix, gefitinib, erlotinib and Zactima;

• HER2 inhibitors such as lapatinib, tratuzumab and pertuzumab;

• mTOR inhibitors such as temsirolimus, sirolimus / rapamycin and everolimus;

• cMet inhibitors;

PBK and AKT inhibitors;

CDK inhibitors such as roscovitine and flavopiridol; • Spindle assembly checkpoint inhibitors and targeted mitotic inhibitors such as PLK inhibitors, Aurora inhibitors (eg hesperadine), checkpoint kinase inhibitors and KSP inhibitors;

• HDAC inhibitors such as Panobinostat, Vorinostat, MS275, Belinostat and LBH589;

Inhibitors of histone methyltransferases such as Vidaza;

• HSP90 and HSP70 inhibitors;

Proteasome inhibitors such as bortezomib and carfϊlzomib;

Serine / threonine kinase inhibitors such as MEK inhibitors and Raf inhibitors such as sorafenib;

• farnesyl transferase inhibitors such as tipifarnib;

Tyrosine kinase inhibitors such as dasatinib, nilotibib, DAST, bosutinib, sorafenib, bevacizumab, sunitinib, AZD2171, axitinib, aflibercept, telatinib, imatinib mesylate, brivanib alaninate, pazopanib, ranibizumab, vatalanib, cetuximab, panitumumab, vectibix, gefitinib, erlotinib , Lapatinib, tratuzumab, pertuzumab and c-kit inhibitors;

• Vitamin D receptor agonists;

Corticoids, e.g. dexamethasone;

Thalidomide or thalidolide analogs, e.g. lenalidomide

Bcl-2 protein inhibitors such as Obatoclax, Oblimersen sodium and Gossypol;

CD20 receptor antagonists such as rituximab;

Ribonucleotide reductase inhibitors such as gemcitabine;

• Tumor necrosis apoptosis inducing ligand receptor 1 agonists such as Mapatumumab;

5-hydroxytryptamine receptor antagonists such as rEV598, xaliprod, palonosetron hydrochloride, granisetron, zindol and AB-1001; • Integrin inhibitors including Alpha5-betal integrin inhibitors. E7820, JSM 6425, Volociximab and Endostatin;

Androgen receptor antagonists including e.g. Nandrolone Decanoate, Fluoxymesterone, Android, Prost-Aid, Andromustine, Bicalutamide, Flutamide, Apo-cyproterone, Apo-Flutamide, Chlormadinone Acetate, Androcur, Tabi, Cyproterone Acetate and Nilutamide;

• aromatase inhibitors such. Anastrozole, letrozole, testolactone, exemestane, amino-glutethimide and formestane;

• matrix metalloproteinase inhibitors;

• Other active ingredients used in cancer therapy, including Alitretinoin, Ampligen, Atrasentan Bexaroten, Bortezomib, Bosentan, Calcitriol, Exisulind, Fotemustin, Brondonat,

Miltefosine, mitoxantrone, I-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazarotene, velcad, gallium nitrate, canfosfamide, darinaparsine and tretinoin.

The compounds of the invention may also be used to treat cancers associated with radiotherapy and / or surgery.

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

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

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

For the oral administration are according to the prior art functioning, the inventive compounds rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as tablets (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control of the compound according to the invention), rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatine capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are suitable, for example Inhalation medicaments (including powder inhalers, nebulizers), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions , Ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, scattering powders, implants or stents.

Preference is given to oral or parenteral administration, in particular oral and intravenous administration.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, 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 odoriferous.

In general, it has proven to be advantageous, when administered parenterally, to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight, in order to achieve effective results. When administered orally, 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 of body weight. Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. For example, in some cases it may be sufficient to make do with less than the minimum amount mentioned above, while in other cases this upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

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

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.

Abbreviations and acronyms:

Section. absolutely

Ac ₂ O acetic anhydride

AcOH acetic acid aq. Aqueous d days

TLC thin layer chromatography

DCI direct chemical ionization (in MS) dd doublet of doublet (in NMR)

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

DIAD diisopropyl azodicarboxylate

DMF dimethylformamide

DMSO dimethyl sulfoxide dt doublet of triplet (by NMR) d. Th. Of theory (in yield) eq. Equivalent (s)

ESI 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 chromatography

MS mass spectrometry mz multiple «, 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. 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 3μ 30 mm x 3.00 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of 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; Flow: 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 x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 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 x 4.6 mm; Eluent A: 1 liter of water + 0.5 ml of 50% formic acid; Eluent B: 1 liter 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 IA

2- (4-Chloφhenyl) -4-methyl-6-oxo-l, 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.

LC-MS (Method 1): R, = 0.87 min; MS (ESIpos): m / z = 295 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ [ppm] = 1.20 (t, 3H), 1.28 (d, 3H), 3.40 (d, IH), 3.97-4.03 (m, IH), 4.16 (q, 2H), 7.52 (d, 2H), 7.85 (d, 2H), 9.53 (sbr, IH).

Example 2A

2- (4-chlorophenyl) -4-methyl-6-oxo-l, 6-dihydropyrimidine-5-carboxylate

A solution of 3.00 g (about 8.753 mmol) Example IA, 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 are stirred at reflux temperature under an argon atmosphere. After cooling, the batch is mixed with water and then with Dichloromethane and ethyl acetate extracted. 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, = 1.04 min; MS (ESIpos): m / z = 293 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d *): 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, IH).

Example 3A

2- (4-chlorophenyl) -4- (l-methylethyl) -6-oxo-l, 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 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 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, = 2.23 min; MS (ESIpos): m / z = 323 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 0.87 (d, 3H), 1.07 (d, 3H), 1.20 (t, 3H), 1.70-1.80 (m, IH), 3.50 (i.e. , IH), 3.76 (dd, IH), 4.16 (q, 2H), 7.53 (d, 2H), 7.88 (d, 2H), 11.01 (sbr, IH).

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) 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 stirred overnight under argon atmosphere at reflux temperature. After cooling, the batch is washed with a saturated aqueous solution

Sodium thiosulfate solution and then the volatile components on

Separated 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, = 2.50 min; MS (ESIpos): m / z = 321 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.18 (d, 6H), 1.26 (t, 3H), 4.23 (q, 2H), 7.54 (d, 2H), 8.20 (d, 2H ).

Example 5A

4-chloro-2- (4-Chlθφhenyl) -6-methylpyrimidine-5-carboxylate

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, = 3.10 min; MS (ESIpos): m / z = 311 [M + H] ⁺ . Example 6A

2- (4-Chloφhenyl) -4-methyl-6 - [(l-methylethyl) amino] pyrimidin-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 ⁰ C. The mixture is concentrated by rotary evaporation and used without further workup. This gives 250 mg (91% of theory) of the target compound

LC-MS (Method 3): R, = 3.29 min; MS (ESIpos): m / z = 334 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.26 (d, 6H), 1.34 (t, 3H), 2.60 (t, 3H), 3.23-3.30 (m, IH), 4.32 (q , 2H), 7.56 (d, 2H), 7.90 (sbr, IH), 8.36 (d, 2H).

Example 7A

2- (4-Chloφhenyl) -4 - [(cyclopropyhnethyl) 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 ⁰ C. 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, = 3.28 min; MS (ESIpos): m / z = 346 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-Cl 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, IH), 8.37 (d, 2H).

Example 8A

4-Chloro-2- (4-chlorophenyl) -6- (1-methylethyl) pyrimidine-5-carboxylic acid ethyl ester

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 column chromatographed on silica gel (mobile phase: cyclohexane / ethyl acetate 50/1 → 20/1). , This gives 540 mg (55% of theory) of crude product in 74% purity (LC-MS), which is reacted without further purification operation.

LC-MS (Method 3): R, = 3.32 min; MS (ESIpos): m / z = 339 [M + H] ⁺ .

Example 9A

2- (4-Chloφhenyl) -4- (diethylamino) -6-methyl-pyrimidin-5-carboxylate

To a solution of 100 mg (0.321 mmol) of Example 5 A in 2 ml of tetrahydrofuran is added 1.8 ml (13,498 mmol) of triethylamine and 35 mg (0.482 mmol) of diethylamine. The reaction mixture is stirred at 80 ⁰ C overnight. 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, = 2.95 min; MS (ESIpos): m / z = 348 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO- (I 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, IH).

Example IQA

Ethyl 2- (4-chloro-phenyl) -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) of ethylamine and 0.8 ml (5.498 mmol) of triethylamine. The reaction mixture is stirred overnight at 80 ⁰ C. 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, = 3.51 min; MS (ESIpos): m / z = 348 [M + H] ⁺ .

Example IIA

2- (4-Chlθφhenyl) -4- (cyclopropylamino) -6- (l-methylethyl) pyrimidin-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 ⁰ C. 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, = 1.90 min; MS (ESIpos): m / z = 360 [M + H] ⁺ .

Example 12A

2- (4-Chloφhenyl) -4- (methylamino) -6- (l-methylethyl) pyrimidin-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 ⁰ C. The mixture is purified by preparative HPLC without further workup (eluent: acetonitrile / water, gradient 10:90 → 90:10). This gives 60 mg (100% Th.) Of the target compound.

LC-MS (Method 1): R, = 1.82 min; MS (ESIpos): m / z = 334 [M + H] ⁺ .

Example 13A

2- (4-Chloφhenyl) -4-ethyl-6-oxo-l, 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 as a solution 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] are added under an 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 4OM 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, = 1.92 min; MS (ESIpos): m / z = 309 [M + H] ⁺ .

Example 14A

2- (4-Chloφhenyl) -4-ethyl-6-oxo-l, 6-dihydropyrimidine-5-carboxylate

1.38 g (4.47 mmol) of Example 13A is dissolved in 40 ml of tetrachloromethane and under argon atmosphere with 0.835 g (4.69 mmol) of N-bromosuccinimide, 0.054 mg (0.223 mmol).

Dibenzoyl peroxide and 6.18 g (44.69 mmol) of potassium carbonate. Subsequently, at

Reflux temperature for 30 min stirred. After cooling, the batch is mixed with 100 ml of water and extracted with dichloromethane (3x). The combined organic phases are with

Dried 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% strength

Purity (LC-MS), which is reacted without further purification operation.

LC-MS (Method 1): R, = 1.17 min; MS (ESIpos): m / z = 307 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-Cl 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, IH).

Example 15A

4-chloro-2- (4-chloφhenyl) -6-ethylpyrimidine-5-carboxylate

1.25 g (3.26 mmol) Example 14A and 12.2 ml of phosphoxyl chloride are added for 2 h

Reflux temperature stirred. 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. Of the

Residue is purified by preparative MPLC (Biotage 4OM cartridge;

Eluent: isohexane / ethyl acetate = 7/3). This gives 560 mg (52% of theory) of the target compound.

LC-MS (Method 3): R, = 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

2- (4-Chlθφhenyl) -4-ethyl-6 - [(l-methylethyl) amino] pyrimidin-5-carboxylate

100 mg (0.31mmol) Example 15A, 39 ul (0:46 mmol) of isopropylamine and 107 .mu.l (0.77 mmol) of triethylamine are dissolved in 3 ml of tetrahydrofuran, and then reacted overnight at 80 ⁰ C. 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, = 1.83 min; MS (ESIpos): m / z = 348 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd 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, IH), 7.58 (d, 2H), 7.75 (d, IH), 8.38 (d, 2H).

Example 17A

2- (4-Chlθφhenyl) -4-ethyl-6- (prop-2-en-l-ylamino) pyrimidin-5-carboxylate

100 mg (0.31mmol) Example 15A, 35 ul (0:46 mmol) of allylamine and 107 .mu.l (0.77 mmol) of triethylamine are dissolved in 3 ml of tetrahydrofuran, and then reacted overnight at 80 ⁰ C. 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, = 1.77 min; MS (ESIpos): m / z = 346 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd 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, IH), 5.23 (dd, IH), 5.99 (mz, IH), 7.57 (d, 2H), 8.02 (t, IH), 8.37 (d, 2H).

Example 18A

2- (4-chlorophenyl) -4- (diethylamino) -6-ethylpyrimidine-5-carboxylate

100 mg (0.31mmol) Example 15A, 48 ul (0:46 mmol) of diethylamine and 107 .mu.l (0.77 mmol) of triethylamine are dissolved in 3 ml of tetrahydrofuran, and then reacted overnight at 80 ⁰ C. 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, = 1.71 min; MS (ESIpos): m / z = 362 [M + H] ⁺ .

¹ H NMR (400 MHz, DMSO-d "): 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 (0.31mmol) Example 15A, 53 ul (0:46 mmol) of cyclohexylamine and 107 .mu.l (0.77 mmol) of triethylamine are dissolved in 3 ml of tetrahydrofuran, and then reacted overnight at 80 ⁰ C. 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, = 2.01 min; MS (ESIpos): m / z = 388 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.18-1.51 (m, HH), 1.61 (m, IH), 1.72 (m, 2H), 1.96 (mz, 2H), 2.91 (q , 2H), 4.17 (mz, IH), 4.34 (q, 2H), 7.58 (d, 2H), 7.89 (d, IH), 8.36 (d, 2H).

Example 2OA

2- (4-Chloφhenyl) -4-ethyl-6-piperidin-l-yl-pyrimidine-5-carboxylate

100 mg (0.31 mmol) of Example 15 A, 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 ⁰ 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, DMSOd 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

4-ethyl-2- (4-methylphenyl) -6-oxo-l, 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] are added under an 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 Purified (Biotage 4OM 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, = 1.44 min; MS (ESIpos): m / z = 289 [M + H] ⁺ .

Example 22A

4-ethyl-2- (4-methylphenyl) -6-oxo-l, 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 2- [4- (bromomethyl) phenyl] -4-ethyl-6-oxo-l, 6-dihydropyrimidine-5-carboxylic acid ethyl ester 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 admixed under argon with 26 mg (0.247 mmol) of palladium on carbon (10 w / w) and 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 then finally purified by means of a preparative MPLC (Biotage 4OM cartridge, mobile phase: isohexane / ethyl acetate = 1/1). This gives 450 mg (35% of theory) of the target compound.

LC-MS (Method 3): R, = 2.18 min; MS (ESIpos): m / z = 287 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.21 (t, 3H), 1.28 (t, 3H), 2.39 (s, 3H), 4.28 (q, 2H), 7.35 (d, 2H ), 8.04 (d, 2H), 12.97 (sbr, IH).

Example 23A

4-chloro-6-ethyl-2- (4-methylphenyl) pyrimidin-5-carboxylate

450 mg (1.60 mmol) of Example 22A and 5.96 ml of phosphoxyl chloride are added for 2 h

Reflux temperature stirred. The mixture is concentrated on a rotary evaporator and the

Carefully collect the residue in water and cool with ice. It is then treated with 25% - aqueous ammonia solution, then neutralized with IN hydrochloric acid and with

Dichloromethane extracted (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 4OM

Cartridge; Eluent: isohexane / ethyl acetate = 7/3). This gives 421 mg (85% of theory) of the target compound.

LC-MS (Method 3): R, = 3.22 min; MS (ESIpos): m / z = 305 [M] ⁺ .

¹ H-NMR (400 MHz, DMSO- (I 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

4- (diethylamino) -6-ethyl-2- (4-methylphenyl) pyrimidin-5-carboxylate

100 mg (0.328 mmol) of Example 23A, 51 ul (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 ⁰ C for 3 h. Then the volatile components are separated on a rotary evaporator. The residue will be 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, = 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

4-ethyl-6 - [(l-methylethyl) amino] -2- (4-methylphenyl) pyrimidin-5-carboxylate

100 mg (0.328 mmol) of Example 23A, 42 ul (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 ⁰ 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, = 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, IH), 7.31 (d, 2H), 7.75 (d, IH), 8.28 (d, 2H).

Example 26A

2- (4-chloro-phenyl) -4- (2-methyl-propyl) -6-oxo-l, 4,5,6-tetrahydropyrimidine-5-carboxylic acid methyl ester

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) - propanoic acid dimethyl ester, 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 5.18 g (-25.89 mmol) of the raw material thus obtained under an argon atmosphere. 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, = 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, IH), 1.46-1.53 (dd, IH), 2.06 (sbr, IH) , 3.44 (d, IH), 3.69 (s, 3H), 3.93-4.00 (dd, IH), 7.52 (d, IH), 7.86 (d, IH), 11.15 (sbr, IH).

Example 27A

2- (4-Chloφhenyl) -4- (2-methylpropyl) -6-oxo-l, 6-dihydropyrimidine-5-carbonsäuremethylester

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 refluxed under argon atmosphere for 3 hours touched. 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, DMSOd ₆ ): δ [ppm] = 0.92 (d, 6H), 2.11-2.21 (m, IH), 2.41 (d, 2H), 3.80 (s, 3H), 7.61 (i.e. , 2H), 8.14 (d, 2H), 13.13 (sbr, IH).

Example 28A

4-Chloro-2- (4-chloro-phenyl) -6- (2-methyl-propyl) -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 at reflux temperature for 1 h. 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, = 1.76 min; MS (EIpos): m / z = 339 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 0.93 (d, 6H), 2.20-2.29 (m, IH), 2.68 (d, 2H), 3.97 (s, 3H), 7.64 (i.e. , 2H), 8.36 (d, 2H). Example 29A

2- (4-chlorophenyl) -4- (diethylamino) -6- (2-methylpropyl) pyrimidine-5-carbonsäuremethylester

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 ⁰ C. 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, = 1.79 min; MS (EIpos): m / z = 376 [M + H] +.

IH-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.89 (d, 6H), 1.17 (t, 6H), 2.15-2.23 (m, IH), 2.44 (d, 2H), 3.49 (q , 4H), 3.85 (s, 3H), 7.56 (d, 2H), 8.32 (d, 2H).

Example 3OA

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 over Night at 80 ⁰ C stirred. 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, = 1.94 min; MS (EIpos): m / z = 376 [M + H] +.

IH-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.91 (d, 6H), 0.93 (d, 2H), 1.93-2.00 (m, IH), 2.10-2.29 (m, IH), 2.73 (d, 2H), 3.39 (t, 2H), 3.87 (s, 3H), 7.57 (d, 2H), 7.85 (t, IH), 8.35 (d, 2H).

Example 31A

2- (4-Chloφhenyl) -4- (cyclopentylamino) -6- (2-methylpropyl) pyrimidine-5-carbonsäuremethylester

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 ⁰ C. 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, = 1.99 min; MS (EIpos): m / z = 388 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-Cl 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, IH), 7.58 (d, 2H), 7.73 (d, IH), 8.36 (d, 2H).

Example 32A

2- (4-Chloφhenyl) -4- (ethylamino) -6- (2-methylpropyl) pyrimidine-5-carbonsäuremethylester

To a solution of 60 mg (0.177 mmol) of Example 28 A in 1.2 ml of THF are added 12 mg (0.265 mmol) of ethylamine and 45 mg (0.442 mmol) of triethylamine. The mixture is stirred at 80 ⁰ 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, = 1.79 min; MS (EIpos): m / z = 348 [M + H] +.

IH-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.91 (d, 6H), 1.21 (t, 3H), 2.08-2.19 (m, IH), 2.70 (d, 2H), 2.54 -3.60 (m, 2H), 3.86 (s, 3H), 7.58 (d, 2H), 7.74 (t, IH), 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 at 8O ⁰ C overnight. 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] +. IH-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.28-0.32 (m, 2H), 0.43-0.49 (m, 2H), 0.91 (d, 6H), 1.13-1.17 (m, IH) , 2.09-2.19 (m, IH), 2.73 (d, 2H), 3.42 (dd, 2H), 3.87 (s, 3H), 7.57 (d, 2H), 7.90 (t, IH), 8.36 (d, 2H ).

Example 34A

2- (4-chlorophenyl) -4 - [(1-methylethyl) arrύn] -6- (2-methylpropyl) pyrimidine-5-carboxylic acid methyl ester

To a solution of 60 mg (0.177 mmol) of Example 28 A 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 over magnesium sulfate, the solvent is evaporated in vacuo and the crude product is purified by chromatography on silica gel (mobile phase: dichloromethane). This gives 35 mg (49% of theory) of the target compound.

LC-MS (Method 3): R, = 3.49 min; MS (EIpos): m / z = 362 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 0.91 (d, 6H), 1.25 (d, 6H), 2.10-2.18 (m, IH), 2.73 (d, 2H), 3.86 (s , 3H), 4.23-4.51 (m, IH), 7.57 (d, 2H), 8.35 (d, 2H). EXAMPLES

example 1

2- (4-chlorophenyl) -4-methyl-6 - [(l-methylethyl) amino] pyrimidin-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 hours. 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, = 1.01 min; MS (ESIpos): m / z = 306 [M + H-HC1] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.27 (d, 6H), 2.68 (s, 3H), 4.45-4.52 (m, IH), 7.58 (d, 2H) , 8.35 (d, 2H), 8.63 (sbr).

Example 2

2- (4-Chloφhenyl) -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 hours. For workup, the reaction mixture with 1N hydrochloric acid to pH. 1 placed and distilled off the volatile components 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, = 1.05 min; MS (ESIpos): m / z = 318 [M + H-HC1] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 0.29-0.33 (m, 2H), 0.46-0.51 (m, 2H), 1.14-1.19 (m, IH), 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-methyl-pyrimidine-5-carboxylic acid hydrochloride

100 mg (0.287 mmol) of Example 9A are taken up in 6 ml of ethanol and admixed with 2.8 ml (5.75 mmol) of a 2M aqueous sodium hydroxide solution. Min is then reacted at 140 ⁰ C in a single Mojé microwave (Emrys Optimizer) 40th The mixture is concentrated to pH 1 with 1N hydrochloric acid and the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 90:10). This gives 15 mg (28% of theory) 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, = 1.62 min; MS (ESIpos): m / z = 320 [M + H] ⁺ -HC1.

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ [ppm] = 1.19 (t, 6H), 2.38 (s, 3H), 3.57 (q, 4H), 7.55 (d, 2H), 8.31 ( d, 2H), 13.58 (sbr, IH).

Example 4

2- (4-Chloφhenyl) -4- (ethylamino) -6- (l-methylethyl) -pyrimidine-5-carboxylic acid hydrochloride

55 mg (about 0.142 mmol) of Example 1OA are taken up in 2 ml of ethanol and treated with 1.4 ml (2,846 mmol) of a 2M aqueous sodium hydroxide solution. It 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): Rt = 1.46 min; MS (ESIpos): m / z = 319 [M + H-HC1] +.

IH-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.20 (t, 3H), 1.22 (d, 6H), 3.51-3.59 (m, 2H), 3.65-3.72 (m, IH), 7.57 (d, 2H), 7.97 (sbr, IH), 8.38 (d, 2H), 13.59 (sbr, IH).

Example 5

2- (4-Chloφhenyl) -4- (cyclopropylamino) -6- (l-methylethyl) -pyrimidine-5-carboxylic acid hydrochloride

80 mg (0.222 mmol) of Example I IA are taken up in 3 ml of ethanol and admixed with 2.2 ml (4.446 mmol) of a 2M aqueous sodium hydroxide solution. Min is then reacted at 140 ⁰ C in a single Λforfe microwave (Emrys Optimizer) 20th 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, = 2.89 min; MS (ESIpos): m / z = 332 [M + H-HC1] ⁺ .

¹ H-NMR (400 MHz, DMSO-dβ): δ [ppm] = 0.56-0.60 (m, 2H), 0.80-0.85 (m, 2H), 1.22 (d, 6H), 2.98-3.03 (m, IH ), 3.61-3.66 (m, IH), 7.58 (d, 2H), 7.86 (sbr, IH), 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. Min is then reacted at 140 ⁰ C in a single Mwfe microwave (Emrys Optimizer) 20th 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, = 2.46 min; MS (ESIpos): m / z = 306 [M + H-HC1] ⁺ .

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, IH), 8.40 (i.e. , 2H).

Example 7

2- (4-Chloφhenyl) -4-ethyl-6 - [(l-methylethyl) amino] pyrimidin-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 hours 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, = 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, IH), 7.58 (d, 2H), 8.13 (d, IH), 8.38 (d, 2H), 13.57 (sbr, IH).

Example 8

2- (4-Chloφhenyl) -4-ethyl-6- (prop-2-en-l-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 hours 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, = 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, IH), 5.23 (dd , IH), 6.00 (mz, IH), 7.57 (d, 2H), 8.32-8.42 (m, 3H), 13.60 (sbr, IH).

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, = 0.94 min; MS (ESIpos): m / z = 334 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.16-1.26 (m, 9H), 2.65 (q, 2H), 3.57 (q, 4H), 7.56 (d, 2H), 8.33 (i.e. , 2H), 13.59 (sbr, IH).

Example 10

2- (4-Chloφhenyl) -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 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 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, = 2.53 min; MS (ESIpos): m / z = 360 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.20-1.51 (m, 9H), 1.60 (m, IH), 1.71 (m, 2H), 1.96 (mz, 2H), 2.98 (q , 2H), 7.58 (d, 2H), 8.30 (mz, IH), 8.36 (d, 2H), 13.59 (sbr, IH).

Example 11

2- (4-chlorophenyl) -4-ethyl-6-piperidin-l-yl-pyrimidine-5-carboxylic acid

126 mg (0.337 mmol) of Example 2OA are taken up in 5 ml of ethanol and treated 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, = 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, IH).

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 ⁰ 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, = 1.60 min; MS (ESIpos): m / z = 314 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.14-1.27 (m, 9H), 2.37 (s, 3H), 2.66 (q, 2H), 3.58 (q, 4H), 7.30 (i.e. , 2H), 8.22 (d, 2H), 13.53 (sbr, IH).

Example 13

4-ethyl-6 - [(l-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 ethyl acetate (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, = 1.82 min; MS (ESIpos): m / z = 300 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 1.23 (t, 3H), 1.26 (d, 6H), 2.38 (s, 3H), 2.97 (q, 2H), 4.44 (mz, IH ), 7.31 (d, 2H), 8.17 (sbr, IH), 8.28 (d, 2H), 13.47 (sbr, IH).

Example 14

2- (4-Chloro-phenyl) -4- (2-methyl-propyl) -6 - [(2-methyl-propyl) -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. The mixture is then reacted for 40 min at 150 ⁰ C in a single Λ / brfe microwave (Emrys Optimizer). 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, = 1.40 min; MS (EIpos): m / z = 362 [M + H-HC1] ⁺ .

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ [ppm] = 0.91 (d, 6H), 0.94 (d, 6H), 1.89-2.03 (m, IH), 2.13-2.23 (m, IH ), 2.86 (d, 2H), 3.42 (dd, 2H), 7.57 (d, 2H), 8.26 (sbr, IH), 8.36 (d, 2H).

Example 15

2- (4-Chloro-phenyl) -4- (cyclopentylamino) -6- (2-methyl-propyl) -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 ⁰ C in a single Λ / oJe 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, = 2.64 min; MS (EIpos): m / z = 374 [M + H-HC1] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 0.91 (d, 6H), 1.48-1.73 (m, 6H), 2.05-2.12 (m, 2H), 2.13-2.22 (m, IH) , 2.88 (d, 2H), 4.47-4.55 (m, IH), 7.57 (d, 2H), 8.18 (d, IH), 8.37 (d, 2H), 13.63 (sbr, IH).

Example 16

2- (4-Chloφhenyl) -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. Min is then reacted at 150 ⁰ C in a single Aforfe microwave (Emrys Optimizer) 40th The mixture is concentrated and the residue taken up in water. Then it is adjusted to pH 1 with 1N hydrochloric acid posed. 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, = 2.14 min; MS (EIpos): m / z = 324 [M + H-HC1] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.91 (d, 6H), 1.21 (t, 3H), 2.12-2.28 (m, IH), 2.85 (d, 2H), 3.55 -3.66 (m, IH), 7.57 (d, 2H), 8.09 (sbr, IH), 8.36 (d, 2H), 13.52 (sbr, IH).

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 ⁰ C in a single-Mwfe 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, = 2.48 min; MS (EIpos): m / z = 360 [M + H-HC1] ⁺ .

¹ H NMR (400 MHz, DMSOd ₆ ): δ [ppm] = 0.25-0.30 (m, 2H), 0.41-0.48 (m, 2H), 0.91 (d, 6H), 1.06-1.15 (m, IH) , 2.13-2.23 (m, IH), 2.87 (d, 2H), 3.43 (dd, 2H), 7.57 (d, 2H), 8.23 (sbr, IH), 8.36 (d, 2H), 13.55 (sbr, IH ). 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. Min is then reacted at 150 ⁰ C in a single Mocfe microwave (Emrys Optimizer) 40th 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, = 2.38 min; MS (EIpos): m / z = 348 [M + H-HC1] ⁺ .

¹ H-NMR (400 MHz, DMSO-O ₆ ): δ [ppm] = 0.91 (d, 6H), 1.26 (d, 6H), 2.13-2.23 (m, IH), 2.87 (d, 2H), 4.37 -4.47 (m, IH), 7.57 (d, 2H), 8.00 (sbr, IH), 8.36 (d, 2H), 13.57 (sbr, IH).

Example 19

2- (4-Chloφhenyl) -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. This is followed by 40 min 150 ⁰ C and 40 min at 170 ⁰ C in a single Afocfe microwave (Emrys Optimizer) implemented. 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, = 2.20 min; MS (EIpos): m / z = 362 [M + H-HC1] ⁺ .

B. Evaluation of Pharmacological Activity

The pharmacological activity of the compounds according to the invention can be demonstrated in the following assays:

B-I: Cellular Transactivation Assav:

a) test principle:

A cellular assay is used to identify activators of the peroxisome proliferator-activated receptor alpha (PPAR-alpha).

Since mammalian cells contain various endogenous nuclear receptors that could complicate unambiguous interpretation of the results, an established chimera system is used in which the ligand-binding domain of the human PPARα receptor is fused to the DNA binding domain of the yeast transcription factor GAL4. 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 PPARa (amino acids 167-468), which is PCR amplified and cloned into the vector pcDNA3.1. This vector already contains the GAL4 DNA binding domain (amino acids 1-147) of the vector pFC2-dbd (Stratagene). The reporter construct, containing five copies of the GAL4 binding site upstream of a thymidine kinase promoter, expresses the firefly luciferase (Photinus pyralis) upon activation and binding of GAL4-PPARα.

c) Test procedure:

CHO (Chinese hamster ovary) cells stably expressing the GAL4-PPARα chimera and the luciferase reporter gene construct described above are in the medium (Optimem, GIBCO), 2% activated charcoal-purified fetal calf serum (Hyclone) the day before the test. , 1.35 mM sodium pyruvate (GIBCO), 0.2% sodium bicarbonate (GIBCO) with 1 x 10 ³ cells plated in 96-well microtitre plates and maintained in a cell incubator (96% humidity, 5% v / v CO ₂ , 37 ° C). 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 give as a function of the substance concentration a sigmoidal stimulation curve. 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

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 determined by the Clauss method [A. Clauss, Acta Haematol. J / 7, 237-46 (1957)] by measuring the thrombin time with human fibrinogen as a standard.

B-3: Test description for the discovery of pharmacologically active substances which increase the apoprotein Al (ApoAl) and HDL-cholesterol (HDL-C) in the serum of transgenic mice transfected with the human ApoAl gene (hApoAl) . the

Lower serum triglycerides (TG):

The substances to be tested for their HDL-C increasing activity in vivo are orally administered to male transgenic hApoAl mice. The animals are randomly assigned to groups with the same number of animals, usually n = 7-10, one day before the start of the experiment. Throughout the experiment, the animals have access to drinking water and food ad libitum. The substances are administered orally once a day for 7 days. For this purpose, the test substances are dissolved in a solution of Solutol HS 15 + ethanol + saline (0.9%). in the ratio 1 + 1 + 8 or dissolved in a solution of Solutol HS 15 + saline (0.9%) in the ratio 2 + 8. The application of the dissolved substances takes place in a volume of 10 ml / kg body weight with a gavage. Animals which are treated in the same way, but only the solvent (10 ml / kg body weight) without test substance, serve as a control group.

Before the first substance administration, each mouse is sampled for the determination of ApoAl, serum cholesterol, HDL-C and serum triglycerides (TG) 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 ApoAl 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) analogously to the method of Garber et al. [J. Lipid Res. 4L, 1020-1026 (2000)].

The effect of the test substances on the HDL-C, hApoAl or TG concentrations is determined by subtracting the measured value of the first blood sample (pre-value) from the measured value of the second blood sample (after treatment). The differences of all HDL-C, hApoAl and TG values of a group are averaged and compared with the mean of the differences of the control group. The statistical evaluation is done with Student's t-test after checking the variances for homogeneity.

Substances which increase the HDL-C of the treated animals statistically significantly (p <0.05) by at least 20% or decrease the TG statistically significantly (p <0.05) by at least 25% compared to those of the control group are considered to be pharmacologically active ,

B-4: DOCA / salt model:

The administration of desoxycorticosterone acetate (DOCA) in combination with a high-salt diet and unilateral kidney removal induces hypertension in the rat, characterized by relatively low renin levels. As a result of this endocrine hypertension (DOCA is a direct precursor of aldosterone), hypertrophy of the heart and other end organ damage, eg kidney, characterized by proteinuria and glomerulosclerosis, depending on the DOCA concentration selected. In this rat model can be thus examine test substances for existing antihypertrophic and end organ protective effect.

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 a subcutaneous injection of desoxycorticosterone acetate (dissolved in sesame oil, Sigma) injected between the shoulder blades (high dose: 100 mg / kg / week sc, normal dose: 30 mg / kg / week sc).

The substances that are to be tested for their protective effect in vivo are administered by gavage or via the feed (Ssniff) or drinking water. The animals are randomized one day before the start of the experiment and assigned to groups with the same number of animals, usually n = 10. Throughout the experiment, the animals have access to drinking water and food ad libitum. The substances are administered once a day for 4-6 weeks by gavage, food or drinking water. The placebo group used is animals that are treated in the same way, but which either only receive the solvent or the feed or drinking water without the test substance.

The effect of the test substances is determined by measuring hemodynamic parameters [blood pressure, heart rate, inotropy (dp / dt), relaxation time (tau), maximum left ventricular pressure, left ventricular end-diastolic pressure (LVEDP)], weight determination of heart, kidney and lung Protein excretion and by measuring the gene expression of biomarkers (eg ANP, Atrial Natriuretic Peptide, and BNP, Brain Natriuretic Peptide) by RT / TaqMan PCR after RNA isolation from cardiac tissue determined.

The statistical evaluation is done with Student's t-test after checking the variances for homogeneity.

B-5: Determination of metabolic stability

To determine the metabolic stability of test compounds, they are incubated 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 metabolite profiles of a complete hepatic phase I and phase II metabolism and compare. 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 mixture. 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 analyzed either directly or stored at -20 ⁰ C until analysis.

The analysis is carried out by high performance liquid chromatography with ultraviolet and mass spectrometric detection (HPLC-UV-MS / MS). For this, the supernatants of the incubation samples are chromatographed with suitable C18 reversed-phase columns and variable eluent mixtures of acetonitrile and 10 mM aqueous ammonium formate solution. The UV chromatograms in combination with mass spectrometric MS / MS data are used to identify and structure the metabolites.

C. Embodiments of Pharmaceutical Compositions

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

Tablet:

Composition:

100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of 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 granulated with a 5% solution (m / m) of the PVP in water. The granules are mixed after drying with the magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (for the tablet format see above). As a guideline for the compression, a pressing force of 15 kN is used.

Orally administrable suspension:

Composition:

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

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

production:

The rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of 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 according to the invention corresponds to 20 g of oral solution.

production:

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

iv solution:

The compound of the invention is dissolved in a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

Claims

claims

1. Compound of formula (I)

in which

R ^{1 is} hydrogen or (C ¹ -C ₃ ) -alkyl,

where (C 1 -C ₆ ) -alkyl having 1 or 2 substituents independently of one another can be substituted from the group of fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy and (C ₃ -C ₇ ) -cycloalkyl,

wherein (C ₃ -C ₇ ) -cycloalkyl in turn having 1 or 2 substituents independently selected from the group fluorine, hydroxy, oxo, (C _r C ₄ ) alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C _r 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 _r C ₄ ) alkoxy and trifluoromethoxy can be substituted,

and

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 ) -alkyl by 1 or 2 substituents , Hydroxy, (C 1 -C ₄ ) -alkoxy and trifluoromethoxy may be substituted,

R ³ is (C _r C ₄₎ -alkyl or cyclopropyl,

wherein (Ci-C ₄₎ -alkyl may be substituted with 1 to 3 substituents independently selected from the group of fluorine and (C _r C ₄₎ alkoxy,

R ^{4 is} hydrogen or fluorine,

R ^{5 is} hydrogen, fluorine, chlorine or methyl,

R ^{7 is} hydrogen, fluorine, chlorine or methyl,

and their salts, solvates and solvates of the 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,

wherein cyclopropyl, cyclopentyl and cyclohexyl in turn with a

Substituents selected from the group fluorine, methyl, ethyl and trifluoromethyl can be substituted,

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 ³ is (C _r 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.

3. 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, 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.

4. A compound of formula (I) according to claim 1 or 2, in which

R ^{1 is} hydrogen or ethyl, R 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.

5. A process for the preparation of compounds of the formula (I) as defined in claims 1 to 4, 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 in claims 1 to 4,

and

R ^{8 is} (C _r C ₄ ) -alkyl,

with the aid of a suitable chlorinating agent, such as phosphorus oxychloride, in a compound of formula (HI)

in which R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ each have the meanings given above überfuhrt

R \

N-H

(IV),

in which R ¹ and R ² each have the meanings given in claims 1 to 4,

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,

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,

transferred

6. A compound of the formula (I) as defined in any one of claims 1 to 4, for the treatment and / or prophylaxis of diseases.

A compound of the formula (I) as defined in any one of claims 1 to 4 for use in a method for the treatment and / or prophylaxis of dyslipidemias, arteriosclerosis and cardiac insufficiency.

8. Use of a compound of formula (I) as defined in any one of claims 1 to 4 for the manufacture of a medicament for the treatment and / or prophylaxis of dyslipidaemias, arteriosclerosis and cardiac insufficiency.

A pharmaceutical composition comprising 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.

10. A medicament comprising a compound of the formula (I) as defined in any one of claims 1 to 4, in combination with one or more further active compounds selected from the group consisting of HMG-CoA reductase inhibitors, diuretics, beta-receptor Blockers, organic nitrates and NO donors, ACE inhibitors, angiotensin antagonists, aldosterone and mineralocorticoid receptor antagonists, vasopressin receptor antagonists, platelet aggregation inhibitors and anticoagulants.

11. Medicament according to claim 9 or 10 for the treatment and / or prophylaxis of dyslipidemia, arteriosclerosis and cardiac insufficiency.

12. A method for the treatment and / or prophylaxis of dyslipidaemias, arteriosclerosis and cardiac insufficiency in humans and animals using an effective amount of at least one compound of formula (I) as defined in any one of claims 1 to 4, or a drug as in one of claims 9 to 11 defined.