SK104099A3 - 2-amino substituted pyridines for use in the treatment of arteriosclerosis and hyperlipoproteinaemia - Google Patents

Abstract

The invention relates to novel 2-amino-substituted pyridines which are produced by first converting corresponding pyridine aldehydes into the corresponding hydroxides by means of metal-organic compounds such as Grignard compounds, and then reducing said hydroxides to a deshydroxy compound. The novel 2-amino-substituted pyridines are suitable for use as active ingredients in medicaments, particularly those used in the treatment of arteriosclerosis

Description

The invention relates to novel 2-amino-substituted pyridines, to a process for their preparation, to pharmaceutical compositions containing them and to their use in medicaments.

BACKGROUND OF THE INVENTION

US 5 169 857 A2 discloses 7- (polysubstituted pyridyl) -6-heptenoates for the treatment of arteriosclerosis, lipoproteinemia and hyperlipoproteinemia. In addition, the preparation of 7- (4-aryl-3-pyridyl) -3,5-dihydroxy-6-heptenoates is described in EP 325 130 A2.

SUMMARY OF THE INVENTION

The present invention provides 2-amino-substituted pyridines of formula I

A

(I)

31259 / H wherein

A represents an aryl group having 6 to 10 carbon atoms which is optionally substituted up to five times equally or differently by a halogen atom, a hydroxy group, a trifluoromethyl group, a trifluoromethoxy group, a nitro group or a straight or branched alkyl, acyl, hydroxyalkyl or alkoxy group having up to 7 carbon atoms; a group of formula -NR ⁴ R ⁵ , wherein

R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a phenyl group or a straight or branched alkyl group of up to 6 carbon atoms,

D represents an aryl group having 6 to 10 carbon atoms, which is optionally substituted by nitro, halogen, trifluoromethyl or trifluoromethoxy, or is a radical of formula

while

R ⁶ and R ⁷ are the same or different and represent a cycloalkyl group having 3 to 6 carbon atoms or an aryl group having 6 to 10 carbon atoms or a 5- to 7-membered aromatic, optionally benzocondensed, saturated or unsaturated, monocyclic, bicyclic or tricyclic heterocycle of up to 4 heteroatoms from the group consisting of sulfur, nitrogen and / or oxygen atoms, wherein the cyclenes, in the case of nitrogen-containing rings also via N-function, are up to five times equally or differently substituted by halogen, trifluoromethyl, trifluoromethoxy, hydroxy, nitro, carboxyl, cyano , straight or branched alkyl, acyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl of up to 6 carbon atoms or aryl of 6 to 10 carbon atoms, or an optionally benzocondensed aromatic 5- to 7-membered het erocycle with up to 3 heteroatoms selected from the group consisting of sulfur, nitrogen and / or oxygen, and / or substituted by a group of the formula -OR ¹⁰ , -SR ¹¹ , -SO ² R ^12, or

-NR ¹³ R ¹⁴ , wherein

31259 / H

R ¹⁰ , R ¹¹ and R ¹² are the same or different and represent an aryl group having 6 to 10 carbon atoms, which itself is up to two times the same or differently substituted by a phenyl group, a halogen atom or a straight or branched alkyl group having up to 4 carbon atoms;

R ¹³ and R ¹⁴ are the same or different and have the meanings given above for R ⁴ and R ⁵ , or

R ⁶ or R ⁷ represents a radical of the formula

L represents a straight or branched chain alkyl or alkenyl chain of from 2 to 10 carbon atoms each optionally substituted up to two times with hydroxy,

R ⁸ represents a hydrogen atom or a halogen atom and

R ⁹ represents a hydrogen atom, a halogen atom, an azido group, a trifluoromethyl group, a hydroxy group, a trifluoromethoxy group, a straight or branched alkoxy group of up to 5 carbon atoms or a radical of the formula -NR ¹⁵ R ¹⁶ , wherein

R ¹⁵ and R ¹⁶ are the same or different and have the meanings given above for R ⁴ and R ⁵ , or

R ⁸ and R ⁹ together form the radical = O or = NR ¹⁷ , wherein

R ¹⁷ represents a hydrogen atom or a straight or branched alkyl, alkoxy or acyl group each having up to 6 carbon atoms,

31259 / H

E represents a cycloalkyl group having from 3 to 8 carbon atoms or a straight or branched alkyl group having up to 8 carbon atoms which is optionally substituted by a cycloalkyl group having 3 to 8 carbon atoms or a hydroxy group or a phenyl group optionally substituted by a halogen atom or a trifluoromethyl group .

R ¹ represents a straight or branched alkyl group having up to 6 carbon atoms which is substituted by a hydroxy group and

R ² and R ³ are the same or different and represent a hydrogen atom, a phenyl group, a benzyl group, a cycloalkyl group of 3 to 7 carbon atoms, a straight or branched alkyl or acyl group of up to 6 carbon atoms or a group of the formula -CO-NR ¹⁸ R ¹⁹ , whereby

R ¹⁸ and R ¹⁹ are the same or different and represent a hydrogen atom, a phenyl group, a benzyl group or a straight or branched alkyl group having up to 6 carbon atoms, or

R ² and R ³ together with the nitrogen atom form a 5- to 7-membered, saturated, partially unsaturated or unsaturated, optionally benzocondensed, monocyclic or bicyclic heterocycle with up to 4 heteroatoms selected from the group consisting of sulfur, nitrogen and / or oxygen, optionally up to three times the same or variously substituted by nitro, cyano, halogen, trifluoromethyl, hydroxy, carboxy, straight or branched alkoxy or alkoxycarbonyl of up to 5 carbon atoms, phenyl or straight or branched alkyl of up to 5 carbon atoms, which may itself be substituted and / or the heterocycle is substituted with a group of the formula -NR ²⁰ R ²¹ , wherein

R ²⁰ and R ²¹ have the meanings given above for R ¹⁸ and R ¹⁹ and are the same or different with them,

31259 / H and their salts.

The 2-amino-substituted pyridines of the present invention may also exist in the form of their salts. In general, salts with organic or inorganic bases or acids can be mentioned.

Physiologically acceptable salts are preferred within the scope of the present invention. Physiologically acceptable salts are salts of the compounds of the present invention with inorganic, carboxylic or sulfonic acids. Particularly preferred are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as acetic acid, maleic acid, fumaric acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

Physiologically acceptable salts may also be metal salts or ammonium salts of the compounds of the present invention having a free carboxyl group. Particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, as well as ammonium salts derived from ammonia or organic amines, such as ethylamine, diethylamine, triethylamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine 2-phenylethylamine.

The compounds of the present invention exist in stereoisomeric forms which behave either as image and mirror image (enantiomers) or not as image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to the corresponding mixtures thereof. These mixtures of enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents by known methods.

Heterocycle, optionally benzocondensed, is generally saturated or unsaturated, 5- to 7-membered, preferably 5- to 6-membered, heterocycle, which may contain up to 3

31259 / H heteroatoms selected from the group consisting of sulfur, nitrogen and / or oxygen. For example, indolyl, isoquinolyl, quinolyl, benzo [b] thiophenyl, benzothiazolyl, benzo [b] furanyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl may be mentioned. Quinolyl, pyridyl, furyl, thienyl or morpholinyl are preferred.

Preferred are compounds of formula I wherein:

A represents a naphthyl or phenyl group, which is optionally up to three times the same or differently substituted by a fluorine, chlorine or bromine atom, a hydroxy group, a trifluoromethyl group, a nitro group, a trifluoromethoxy group or a straight or branched alkyl, acyl or alkoxy group each having up to 6 carbon atoms or group of formula -NR ⁴ R ⁵ , wherein

R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a phenyl group or a straight or branched alkyl group having up to 4 carbon atoms,

D represents a phenyl group which is optionally substituted by a nitro group, a fluorine, chlorine or bromine atom, a trifluoromethyl group or a trifluoromethoxy group, or represents a radical of the formula

R ⁶ -Lalebo

while

R ⁶ and R ⁷ are the same or different and are cyclopropyl, cyclopentyl or cyclohexyl,

31259 / H or phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2-yl, quinolyl or purin-8-yl, wherein the cyclenes, in the case of nitrogen-containing rings, also via the N-function, are optionally substituted up to three times equally or differently with fluorine, chlorine or bromine, trifluoromethyl, trifluoromethoxy, hydroxy, cyano, carboxyl , straight or branched alkyl, acyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl of up to 4 carbon atoms or triazolyl, tetrazolyl, benzoxathiazolyl or phenyl, and / or substituted by -OR ¹⁰ , -SR ¹¹ or -SO ² R ¹² wherein

R ¹⁰ , R ¹¹ and R ¹² are the same or different and represent a phenyl group which itself is up to two times the same or differently substituted by a phenyl group, a fluorine or chlorine atom, or a straight or branched alkyl group having up to 4 carbon atoms, or

R ⁶ or R ⁷ represents a radical of the formula

L is a straight or branched alkyl or alkenyl group having from 2 to 8 carbon atoms each optionally substituted up to two times with hydroxy,

R ⁸ represents a hydrogen atom or a fluorine, chlorine or bromine atom;

R ⁹ represents a hydrogen atom, a fluorine, chlorine or bromine atom, an azido group, a trifluoromethyl group, a hydroxy group, a trifluoromethoxy group,

31259 / H straight or branched alkoxy of up to 4 carbon atoms or a radical of the formula -NR ^1S R ¹⁶ , wherein

R ¹⁵ and R ¹⁶ are the same or different and have the meanings given above for R ⁴ and R ⁵ , or

R ⁸ and R ⁹ together form the radical = O or = NR ¹⁷ , wherein

R ¹⁷ represents a hydrogen atom or a straight or branched alkyl, alkoxy or acyl group of up to 4 carbon atoms in each case,

E represents a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group, or a straight or branched alkyl group having up to 6 carbon atoms optionally substituted by a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group or cycloheptyl group or a phenyl group optionally substituted by a fluorine or chlorine atom or a trifluoromethyl group,

R ¹ represents a straight or branched alkyl group having up to 5 carbon atoms which is substituted by a hydroxy group; and

R ² and R ³ are identical or different and denote hydrogen, phenyl, benzyl, cyclopropyl, cyclopentyl, cyclohexyl, straight-chain or branched alkyl or acyl having up to 5 carbon atoms or a group -CO-NR ¹⁸ R ¹⁹ , whereby

R ¹⁸ and R ¹⁹ are the same or different and represent a hydrogen atom, a phenyl group, a benzyl group or a straight or branched alkyl group of up to 5 carbon atoms, or

31259 / H

R ² and R ³ together with the nitrogen atom form a pyryl, imidazolyl, pyrrolidinyl, morpholine, piperidinyl or piperazinyl ring or a radical of formula

wherein the heterocyclenes are optionally substituted with hydroxy, trifluoromethyl, fluoro, chloro or bromo, methylhydroxy, carboxy, or straight or branched alkoxy or alkoxycarbonyl of up to 4 carbon atoms, and salts thereof.

Particularly preferred are compounds of formula I in which

A represents a naphthyl or phenyl group optionally substituted by a fluorine, chlorine or bromine atom, a hydroxy group, a trifluoromethyl group, a nitro group, a trifluoromethoxy group or a straight or branched alkyl, acyl or alkoxy group each having up to 5 carbon atoms or -NR ⁴ R ⁵ , whereby

R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a phenyl group or a straight or branched alkyl group having up to 3 carbon atoms,

D represents a phenyl group which is optionally substituted by a nitro group, a fluorine, chlorine or bromine atom, or represents a radical of the formula

31259 / H

while

R ⁶ and R ⁷ are the same or different and are cyclopropyl, cyclopentyl or cyclohexyl, or phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl, imidazolyl, imidazolyl , benzothiazolyl, phenoxathin-2-yl, benzoxazolyl, furyl, quinolyl or purin-8-yl, wherein the cyclenes, in the case of nitrogen-containing rings also via the N-function, may optionally be up to three times the same or differently substituted by an atom fluorine or chlorine, trifluoromethyl, trifluoromethoxy, hydroxy, cyano, carboxyl, straight or branched alkyl, acyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl of up to 3 carbon atoms or triazolyl, tetrazolyl another, a benzoxathiazolyl group or a phenyl group, and / or are substituted by a group of the formula -OR ¹⁰ , -SR ¹¹ or -SO ² R ¹² wherein:

R ¹⁰ , R ¹¹ and R ¹² are the same or different and represent a phenyl group which itself is up to two times the same or differently substituted by a phenyl group, a fluorine or chlorine atom, or a straight or branched alkyl group having up to 3 carbon atoms, or

R ⁶ or R ⁷ represents a radical of the formula

31259 / H

L represents a straight or branched alkyl or alkenyl group having in each case up to 8 carbon atoms optionally substituted up to two times by hydroxy,

R ⁸ represents a hydrogen atom or a fluorine atom and

R ⁹ represents a hydrogen atom, a fluorine, chlorine or bromine atom, an azido group, a trifluoromethyl group, a hydroxy group, a trifluoromethoxy group, a methoxy group or a radical of the formula -NR ¹⁵ R ¹⁶ , wherein:

R ¹⁵ and R ¹⁶ are the same or different and have the meanings given above for R ⁴ and R ⁵ , or

R ⁸ and R ⁹ together form the radical = O or = NR ¹⁷ , wherein

R ¹⁷ represents a hydrogen atom or a straight or branched alkyl, alkoxy or acyl group each having up to 3 carbon atoms,

E represents a cyclopropyl group, a cyclopentyl group, a cyclohexyl group or a phenyl group optionally substituted by a fluorine atom or a trifluoromethyl group, or a straight or branched alkyl group having up to 4 carbon atoms optionally substituted by a hydroxy group,

R ¹ represents a straight or branched alkyl group having up to 4 carbon atoms which is substituted by a hydroxy group and

R ² and R ³ are identical or different and denote hydrogen, phenyl, benzyl, cyclopropyl, cyclopentyl or straight-chain or branched alkyl or acyl having up to 5 carbon atoms or a group -CO-NR ¹⁸ R ^19, while

31259 / H

R ¹⁸ and R ¹⁹ are the same or different and represent a hydrogen atom, a phenyl group, a benzyl group or a straight or branched alkyl group of up to 4 carbon atoms, or

R ² and R ³ together with the nitrogen atom form a pyryl, pyrrolidinyl, morpholine or piperidinyl ring or a radical of formula

wherein the heterocyclenes are optionally substituted with hydroxy, trifluoromethyl, fluorine, chlorine or bromine, hydroxy, methylhydroxy, carboxy or a straight or branched alkoxy or alkoxycarbonyl of up to 3 carbon atoms, and salts thereof.

The present invention further provides a process for the preparation of the compounds of the formula I according to the invention, which comprises:

A) to compounds of formula II

31259 / H in which A, E, R ² and R ³ as defined above, and

R ²² is as defined above for R ¹ , wherein the hydroxyfunctions occur in protected form, preferably by tetrahydropyranyl, firstly, in the sense of the Grignard / Wittig reaction, residue D is introduced, optionally at this stage the substituents are known by preferential methods, preferably reduction, In this step, the hydroxy protecting group is cleaved, or is removed

B) compounds of formula III

in which A, D, E, R ² and R ³ as defined above, and

R ²³ represents an alkyl group having 1 to 4 carbon atoms, converted by oxidation to compounds of formula IV

A

wherein A, D, E, R ² , R ³ and R ^{23 are} as defined above, optionally the D substituents are changed at this stage and then the alkoxycarbonyl groups are reduced to hydroxymethyl functions by conventional methods under argon, and optionally all substituents they are changed and / or introduced using conventional methods.

The process of the invention can be represented as _{AJ by the following equation:

31259 / H

Suitable solvents for the process are ethers such as diethyl ether, dioxane, tetrahydrofuran and glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloromethane , trichlorethylene or chlorobenzene or ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Toluene and tetrahydrofuran are preferred.

31259 / H

Suitable bases for the individual steps are the usual strongly basic compounds. These preferably include organolithium compounds such as n-butyl lithium, sec-butyl lithium, tert-butyl lithium or phenyl lithium or amides such as lithium diisopropylamide, sodium amide or potassium amide, furthermore lithium hexamethylsilylamide or alkali metal hydrides such as sodium hydride or potassium hydride. Particular preference is given to n-butyllithium, sodium hydride or lithium diisopropylamide.

Suitable organometallic reagents are, for example, systems such as Mg / bromobenzotrifluoride and p-trifluoromethylphenyl lithium.

Conventional reagents are suitable as Wittig reagents. 3-Trifluoromethylbenzyltriphenylphosphonium bromide is preferred.

Suitable bases are in general the abovementioned bases, preferably sodium amide.

The bases are used in an amount of 0.1 mol to 5 mol, preferably 0.5 mol to 2 mol, in each case based on one mol of the starting compound.

The reaction with the Wittig reagents is generally carried out at a temperature in the range of 0 ° C to 150 ° C, preferably 25 ° C to 40 ° C.

The Wittig reaction is generally carried out under normal pressure, but it is also possible to operate under reduced or elevated pressure, for example in the range of 0.5 to 5 bar.

Suitable solvents for the oxidation of process (B) are ethers such as diethyl ether, dioxane, tetrahydrofuran and glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichlorethylene or chlorobenzene or ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, nitromethane or water. It is also possible to use mixtures of the solvents mentioned. Acetonitrile and water are preferred.

31259 / H

Suitable oxidizing agents are, for example, cerium ammonium nitrate, 2,3-dichloro-5,6-dicyanobenzoquinone, pyridinium chlorochromate (PCC), osmium tetroxide and manganese dioxide. Cerium ammonium nitrate is preferred.

The oxidizing agent is used in an amount of 1 mol to 10 mol, preferably 2 mol to 5 mol, based on 1 mol of the compound of the general formula (IV).

The oxidation is generally carried out at a temperature in the range of -50 ° C to 100 ° C, preferably 0 ° C to room temperature.

The oxidation is generally carried out under normal pressure, but it is also possible to work under reduced or elevated pressure.

The reductions are generally carried out using conventional reducing agents, preferably those suitable for the reduction of ketones to hydroxy compounds. Particularly suitable in this connection is reduction with metal hydrides or complex metal hydrides in inert solvents, optionally in the presence of a trialkyl borate. Reduction with complex metal hydrides such as lithium borate, sodium borate, potassium borate, zinc borate, lithium trialkyl borohydride or lithium aluminum hydride or diisobutylaluminum hydride (DIBAH) is preferred. Particular preference is given to reduction with sodium borohydride or diisobutylaluminium hydride in the presence of triethyl borate.

The reducing agent is generally used in an amount of 4 mol to 10 mol, preferably 4 mol to 5 mol, based on 1 mol of the reduced compound.

The reduction is generally carried out at a temperature in the range of -78 ° C to 50 ° C, preferably -78 ° C to 0 ° C, particularly preferably -78 ° C, depending on the choice of reducing agent and solvent.

The reduction is generally carried out at normal pressure, but it is also possible to work at elevated or reduced pressure.

The reduction is generally carried out using conventional reducing agents, preferably those suitable for reducing ketones to hydroxy compounds. Particularly suitable here is the reduction by means of metal hydrides or complex metal hydrides in inert solvents or

31259 / H presence of trialkylborane. Reduction with complex metal hydrides such as lithium borate, sodium borate, potassium borate, zinc borate, lithium trialkyl borohydride, diisobutylaluminum hydride or lithium aluminum hydride is preferred. Particularly preferred is the reduction with sodium borohydride or diisobutylaluminium hydride.

The reducing agent is generally used in an amount of 1 mol to 6 mol, preferably 1 mol to 4 mol, based on 1 mol of the reduced compound.

The reduction is generally carried out at a temperature in the range of -78 ° C to 50 ° C, preferably -78 ° C to 0 ° C, in the case of DIBAH 0 ° C, room temperature in the case of NaBH ₄ .

The reduction is generally carried out at normal pressure, but it is also possible to work at elevated or reduced pressure.

The deprotection is generally carried out in one of the abovementioned alcohols and tetrahydrofuran, preferably in a mixture of methanol and tetrahydrofuran, in the presence of hydrochloric or p-toluenesulfonic acid in methanol, at a temperature between 0 ° C and 50 ° C, preferably at room temperature. at normal pressure.

Derivatization reactions include the following types of reactions: reduction, hydrogenation, halogenation, Wittig / Grignard reaction, alkylation and amidation.

Suitable bases for the individual steps are the usual strongly basic compounds. These preferably include organolithium compounds such as n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium or amides such as lithium diisopropylamide, sodium amide or potassium amide, furthermore lithium hexamethylsilylamide or alkali metal hydrides such as sodium hydride or potassium hydride. Particular preference is given to n-butyllithium, sodium hydride or lithium diisopropylamide.

In addition, customary inorganic bases are suitable as bases. These preferably include alkali metal or alkaline earth metal hydroxides such as

31259 / H is, for example, sodium hydroxide, potassium hydroxide or barium hydroxide or alkali metal carbonates such as sodium carbonate, potassium carbonate or sodium bicarbonate. Sodium hydroxide or potassium hydroxide is particularly preferred.

Suitable solvents for the individual reaction steps are also alcohols, such as, for example, methanol, ethyl alcohol, propyl alcohol, butyl alcohol or tert-butyl alcohol. Tert-Butyl alcohol is preferred.

Alternatively, some reaction steps need to be carried out under a shielding gas atmosphere.

The halogenation is generally carried out in one of the abovementioned chlorinated hydrocarbons or in toluene.

Suitable halogenating agents are, for example, dimethylamino-sulfur trifluoride (DAST) or SOCl _second

The halogenation is generally carried out at a temperature in the range of -78 ° C to 50 ° C, preferably -78 ° C to 0 ° C.

Halogenation is generally carried out at normal pressure, but it is also possible to work at elevated or reduced pressure.

Suitable solvents for amidation are inert organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether or tetrahydrofuran, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane and petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, trichloroethane, trichloroethane, trichloroethane, tetrachloroethane, dichloroethylene or trichloroethylene, furthermore nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric triamide. It is also possible to use mixtures of the solvents mentioned. Dichloromethane, tetrahydrofuran, acetone or dimethylformamide is particularly preferred.

Suitable bases for amidation are generally the customary inorganic or organic bases. These preferably include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, hydroxide

31259 / H potassium or barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate or sodium bicarbonate, alkaline earth metal carbonates such as calcium carbonate, alkali metal or alkaline earth metal alcoholates such as sodium and potassium ethanolate, methanolate sodium and potassium or potassium tert-butylate or organic amines (trialkyl- (C 1 -C 6) amines) such as triethylamine or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [ 5.4.0] undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. However, it is also possible to use alkali metals such as sodium or their hydrides such as sodium hydride as bases. Sodium or potassium carbonate and triethylamine are particularly preferred.

The base is used in an amount of 1 mol to 5 mol, preferably 1 mol to 3 mol, based on 1 mol of the amidated compound.

The amidation is generally carried out at a temperature in the range of 0 ° C to 150 ° C, preferably 20 ° C to 110 ° C.

The amidation can be carried out at normal, elevated or reduced pressure, for example in the range of 0.05 to 0.5 MPa, usually at normal pressure.

Suitable solvents for the alkylation are customary organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran and glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene chlorobenzene or ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Dimethylformamide is preferred.

The alkylation is carried out in one of the abovementioned solvents at a temperature ranging from 0 ° C to 150 ° C, preferably room temperature to 100 ° C.

The reduction is carried out by one of the above methods.

31259 / H

The compounds of formula (II) are partly known or novel and can then be prepared, for example, by reacting compounds of formula (V)

wherein A and E are as defined above and

R ²⁴ and R ²⁵ are the same or different and are C 1 -C 4 alkyl, first reacted with amines of formula VI

HNR ² R ³ (VI), wherein R ² and R ^{3 are} as defined above, to compounds of formula VII

CO.R í

NRT?

(VII) in which A, E, R, R, R and R are as defined above, and in the next step, first the alkoxycarbonyl group CO 2 R ^{24 is} reduced to the corresponding alkylhydroxyfunction and finally another alkoxycarbonyl function is reacted to the formyl group.

Suitable solvents for all processes are the customary organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran and glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene or

31259 / H chlorobenzene or ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Acetonitrile and dimethylformamide are preferred.

Suitable bases for the individual steps are the usual strongly basic compounds. These preferably include organolithium compounds such as n-butyl lithium, sec-butyl lithium, tert-butyl lithium or phenyl lithium or amides such as lithium diisopropylamide, sodium amide or potassium amide, furthermore lithium hexamethylsilylamide or alkali metal hydrides such as sodium hydride or hydride potassium.

The bases are used in an amount of 1 mol to 10 mol, preferably 1 mol to 3 mol, in each case based on 1 mol of the compound of the general formula (V).

The reaction is generally carried out at a temperature ranging from room temperature to 120 ^° C, preferably 80 ° C to 120 ° C, depending on the solvent selected.

The reaction is generally carried out under normal pressure, but it is also possible to work under reduced or elevated pressure, for example in the range of 0.5 to 5 bar.

The compounds of formulas V and VI are known per se or are obtainable by conventional methods.

The compounds of formula (VI) are partially known or novel and can then be prepared as described above.

The compounds of formula III are partially novel and can be prepared by the preparation of compounds of formula VIII

D'-CO-CH ₃ (VIII) wherein

D 'is an aryl radical mentioned above under D, first reacted with compounds of formula IX

31259 / H

E-CO ₂ -R ²⁶ (IX), wherein E is as defined above a

R ²⁶ represents an alkyl group having 1 to 4 carbon atoms, to give compounds of formula X

ABOUT

wherein D 'and E are as defined above, in inert solvents and in the presence of a base, in a second step, are reacted with aldehydes of formula XI A-CHO (XI), wherein A is as defined above, to compounds of formula XII

in which A, D 'and E are as defined above, and are finally reacted with compounds of formula XIII

CO, R (XIII)

H, N 'nr ² r ³ in which R ²³ , R ² and R ^{3 are} as defined above.

31259 / H

Suitable solvents for the individual steps are conventional solvents which do not change under the reaction conditions. These preferably include water, ethers such as diethyl ether, dioxane, tetrahydrofuran and glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene , trichlorethylene or chlorobenzene, or ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, nitromethane or alcohols such as methanol, ethyl alcohol or propyl alcohol. It is also possible to use mixtures of the solvents mentioned. Toluene is preferred.

The reaction is generally carried out under normal pressure, but it is also possible to carry out the reaction under reduced or elevated pressure, for example in the range of 0.5 to 5 bar.

The compounds of formulas VIII, IX, XI and XIII are partially known or can be prepared by conventional methods.

The compounds of formulas (X) and (XII) are partially novel and can be prepared as described above.

The compounds of the formula I according to the invention have an unpredictable spectrum of pharmacological effects.

The compounds according to the invention of the general formula (I) have valuable pharmacological properties which are superior to those of the prior art, in particular they are highly effective cholesterol-ester-transfer-protein (CETP) inhibitors and stimulate reverse cholesterol transport. The active ingredients of the present invention cause a decrease in the LDL cholesterol level in the blood while increasing the HDL-cholesterol level. Thus, they can be used to treat and prevent hyperlipoproteinaemia, hypolipoproteinaemia, dislipidemia, hypertriglyceridemia, combined hyperlipidemia or arteriosclerosis.

The pharmacological effects of the compounds of the present invention were ascertained in the following tests.

31259 / H

CETP-inhibition assay

Obtaining CETP

CETP is obtained from human plasma by differential centrifugation and column chromatography in a partially purified form is used for the assay. To this end, the human plasma density is adjusted to 1.21 g / ml with sodium bromide and centrifuged at 4 ° C for 18 hours at 50,000 rpm. The bottom fraction (d> 1.21 g / ml) was applied to a Sephadex ^R PhenylSepharose 4B column (Pharmacia), washed with 0.15 ml NaCl / 0.001 ml Tris / HCl pH 7.4 and then eluted with distilled water. The CETP-active fractions were pooled, dialyzed against 50 mM sodium acetate pH 4.5 and loaded onto a CMSepharose ® column (Pharmacia), eluting with a linear NaCl gradient (0 -1 M). The pooled CETP fractions were dialyzed against 10 mM Tris / HCl pH 7.4 and then further purified by chromatography on a Mono Q ^R column (Pharmacia).

The recovery of radiolabeled HDL ml of fresh human EDTA-plasma, whose density was adjusted to 1.12 with sodium bromide, was centrifuged for 18 hours in a Ty 65-rotor at 50,000 rpm at 4 ° C. The upper phase is used to obtain cold LDL. The lower phase was dialyzed against 3 * 4 L PDB buffer (10 mM Tris / HCl pH 7.4, 0.15 mM NaCl, 1 mM EDTA, 0.02% NaN ₃ ). 20 μΙ of ³ H-cholesterol (Dupont NET-725; 1 pC / µl, dissolved in ethyl alcohol) is then added per 10 ml of retentate volume and incubated for 72 hours at 37 ° C under nitrogen.

The batch is then adjusted to a density of 1.21 g / ml with sodium bromide and centrifuged for 18 hours in a Ty 65-rotor at 50,000 rpm. The upper phase is separated and the lipoprotein fractions are purified by gradient centrifugation. For this, the isolated labeled lipoprotein fraction is adjusted to 1.26 with sodium bromide. 4 ml of this solution is overlaid in a centrifuge tube (SW 40 - Rotor) with 4 ml of 1.21 density solution.

31259 / H g / ml and 4.5 ml of a solution with a density of 1.063 g / ml (density solutions from PDB buffer and sodium bromide) and then centrifuged for 24 hours at 20 ° C in a SW 40-Rotor at 38,000 rpm minute. The intermediate layer containing labeled HDL, lying between a density of 1.063 and 1.21, is dialyzed against 3 * 100 volumes of PDB buffer at 4 ° C.

The retentate contains radiolabeled ³ H-CE-HDL, which is used for the assay, set to about 5 x 10 ⁶ cpm per ml.

CETP Test

To test CETP activity, the transfer of the ³ H-cholesterol ester of human HD-lipoproteins to biotinylated LD-lipoproteins is measured.

The reaction is terminated by the addition of Streptavidin-SPA ^R beads (Amersham) and the transferred radioactivity is determined directly in the Liquid Scintilation Counter.

Dissolve 10 μΙ of HDL- ³ H-cholesterol ester (-50000 cpm) with 10 μΙ biotin-LDL (Amersham) in 50 mM hepes / 0.15 ml NaCl / 0.1% bovine albumin / 0.05% NaN3 in the test batch. pH 7.4 with 10 μΙ CETP (1 mg / ml) and 3 μΙ solution of test substance (in 10% DMSO / 1% RSA) and incubate for 18 hours at 37 ° C. Then 200 μΙ of SPA-Streptavidin-Bead solution (TRkQ 7005) is added, incubated for one hour with shaking and then measured in a scintillation counter. Appropriate incubation with 10 μΙ buffer and 10 μΙ CETP at 4 ° C as well as 10 μΙ CETP at 37 ° C serves as a control.

The activity transferred in control batches with CETP at 37 ° C is evaluated as 100% transfer. The substance concentration at which this transfer is reduced by half is reported as an IC ₅₀ value. In the following table, IC 50 values (mol / l) for CETP inhibitors are reported.

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table Example IC ₅ o (mol / l) 6 2,4x10 '' 9 6x10 ' ^a 10 iíxíČŤ ⁷

Ex vivo activity of the compounds of the present invention

Syrian gold hamsters of their own breeding are anesthetized after 24 hours of fasting (0.8 mg / kg atropine, 0.8 mg / kg Ketavet ^R sc, 30 minutes later 50 mg / kg Nembutal ip). The jugular vein is then dissected and cannulated. The test substance is dissolved in a suitable solvent (typically Adalatplacebo solution: 60 g glycerol, 100 ml water, to 1000 ml PEG-400) and administered to the animals via a PE catheter inserted into the jugular vein. Control animals receive an equal volume of solvent without test substance. Then the vein is ligated and the wound is closed.

Administration of test substances can also be carried out orally by dissolving the substance in dimethylsulfoxide and suspending 0.5% tylose with the aid of an esophagus probe. Control animals receive an identical volume of solvent without test substance.

After various time periods - up to 24 hours after administration, animals are bled by retro-orbital venenplexus puncture (about 250 μΙ). Incubation at 4 ° C overnight closes the clot and then centrifuged for 10 minutes at 6000 x g. In the serum thus obtained, the CETP activity is determined using a modified CETP assay. As measured by the CETP assay described above, the transfer of ³ H-cholesterol from HD-lipoproteins to biotinylated LD-lipoproteins is measured.

The reaction is terminated by the addition of Streptavidin-SPA ^R beads (Amersham) and the transferred radioactivity is measured directly in the Liquid Scintilation Counter.

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The test is performed as described in the CETP test. Only 10 μΙ CETP is replaced by 10 μΙ of the corresponding sample for serum testing. Appropriate incubation with serum from untreated animals serves as a control.

The activity transferred in the control batches with control serum is evaluated as 100% transfer. The concentration of compound at which this transfer is reduced by half is indicated as the value of ED _50th

In vivo activity of the compounds of the present invention

In experiments to determine the oral effect on lipoproteins and triglycerides, a self-breeding Syrian Gold Hamster is administered orally dissolved in dimethylsulfoxide and suspended in 0.5% tylose by an esophagus probe. To determine CETP activity, blood is drawn by retro-orbital puncture (about 250 μΙ) prior to the start of the experiment. Thereafter, the test substances are administered orally by means of an esophagus probe. Control animals receive identical volumes of solvent without test substance. The animals are then fed and, at various times - up to 24 hours after application, the animals are bled by retro-orbital venenplexus puncture.

Incubation at 4 ° C overnight closes the clot and then centrifuged for 10 minutes at 6000 x g. In the serum thus obtained, the cholesterol and triglyceride content is determined by a commercially available enzyme assay (Cholesterin enzymatisch 14366 Merck, Triglyceride 14364 Merck). Serum is suitably diluted with saline.

100 μΙ of diluted serum is mixed with 100 μΙ of the test substance in a 96-well microtiter plate and incubated for 10 minutes at room temperature. The optical density at 492 nm was then determined using an automatic reading device. Triglyceride and cholesterol concentrations are determined using a parallel measured standard curve.

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The HDL-Cholesterol content is determined after precipitation of ApoB-containing lipoproteins with Sigma 352-4 HDL Cholesterol Reagent according to the manufacturer's specifications.

In vivo efficacy in transgenic hCETP-mice

Self-breeding transgenic mice (Dinchuck, Hart, Gonzalez, Karmann, Schmidt, Wirak; BBA (1995), 1295, 301) are administered test substances in the diet. Prior to the start of the experiment, the animals are bled retroorbitally to determine the blood cholesterol and triglyceride content. Serum is obtained as above in hamsters by incubation at 4 ° C overnight followed by centrifugation at 6000 x g. After one week, the animals are bled again for cholesterol and triglyceride determination. The change in measured parameters is expressed as a percentage change from baseline.

The present invention further provides a combination of the 2-amino-substituted pyridines of Formula I with glucosidase and / or amylase inhibitors for the treatment of familial hyperlipidemia, adipositase and diabetes mellitus. Glucosidase and / or amylase inhibitors within the scope of the present invention are, for example, acarbose, adipinosine, voglibose, miglitol, emiglitate, MDL-25637, camiglibose (MDL-73945), tendamistate, AI-3688, puncatin, paradimicin Q and salbostatin.

Preferred is a combination of acarbose, miglitol, emiglitate or voglibose with any of the above compounds of the present invention of Formula I.

Further, the compounds of the present invention may be combined with cholesterol-lowering ligands or Apo B-lowering agents for the treatment of dyslipidemia, combined hyperlipidemia, hypercholesterolemia, or hypertriglyceridemia.

Said combinations are also useful for the primary or secondary prevention of coronary heart disease, for example myocardial infarction.

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Vastatins within the scope of the present invention are, for example, lovastatin, imvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin. Apo B-lowering agents are, for example, MTP-inhibitors.

Preferred is a combination of cervistatin or Apo B inhibitors with any of the above compounds of the present invention of Formula I.

The novel active compounds can be converted into conventional preparations such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions using known methods, using inert, non-toxic, pharmaceutically acceptable carriers or solvents. The therapeutically active compound should be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in an amount sufficient to achieve the claimed effect.

For example, the formulations are prepared by dispersing the active ingredient in solvents and / or carriers, optionally using emulsifying and / or dispersing agents, where, for example, in the case of using water as a diluent, organic solvents may optionally be used as solubilizers.

Administration is carried out intravenously, orally, parenterally or perlingually, preferably orally, by conventional means.

For parenteral administration, the active ingredient solutions may be administered using appropriate liquid carrier materials.

In general, it has been found advantageous to administer the active compounds by intravenous administration in a total amount of about 0.001 to 1 mg / kg, preferably about 0.01 mg / kg to 0.5 mg / kg body weight, and for oral administration the dosage is about 0.01 to 20 mg / kg body weight, preferably 0.1 to 10 mg / kg body weight.

Nevertheless, it may be necessary to dispense with the abovementioned amounts, depending on the body weight or the type of application, the severity of the disease, but also the individual tolerance to the disease.

31259 / H of the medicament, optionally from the kind and type of the medicament and from the moment or the interval at which the administration takes place. Thus, in some cases it may be sufficient to start from lower than the abovementioned minimum amounts, while in other cases the upper limit must be exceeded. In the case of administration of larger amounts, it is advisable to divide this dose into several individual doses during the day.

DETAILED DESCRIPTION OF THE INVENTION

Abbreviations used

CY = cyclohexane

PE = petroleum ether

EE = ethyl acetate

THF = tetrahydrofuran

DAST = dimethylaminosulfatrifluoride

PST = p-toluenesulfonic acid

PDC = pyridinium dichromate

PE / EE = petroleum ether / ethyl acetate

DIBAH = diisobutylaluminium hydride

Starting compounds

Example I

2-Benzylamino-6-cyclopentyl-4- (4-fluorophenyl) pyridine-3,5-dicarboxylic acid 3-ethyl ester-5-methyl ester

31259 / H g (64 mmol) of 3-ethyl-5-methyl 2-chloro-6-cyklopentyl4- (4-fluorophenyl) pyridin-3 _I, 5-dicarboxylic acid ₁ 14 ml (130 mmol) of benzylamine and 17 g (160 mmol) of sodium carbonate was stirred in 220 ml of acetonitrile for 2 days at reflux. Then, 6.9 ml (64 mmol) of benzylamine and 6.8 g (64 mmol) of sodium carbonate are added and stirred for a further 20 hours under reflux. After cooling to room temperature, the mixture is filtered off with suction through silica gel and washed with 100 ml of ethyl acetate. After concentration in vacuo, the partially crystallizing residue is taken up with stirring into 100 ml of petroleum ether. The solid is filtered off with suction, washed with a small amount of petroleum ether and dried under high vacuum. The remaining mother liquor is concentrated and chromatographed on silica gel (200 g silica gel 230-400 mesh, d = 3.5 cm, toluene).

Yield: 25.1 g (82% of theory).

R f = 0.54 (PE / EE 8: 1).

Example II

6-Benzylamino-2-cyclopentyl-4- (4-fluoro-phenyl) -5-hydroxymethyl-nicotinic acid methyl ester

To a 32.6 ml 1.0 M solution of lithium aluminum hydride in tetrahydrofuran under a argon atmosphere was added dropwise a solution of 14.8 g (31.1 g) at -40 ° C.

31259 (H mmol) of the compound of Example 1 over 5 minutes and allowed to warm to room temperature over 40 minutes. Stir for 30 minutes, cool to -15 ° C and quench with 5.0 mL of water. The mixture is filtered off with suction over kieselguhr and the residue is washed with ethyl acetate. The combined organic phases were washed with water (2x) and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated and the product obtained was chromatographed on silica gel 60 (petroleum ether / ethyl acetate = 5: 1).

Yield: 13.2 g (97% of theory).

R f = 0.25 (PE / EE 5: 1).

Example III

6-Benzylamino-2-cyclopentyl-4- (4-fluoro-phenyl) -5-tetrahydropyran-2-yl-oxymethyl-methyl] methyl

To a solution of 13.5 g (31.0 mmol) of the compound of Example II in 300 mL of dried dichloromethane was added 779 mg (3.1 mmol) of pyridinium p-toluenesulfonate (PPTS) and 8.8 mL (93 mmol) of 3,4- of dihydro-2H-pyran and the reaction mixture was stirred for 16 hours at room temperature, then diluted with diethyl ether and washed with saturated sodium chloride solution. The organic phase is separated, dried over anhydrous sodium sulphate, concentrated and the crude product is chromatographed on silica gel 60 (PE / EE = 20: 1 then EE).

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Yield: 9.9 g (59% of theory). R f = 0.53 (PE / EE5: 1).

Example IV [6-Benzylamino-2-cyclopentyl-4- (4-fluoro-phenyl) -5- (tetrahydro-pyran-2-yloxymethyl) -pyridin-3-yl] -methanol

To a solution of 4.21 g (8.58 mmol) of the compound of Example III, 23 ml (34.3 mmol) of a 1.5 M solution of diisobutyl-aluminum hydride (DIBAH) in toluene was slowly added dropwise over 10 minutes under argon. The reaction mixture was allowed to warm to 0 ° C and stirred at this temperature for one hour, after which 5.7 mL of a 1.5 M DIBAH solution was added again. After one hour, 10 ml of water are hydrolyzed and mixed with 2 x 300 ml of ethyl acetate. The gelled aqueous phase is filtered off with suction over kieselguhr, washed twice with water and three times with ethyl acetate. After phase separation, the combined organic phases are washed with saturated sodium chloride solution, dried over anhydrous sodium sulphate, concentrated and the residue is chromatographed on silica gel 60 (CH 2 Cl 2 then EE).

Yield: 3.5 g (83% of theory).

R f = 0.31 (PE / EE5: 1).

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Example V

6-benzylamino-2-cyclopentyl-4- (4-fluóľ-phenyl) -5- (tetrahydro-pyran-2-yloxymethyl) -pyridine-3-carbaldehyde

To a solution of 3.6 g (7.3 mmol) of the compound of Example IV in 200 mL of absolute dichloroethane was added at 0 ° C 8.5 g (22.2 mmol) of pyridinium dichloride (PDC) in six portions over 3 hours and the reaction mixture is then stirred for 30 minutes at room temperature. The mixture is then placed on 50 g of silica gel 60 and the product is eluted with CH ₂ Cl ₂ / triethylamine 100: 1. After concentration, it is chromatographed on silica gel 60 (petroleum ether / ethyl acetate = 20: 1, then 2: 1). Yield: 1.64 g (45% of theory) + 417 mg (11% of theory) of the starting material obtained.

_Rf = 0.50 (PE / EA = 10: 1).

A

Example VI [6-Benzylamino-2-cyclopentyl-4- (4-fluoro-phenyl) -5- (tetrahydro-pyran-2yloxymethyl) -pyridin-3-yl] - (4-trifluoromethyl-phenyl) -methanol

31259 / H

To 800 mg (1.64 mmol) of the compound of Example V in absolute tetrahydrofuran under argon at -20 ° C was added 32 mL (4.6 mmol) of a freshly prepared 0.144 M solution of p-trifluoromethylphenyl magnesium bromide in tetrahydrofuran. The reaction mixture is allowed to stir for 2 hours at room temperature, 30 ml of 10% ammonium chloride solution are added and extracted with ethyl acetate. After washing with water and saturated sodium chloride solution, drying over anhydrous sodium sulphate and concentration, the residue is chromatographed on silica gel 60 (dichloromethane and then ethyl acetate).

Yield: 555 mg (54% of theory).

_Rf = 0.53 (PE / EE 2: 1).

Example VII

Benzyl- [6-cyclopentyl-4- (4-fluoro-phenyl) -3- (tetrahydro-pyran-2-yloxymethyl) -5- (4-trifluoromethyl-benzyl) -pyridine-2-yl] -amine

To a solution of 549 mg (0.865 mmol) of the compound of Example VI in absolute dichloromethane was added 171 μΙ (1.3 mmol) at -30 ° C.

31259 / H diethylaminosulfatrifluoride (DAST), stirred at this temperature for 3 hours, then 2.6 mL (3.89 mmol) of a 1.5 M solution of DIBAH in toluene was added. Remove the cooling bath, stir for 90 minutes at room temperature and add 2 mL of saturated sodium chloride solution at 0 ° C. The reaction mixture is filtered off with suction over kieselguhr and the residue is washed with water, dichloromethane and ethyl acetate. After phase separation, the aqueous phase is washed with dichloromethane, the organic phases are combined, dried over sodium sulphate and concentrated. Further purification is performed by chromatography on silica gel 60 (PE / EE = 40: 1).

Yield: 482 mg (90% of theory).

_Rf = 0.43 (PE / EA 10: 1).

Example VIII

Benzyl- [6-cyclopentyl-4- (4-fluoro-phenyl) -3- (tetrahydro-pyran-2-yloxymethyl) -5 '(4-trifluoromethyl) benzyl) pyridin-2-yl] -methylamine

To a solution of 60 mg (0.097 mmol) of the compound of Example VII and 109 mg (0.97 mmol) of potassium tert-butanolate (KOtBu) in 2 mL of absolute dimethylformamide was added 0.36 mL of methyl iodide (5.82 mmol) and stirred for 40 minutes. Then 3 ml of saturated sodium bicarbonate solution are added, extracted three times with diethyl ether, the combined organic phases are washed with saturated sodium chloride solution and dried over anhydrous sulphate.

31259 / H sodium and concentrated. Further purification is performed by chromatography on silica gel 60 (PE / EE = 40: 1).

Yield: 35 mg (57% of theory).

Rf = 0.18 (PE / EE 10: 1).

Production examples

Example 1 [2-Benzyl-methyl-amino-6-cyclopentyl-4- (4-fluoro-phenyl) -5- (4-trifluoromethyl-benzyl) -pyridin-3-yl] -methanol

A solution of 32 mg (0.051 mmol) of the compound of Example VIII in 2 ml of tetrahydrofuran was treated with 0.5 ml of 3M hydrochloric acid and stirred for 90 minutes at room temperature. 4 ml of saturated sodium bicarbonate solution are then added, extracted with ethyl acetate (3 *), the combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated. Further purification is performed by chromatography on silica gel 60 (PE / EE = 20: 1).

Yield: 24 mg (86% of theory).

_Rf = 0.28 (PE / EA 10: 1).

31259 / H

Correspondingly, in Table 1 below.

to produce the above compounds

Pr. R = R ³ R ³ R, * 2 0 H 0.41 /Ε / ΞΕ (5.1 R J C u ₂ .. ₅ to 1 H 0.30 ΞΞ / ΡΞ (1.10) 1 T (CH ₂ ) -CH ₃ 0 The 0.40 EE / ΡΞ 1:10 5 _{CH-C e} Hj 1 H 00:35 ΕΞ / ΡΞ 1:10 about ï och ₃ 0.3s Cy / EE 7 about' F 00:33 Cy / EE

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Table 1 (continued)

Pr. R ^: R ³ R ^s rr * WITH & H 0.25 Cy / Ec (9: 1) 9 about H 0.37 Cy / EB (8: 1) 10 H H 0.47 Tol / EE 11 H H

31259 / H

Claims (10)

1. 2-Amino-substituted pyridines of the formula I A D R d) N in which A represents an aryl group having 6 to 10 carbon atoms which is optionally substituted up to five times equally or differently by a halogen atom, a hydroxy group, a trifluoromethyl group, a trifluoromethoxy group, a nitro group or a straight or branched alkyl, acyl, hydroxyalkyl or alkoxy group having up to 7 carbon atoms; a group of formula -NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a phenyl group or a straight or branched alkyl group of up to 6 carbon atoms, D represents an aryl group having 6 to 10 carbon atoms which is optionally substituted by nitro, halogen, trifluoromethyl or trifluoromethoxy, or represents a radical of formula wherein: 31259 / H R ⁶ and R ⁷ are the same or different and represent a cycloalkyl group having 3 to 6 carbon atoms or an aryl group having 6 to 10 carbon atoms or a 5- to 7-membered aromatic, optionally benzocondensed, saturated or unsaturated, monocyclic, bicyclic or tricyclic heterocycle of up to 4 heteroatoms from the group consisting of sulfur, nitrogen and / or oxygen atoms, wherein the cyclenes, in the case of nitrogen-containing rings also via the N-function, are up to five times equally or differently substituted by halogen, trifluoromethyl, trifluoromethoxy, hydroxy, nitro, carboxyl, cyano , straight or branched alkyl, acyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl of up to 6 carbon atoms or aryl of 6 to 10 carbon atoms, or an optionally benzocondensed aromatic of 5- to 7-membered het with an erocycle of up to 3 heteroatoms selected from the group consisting of sulfur, nitrogen and / or oxygen, and / or substituted by a group of the formula -OR ¹⁰ , -SR ¹¹ , -SO ² R ¹² or -NR ¹³ R ¹⁴ , wherein: R ¹⁰ , R ¹¹ and R ¹² are the same or different and represent an aryl group having 6 to 10 carbon atoms, which itself is up to two times the same or differently substituted by a phenyl group, a halogen atom or a straight or branched alkyl group having up to 4 carbon atoms; R ¹³ and R ¹⁴ are the same or different and have the meanings given above for R ⁴ and R ⁵ , or R ⁶ or R ⁷ represents a radical of the formula 31259 / H L represents a straight or branched chain alkyl or alkenyl chain of from 2 to 10 carbon atoms each optionally substituted up to two times with hydroxy, R ⁸ represents a hydrogen atom or a halogen atom and R ⁹ represents a hydrogen atom, a halogen atom, an azido group, a trifluoromethyl group, a hydroxy group, a trifluoromethoxy group, a straight or branched alkoxy group of up to 5 carbon atoms or a radical of the formula -NR ¹⁵ R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are the same or different and have the meanings given above for R ⁴ and R ⁵ , or R ⁸ and R ⁹ together form the radical = O or = NR ¹⁷ , wherein R ¹⁷ represents a hydrogen atom or a straight or branched alkyl, alkoxy or acyl group each having up to 6 carbon atoms, E represents a cycloalkyl group having from 3 to 8 carbon atoms or a straight or branched alkyl group having up to 8 carbon atoms which is optionally substituted by a cycloalkyl group having 3 to 8 carbon atoms or a hydroxy group or a phenyl group optionally substituted by a halogen atom or a trifluoromethyl group . R ¹ represents a straight or branched alkyl group having up to 6 carbon atoms which is substituted by a hydroxy group and R ² and R ³ are the same or different and represent a hydrogen atom, a phenyl group, a benzyl group, a cycloalkyl group of 3 to 7 carbon atoms, a straight or branched alkyl or acyl group of up to 6 carbon atoms or a group of the formula -CO-NR ¹⁸ R ¹⁹ , whereby R ¹⁸ and R ¹⁹ are the same or different and represent a hydrogen atom, a phenyl group, a benzyl group or a straight or branched alkyl group of up to 6 carbon atoms, 31259 / H or R ² and R ³ together with the nitrogen atom form a 5- to 7-membered, saturated, partially unsaturated or unsaturated, optionally benzocondensed, monocyclic or bicyclic heterocycle with up to 4 heteroatoms selected from the group consisting of sulfur, nitrogen and / or oxygen, optionally up to three times the same or differently substituted by nitro, cyano, halogen, trifluoromethyl, hydroxy, carboxy, straight or branched alkoxy or alkoxycarbonyl of up to 5 carbon atoms, phenyl or straight or branched alkyl of up to 5 carbon atoms, which may itself be substituted and / or the heterocycle is substituted with a group of the formula -NR ²⁰ R ²¹ , wherein R ²⁰ and R ²¹ have the meanings given above for R ¹⁸ and R ¹⁹ and are the same or different, and salts thereof. 2. A compound according to claim 1, in which: EMI4.0 [0025] 2. A compound according to claim 1 wherein: EMI2.0 A represents a naphthyl or phenyl group, which is optionally up to three times the same or differently substituted by a fluorine, chlorine or bromine atom, a hydroxy group, a trifluoromethyl group, a nitro group, a trifluoromethoxy group or a straight or branched alkyl, acyl or alkoxy group each having up to 6 carbon atoms or group of formula -NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a phenyl group or a straight or branched alkyl group having up to 4 carbon atoms, D represents a phenyl group which is optionally substituted by nitro, fluorine, chlorine or bromine, trifluoromethyl or trifluoromethoxy, or 31259 / H is a radical of formula wherein R ⁶ and R ⁷ are the same or different and represent cyclopropyl, cyclopentyl or cyclohexyl, or phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl, imidazolyl , benzothiazolyl, phenoxathin-2-yl, benzoxazolyl, furyl, quinolyl or purin-8-yl, wherein the cyclenes, in the case of nitrogen-containing rings also via the N-function, may optionally be up to three times the same or differently substituted by an atom fluorine, chlorine or bromine, trifluoromethyl, trifluoromethoxy, hydroxy, cyano, carboxyl, straight or branched alkyl, acyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl of up to 4 carbon atoms or tetrazolyl, , benzoxathiazolyl or phenyl, and / or are substituted with -OR ¹⁰ , -SR ^11, or -SO ² R ¹² wherein: R ¹⁰ , R ¹¹ and R ¹² are the same or different and represent a phenyl group which itself is up to two times the same or differently substituted by a phenyl group, a fluorine or chlorine atom, or a straight or branched alkyl group having up to 4 carbon atoms, or R ⁶ or R ⁷ represents a radical of the formula 31259 / H L is a straight or branched alkyl or alkenyl group having from 2 to 8 carbon atoms each optionally substituted up to two times with hydroxy, R ⁸ represents a hydrogen atom or a fluorine, chlorine or bromine atom; R ⁹ represents a hydrogen atom, a fluorine, chlorine or bromine atom, an azido group, a trifluoromethyl group, a hydroxy group, a trifluoromethoxy group, a straight or branched alkoxy group having up to 4 carbon atoms or a radical of the formula -NR ¹⁵ R ¹⁶ ; R ¹⁵ and R ¹⁶ are the same or different and have the meanings given above for R ⁴ and R ⁵ , or R ⁸ and R ⁹ together form the radical = O or = NR ¹⁷ , wherein R ¹⁷ represents a hydrogen atom or a straight or branched alkyl, alkoxy or acyl group of up to 4 carbon atoms in each case, E represents a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group, or a straight or branched alkyl group having up to 6 carbon atoms optionally substituted by a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group or cycloheptyl group or a phenyl group optionally substituted by a fluorine or chlorine atom or a trifluoromethyl group, 31259 / H R ¹ represents a straight or branched alkyl group having up to 5 carbon atoms which is substituted by a hydroxy group; and R ² and R ³ are identical or different and denote hydrogen, phenyl, benzyl, cyclopropyl, cyclopentyl, cyclohexyl, straight-chain or branched alkyl or acyl having up to 5 carbon atoms or a group -CO-NR ¹⁸ R ¹⁹ , whereby R ¹⁸ and R ¹⁹ are the same or different and represent a hydrogen atom, a phenyl group, a benzyl group or a straight or branched alkyl group of up to 5 carbon atoms, or R ² and R ³ together with the nitrogen atom form a pyryl, imidazolyl, pyrrolidinyl, morpholine, piperidinyl or piperazinyl ring or or wherein the heterocycles are optionally substituted by hydroxy, trifluoromethyl, fluorine, chlorine or bromine, methylhydroxy, alkoxy or straight or straight alkoxycarbonyl having up to 4 carbon atoms each, and salts thereof. The 2-amino-substituted pyridines of claim 1 of formula (I) wherein: A represents a naphthyl group or a phenyl group optionally substituted by a fluorine, chlorine or bromine atom, a hydroxy group, 31259 / H trifluoromethyl, nitro, trifluoromethoxy or straight or branched alkyl, acyl or alkoxy of up to 5 carbon atoms or -NR ⁴ R ⁵ , wherein: R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a phenyl group or a straight or branched alkyl group having up to 3 carbon atoms, D represents a phenyl group which is optionally substituted by a nitro group, a fluorine, chlorine or bromine atom, or represents a radical of formula wherein: R ⁶ and R ⁷ are the same or different and represent cyclopropyl, cyclopentyl or cyclohexyl, or phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl, imidazolyl benzothiazolyl, phenoxathin-2-yl, benzoxazolyl, furyl, quinolyl or purin-8-yl, the cyclenes, in the case of nitrogen-containing rings also via the N-function, optionally being optionally up to three times the same or differently substituted by a fluorine atom or chlorine, trifluoromethyl, trifluoromethoxy, hydroxy, cyano, carboxyl, straight or branched alkyl, acyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl of up to 3 carbon atoms or triazolyl, tetrazolyl another, a benzoxathiazolyl group or a phenyl group, 31259 / H and / or are substituted by the group -OR ¹⁰ , -SR ¹¹ or -SO ₂ R ¹² , wherein R ¹⁰ , R ¹¹ and R ¹² are the same or different and represent a phenyl group which itself is up to two times the same or differently substituted by a phenyl group, a fluorine or chlorine atom, or a straight or branched alkyl group having up to 3 carbon atoms, or R ⁶ or R ⁷ represents a radical of the formula L represents a straight or branched alkyl or alkenyl group having in each case up to 8 carbon atoms optionally substituted up to two times by hydroxy, R ⁸ represents a hydrogen atom or a fluorine atom and R ⁹ represents a hydrogen atom, a fluorine, chlorine or bromine atom, an azido group, a trifluoromethyl group, a hydroxy group, a trifluoromethoxy group, a methoxy group or a radical of the formula -NR ^1S R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are the same or different and have the meanings given above for R ⁴ and R ⁵ , or R ⁸ and R ⁹ together form the radical = O or = NR ¹⁷ , wherein R ¹⁷ represents a hydrogen atom or a straight or branched alkyl, alkoxy or acyl group each having up to 3 carbon atoms, 31259 / H E represents a cyclopropyl group, a cyclopentyl group, a cyclohexyl group or a phenyl group optionally substituted by a fluorine atom or a trifluoromethyl group, or a straight or branched alkyl group having up to 4 carbon atoms optionally substituted by a hydroxy group, R ¹ represents a straight or branched alkyl group having up to 4 carbon atoms which is substituted by a hydroxy group and R ² and R ³ are identical or different and denote hydrogen, phenyl, benzyl, cyclopropyl, cyclopentyl or straight-chain or branched alkyl or acyl having up to 5 carbon atoms or a group -CO-NR ¹⁸ R ^19, while R ¹⁸ and R ¹⁹ are the same or different and represent a hydrogen atom, a phenyl group, a benzyl group or a straight or branched alkyl group of up to 4 carbon atoms, or R ² and R ³ together with the nitrogen atom form a pyryl, pyrrolidinyl, morpholine or piperidinyl ring or a radical of formula wherein the heterocyclenes are optionally substituted by hydroxy, trifluoromethyl, fluorine, chlorine or bromine, hydroxy, methylhydroxy, carboxy or alkoxy or straight or branched a group of up to 3 carbon atoms in each case, and salts thereof. 31259 / H A process for the preparation of 2-amino-substituted pyridines of the formula I according to claim 1, characterized in that A) is added to the compounds of the formula II OH ¹ (Π) in which A, E, R ² and R ^{3 are} as defined above and R < ²² & gt ^; is as defined above for R &^lt; ¹ > where the hydroxyfunction occurs in protected form, preferably by tetrahydropyranyl, firstly introducing a D moiety in the Grignard / Wittig reaction or optionally at this stage substituents by known methods, preferably by reduction; the hydroxy protecting group is cleaved, or is removed B) compounds of formula III wherein A, D, E, R ² and R ^{3 are} as defined above, and R ²³ represents an alkyl group having 1 to 4 carbon atoms, converted by oxidation to compounds of formula IV A 31259 / H in which A, D, E, R ² , R ³ and R ^{23 are} as defined above, or alternatively the D substituents are changed at this stage and then the alkoxycarbonyl groups are reduced to hydroxymethyl functions by customary methods under argon, and optionally all substituents are varied and / or introduced by conventional methods. A medicament comprising at least one 2-amino-substituted pyridine according to claims 1 to 3 as well as a pharmacologically acceptable excipient. Medicament according to claim 5 for the treatment of arteriosclerosis. A medicament according to claim 5 for the treatment of hyperlipoproteinaemia. Use of 2-amino-substituted pyridines according to claims 1 to 3 for the manufacture of medicaments. Use according to claim 8 for the manufacture of medicaments for the treatment of arteriosclerosis. Use according to claim 8 for the manufacture of medicaments for the treatment of 1 hyperlipoproteinemia.