EP1866289A1

EP1866289A1 - Pyrimidine carboxylic acid derivatives and use thereof

Info

Publication number: EP1866289A1
Application number: EP06707442A
Authority: EP
Inventors: Elisabeth Woltering; Arounarith Tuch; Elke Dittrich-Wengenroth; Axel Kretschmer; Lars BÄRFACKER; Marcus Bauser; Peter Ellinghaus; Klemens Lustig; Elisabeth Pook; Olaf Weber
Original assignee: Bayer Healthcare AG
Current assignee: Bayer Pharma AG
Priority date: 2005-03-12
Filing date: 2006-03-07
Publication date: 2007-12-19
Also published as: DOP2006000062A; US20080194598A1; WO2006097220A1; AR055744A1; BRPI0609207A2; UY29416A1; IL185895A0; AU2006224812A1; MX2007011070A; PE20061348A1; TW200724532A; DE102005027150A1; CA2600681A1; GT200600109A; KR20070116876A; JP2008533063A

Abstract

The invention relates to pyrimidine carboxylic acid derivatives of formula (I), to methods for the production thereof, to their use for treating and/or preventing diseases, and their use for producing medicaments for treating and/or preventing diseases, preferably for treating and/or preventing cardiovascular diseases, in particular, dyslipidemias and arteriosclerosis.

Description

Pyrimidinecarboxylic acid derivatives and their use

The present application relates to pyrimidinecarboxylic acid derivatives, processes for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the production of medicaments for the treatment and / or prophylaxis of diseases, preferably for the treatment and / or prevention of cardiovascular diseases , in particular of dyslipidaemias and arteriosclerosis.

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%, alter 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.

The object of the present invention was to provide novel compounds which can be used as PPAR-alpha modulators for the treatment and / or prevention, in particular cardiovascular diseases.

Ethyl 4- (2-methylphenoxy) -2-phenylpyrimidine-5-carboxylate and the corresponding carboxylic acid are described in WO 02/42280 as synthesis intermediates; a pharmacological Activity of these compounds is not reported herein. In US 3,759,922, US 3,850,931 and J. Heterocyclic Chem. 9 (6), 1347-54 (1972) certain 4-phenoxy-2-phenylpyrimidin-5-carboxylic acid derivatives are described as synthesis intermediates, some of which a mydriatic or have the activity of the central nervous system diminishing effect. In WO 02/076438, inter alia, pyrimidine derivatives are claimed as FIt 1 ligands for the treatment of cancer and various other diseases.

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

in which

A is CH ₂ or O,

R ^{1 is} halogen, cyano or (C 1 -C ₄ ) -alkyl,

R ^{2 is} a substituent selected from the group halogen, cyano, (C _r C ₆ ) alkyl and (Ci-C ₆ ) alkoxy, wherein alkyl and alkoxy in turn may be mono- or polysubstituted by fluorine, or a group of the formula -NR ⁷ -C (= O) -R ⁸ , in which

R ^{7 is} hydrogen or (C _r C ₆ ) -alkyl

and

R ^{8 is} hydrogen, (C 1 -C ₆ ) -alkyl or (C 1 -C ₆ ) -alkoxy,

n is the number 0, 1, 2 or 3,

wherein, in the event that the substituent R ² occurs several times, its meanings may be the same or different,

R ^{3 is} hydrogen, fluorine or chlorine, R ^4, halogen, nitro, cyano, Atnino, trifluoromethyl, (C _r _C4) alkyl or hydrogen (C ₁ - C ₄₎ alkoxy is,

R ⁵ and R ^{6 are the} same or different and are independently hydrogen, halogen,

Nitro, cyano, (C _r _C6) alkyl or (dC ₆₎ alkoxy, wherein alkyl and alkoxy part may be substituted one or more times by fluorine, amino, mono- or di- (C _r _C6) - Alkylamino, a 4- to 7-membered, bonded via an N-atom heterocycle or a group of the formula -NR ⁹ -C (= O) -R ¹⁰ , wherein

R ^{9 is} hydrogen or (C _r C ₆ ) -alkyl

and

R ¹⁰ is hydrogen, (C _r _C6) alkyl or (C _r C ₆₎ alkoxy means,

and

Z is hydrogen or (C _r C ₄₎ -alkyl,

and their salts, solvates and solvates of the salts,

for the treatment and / or prophylaxis of diseases, in particular the use of these compounds for the production of a medicament for the treatment and / or prophylaxis of cardiovascular diseases.

The aforementioned compounds are mostly new, partly also known from the literature [see WO 02/42280 and the compounds with the Chemical Abstracts Registry no. 477859-49-7, 477859-47-5, 477854-82-3 and 477854-79-8]. However, no therapeutic application has been reported for the known compounds heretofore. This happens for the first time in the context of the present invention.

Another object of the present invention are compounds of general formula (I), in which

A is CH ₂ or O,

R ^{1 is} halogen, cyano or (C _r C ₄ ) -alkyl,

R ^{2 is} a substituent selected from the group halogen, cyano, (C _r C ₆ ) alkyl and (Ci-C _ß ) alkoxy, wherein alkyl and alkoxy in turn may be mono- or polysubstituted by fluorine, or a group of the formula -NR ⁷ -C (= O) -R ⁸ , in which - A -

R ^{7 is} hydrogen or (C _r C ₆ ) -alkyl

and

R ⁸ is hydrogen, (C _r _C6) alkyl or (C _r C ₆₎ alkoxy means,

n is the number 0, 1, 2 or 3,

R ^{3 is} hydrogen, fluorine or chlorine,

R ^{4 is} hydrogen, halogen, nitro, cyano, amino, trifluoromethyl, (C 1 -C ₄ ) -alkyl or (Q-C ₄ ) -alkoxy,

R ⁵ and R ^{6 are} identical or different and are each independently hydrogen, halogen, nitro, cyano, (C _r C ₆ ) alkyl or (Ci-C ₆ ) alkoxy, wherein alkyl and alkoxy in turn one or more times with fluorine may be substituted, for amino, mono- or di- (Ci-C ₆ ) - alkylamino, a 4- to 7-membered, bonded via an N-atom heterocycle or a group of the formula -NR ⁹ -C (= O ) -R ¹⁰ , in which

R ^{9 is} hydrogen or (C _r C ₆ ) -alkyl

and

R ¹⁰ is hydrogen, (C _r _C6) alkyl or (C _r C ₆₎ alkoxy means,

and

Z is hydrogen or (C _r C ₄₎ -alkyl,

and their salts, solvates and solvates of the salts,

with the exception of the compounds 4- (2-methylphenoxy) -2-phenyl-pyrimidine-5-carboxylic acid ethyl ester, 4- (2-methylphenoxy) -2-phenyl-pyrimidine-5-carboxylic acid, 4- (2,3-dimethylphenoxy) -2- phenylpyrimidine-5-carboxylic acid ethyl ester, 4- (2,3-dimethylphenoxy) -2-phenyl-pyrimidine-5-carboxylic acid, 2-phenyl-4- (2,4,5-trichloro-phenoxy) -pyrimidine-5-carboxylic acid ethyl ester and 2-phenyl -4- (2,4,5-trichlorophenoxy) pyrimidine-5-carboxylic acid.

Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, of the compounds of the formula (I) mentioned below 2006/097220 _ ₅ _

Formulas and their salts, solvates and solvates of the salts and the compounds of formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as in the case of the compounds of formula (I), the following compounds not already salts, solvates and solvates of the salts.

Depending on their structure, the compounds according to the invention can 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 which are preferred in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are not suitable for pharmaceutical applications themselves, but can be used, for example, for the isolation or purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic 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 1 to 16 carbon atoms, such as, by way of example and by way of illustration, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

As solvates in the context of the invention, those forms of the compounds according to the invention are referred to which in solid or liquid state by coordination with

Solvent molecules form a complex. Hydrates are a special form of solvate, at which is coordinated 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 may themselves be biologically active or inactive, but during their residence time in the body are converted to compounds of the invention (for example metabolically or hydrolytically).

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:

(C ₁ -C 5 -alkyl and (C ₁ -C 6) -alkyl in the context of the invention represent a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms, preferably a straight-chain or branched alkyl radical having 1 to 4 carbon atoms The following are preferably mentioned: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethyl-propyl, n-pentyl and n-hexyl.

In the context of the invention, (C ₁ -Q) -alkoxy and (C ₁ -Q) -AlkQXV are a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. By way of example and by way of preference: methoxy, ethoxy, n-propoxy, isopropoxy and tert-butoxy.

in the context of the invention are an amino group having a straight-chain or branched alkyl substituent which has 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms. Examples which may be mentioned by way of example include methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.

In the context of the invention, di (C ₁ -C 15) -AH-ylamino and DHCirCa-alkylamino represent an amino group having two identical or different straight-chain or branched alkyl substituents, each having 1 to 6 or 1 to 4 carbon atoms. Straight-chain or branched dialkylamino radicals having in each case 1 to 4 carbon atoms are preferred. Examples which may be mentioned are: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N-tert-butyl N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-niethylamino.

A 4- to 7-membered heterocycle in the context of the invention is a saturated or partially unsaturated heterocycle having 4 to 7 ring atoms, which contains a ring nitrogen, is linked via this and another heteroatom from the series Ν, O, S, SO and SO ₂ can hold. Preference is given to a 5- or 6-membered saturated, N-linked heterocycle which may contain a further heteroatom from the series N, O and S. Examples include: pyrrolidinyl, pyrrolinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aze- pinyl and 1,4-diazepinyl. Preference is given to piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and pyrrolidinyl.

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. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. 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

A is CH ₂ or O,

R ^{1 is} halogen, cyano or (C _r C ₄ ) -alkyl,

R ^{2 represents} a substituent selected from the group consisting of halogen, cyano, (C 1 -C ₄ ) -alkyl and (C 1 -C ₄ ) -alkoxy, in which alkyl and alkoxy may in turn be substituted one or more times by fluorine,

n is the number 0, 1, 2 or 3,

R ^{3 is} hydrogen, fluorine or chlorine,

R ⁴ is hydrogen, halogen, cyano, trifluoromethyl, (C _r _C4) alkyl or (C _r C ₄₎ alkoxy;

R ⁵ and R ^{6 are} identical or different and independently of one another represent hydrogen, halogen, nitro, cyano, (C 1 -C ₄ ) -alkyl or (C 1 -C ₄ ) -alkoxy, in which alkyl and alkoxy are in turn mono- or polysubstituted by fluorine may be substituted, or represent amino, mono- or di (C] -C ₄ ) alkylamino,

and Z is hydrogen, methyl or ethyl,

wherein at least one of R ³ , R ⁴ , R ⁵ and R ^{6 is} different from hydrogen,

and their salts, solvates and solvates of the salts.

Particularly preferred in the context of the present invention are compounds of the formula (I) in which

A stands for O,

R ^{1 is} fluorine, chlorine, bromine, cyano or methyl,

R ² is selected for a substituent from the group fluorine, chlorine, bromine, cyano, (C ₁ -C ₄₎ - alkyl, trifluoromethyl, (C _r C ₄₎ -alkoxy and trifluoromethoxy,

n is the number 0, 1, 2 or 3,

R ^{3 is} hydrogen or fluorine,

R ^{4 is} hydrogen, fluorine, chlorine, trifluoromethyl or methyl,

R ⁵ and R ^{6 are} identical or different and independently of one another represent hydrogen, fluorine, chlorine, bromine, nitro, cyano, (C 1 -C ₄ ) -alkyl, trifluoromethyl, (C 1 -C 4) -alkoxy, trifluoromethoxy or amino,

and

Z is 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 (T) according to the invention in which A is O, characterized in that compounds of the formula (TC)

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

Z ¹ for (C ₁ -Q) -alkyl

and

X represents a suitable leaving group, for example halogen, in particular chlorine,

in an inert solvent in the presence of a base with a compound of the formula (TS)

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

to compounds of the formula (I-A)

(I-A),

in which R, R, R, R, R, R, Z and n are each as defined above,

and these by basic or acidic hydrolysis into the carboxylic acids of the formula (I-B)

in which R ¹ , R ² , R ³ , R ⁴ , R ^s , R ^δ and n in each case have the meanings given above, converted

and the compounds of formula (I-A) or (I-B) optionally 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 (IT) can be prepared by reacting nitriles of the formula (IV)

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

initially in an inert solvent with ammonium chloride in the presence of trimethylaluminum to amidines of the formula (V)

in which R> 3, τ R.4, r R, 5 and R each have the meanings given above,

then in the presence of a base with a compound of formula (VT)

in which Z ^{1 has} the abovementioned meaning and

is methyl or ethyl,

to compounds of the formula (VII)

in which R ³ , R ⁴ , R ⁵ , R ⁶ and Z ¹ each have the meanings given above,

condensed and then converted in an inert solvent with the aid of a suitable HaIo- genierungsmittels, such as thionyl chloride, in the compounds of formula (IT).

The compounds of the formulas (TS), (TV) and (VI) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature.

Inert solvents for process step (II) + (IH) -> (I-A) are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether,

Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylsulfoxide, N, N'-dimethylpropyleneurea

(DMPU), N-methylpyrrolidinone (ΝMP), pyridine or acetonitrile. It is also possible

Use mixtures of these solvents. Preference is given to dimethylformamide or acetonitrile. AIs base for the process step (IT) + (ET) -> ■ (IA) are customary inorganic 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, or alkali metal hydrides such as sodium or potassium hydride. Preference is given to potassium carbonate or sodium hydride.

The base is used here in an amount of 1 to 3 mol, preferably in an amount of 1.2 to 2 mol, based on 1 mol of the compound of formula (EI). The reaction is generally carried out in a temperature range from ⁰ ° C to +100 ⁰ C, preferably +20 ⁰ C to +60 ⁰ C. The reaction can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 5 bar ). Generally, one works at normal pressure.

The hydrolysis of the carboxylic acid esters in process steps (IA) - »(IB) and (IC) -» (ID) is carried out by customary methods, by treating the esters in bases with inert solvents, the salts initially formed by treatment with acid in the free carboxylic acids are transferred. In the case of the dead-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, preferably, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert. Butanol, or 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 also possible to use mixtures of said solvents. 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 preferably alkali or alkaline earth hydroxides such as sodium, lithium, potassium or barium hydroxide, or alkali or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate. Particular preference is given to using sodium hydroxide or lithium hydroxide.

Suitable acids for the ester cleavage are generally sulfuric acid, hydrogen chloride / hydrochloric acid, hydrobromic / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof. if necessary 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 +40 ⁰ C. The reaction can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 5 bar) , Generally, one works at normal pressure.

Inert solvents for process step (IV) → (V) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichlorethylene or chlorobenzene, or hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to toluene.

The reaction partners ammonium chloride and trimethylaluminum used in process step (IV) -> (V) are each in an amount of 2 to 4 mol, preferably in an amount of 2 to 3 mol, based on 1 mol of the compound of formula (IV) , used. The reaction is generally carried out in a temperature range of +20 ⁰ C to + 15O ⁰ C, preferably from +80 ⁰ C to +120 ⁰ C. The reaction can be carried out at normal, elevated or at reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.

Inert solvents for process step (V) + (VI) -> (VIT) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert. Butanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether. It is likewise possible to use mixtures of the solvents mentioned. Preferred is ethanol.

Suitable bases for process step (V) + (VI) -> (VII) are, in particular, alkali metal alkoxides, such as sodium or potassium methoxide, sodium or potassium ethanolate or potassium bis-butoxide. Preferred is sodium ethanolate.

The base is used here in an amount of 2 to 3 mol, preferably in an amount of 2 to 2.5 mol, based on 1 mol of the compound of formula (V). The reaction is generally carried out in a temperature range of +20 ⁰ C to +100 ⁰ C, preferably from + 5O ⁰ C to +80 ⁰ C. The reaction can be carried out at normal, elevated or at reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.

The halogenation in process step (VD) - »(H) is preferably carried out with the aid of thionyl chloride or with para-toluenesulfonyl chloride or methanesulfonyl chloride, the latter in each case in a tertiary amine such as triethylamine, N-methylmorpholine, N-methylpiperidine or NN-diisopropylethylamine.

Inert solvents for process step (VIT) - »(D) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to dimethylformamide and dichloromethane.

The reaction is generally carried out in a temperature range of 0 ⁰ C to +60 ⁰ C, preferably from 0 ⁰ C to 3O ⁰ C. The reaction can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 5 bar) , Generally, one works at normal pressure.

The invention further provides a process for preparing the compounds of the formula (I) according to the invention in which A is CH ₂ , which comprises either

[A] Compounds of the formula (VIH)

in which R ¹ , R ² and n are each as defined above and

Z ¹ is ₍₄ C _r C) -alkyl,

with a compound of the formula (IX)

to compounds of the formula (X)

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

reacts and then in an inert solvent in the presence of a base with an amidine of the formula (V)

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

to compounds of the formula (I-C)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Z ¹ and n each have the meanings given above, is reacted

or

[B] Compounds of the formula (XI)

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

into the zinc-organic compounds of the formula (XU)

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

transferred and then in an inert solvent in the presence of a suitable palladium catalyst with a compound of formula (II)

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

for (Ci-GO-alkyl

and

to compounds of the Foπnel (IC)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Z ¹ and n each have the meanings given above, coupling

and the compounds of the formula (I-C) thus obtained by basic or acid hydrolysis into the carboxylic acids of the formula (I-D)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and n each have the meanings given above, transferred

and the compounds of formula (I-C) or (I-D) optionally 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 formulas (Vm), (IX) and (XI) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature. The compounds of formulas (IT) and (V) can be prepared as previously described.

The preparation of the compounds according to the invention can be illustrated by the following synthesis schemes: Scheme 1

[a): NH ₄ Cl, Al (CH ₃ ) ₃ , toluene, 110 ^° C; b): 2-Ethoxymethylenmalonsäurediethylester, NaOEt, EtOH, 78 ° C; c): SOCl ₂ , DMF, RT; d): K ₂ CO ₃ , DMF, RT or NaH, acetonitrile, RT; e): aq. NaOH, dioxane, THF or EtOH, RT].

Scheme 2

[a): cf. P. Schenone et al., J. Heterocyclic Chem. TA, 1669-1675 (1987); id., Il Farmaco 48, 335-355 (1993); b): NaOEt, EtOH, 78 ° C; c): aq. NaOH, dioxane or THF, RT].

Scheme 3

[a): Pd (PPh ₃ ) ₄ , THF, 70 ^° C; for the preparation of the organozinc compounds (XII) cf. also Shiota et al., J. Org. Chan. 64, 453-457 (1999); b): aq. NaOH, THF or dioxane, RT].

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 are suitable as such, in particular for the primary and / or secondary prevention and treatment of cardiovascular diseases, which are caused by disorders in fatty acid and glucose metabolism. Such disorders include dyslipidaemias (hypercholesterolemia, hypertriglyceridemia, elevated levels of postprandial plasma triglycerides, hypoalalipoproteinemia, 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). Other independent cardiovascular disease risk factors that can be treated by the compounds of this invention are hypertension, ischemia, myocardial infarction, angina pectoris, heart failure, myocardial insufficiency, restenosis, increased levels of fibrinogen and low density LDL, and elevated levels of plasminogen activator inhibitor 1 (PAI-I).

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 and venous thrombosis, edema, cancer (skin cancer, liposarcoma, carcinomas of the gastrointestinal tract, liver, pancreas , Lung, kidney, ureter, prostate and genital tract), diseases of the central nervous system and neurodegenerative disorders (stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, depression, multiple sclerosis), inflammatory diseases, immune diseases (Morbus Crohn's disease, ulcerative colitis, lupus erythematosus, rheumatoid arthritis, asthma), kidney diseases (glomerulonephritis), thyroid diseases, diseases of the pancreas (pancreatitis), liver fibrosis, skin diseases (psoriasis, acne, eczema, neurodermatitis, dermatitis, keratitis, scarring, wart formation, Chilblains), vira diseases (HPV, HCMV, HFV), cachexia, osteoporosis, gout, incontinence as well as wound healing and angiogenesis.

The activity 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 compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, 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 compounds of the invention. ^

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 according to the invention and one or more further active compounds, in particular for the treatment and / or prevention of the aforementioned diseases.

Examples of suitable combination active ingredients are lipid metabolism-altering agents, antidiabetic agents, hypotensive agents, circulation-promoting and / or antithrombotic agents, antioxidants, chemoMn 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 fat metabolism-altering agents, by way of example and preferably from the group of HMG-CoA reductase inhibitors, inhibitors of HMG-CoA reductase expression, squalene synthesis inhibitors, ACAT inhibitors, LDL receptor inducers, cholesterol absorption inhibitors, polymeric Bile acid adsorber, bile acid reabsorption inhibitor,

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 / radical scavengers,

• Antidiabetic agents mentioned in the Red List 2004/11, Chapter 12, and by way of example and preferably those from the group of sulfonylureas, biguanides, meglitinide derivatives, glucosidase-mediators, oxadiazolidinones, thiazolidinediones, GLP 1 receptor agonists, glucagon Antagonists, insulin sensitizers, CCK1 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, Anti-hypertensive agents, by way of example and preferably from the group of calcium antagonists, angiotensin Aue antagonists, ACE inhibitors, beta-receptor blockers, alpha-receptor blockers, diuretics, phosphodiesterase-mediators, sGC stimulators, Enhancers of cGMP levels, aldosterone antagonists, mineralocorticoid receptor antagonists, ECE inhibitors and the vasopeptidase inhibitors, and / or

Antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors or anticoagulants

be combined.

Among the lipid metabolism-changing active compounds are preferably compounds from the group of HMG-Co A reductase inhibitors, squalene synthesis inhibitors, ACAT inhibitors, cholesterol absorption inhibitors, MTP inhibitors, lipase-miibitoren, 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 mimic, such as by way of example and with preference 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 melamine, pactimibe, eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a cholesterm 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 meibitor, such as by way of 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 of the invention are administered in combination with a PPAR-gamma agonist such as, by way of example and by way of preference, 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, by way of example and by way of preference, ASBT (= D3AT) inhibitors, 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 scavenger 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 according to 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, butylidamide, 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 according to 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 migolith 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 AH antagonists, ACE inhibitors, beta-receptor blockers, alpha-receptor blockers and diuretics.

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 AH 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, by way of example and by way of preference, 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 by way of preference, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, Caroteneol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucinolol.

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 administered in combination with a diuretic, such as by way of example and preferably furosemide.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with antisympathotonics such as reserpine, clonidine or alpha-methyl-dopa, with potassium channel agonists such as minoxidil, diazoxide, dihydralazine or hydralazine, or with nitric oxide-releasing substances such as glyceryl nitrate or nitroprusside sodium.

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 by way of preference, ximelagatran, 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 by way of preference, 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 DX-9065a, DPC 906, JTV 803, BAY 59-7939, DU-176b, fidexaban, razaxaban, fondaparinux, Idra- parinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, 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.

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, conjunctivae 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 compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphous and / or dissolved form, such. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates, capsules (e.g. Soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

The parenteral administration can be done bypassing a resorption step (eg intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with the involvement of a Resorption (eg intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). For parenteral administration, suitable application forms include 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 plasters), milk, pastes, foams, powdered powders, implants or stents.

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

A. Examples

Abbreviations and acronyms:

aq

TLC thin layer chromatography

DCI direct chemical ionization (in MS)

DMF dimethylformamide

DMSO dimethyl sulfoxide d. Th. Of theory (in yield) eq. Equivalent (s)

ESI electrospray ionization (in MS)

Et ethyl

GC gas chromatography h hour (s)

HPLC high pressure, high performance liquid chromatography

LC-MS liquid chromatography-coupled mass spectroscopy min minute (s)

MS mass spectroscopy

NMR nuclear magnetic resonance spectroscopy

Ph phenyl

RP reverse phase (on HPLC)

RT room temperature

Retention time (by HPLC) THF tetrahydrofuran

UV ultraviolet spectroscopy

LC-MS and HPLC methods:

Method 1:

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2μ Hydro-RP 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 → - 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:

Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Synergi 2μ Hydro-RP 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 -> 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: 5O ⁰ C; UV detection: 210 nm.

Method 3:

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2μ Hydro-RP 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 - »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: 208-400 nm.

Method 4:

Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 1 water + 0.5 ml of 50% formic acid, eluent B: 1 1 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: 5O ⁰ C; UV detection: 210 nm.

Method 5:

Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Thermo HyPURITY Aquastar 3μ 50 mm x 2.1 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 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → - 5.5 min 10% A; Oven: 50 ^° C .; Flow: 0.8 ml / min; UV detection: 210 nm.

Method 6:

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Merck Chromolith SpeedROD RP-18e 50 mm 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 -> 3.0 min 95% B → 4.0 min 95% B; Oven: 35 ° C; Flow: 0.0 min 1.0 ml / min → 3.0 min 3.0 ml / min → 4.0 min 3.0 ml / min; UV detection: 210 nm. Method 7:

Instrument: HP 1100 with DAD detection; Column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 μm; Eluent A: 5 ml HClO ₄ (70%) / 1 water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 9 min 90% B → »9.2 min 2% B → 10 min 2% B; Flow: 0.75 ml / min; Column temperature: 30 ^° C .; UV detection: 210 nm.

Method 8:

Instrument: HP 1100 with DAD detection; Column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 μm; Eluent A: 5 ml HClO ₄ (70%) / 1 water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 15 min 90% B → 15.2 min 2% B → 16 min 2% B; Flow: 0.75 ml / min; Column temperature: 30 ^° C .; UV detection: 210 nm.

Method 9:

Instrument: HP 1100 with DAD detection; Column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 μm; Eluent A: 5 ml HClO ₄ (70%) / 1 water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 6.5 min 90% B → 6.7 min 2% B → 7.5 min 2% B; Flow: 0.75 ml / min; Column temperature: 30 ^° C .; UV detection: 210 nm.

Method 10:

Instrument MS: Micromass TOF (LCT); Instrument HPLC: 2-column circuit, Waters 2690; Column: YMC-ODS-AQ, 50 mm x 4.6 mm, 3.0 μm; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0.0 min 100% A → 0.2 min 95% A -> 1.8 min 25% A → 1.9 min 10% A → 2.0 min 5% A → 3.2 min 5% A; Oven: 40 ° C; Flow: 3.0 ml / min; UV detection: 210 nm.

Method l l:

Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Thermo Hypersil GOLD 3 μ, 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 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 5.5 min 10% A; Oven: 50 ^° C .; Flow: 0.8 ml / min; UV detection: 210 nm. Starting compounds and intermediates:

Example IA

4-hydroxy-2-phenylpyrimidine-5-carboxylate

To 47.7 ml of ethanolic sodium ethylate solution (21%, 41.40 g, 128 mmol) are added 10.0 g of benzamidine hydrochloride (63.9 mmol) and a solution of 13.8 g of diethyl 2-ethoxymethylenemalonate (63.9 mmol) in 25 ml of ethanol. The mixture is refluxed for 2 h and then added to 100 mL of 6 N hydrochloric acid. The precipitated solid is filtered off with suction, washed with water and dried. This gives 11.6 g (73% of theory) of the product.

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 1.30 (t, 3H), 4.27 (q, 2H), 7.52-7.59 (m, 2H), 7.61-7.68 (m, IH), 8.17 (d, 2H), 8.66 (s, IH), 13.17 (brs, IH).

LC-MS (Method 3): R _t = 1.65 min; m / z = 245.1 [M + H] ⁺ .

Example 2A

4-chloro-2-phenylpyrimidine-5-carboxylate

6.57 ml of thionyl chloride (10.70 g, 90.1 mmol) are slowly added dropwise at room temperature to 11.00 g of the compound from Example IA (45.0 mmol) in 120 ml of DMF. The mixture is stirred for 2 h at room temperature. Then 7.50 g of potassium carbonate (54.0 mmol) are added and the mixture poured into 100 ml of ice water. The precipitated solid is filtered off, washed with water and dried at 30 ⁰ C in a vacuum oven. This gives 11.4 g (96% of theory) of the product. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.38 (t, 3H), 4.40 (q, 2H), 7.56-7.68 (m, 3H), 8.40 (d, 2H), 9.26 (s, IH).

HPLC (Method 9): R _t = 5.20 min.

MS (DCI): m / z = 263 [M + H] ⁺ .

Example 3A

2-Fluorbenzolcarboximidamid hydrochloride

2.65 g of ammonium chloride (49.5 mmol) are suspended under argon in 70 ml of toluene. At 0 ⁰ C 3:57 g of trimethylaluminum (49.5 mmol) are slowly added. The mixture is stirred until the end of gas evolution at room temperature. Then 3.00 g of 2-fluorobenzonitrile (24.8 mmol) are added, and the mixture is heated at reflux overnight. After cooling to room temperature, 10 g of silica gel are added and the mixture is stirred for 15 min. The silica gel is filtered off and washed with methanol / methylene chloride (1: 1). The filtrate is concentrated at reduced pressure and the residue washed with methylene chloride / methanol (10: 1) and with methylene chloride. The residue obtained is 2.50 g (58% of theory) of the product.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 7.39-7.51 (m, 2H), 7.65-7.77 (m, 2H), 9.45 (s, 4H).

HPLC (Method 9): R _t = 0.99 min.

MS (DCI): m / z = 139.1 [M + HJ ⁺ .

Example 4A

2- (3-fluoro-4-methylphenyl) -4-hydroxypyrimidine-5-carboxylate

The representation of the title compound is carried out by analogous reaction sequence as described in Example IA.

LC-MS (Method 3): R _t = 1.99 min; m / z = 277.2 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.28 (t, 3H), 2.32 (s, 3H), 4.24 (q, 2H), 7.47 (dd, IH), 7.91- 7.99 (m, 2H), 8.61 (s, IH).

Example 5A

4-chloro-2- (3-fluoro-4-methylphenyl) pyrimidine-5-carboxylate

The preparation of the title compound is carried out starting from Example 4A by analogous reaction sequence as described in Example 2A.

LC-MS (Method 3): R _t = 3.04 min; m / z = 295.1 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.36 (t, 3H), 2.34 (s, 3H), 4.39 (q, 2H), 7.52 (dd, IH), 8.03 (dd, IH) , 8.15 (dd, IH), 9.26 (s, IH).

Example 6A

2- [3,5-di (trifluoromethyl) phenyl] -4-hydroxypyrimidine-5-carboxylate

LC-MS (Method 3): R _t = 2.61 min; m / z = 381.2 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.29 (t, 3H), 4.27 (q, 2H), 8.38 (s, IH), 8.71 (s, IH), 8.82 (s, 2H) ,

Example 7A

2- [3,5-di (trifluoromethyl) phenyl] -4-chlθφyrimidin-5-carboxylate

The preparation of the title compound is carried out starting from Example 6A by analogous reaction sequence as described in Example 2A.

LC-MS (Method 3): R _t = 3.19 min; m / z = 399.1 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.37 (t, 3H), 4.42 (q, 2H), 8.47 (s, IH), 8.88 (s, 2H), 9.37 (s, IH) ,

Example 8A

3-fluoro-4- (trifluoromethyl) benzenecarboximidamide hydrochloride

The representation of the title compound is carried out by analogous reaction sequence as described in Example 3A.

HPLC (Method 9): R _t = 3.66 min.

MS (DCI): m / z = 206.9 [M + H] ⁺ .

¹ H NMR (300 MHz, DMSO-d ₆ ): δ-7.85 (d, IH), 7.99-8.14 (m, 2H), 9.50 (br, s, 4H).

Example 9A

2- [3-fluoro-4- (trifluoromethyl) ρhenyl] -4-hydroxypyrimidine-5-carboxylate

The preparation of the title compound is carried out starting from Example 8A by analogous reaction sequence as described in Example IA.

LC-MS (Method 3): R ₁ = 2.32 min; m / z = 331.3 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.30 (t, 3H), 4.28 (q, 2H), 7.97-8.06 (m, IH), 8.18-8.28 (m, 2H), 8.72 ( s, IH).

Example IQA

4-chloro-2- [3-fluoro-4- (trifluoromethyl) phenyl] -pyrimidine-5-carboxylic acid ethyl ester

The preparation of the title compound is carried out starting from Example 9A by analogous reaction sequence as described in Example 2A.

LC-MS (Method 3): R _t = 3.17 min; m / z = 349.2 [M + H] ⁺ .

¹ H NMR (400 MHz, DMSOd ₆ ): δ = 1.37 (t, 3H), 4.41 (q, 2H), 8.01-8.07 (m, IH), 8.32 (d, IH), 8.40 (d, IH) , 9.34 (s, IH).

Example IIA

4-chloro-3-methylbenzolcarboximidamid hydrochloride

HPLC (Method 9): R _t = 3.35 min.

MS (DCI): m / z = 169.0 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 2.43 (s, 3H), 7.61 (d, IH), 7.74 (dd, IH), 7.95 (d, IH), 9.31 (br. 4H).

Example 12A

2- (4-chloro-3-methylphenyl) -4-hydroxypyrimidine-5-carboxylate

The preparation of the title compound is carried out starting from Example 1 IA by analogous reaction sequence as described in Example IA.

¹ H-NMR (300 MHz, DMSOd ₆ ): δ = 1.29 (t, 3H), 2.41 (s, 3H), 4.26 (q, 2H), 7.55 (d, IH), 8.06 (dd, IH), 8.23 (d, IH), 8.64 (s, IH).

Example 13A

4-chloro-2- (4-chloro-3-methylphenyl) pyrimidine-5-carboxylate

The title compound is prepared starting from Example 12A by an analogous reaction sequence as described in Example 2A.

LC-MS (Method 3): R _t = 3.28 min; m / z = 311.2 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 1.36 (t, 3H), 2.43 (s, 3H), 4.39 (q, 2H), 7.59 (d, IH), 8.25 (dd, IH), 8.33 (d, IH) ₅ 9.26 (s, IH).

Example 14A

3,4-Dimethylbenzolcarboximidamid hydrochloride

HPLC (Method 9): R _t = 3.43 min.

MS (DCI): m / z = 149.0 [M + H].

¹ H NMR (300 MHz, DMSOd ₆ ): δ = 2.30 (s, 3H), 2.32 (s, 3H), 7.38 (d, IH), 7.59 (dd, IH), 7.66 (d, IH), 9.20 (brs, 4H).

Example 15A

2- (3,4-dimethylphenyl) -4-hydroxypyrimidine-5-carboxylate

The preparation of the title compound is carried out starting from Example 14A by analogous reaction sequence as described in Example IA.

LC-MS (Method 3): R _t = 1.96 min; m / z = 273.3 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.28 (t, 3H), 2.30 (s, 6H), 4.25 (q, 2H), 7.31 (d, IH), 7.92 (dd, IH) , 8.00 (s, IH), 8.61 (s, IH).

Example 16A

4-chloro-2- (3,4-dimethylphenyl) -pyrimidine-5-carboxylic acid ethyl ester

The preparation of the title compound is carried out starting from Example 15A by analogous reaction sequence as described in Example 2A.

LC-MS (Method 1): R _t = 2.97 min; m / z = 291.1 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 1.36 (t, 3H), 2.32 (s, 3H), 2.33 (s, 3H), 4.39 (q, 2H), 7.35 (d, IH), 8.13 (d, IH), 8.18 (s, IH), 9.22 (s, IH).

Example 17A

4-hydroxy-2- (2-fluoφhenyl) pyrimidine-5-carboxylate

The preparation of the title compound is carried out starting from Example 3 A by analogous reaction sequence as described in Example IA.

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 1.30 (t, 3H), 4.26 (q, 2H), 7.35-7.46 (m, 2H), 7.62-7.71 (m, IH), 7.73-7.82 ( m, IH), 8.61 (s, IH), 13.30 (br s, IH).

LC-MS (Method 1): R _t = 1.38 min; m / z = 263.2 [MH-H] ⁺ .

Example 18A

4-chloro-2- (2-fluorophenyl) pyrimidin-5-carboxylate

The preparation of the title compound is carried out starting from Example 17A by analogous reaction sequence as described in Example 2A.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.37 (t, 3H), 4.40 (q, 2H), 7.38-7.44 (m, 2H), 7.63-7.71 (m, IH), 8.12 ( dd, IH), 9.31 (s, IH).

HPLC (method 7): R _t = 4.60 min.

MS (ESIpos): m / z = 280.2 [M + H] ⁺ .

Example 19A

4-hydroxy-2- (4-methyl-3-nitrophenyl) pyrimidine-5-carboxylic acid ethyl ester

LC-MS (Method 2): R _t = 2.08 min; m / z = 304.1 [M + H] ⁺ .

Example 2OA

4-Chloro-2- (4-methyl-3-nitrophenyl) pyrirnidine-5-carboxylic acid ethyl ester

The preparation of the title compound is carried out starting from Example 19A by analogous reaction sequence as described in Example 2A.

LC-MS (method 2): R _t = 2.96 min; m / z = 322.0 [M + H] ⁺ .

Example 21A

4-fluoro-3-methoxybenzolcarboximidamid hydrochloride

LC-MS (Method 11): R _t = 1.70 min; m / z = 169.0 [M + H] ⁺ .

¹ H NMR (400 MHz, DMSOd ₆ ): δ = 4.36 (s, 3H), 7.85-7.94 (m, 2H), 8.10 (d, IH), 7.90 (br, s, 4H).

Example 22A

4-hydroxy-2- (4-fluoro-3-methoxyphenyl) pyrimidine-5-carboxylate

LC-MS (Method 1): R _t = 1.63 min; m / z = 293.2 [M + H] ⁺ .

Example 23A

4-chloro-2- (4-fluoro-3-methoxyphenyl) pyrimidine-5-carboxylate

The preparation of the title compound is carried out starting from Example 22A by analogous reaction sequence as described in Example 2A.

LC-MS (Method 3): R _t = 2.83 min; m / z = 311.2 [M + H] ⁺ .

Example 24A

3,4,5-Trifluorbenzolcarboximidamid hydrochloride

LC-MS (Method 11): R _t = 0.7 min; m / z = 175.0 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.28-8.38 (m, 2H), 9.46 (br. S, 4H).

Example 25A

4-hydroxy-2- (3,4,5-trifluoφhenyl) pyrimidine-5-carboxylate

LC-MS (Method 3): R ₄ = 2.17 min; m / z = 299.2 [M + H] ⁺ .

Example 26A

4-chloro-2- (3,4,5-trifluorophenyl) pyrimidine-5-carboxylic acid ethyl ester

The preparation of the title compound is carried out starting from Example 25A by analogous reaction sequence as described in Example 2A.

LC-MS (Method 1): R ₁ = 2.91 min; m / z = 317.1 [M + H] ⁺ .

Example 27A

3,4-Difluorbenzolcarboximidamid hydrochloride

x HCl

The representation of the Titelverbindimg carried out by analogous reaction sequence as described in Example 3A.

LC-MS (Method 11): R _t = 0.88 min; m / z = 157.0 [M + H] ⁺ .

Example 28A

4-Hydroxy-2- (3, 4-difluorophenyl) pyrimidine-5-carboxylic acid ethyl ester

LC-MS (Method 3): R _t = 1.91 min; m / z = 281.2 [M + H] ⁺ .

Example 29A

4-Chloro-2- (3,4-difluoro-phenyl) -pyrimidine-5-carboxylic acid ethyl ester

The preparation of the title compound is carried out starting from Example 28A by analogous reaction sequence as described in Example 2A.

LC-MS (Method 3): R _t = 2.98 min; m / z = 299.2 [M + H] ⁺ .

Example 3OA

Bromo (2-chlorobenzyl) zinc

725.56 mg (11.1 mmol) of zinc dust in 2.5 mL of DMF and 84.11 mg (0.4 mmol) of 1,2-dibromoethane are stirred for 10 minutes at 70 ⁰ C. After cooling to room temperature, 44.47 μL (0.4 mmol) of chlorotrimethylsilane are added and the mixture is stirred for a further 30 minutes. The mixture is then cooled to ⁰ ° C. and 2.00 g (9.7 mmol) of 2-chlorobenzylbromide dissolved in 10 ml of DMF are added dropwise. After one hour at room temperature, the mixture is stirred for a further hour at 70 ⁰ C. After cooling, 7.5 mL of DMF are added. The thus obtained about 0.5 M solution of bromine (2-chlorobenzyl) zinc in DMF is used as such in the subsequent reaction (see Example 51).

Attsführungsbeispiele:

General Method 1 for the Preparation of the Phenoxyester Derivatives

To the phenol derivative (1.5 eq.) In acetonitrile is added sodium hydride (2.0 eq.) And the mixture is then stirred at room temperature for 10 minutes. Then the 2-chloropyrimidine derivative (1.0 eq.) Is added. After stirring overnight at room temperature, the mixture is concentrated and the residue is treated with water. It is extracted twice with ethyl acetate. The aqueous phase is acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate and freed from the solvent under reduced pressure. The crude product is purified by column chromatography.

General Method 2 for the Preparation of the Phenoxyester Derivatives

Potassium carbonate (2.0 eq) is added to the phenol derivative (1.2 eq.) And the 2-chloropyrimidine derivative (1.0 eq.) In N, N-dimethylformamide, and the mixture is then stirred at room temperature overnight. The mixture is filtered off with suction and the residue is washed with a little THF. The filtrate is concentrated. The crude product is purified by column chromatography.

General Method 3 for the Preparation of Phenoxycarboxylic Acid Derivatives (Examples 34-38):

The compound of Example 2A (100 μM) and the phenol derivative (100 μM) in DMF (500 μL) are combined, then potassium carbonate (2 eq.) Added and the mixture over Stirred at room temperature overnight. Then 0.2 mL of ethanol and 0.2 mL of 1 N sodium hydroxide solution are added and the mixture is stirred for 2 h at room temperature. After addition of 0.1 mL 2N hydrochloric acid and dilution with DMSO, the mixture is purified directly by chromatography.

example 1

4- (2-Chloφhenoxy) -2-phenylpyrimidine-5-carboxylate

To 183 mg of 2-chlorophenol (1.4 mmol) in 3 mL acetonitrile are added 76 mg sodium hydride (1.9 mmol) and the mixture is stirred for 10 min at room temperature. Then 250 mg of the compound from Example 2A (0.9 mmol) are added. After stirring overnight at room temperature, the mixture is added to 20 mL of water. It is extracted twice with 20 mL methylene chloride each time. The combined organic phases are washed with 20 ml of 1N sodium hydroxide solution, dried over magnesium sulfate and freed from the solvent under reduced pressure. 335 mg (99% of theory) of the product are obtained.

¹ H-NMR (300 MHz, DMSOd ₆ ): δ = 1.38 (t, 3H), 4.41 (q, 2H), 7.39-7.59 (m, 5H), 7.70 (d, IH), 8.01-8.07 (m, 2H), 9.24 (s, IH).

LC-MS (method 2): R ₁ = 3.13 min; m / z = 355.2 [M + H] ⁺ .

Example 2

4- (2-chlorophenoxy) -2-phenylpyrimidine-5-carboxylic acid

To 330 mg of the compound from Example 1 (0.9 mmol) in 1.50 ml of dioxane, 37 mg of sodium hydroxide (0.9 mmol) are added. The mixture is stirred overnight at room temperature and then added to 10 mL of water. After acidification with 1 N hydrochloric acid is extracted three times with 10 mL of methylene chloride. The combined organic phases are dried over magnesium sulfate and freed from the solvent under reduced pressure. The residue is purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 10:90-> 95: 5). This gives 262 mg (86% of theory) of the product.

¹ H-NMR (300 MHz, DMSOd ₆ ): δ = 7.38-7.59 (m, 6H), 7.70 (dd, IH), 8.03 (dd, 2H), 9.22 (s, IH), ca. 13.60 (br. s, IH).

LC-MS (Method 3): R _t = 2.43 min; m / z = 327.2 [M + H] ⁺ .

Example 3

4- (2-Fluoφhenoxy) -2-phenylpyrimidine-5-carboxylic acid

The representation of the title compound is carried out analogously to Example 1 and 2.

¹ H-NMR (400 MHz ₃ DMSOd ₆ ): δ = 7.32-7.56 (m, 7H), 8.06 (d, 2H), 9.18 (s, IH).

HPLC (Method 9): R ₁ = 4.53 min. MS (ESIpos): m / z = 311.2 [M + H] ⁺ .

Example 4

4- (2-methylphenoxy) -2-phenylpyrimidine-5-carboxylic acid

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 2.12 (s, 3H), 7.22-7.30 (m, 2H), 7.30-7.37 (m, IH), 7.38-7, (m, 3H) , 7.49-7.54 (m, IH), 8.05 (d, 2H), 9.16 (s, IH), 13.53 (brs, IH).

HPLC (Method 9): R _t = 4.67 min.

MS (ESIpos): m / z = 307.3 [M + H] ⁺ .

Example 5

4- (2-bromophenoxy) -2-phenylpyrimidine-5-carboxylic acid

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.31-7.38 (m, IH), 7.42-7.59 (m, 5H), 7.83 (d, IH), 8.03 (d, 2H), 9.22 ( s, IH), ca. 13.50 (brs s, IH). LC-MS (Method 3): R _t = 2.46 min; m / z = 371.1 [M + H] ⁴

Example 6

4- (2-chloro-4-methylphenoxy) -2-phenylpyrimidine-5-carboxylic acid

¹ H-NMR (400 MHz ₅ DMSOd ₆ ): δ = 7.36-7.56 (m, 8H), 7.76 (d, 2H), 7.83 (d, 2H), 8.14 (d, 2H), 9.19 (s, IH) , about 13.60 (brs s, IH).

HPLC (Method 7): R _t = 5.09 min.

MS (ESIpos): m / z = 369.4 [M + H] ⁺ .

Example 7

4- (2-chloro-4-methoxyphenoxy) -2-phenylpyrimidine-5-carboxylic acid

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 3.85 (s, 3H), 7.07 (dd, IH), 7.27 (d, IH), 7.41 (d, IH), 7.44-7.57 (m, 3H), 8.06 (d, 2H), 9.30 (s, IH), 13.61 (brs, IH). HPLC (Method 9): R _t = 4.67 min.

MS (ESIpos): m / z = 357.0 [M + H] ⁺ .

Example 8

4- (2,5-dichlorophenoxy) -2-phenylpyrimidine-5-carboxylic acid

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 7.45-7.58 (m, 4H), 1.12-1.1% (m, 2H), 8.06 (d, 2H), 9.24 (s, IH).

HPLC (Method 7): R _t = 4.89 min.

MS (ESIpos): m / z = 360.9 [M + H] ⁺ .

Example 9

4- (2,5-dimethylphenoxy) -2-phenylpyrimidine-5-carboxylate

The representation of the title compound is carried out analogously to Example 1. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.35 (t, 3H), 2.09 (s, 2H), 2.34 (s, 3H), 4.40 (q, 2H), 7.06-7.12 (m, 2H), 7.28 (d, IH), 7.42-7.58 (m, 3H), 8.06 (d, 2H), 9.20 (s, IH).

HPLC (Method 9): R ₁ = 5.67 min.

MS (ESIpos): m / z = 349.1 [M + H] ⁺ .

Example 10

4- (2,5-dimethylphenoxy) -2-phenylpyrimidine-5-carboxylic acid

The representation of the title compound is carried out analogously to Example 2.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 2.07 (s, 3H), 2.32 (s, 3H), 7.05 (s, IH), 7.08 (d, IH), 7.28 (d, IH) , 7.42-7.49 (m, 2H), 7.50-7.55 (m, IH), 8.06 (d, 2H), 9.18 (s, IH).

HPLC (Method 7): R _t = 4.83 min.

MS (ESIpos): m / z = 321.0 [M + H] ⁺ .

Example 11

4- (2-chlorophenoxy) -2- (3-fluoφhenyl) -pyrimidine-5-carboxylic acid

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 7.37-7.58 (m, 5H), 7.63-7.73 (m, 2H), 7.87 (d, IH), 9.22 (s, IH), 13.71 ( br. s, IH).

LC-MS (Method 3): R _t = 2.52 min; m / z = 345.1 [M + H] ⁺ .

Example 12

4- (2-Chloφhenoxy) -2- (4-methylphenyl) pyrimidine-5-carboxylic acid

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 2.32 (s, 3H), 7.27 (d, 2H), 7.39-7.45 (m, IH), 7.45-7.57 (m, 2H), 7.70 ( dd, IH), 8.01 (d, 2H), 9.20 (s, IH), 13.58 (brs, IH).

LC-MS (Method 3): R _t = 2.58 min; m / z = 341.2 [M + H] ⁺ .

Example 13

4- (2-chlorophenoxy) -2- (4-fluorophenyl) -pyrimidine-5-carboxylic acid

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 7.27-7.36 (m, 2H), 7.39-7.46 (m, IH), 7.46-7.55 (m, 2H), 7.70 (dd, IH), 8.02-8.11 (m, 2H), 9.21 (s, IH), ca. 13.62 (brs s, IH).

HPLC (Method 7): R _t = 4.73 min.

MS (DCI): m / z = 345.1 [M + H] ⁺ .

Example 14

4- (2-chlorophenoxy) -2- (4-methoxyphenyl) -pyrimidine-5-carboxylic acid

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 3.30 (s, 3H), 7.00 (d, 2H), 7.39-7.44 (m, IH), 7.45-7.54 (m, 2H), 7.79 ( d, IH), 7.98 (d, 2H), 9.16 (s, IH), 13.50 (brs, IH).

HPLC (method 7): R _t = 4.60 min.

MS (ESIpos): m / z = 357.2 [M + H] ⁺ . Example 15

4- [2-chloro-5- (trifluoromethyl) phenoxy] -2-phenylpyrimidine-5-carboxylate

According to General Method 1, 168.0 mg (0.9 mmol) of 2-chloro-5- (trifluoromethyl) phenol, 45.0 mg (1.1 mmol) of sodium hydride and 150.0 mg (0.6 mmol) of the compound from Example 2A are reacted.

Yield: 103 mg (43% of theory)

LC-MS (Method 1): R _t = 3.09 min; m / z = 423.1 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 1.36 (t, 3H), 4.41 (q, 2H), 7.44-7.51 (m, 2H), 7.52-7.58 (m, IH), 7.80 (d, IH), 7.93 (dd, IH), 8.19 (d, IH), 9.29 (s, IH).

Example 16

4- (5-chloro-2-methylphenoxy) -2-phenylpyrimidine-5-carboxylate

According to General Method 2, 130.26 mg (0.9 mmol) of 5-chloro-2-methylphenol, 200.0 mg (0.8 mmol) of the compound from Example 2A and 210.44 mg (1.5 mmol) of potassium carbonate are reacted. Yield: 232 mg (83% of theory)

LC-MS (method 2): R _t = 3.34 min; m / z = 369.1 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSOd ₆ ): δ = 1.36 (t, 3H), 2.13 (s, 3H), 4.39 (q, 2H), 7.36 (dd, IH), 7.43-7.58 (m, 5H) , 8.05-8.11 (m, 2H), 9.21 (s, IH).

Example 17

4- (2-chlorophenoxy) -2- (3-fluoro-4-methylphenyl) pyrimidine-5-carboxylate

According to General Method 2, 104.69 mg (0.1 mmol) of 2-chlorophenol, 200.0 mg (0.7 mmol) of the compound from Example 5A and 187.58 mg (1.4 mmol) of potassium carbonate are reacted.

Yield: 236 mg (90% of theory)

LC-MS (Method 3): Rt = 3.18 min; m / z = 387.1 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSOd ₆ ): δ = 1.36 (t, 3H), 2.26 (s, 3H), 4.40 (q, 2H), 7.36-7.47 (m, 2H), 7.49-7.56 (m, 2H), 7.63 (dd, IH), 7.70 (dd, IH), 7.78 (dd, IH), 9.23 (s, IH).

Example 18

4- (2-chlorophenoxy) -2- (3-fluoro-4-methylphenyl) pyrimidine-5-carboxylic acid

To 345.0 mg (0.9 mmol) of the compound from Example 17 in 6 mL ethanol / tetrahydrofuran (1: 2) are added 1.07 mL (1.1 mmol) of 1 N sodium hydroxide solution. The solution is stirred overnight at room temperature and then concentrated. After taking up in water and acidifying with 1N hydrochloric acid, the milky solution is aspirated. The residue is dissolved in 5 ml of ethyl acetate and washed with 5 ml of saturated sodium chloride solution. After separation of the phases, the organic phase is dried over magnesium sulfate and freed from the solvent under reduced pressure. 311 mg (97% of theory) of the product are obtained.

LC-MS (Method 3): R _t = 2.68 min; m / z = 359.2 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSOd ₆ ): δ = 2.26 (s, 3H), 7.35-7.56 (m, 4H), 7.49-7.56 (m, 2H), 7.62 (dd, IH), 7.70 (dd, IH), 7.76 (dd, IH), 9.21 (s, IH).

Example 19

4- (2,5-dichlorophenoxy) -2- (3-fluoro-4-methylphenyl) pyrimidine-5-carboxylate

According to General Method 2, 132.72 mg (0.8 mmol) of 2,5-dichlorophenol, 200.0 mg (0.7 mmol) of the compound from Example 5A and 187.58 mg (1.4 mmol) of potassium carbonate are reacted. Yield: 239 mg (84% of theory)

LC-MS (Method 2): R ₁ = 3.44 min; m / z = 421.0 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.35 (t, 3H), 2.27 (s, 3H), 4.39 (q, 2H), 7.42 (dd, IH), 7.54 (dd, IH) , 7.67 (dd, IH), 7.74-7.81 (m, 3H), 9.25 (s, IH).

Example 20

4- (2,5-dichlorophenoxy) -2- (3-fluoro-4-methylphenyl) pyrimidine-5-carboxylic acid

To 100.0 mg (0.2 mmol) of the compound from Example 19 in 4 mL of ethanol are added 0.29 mL (0.9 mmol) 1 N sodium hydroxide solution. The solution is stirred overnight at room temperature and then concentrated. After taking up in water and acidifying with 1 N hydrochloric acid, it is extracted twice with 5 ml of ethyl acetate each time. The organic phases are dried over magnesium sulfate and freed from the solvent under reduced pressure. The residue is purified by preparative HPLC (YMC gel ODS-AQ S-IIμm column, eluent: water / acetonitrile, gradient 90:10 → 5:95). This gives 59 mg (63% of theory) of the product.

LC-MS (Method 1): R _t = 2.62 min; m / z = 393.1 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 2.27 (s, 3H), 7.41 (dd, IH), 7.53 (dd, IH), 7.65 (dd, IH), 7.72-7.80 (m, 3H), 9.22 (s, IH).

Example 21

2- [3,5-di (trifluoromethyl) phenyl] -4- (2-chloφhenoxy) -pyrimidine-5-carboxylic acid ethyl ester

According to General Method 2, 77.39 mg (0.6 mmol) of 2-chlorophenol, 200.0 mg (0.5 mmol) of the compound from Example 7A and 138.68 mg (1.0 mmol) of potassium carbonate are reacted.

Yield: 215 mg (87% of theory)

LC-MS (Method 3): R _t = 3.32 min; m / z = 491.1 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.37 (t, 3H), 4.43 (q, 2H), 7.43-7.49 (m, IH), 7.51-7.58 (m, 2H), 7.72 ( dd, IH), 8.36 (s, IH), 8.51 (s, 2H), 9.33 (s, IH).

Example 22

2- [3,5-di (trifluoromethyl) phenyl] -4- (2-chlorophenoxy) -pyrimidine-5-carboxylic acid

The preparation of the title compound is carried out starting from Example 21 by analogous reaction sequence as described in Example 18.

LC-MS (Method 1): R _t = 2.84 min; m / z = 463.0 [M + H] ⁺ . ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 7.40-7.50 (m, IH), 7.51-7.56 (m, 2H), 7.71 (d, IH), 8.35 (s, IH), 8.50 ( s, 2H), 9.29 (s, IH).

Example 23

2- [3,5-di (trifluoromethyl) phenyl] -4- (2,5-dichlorophenoxy) -pyrimidine-5-carbonsäιireetliylester

According to General Method 2, 98.12 mg (0.6 mmol) of 2,5-dichlorophenol, 200.0 mg (0.5 mmol) of the compound from Example 7A and 138.66 mg (1.0 mmol) of potassium carbonate are reacted.

Yield: 216 mg (82% of theory)

LC-MS (Method 2): R _t = 3.52 min; m / z = 524.9 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 1.37 (t, 3H), 4.43 (q, 2H), 7.56 (dd, IH), 7.76 (d, IH), 7.85 (d, IH), 8.38 (s, IH), 8.55 (s, 2H), 9.35 (s, IH).

Example 24

2- [3,5-di (trifluoromethyl) phenyl] -4- (2,5-dichlorophenoxy) -pyrimidine-5-carboxylic acid

The preparation of the title compound is carried out starting from Example 23 by analogous reaction sequence as described in Example 18.

LC-MS (Method 1): R _t = 2.95 min; m / z = 497.0 [M + H] ⁺ .

¹ H NMR (300 MHz, DMSOd ₆ ): δ = 7.56 (dd, IH), 7.76 (d, IH), 7.81 (d, IH), 8.37 (s, IH), 8.53 (s, 2H), 9.30 (s, IH).

Example 25

4- [2-chloro-5- (trifluoromethyl) phenoxy] -2-phenylpyrimidine-5-carboxylic acid

The title compound is prepared starting from Example 15 by an analogous reaction sequence as described in Example 18.

LC-MS (Method 2): R _t = 2.80 min; m / z = 394.9 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 7.42-7.58 (m, 3H), 7.77 (d, IH), 7.92 (d, IH), 8.03 (dd, IH), 8.19 (d, IH), 9.24 (s, IH).

Example 26

4- (5-chloro-2-methylphenoxy) -2-phenylpyrimidine-5-carboxylic acid

The preparation of the title compound is carried out starting from Example 16 by analogous reaction sequence as described in Example 18.

LC-MS (method 2): R _t = 2.72 min; m / z = 341.0 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 7.35 (dd, IH), 7.42-7.57 (m, 5H), 8.06 (dd, 2H), 9.18 (s, IH).

Example 27

4- (2-Chloφhenoxy) -2- [3-fluoro-4- (trifluoromethyl) phenyl] -pyrimidm-5-carboxylate

According to General Method 2, 113.22 mg (0.9 mmol) of 2-chlorophenol, 300.0 mg (0.7 mmol) of the compound from Example 10A and 202.86 mg (1.5 mmol) of potassium carbonate are reacted.

Yield: 269 mg (83% of theory)

LC-MS (Method 2): R _t = 3.41 min; m / z = 440.9 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSOd ₆ ): δ = 1.37 (t, 3H), 4.41 (q, 2H), 7.41-7.50 (m, IH), 7.53 (d, 2H), 7.71 (d, IH) , 7.88-8.04 (m, 3H), 9.31 (s, IH).

Example 28

4- (2-chlorophenoxy) -2- [3-fluoro-4- (trifluoromethyl) phenyl] -pyrimidine-5-carboxylic acid

The preparation of the title compound is carried out starting from Example 27 by analogous reaction sequence as described in Example 18.

LC-MS (Method 3): R _t = 2.80 min; m / z = 413.2 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSOd ₆ ): δ = 7.40-7.56 (m, 3H), 7.53 (d, 2H), 7.70 (d, IH), 7.86-8.02 (m, 3H), 9.26 (s, IH).

Example 29

2- (4-chloro-3-methylphenyl) -4- (2-chlorophenoxy) -pyrimidin-5-carboxylate

According to General Method 2, 99.15 mg (0.8 mmol) of 2-chlorophenol, 200.0 mg (0.6 mmol) of the compound from Example 13A and 177.66 mg (1.3 mmol) of potassium carbonate are reacted.

Yield: 223 mg (86% of theory)

LC-MS (Method 1): R _t = 3.23 min; m / z = 403.1 [M + H] ⁺ . ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.36 (t, 3H), 2.35 (s, 3H), 4.40 (q, 2H), 7.40-7.58 (m, 4H), 7.71 (d, IH), 7.88 (d, IH), 7.96 (d, IH), 9.24 (s, IH).

Example 30

2- (4-chloro-3-methylphenyl) -4- (2-chlorophenoxy) -pyrimidin-5-carboxylic acid

The preparation of the title compound is carried out starting from Example 29 by analogous reaction sequence as described in Example 18.

LC-MS (Method 3): R _t = 2.82 min; m / z = 374.9 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 2.35 (s, 3H), 7.40-7.55 (m, 4H), 7.70 (d, IH), 7.86 (d, IH), 7.95 (s, IH), 9.20 (s, IH).

Example 31

4- (2-chlorophenoxy) -2- (3,4-dimethylphenyl) -pyrimidine-5-carboxylic acid ethyl ester

According to General Method 2, 106.12 mg (0.8 mmol) of 2-chlorophenol, 200.0 mg (0.7 mmol) of the compound from Example 16A and 190.14 mg (1.4 mmol) of potassium carbonate are reacted.

Yield: 229 mg (87% of theory)

LC-MS (Method 3): R _t = 3.27 min; m / z = 383.3 [M + H] ⁺ .

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.35 (t, 3H), 2.20 (s, 3H), 2.25 (s, 3H), 4.39 (q, 2H), 7.20 (d, IH) , 7.39-7.56 (m, 3H), 7.67-7.74 (m, 2H), 7.86 (s, IH), 9.20 (s, IH).

Example 32

4- (2-chlorophenoxy) -2- (3,4-dimethylphenyl) -pyrimidine-5-carboxylic acid

The preparation of the title compound is carried out starting from Example 31 by analogous reaction sequence as described in Example 18.

LC-MS (Method 3): R _t = 2.67 min; m / z = 355.2 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 2.20 (s, 3H), 2.24 (s, 3H), 7.19 (d, IH), 7.38-7.59 (m, 3H), 7.69 (d, 2H), 7.85 (s, IH), 9.16 (s, IH).

Example 33

4- (2-Chlθφhenoxy) -2- (2-fluorophenyl) pyrimidine-5-carboxylic acid

¹ H-NMR (300 MHz, DMSOd ₆ ): δ = 7.22-7.31 (m, 2H), 7.32-7.41 (m, IH), 7.42-7.49 (m, 2H), 7.50-7.59 (m, IH), 7.54 (d, IH), 7.77-7.87 (m, IH), 9.21 (s, IH), ca. 13.58 (brs s, IH).

HPLC (Method 7): R ₁ = 4.44 min.

MS (DCI): m / z = 345.1 [M + H] ⁺ .

Example 34

4- (2,4-dimethylphenoxy) -2-phenylpyrimidine-5-carboxylic acid

The title compound is prepared according to General Method 3.

LC-MS (Method 10): R _t = 2.31 min; m / z = 320.1 [M] ⁺

Example 35

4- (2,4-dichloro-3,5-dimethylphenoxy) -2-phenylpyrimidine-5-carboxylic acid

The title compound is prepared according to General Method 3.

LC-MS (Method 10): R _t = 2.49 min; m / z = 388.0 [M] ⁺

Example 36

4- (2,3-dichlorophenoxy) -2-phenylpyrimidine-5-carboxylic acid

The title compound is prepared according to General Method 3.

LC-MS (Method 10): R _t = 2.31 min; m / z = 360.0 [M] ⁴

Example 37

4- (2,5-fluorophenoxy) -2-phenylpyrimidine-5-carboxylic acid

The title compound is prepared according to General Method 3.

LC-MS (Method 10): R _t = 2.21 min; m / z = 328.0 [M] ⁺ .

Example 38

4- (2-chloro-4-methoxyphenoxy) -2-phenylpyrimidine-5-carboxylic acid

The title compound is prepared according to General Method 3.

LC-MS (Method 10): R _t = 2.19 min; m / z = 356.0 [M] ⁺ .

Example 39

4- (2-cyanophenoxy) -2-phenyl-pyrimidine-5-carboxylic acid ethyl ester

According to General Method 2, 54.42 mg (0.5 mmol) of 2-hydroxybenzonitrile, 100.0 mg (0.4 mmol) of the compound from Example 2A and 105.22 mg (0.8 mmol) of potassium carbonate are reacted.

Yield: 124 mg (94% of theory)

LC-MS (Method 2): R ₄ = 2.80 min; m / z = 346.0 [M + Hf.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.36 (t, 3H), 4.41 (q, 2H), 7.52 (m, 2H), 7.53-7.62 (m, 2H), 7.66 (d, IH), 7.87-7.94 (m, IH), 8.04-8.12 (m, 3H), 9.29 (s, IH).

Example 40

4- (2-cyanophenoxy) -2-phenyl-pyrimidine-5-carboxylic acid

The preparation of the title compound is carried out starting from Example 39 by an analogous reaction sequence as described in Example 18.

LC-MS (Method 2): R _t = 2.25 min; m / z = 318.1 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 7.44-7.50 (m, 2H), 7.52-7.56 (m, 3H), 7.87-7.93 (m, IH), 8.04-8.09 (m, 3H), 9.27 (s, IH). Example 41

4- (5-cyano-2-methylphenoxy) -2-phenylpyrimidine-5-carboxylate

According to General Method 2, 76.03 mg (0.6 mmol) of 3-hydroxy-4-methylbenzonitrile, 150.0 mg (0.6 mmol) of the compound from Example 2A and 157.83 mg (1.1 mmol) of potassium carbonate are reacted.

Yield: 180 mg (88% of theory)

LC-MS (method 2): R _t = 2.97 min; m / z = 360.1 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 1.36 (t, 3H), 2.24 (s, 3H), 4.40 (q, 2H), 7.44-7.58 (m, 3H), 7.65 (d, IH) , 7.78 (d, IH), 7.90 (s, IH), 8.06 (d, 2H), 9.23 (s, IH).

Example 42

4- (5-cyano-2-methylphenoxy) -2-phenylpyrimidine-5-carboxylic acid

The title compound is prepared starting from Example 41 by an analogous reaction sequence as described in Example 18.

LC-MS (Method 3): R _t = 2.31 min; m / z = 332.2 [M + H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 2.24 (s, 3H), 7.43-7.57 (m, 3H), 7.64 (d, IH), 7.77 (d, IH), 7.88 (s, IH), 8.04 (d, 2H), 9.22 (s, IH).

Example 43

4- (2-chlorophenoxy) -2- (4-methyl-3-nitrophenyl) pyrimidm-5-carboxylate

According to General Method 2, 513.08 mg (4.0 mmol) of 2-chlorophenol, 1.07 g (3.3 mmol) of the compound from Example 2OA and 919.30 mg (6.65 mmol) of potassium carbonate are reacted.

Yield: 1.02 g (74% of theory)

LC-MS (Method 2): R _t = 3.18 min; m / z - 414.1 [M + H] ⁺ .

Example 44

4- (2-chlorophenoxy) -2- (4-methyl-3-nitrophenyl) pyrimidine-5-carboxylic acid

The preparation of the title compound is carried out starting from Example 43 by analogous reaction sequence as described in Example 18. 02054

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LC-MS (Method 1): R _t = 2.37 min; m / z = 386.1 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 2.56 (s, 3H), 7.41-7.48 (m, IH), 7.50-7.56 (m, 2H), 7.62 (d, IH), 7.70 (d, IH), 8.16 (dd, IH), 9.26 (s, IH).

Example 45

4- (2-chlorophenoxy) -2- (4-fluoro-3-methoxyphenyl) pyrimidine-5-carboxylate

According to General Method 2, 138.52 mg (1.1 mmol) of 2-chlorophenol, 279.0 mg (0.9 mmol) of the compound from Example 23A and 248.20 mg (1.8 mmol) of potassium carbonate are reacted.

Yield: 294 mg (81% of theory)

LC-MS (Method 3): R _t = 3.10 min; m / z = 403.2 [M + H] ⁺ .

Example 46

4- (2-chlorophenoxy) -2- (4-fluoro-3-methoxyphenyl) -pyrimidine-5-carboxylic acid

The title compound is prepared starting from Example 45 by an analogous reaction sequence as described in Example 18. 54

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LC-MS (Method 2): R ₁ = 2.52 min; m / z = 375.1 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 3.75 (s, 3H), 7.31 (dd, IH), 7.38-7.46 (m, IH), 7.48-7.55 (m, 2H), 7.58-7.65 ( m, IH), 7.70 (d, IH), 7.76 (dd, IH), 9.21 (s, IH).

Example 47

4- (2-chlorophenoxy) -2- (3,4,5-trifluorophenyl) pyrimidine-5-carboxylic acid ethyl ester

According to General Method 2, 70.64 mg (0.6 mmol) of 2-chlorophenol, 145.0 mg (0.5 mmol) of the compound from Example 26A and 126.57 mg (0.9 mmol) of potassium carbonate are reacted.

Yield: 84 mg (45% of theory)

LC-MS (Method 3): R _t = 3.31 min; m / z = 409.2 [M + H] ⁺ .

Example 48

4- (2-chlorophenoxy) -2- (3,4,5-trifluoφhenyl) -pyrimidine-5-carboxylic acid

54

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The preparation of the title compound is carried out starting from Example 47 by analogous reaction sequence as described in Example 18.

LC-MS (method 2): R _t = 2.79 min; m / z = 381.0 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 7.42-7.57 (m, 3H), 7.69-7.78 (m, 3H), 9.24 (s, IH).

Example 49

4- (2-chlorophenoxy) -2- (3,4-difluoφhenyl) pyrimidine-5-carboxylate

According to General Method 2, 1.53 g (11.9 mmol) of 2-chlorophenol, 2.96 g (9.9 mmol) of the compound from Example 29A and 2.74 g (19.8 mmol) of potassium carbonate are reacted.

Yield: 1.75 g (45% of theory)

LC-MS (Method 3): R ₁ = 3.20 min; m / z = 391.3 [M + H] ⁺ .

Example 50

4- (2-chlorophenoxy) -2- (3,4-difluorophenyl) pyrimidine-5-carboxylic acid

The preparation of the title compound is carried out starting from Example 49 by analogous reaction sequence as described in Example 18.

LC-MS (Method 3): R _t = 2.60 min; m / z = 363.1 [M + H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 7.41-7.45 (m, IH), 7.47-7.61 (m, 3H), 7.71 (dd, IH), 7.82-7.93 (m, 2H), 9.23 (s, IH).

Example 51

4- (2-chlorobenzyl) -2-phenylpyrimidine-5-carboxylate

400.0 mg (1.5 mmol) of the compound from Example 2A in 8 ml of DMF are mixed with 6.1 ml (ca. 3.0 mmol) of the bromine (2-chlorobenzyl) zinc solution in DMF from Example 30A and 87.98 mg (0.1 mmol) of tetrakis (triphenylphosphine ) Palladium and the mixture stirred overnight at room temperature. Purification by preparative RP-HPLC (YMC gel ODS-AQ S-I lμm column, eluent: water / acetonitrile, gradient 90:10 → 5:95) gives 444.0 mg (83% of theory) of the title compound.

LC-MS (Method 1): R _t = 3.09 min; m / z = 353.1 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.32 (t, 3H), 4.37 (q, 2H) ₃ 4.67 (s, 2H), 7.28-7.36 (m, 3H), 7.45-7.58 ( m, 4H), 8.24 (d, 2H), 9.25 (s, IH).

Example 52

4 ~ (2-chlorobenzyl) -2-phenylpyrimidm-5-carboxylic acid T / EP2006 / 002054

100.0 mg (0.3 mmol) of the compound from Example 51 in 2 ml of THF are mixed with 425.0 μL (0.4 mmol) of 1N sodium hydroxide solution. The solution is stirred overnight at room temperature and then concentrated. After acidification with 1 N hydrochloric acid, the solution is extracted twice with ethyl acetate. The combined organic phases are washed with 5 ml of saturated sodium chloride solution, dried on sodium sulfate and freed from the solvent under reduced pressure. 85 mg (92% of theory) of the title compound are obtained.

LC-MS (Method 2): R _t = 2.68 min; m / z = 325.2 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 4.71 (s, 2H), 7.30-7.35 (m, 3H), 7.45-7.56 (m, 4H), 8.23 (d, 2H), 9.25 ( s, IH).

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B. Evaluation of Pharmacological Activity

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

1. Cellular Transactivation Assay:

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) after activation and binding of GAL4-PPARα.

c) Transactivation Assay (Luciferase Reporter):

CHO (Chinese hamster ovary) cells are supplemented in DMEM / F12 medium (BioWhittaker) supplemented with 10% fetal calf serum, 1% penicillin / streptomycin (GIBCO), with a cell density of 2 × 10 ³ cells per well in one Seeded 384 well plate (Greiner). After culturing for 48 h at 37 ° C, the cells are stimulated. For this, the substances to be tested are taken up in CHO-A-SFM medium (GlBCO) supplemented with 10% fetal calf serum, 1% penicillin / streptomycin (GIBCO) and added to the cells. After a stimulation time of 24 hours, luciferase activity is measured using a video camera. The measured relative light units give a sigmoide depending on the substance concentration 002054

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Stimulation curve. The EC ₅₀ values are calculated using the computer program GraphPad PRISM (version 3.02).

The compounds according to the invention show EC ₅₀ values of 5 μM to 10 nM in this test.

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. 17, 237-46 (1957)] by measuring the thrombin time with human fibrinogen as a standard.

3. Test description for the discovery of pharmacologically active substances which increase the apoprotein Al (ApoAl) and the HDL cholesterol ( ^" HDL-C) in the serum of transgenic mice transfected with the human ApoAl gene ChApoAl), or 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 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 with a Cobas Integra 400 plus device (Cobas Integra, Fa. Roche Diagnostics GmbH, Mannheim) under 006/002054

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Use of 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. 41, 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 ,

C. Examples for 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 of the compound of the invention, 1000 mg of ethanol mg (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 correspond 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

A is CH ₂ or O,

R ^{1 is} halogen, cyano or (C 1 -C ₄ ) -alkyl,

R ^{2 represents} a substituent selected from the group consisting of halogen, cyano, (C ₁ -C ₆ ) -alkyl and (C ₁ -C ₆ ) -alkoxy, in which alkyl and alkoxy in turn may be mono- or polysubstituted by fluorine, or a group of Formula is -NR ⁷ -C (= O) -R ⁸ wherein

R ^{7 is} hydrogen or (C ₁ -C ₆ ) -alkyl

and

R ⁸ is hydrogen, (C _r _C6) alkyl or (C _r C ₆₎ alkoxy means,

stands for the number 0, 1, 2 or 3,

R ^{3 is} hydrogen, fluorine or chlorine,

R ^{4 is} hydrogen, halogen, nitro, cyano, amino, trifluoromethyl, (QC ^ -alkyl or (QC ^ -alkoxy), P2006 / 002054

- 84 -

R ⁵ and R ^{6 are} identical or different and independently of one another represent hydrogen, halogen, nitro, cyano, (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₆ ) -alkoxy, in which alkyl and alkoxy are in turn mono- or polysubstituted by fluorine may be substituted for amino, mono- or di- (Ci-C ₆ ) -alkylamino, a 4- to 7-membered, bonded via an N atom heterocycle or a group of the formula -NR ⁹ -C (= O ) -R ¹⁰ , in which

R ^{9 is} hydrogen or (C _r C ₆ ) -alkyl

and

R ^{1U is} hydrogen, (C _r C ₆ ) -alkyl or (C _r C ₆ ) -alkoxy,

and

is hydrogen or (C _r C ₄₎ -alkyl,

and their salts, solvates and solvates of the salts,

for the treatment and / or prophylaxis of diseases.

2. Compound of formula (I)

in which

A is CH ₂ or O,

R ^{1 is} halogen, cyano or (C _r C ₄ ) -alkyl,

R ^{2 is} a substituent selected from the group halogen, cyano, (C _r C ₆ ) alkyl and (C _r C ₆ ) alkoxy, wherein alkyl and alkoxy in turn one or more times with 006/002054

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Fluorine may be substituted or a group of the formula -NR ⁷ -C (= O) -R ^S , wherein

R ^{7 is} hydrogen or (C ₁ -C ₆ ) -alkyl

and

R ^{8 is} hydrogen, (C ₁ -Q) -alkyl or (C ₁ -C ₆ ) -alkoxy,

n is the number 0, 1, 2 or 3,

R ^{3 is} hydrogen, fluorine or chlorine,

R ^4, halogen, nitro, cyano, amino, trifluoromethyl, (C _r _C4) alkyl or (C _r C ₄₎ alkoxy stands for hydrogen,

R ⁵ and R ^{6 are} identical or different and independently of one another represent hydrogen, halogen, nitro, cyano, (C _r C ₆ ) -alkyl or (C _r Co) -alkoxy, in which alkyl and alkoxy in turn substitute one or more times with fluorine for amino, mono- or di- (C ₁ -C ₆ ) -alkylamino, a 4- to 7-membered, via an N-

Atom-bonded heterocycle or a group of the formula - NR ⁹ -C (= O) -R ¹⁰ , in which

R ^{9 is} hydrogen or (C _r C ₆ ) -alkyl

and

R ¹⁰ is hydrogen, (C _r _C6) alkyl or (C _r C ₆₎ alkoxy means,

and

Z is hydrogen or (C _r C ₄₎ -alkyl,

and their salts, solvates and solvates of the salts,

with the exception of the compounds 4- (2-methylphenoxy) -2-phenyl-pyrimidine-5-carboxylic acid ethyl ester, 4- (2-methylphenoxy) -2-phenyl-pyrimidine-5-carboxylic acid, 4- (2,3-dimethylphenoxy) - 2-phenylpyrimidine-5-carboxylic acid ethyl ester, 4- (2,3-dimethylphenoxy) -2-phenylpyri P2006 / 002054

- mid-5-carboxylic acid, 2-phenyl-4- (2,4,5-trichlorophenoxy) pyrimidine-5-carboxylic acid ethyl ester and 2-phenyl-4- (2,4,5-trichlorophenoxy) pyrimidine-5 carboxylic acid.

3. A compound of the formula (I) according to claim 2, in which

A is CH ₂ or O,

R ^{1 is} halogen, cyano or (Q-GO-alkyl,

R ² represents a substituent selected from the group halogen, cyano, (Ci-C ₄₎ -alkyl and (C _r C ₄₎ alkoxy, wherein alkyl and alkoxy may be in turn substituted one or more times by fluorine,

n is the number 0, 1, 2 or 3,

R ^{3 is} hydrogen, fluorine or chlorine,

R ⁴ is hydrogen, halogen, cyano, trifluoromethyl, (CrC ₄₎ alkyl or (C ₁ -C ₄₎ - alkoxy;

R ⁵ and R ^{6 are the} same or different and independently of one another represent hydrogen,

Halogen, nitro, cyano, (C _r C ₄ ) alkyl or (C _r C ₄ ) alkoxy, wherein alkyl and alkoxy in turn may be mono- or polysubstituted by fluorine, or amino, mono- or di- (C ₁ -C ₄ ) -alkylamino,

and

Z is hydrogen, methyl or ethyl,

and their salts, solvates and solvates of the salts.

4. A compound of formula (I) according to claim 2 or 3, in which

A stands for O,

R ^{1 is} fluorine, chlorine, bromine, cyano or methyl, 02054

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R ² represents a substituent selected from the group of fluorine, chlorine, bromine, cyano, (C _r _C4) alkyl, trifluoromethyl, (C _r C ₄₎ is alkoxy and trifluoromethoxy,

n is the number 0, 1, 2 or 3,

R ^{3 is} hydrogen or fluorine,

R ^{4 is} hydrogen, fluorine, chlorine, trifluoromethyl or methyl,

R, fluorine, chlorine, bromine, nitro, cyano, (C _r C ₄₎ are alkyl, trifluoromethyl, (C _r _C4) alkoxy, trifluoromethoxy or amino ⁵ and R ⁶ are identical or different and are each independently hydrogen,

and

stands for hydrogen,

where at least one of the radicals R, R, R and R is different from hydrogen,

and their salts, solvates and solvates of the salts.

Process for the preparation of a compound of the formula (I) as defined in claims 1 to 4, in which A is O, characterized in that compounds of the formula (II)

in which R ³ , R ⁴ , R ⁵ and R ⁶ each have the meanings given in claims 1 to 4 and

Z ¹ for (C _r C ₄ ) -alkyl

and X represents a suitable leaving group, for example halogen, in particular chlorine,

in an inert solvent in the presence of a base with a compound of formula m

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

to compounds of the formula (I-A)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Z ¹ and n each have the meanings given above,

and these by basic or acidic hydrolysis into the carboxylic acids of the formula (IB)

and the compounds of the formula (I-A) or (I-B), if appropriate, with the corresponding (i) solvents and / or (ii) bases or acids to give their solvates, salts and / or

Solvates of the salts.

A process for the preparation of a compound of formula (I) as defined in claims 1 to 3 in which A is CH ₂ , characterized in that either

[A] Compounds of the formula (VIH)

in which R ¹ , R ² and n each have the meanings given in claims 1 to 3 and

Z ^{1 is} (Ci-GO-alkyl,

with a compound of the formula (IX)

to compounds of the formula (X)

in which R, R, n and Z each have the meanings given above,

in which R ³ , R ⁴ , R ⁵ and R ⁶ each have the meanings given in claims 1 to 3,

to compounds of the formula (I-C)

or

[B] Compounds of the formula (XI)

in which R ¹ , R ² and n each have the meanings given in claims 1 to 3,

into the zinc-organic compounds of the formula (Xu)

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

überfuhrt and then in an inert solvent in the presence of a suitable palladium catalyst with a compound of formula (IT)

in which R ³ , R ⁴ , R ⁵ and R ^δ each have the meanings given in claims 1 to 3 and

Z ^{1 is} (C ¹ -C ₄ ) -alkyl

and

to compounds of the formula (IC) 006/002054

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A compound as defined in any one of claims 2 to 4 for the treatment and / or prophylaxis of diseases.

Use of a compound as defined in any one of claims 1 to 4 for the manufacture of a medicament for the treatment and / or prevention of dyslipidaemias and arteriosclerosis. 9. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 4, in combination with an inert, non-toxic, pharmaceutically suitable excipient.

10. A medicament containing a compound as defined in any one of claims 1 to 4, in combination with another active ingredient selected from the group consisting of CETP inhibitors, HMG-CoA reductase inhibitors, squalene synthesis inhibitors,

ACAT inhibitors, cholesterol absorption inhibitors, MTP inhibitors, fibrates, niacin, lipase inhibitors, PPAR-γ and / or PPAR-δ agonists, thyroid hormones and / or thyroid mimetics, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, antioxidants, cannabinoid Receptor 1 antagonists, insulin and insulin derivatives, anti-diabetics, calcium antagonists, angiotensin AII antagonists, ACE inhibitors, beta

Receptor blockers, alpha-receptor blockers, diuretics, platelet aggregation inhibitors and anticoagulants.

11. Medicament according to claim 9 or 10 for the treatment and / or prevention of dyslipidemia and arteriosclerosis.

12. A method for the treatment and / or prevention of dyslipidaemias and arteriosclerosis in humans and animals by administering an effective amount of at least one compound as defined in any one of claims 1 to 4, or a pharmaceutical composition as defined in any one of claims 9 to 11.