KR20000070756A - 2-Amino Substituted Pyridines for Use in The Treatment of Arteriosclerosis and Hyperlipoproteinaemia - Google Patents

Abstract

The present invention relates to a novel 2-amino-substituted pyridine prepared by first converting the corresponding pyridine aldehyde to the corresponding hydroxide by a metal-organic compound, such as a Grignard compound, and then reducing the hydroxide to a dihydroxy compound. It is about. The novel 2-amino-substituted pyridine is suitable for use as an active ingredient in medicines, especially medicines used to treat atherosclerosis.

Description

2-Amino Substituted Pyridines for Use in The Treatment of Arteriosclerosis and Hyperlipoproteinaemia}

The present invention relates to novel 2-amino-substituted pyridines, methods for their preparation and their use as pharmaceuticals.

US Pat. No. 5 169 857 A2 describes 7- (polysubstituted pyridyl) -6-heptenoate for the treatment of atherosclerosis, lipoproteinemia and lipoprotein hyperemia. The preparation of 7- (4-aryl-3-pyridyl) -3,5-dihydroxy-6-heptenoate is also described in European Patent No. 325 130 A2.

The present invention relates to novel 2-amino-substituted pyridine of formula (I) and salts thereof.

Wherein A is halogen, hydroxyl, trifluoromethyl, nitro, trifluoromethoxy, or straight or branched chain alkyl, acyl, hydroxyalkyl or alkoxy having up to 7 carbon atoms, or To the same or different groups up to 5 times by a group of NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are the same or different and represent hydrogen, phenyl or straight or branched chain alkyl having up to 6 carbon atoms Optionally substituted aryl of 6 to 10 carbon atoms;

D represents aryl of 6 to 10 carbon atoms optionally substituted by nitro, halogen, trifluoromethyl or trifluoromethoxy, or is represented by the formula R ⁶ -L or

[Wherein R ⁶ and R ⁷ are the same or different and represent cycloalkyl having 3 to 6 carbon atoms, or aryl having 6 to 10 carbon atoms, or as S, N and / or O To form an optionally benzo-fused, saturated or unsaturated, mono-, non- or tricyclic 5- to 7-membered heterocycle having up to 4 carbon atoms with a heteroatom selected from the group consisting of

Here, in the case of nitrogen-containing rings, the ring system is halogen, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy, nitro, straight or branched chain acyl with up to 6 carbon atoms via the N functional group. Optionally having 3 or less heteroatoms in the group consisting of S, N and / or O, by alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl, by aryl of 6 to 10 carbon atoms Optionally substituted by the same or different groups by a 5-7 membered heterocycle of benzo-fused aromatics and / or 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 have from 6 to 6 carbon atoms, some of which may be substituted by the same or different groups up to 2 times by phenyl, halogen, or by straight or branched chain alkyl having up to 4 carbon atoms. represents a 10 aryl, R ¹³ R ¹⁴ are the same or different, or substituted by a group of R ⁴ and R ⁵ has the meaning of a) described above,

Alternatively, R ⁶ or R ⁷ is represented by the formula Represents a group of

L represents straight or branched chain alkyl or alkenyl of 2 to 10 carbon atoms optionally substituted up to 2 times by hydroxyl,

R ⁸ represents hydrogen or halogen,

R ⁹ is hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight or branched chain alkoxy having up to 5 carbon atoms or the formula -NR ¹⁵ R ¹⁶ wherein R ¹⁵ and R ¹⁶ The same or different, having the meanings of R ⁴ and R ⁵ mentioned above); or

R ⁸ and R ⁹ together form a group of formula = O or = NR ¹⁷ , wherein R ¹⁷ represents hydrogen or straight or branched chain alkyl, alkoxy or acyl of up to 6 carbon atoms Group;

E represents a cycloalkyl of 3 to 8 carbon atoms, or a straight or branched chain alkyl of 8 or less carbon atoms, optionally substituted by cycloalkyl or hydroxyl of 3 to 8 carbon atoms, or Phenyl optionally substituted by halogen or trifluoromethyl;

R ¹ represents a straight or branched chain alkyl of up to 6 carbon atoms substituted by hydroxyl;

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

R ² and R ³ together with a nitrogen atom are nitro, cyano, halogen, trifluoromethyl, hydroxyl, carboxyl, straight or branched chain alkoxy or alkoxycarbonyl, phenyl having up to 5 carbon atoms, or Or optionally substituted by the same or different groups up to three times with straight or branched chain alkyl of up to 5 carbon atoms which may be partly substituted by hydroxyl, and / or of the formula -NR ²⁰ R ²¹ , wherein R ²⁰ and R ²¹ have the meanings R ¹⁸ and R ¹⁹ mentioned above and may be the same or different) and are no more than 4 heteroatoms in the group consisting of S, N and / or O To form an optionally benzo-fused, 5-7 membered saturated, partially unsaturated or unsaturated mono- or bicyclic heterocycle having

The novel 2-amino-substituted pyridine according to the invention may also exist in the form of its salts. Generally, salts with organic or inorganic bases or acids are mentioned.

In the present invention, physiologically acceptable salts are preferable. Physiologically acceptable salts of the compounds according to the invention may be salts of the substances according to the invention with inorganic acids, carboxylic acids or sulfonic acids. For example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid, in particular desirable.

Physiologically acceptable salts may be metal salts or ammonium salts of the compounds according to the invention with free carboxyl groups. For example, sodium, potassium, magnesium or calcium salts, and also ammonium salts derived from ammonia, or ethylamine, diethylamine, triethylamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, Particular preference is given to organic amines such as arginine, lysine, ethylene diamine or 2-phenylethylamine.

The compounds according to the invention can exist in the form of enantiomeric (enantiomers) in phase and enantiomeric (diastereoisomer) stereoisomers. The present invention relates to enantiomers or diastereomers, or mixtures thereof, respectively. Mixtures of enantiomers and diastereomers can be separated into a single component of the stereoisomer in a known manner.

Optionally benzo-fused heterocycles in the present invention are generally saturated or unsaturated 5-7 membered, preferably 5-7, which may contain up to 3 heteroatoms in the group consisting of S, N and / or O. 6-membered heterocycle. Examples that may be mentioned are indolyl, isoquinolyl, quinolyl, benzo [b] thiophenyl, benzo [b] furaryl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl , Morpholinyl or piperidyl. Preference is given to quinolyl, furyl, pyridyl, thienyl or morpholinyl.

Preferred are the compounds of formula (I) and salts thereof according to the invention, as follows.

A is fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, nitro, trifluoromethoxy, or straight or branched chain alkyl, acyl or alkoxy of up to 6 carbon atoms, or of formula -NR ⁴ R Naph optionally substituted with the same or different groups up to 3 times by groups of ⁵ (wherein R ⁴ and R ⁵ are the same or different and represent hydrogen, phenyl or straight or branched chain alkyl having up to 4 carbon atoms) Butyl or phenyl;

D represents phenyl optionally substituted by nitro, fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy, or is represented by the formula R ⁶ -L or

[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, benzothiazolyl, phenoxatiin-2-yl, benzoxazolyl, furyl, quinolyl or furin-8-yl,

Here, in the case of nitrogen-containing rings, the ring system is fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight or branched chain having up to 4 carbon atoms via N functional groups. acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl, triazolyl, tetrazolyl, benzoxazolyl or thiazolyl which is optionally substituted by identical or different groups to the phenyl up to three times (or), the formula -OR ^10, - SR ¹¹ or —SO ₂ R ¹² , wherein R ¹⁰ , R ¹¹ and R ¹² are the same or different, partially by phenyl, fluorine or chlorine, or by straight or branched chain alkyl of up to 4 carbon atoms Substituted with the same or different groups up to

R ⁶ or R ⁷ is Represents a group of

L represents straight or branched chain alkyl or alkenyl of 2 to 8 carbon atoms, optionally substituted up to 2 times by hydroxyl,

R ⁸ represents hydrogen, fluorine, chlorine or bromine,

R ⁹ is hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight or branched alkoxy having up to 4 carbon atoms or a formula -NR ¹⁵ R ¹⁶ (wherein R ¹⁵ And R ¹⁶ are the same or different and have the meanings of R ⁴ and R ⁵ mentioned above; or

R ⁸ and R ⁹ together form a group of formula = O or = NR ¹⁷ , wherein R ¹⁷ represents hydrogen or straight or branched chain alkyl, alkoxy or acyl of up to 4 carbon atoms. Group;

E represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or up to 6 carbon atoms optionally substituted by cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cycloheptyl, or by hydroxyl A straight or branched chain alkyl of or phenyl optionally substituted by fluorine, chlorine or trifluoromethyl;

R ¹ represents straight or branched chain alkyl of up to 5 carbon atoms substituted by hydroxyl;

R ² and R ³ are the same or different and represent hydrogen, phenyl, benzyl, cyclopropyl, cyclopentyl, cyclohexyl, or straight or branched chain alkyl of 5 or less carbon atoms, acyl, or formula -CO-NR ¹⁸ R ¹⁹ , wherein R ¹⁸ and R ¹⁹ are the same or different and represent hydrogen, phenyl, benzyl, or represent straight or branched chain alkyl of up to 5 carbon atoms, or

R ² and R ³ together with the nitrogen atom are a pyryl, imidazolyl, pyrrolidinyl, morpholine, piperidinyl or piperazinyl ring or Wherein the heterocycle is hydroxyl, trifluoromethyl, fluorine, chlorine, bromine, hydroxyl, carboxyl, methylhydroxyl, or straight or branched chain alkoxy or alkoxycarbonyl having up to 4 carbon atoms A compound of formula I optionally substituted by.

Particular preference is given to compounds of the formula (I) and salts thereof according to the invention, as follows.

A is fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, nitro, trifluoromethoxy, or straight or branched chain alkyl, acyl or alkoxy of up to 5 carbon atoms, or of formula -NR ⁴ R Naphthyl or phenyl optionally substituted by a group of ⁵ (wherein R ⁴ and R ⁵ are the same or different and represent hydrogen, phenyl or straight or branched chain alkyl having up to 3 carbon atoms);

D represents phenyl optionally substituted by nitro, fluorine, chlorine or bromine, or is of the formula R ⁶ -L or

[Wherein R ⁶ and R ⁷ are the same or different and represent cyclopropyl, cyclopentyl or cyclohexyl or phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, phenoxatiin-2 -Yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl or furin-8-yl,

Here, in the case of nitrogen-containing rings, the ring system is fluorine, chlorine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight or branched chain acyl with up to 3 carbon atoms via N functional groups. Optionally substituted with the same or different groups up to 3 times by alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl, triazolyl, tetrazolyl, benzothiazolyl or phenyl and are represented by 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 partially up to 2 times with phenyl, fluorine, chlorine, or with straight or branched chain alkyl of up to 3 carbon atoms Substituted with the same or different groups)

R ⁶ or R ⁷ is Represents a group of

L represents straight or branched chain alkyl or alkenyl of up to 6 carbon atoms optionally substituted up to 2 times by hydroxyl,

R ⁸ represents hydrogen or fluorine,

R ⁹ is hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, methoxy or the formula -NR ¹⁵ R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are the same or different, Group having the meanings of R ⁴ and R ⁵ mentioned above), or

R ⁸ and R ⁹ together form a group of formula = O or = NR ¹⁷ , wherein R ¹⁷ represents hydrogen or straight or branched chain alkyl, alkoxy or acyl of up to 3 carbon atoms Group;

E represents cyclopropyl, cyclopentyl or cyclohexyl, or phenyl optionally substituted by fluorine or trifluoromethyl, or straight or branched chain alkyl of up to 4 carbon atoms optionally substituted by hydroxyl;

R ¹ represents straight or branched chain alkyl of up to 4 carbon atoms substituted by hydroxyl;

R ² and R ³ are the same or different and represent hydrogen, phenyl, benzyl, cyclopropyl, cyclopentyl, or straight or branched chain alkyl, acyl with up to 5 carbon atoms, or formula -CO-NR ¹⁸ R ¹⁹ Wherein R ¹⁸ and R ¹⁹ are the same or different and represent hydrogen, phenyl, benzyl, or represent straight or branched chain alkyl of up to 4 carbon atoms, or

R ² and R ³ together with the nitrogen atom are a pyryl, morpholinyl, pyrrolidinyl or piperidinyl ring or formula Wherein the heterocycle is hydroxyl, trifluoromethyl, fluorine, chlorine, bromine, hydroxyl, carboxyl, methylhydroxyl, or straight or branched chain alkoxy or alkoxycarbonyl having up to 3 carbon atoms A compound of formula I optionally substituted by.

In addition, a process for preparing a compound of formula (I) according to the invention has also been found, which has the following characteristics.

[A] As a Grignard / Wittig reaction, group D is first introduced into the compound of formula II, in which case the substituents are induced in this step by conventional methods, preferably by reduction, and The roxyl protecting group is removed at the final stage.

Wherein A, E, R ² and R ³ have the meanings mentioned above,

R ²² has the meaning of R ¹ mentioned above, wherein the hydroxyl functional group is preferably in a form protected by tetrahydropyranyl.

[B] The compound of formula III is converted by oxidation to a compound of formula IV, where appropriate, the substituent D is changed in this step, and finally the alkoxycarbonyl group is hydroxymethyl functional group under argon atmosphere by a conventional method. Reduced, and if appropriate all substituents are changed and / or introduced by conventional methods.

Wherein A, D, E, R ² and R ³ have the meanings mentioned above,

R ²³ represents C ₁ -C ₄ -alkyl.

The process according to the invention can be illustrated, for example, by the following scheme:

[A]

[B]

Suitable solvents for process [A] include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fraction, or dichloromethane Halogenohydrocarbons such as trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoramide, Acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Toluene or tetrahydrofuran is preferred.

Suitable bases in each step are conventional strongly basic compounds. Such compounds are preferably organolithium compounds such as, for example, N-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or for example lithium diisopropylamide, sodium amide, potassium amide or Amides such as lithium hexamethylsilylamide, or hydrogenated alkali metals such as sodium hydride or potassium hydride. N-butyllithium, sodium hydride and lithium diisopropylamide are particularly preferably used.

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

As the Wittich reagent, conventional reagents are suitable. Brominated 3-trifluoromethylbenzyltriphenylphosphonium is preferred.

The base is generally suitable for one of the bases, with sodium amide being preferred.

The base is used from 0.1 mol to 5 mol, preferably from 0.5 mol to 2 mol with respect to 1 mol of the starting compound.

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

The Wittich reaction is generally carried out at atmospheric pressure. However, it is also possible to carry out the process at reduced or elevated pressure (eg in the range from 0.5 to 5 bar).

Suitable solvents for the oxidation of Method [B] include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum oil, or Halogenohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphora Mid, acetonitrile, acetone, nitromethane or water. It is also possible to use mixtures of the solvents mentioned. Acetonitrile and water are preferred.

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

The oxidant uses 1 to 10 moles, preferably 2 to 5 moles, per 1 mole of the compound of formula IV.

In general, the oxidation proceeds in the temperature range of -50 ° C to + 100 ° C, preferably 0 ° C to room temperature.

In general, oxidation proceeds at atmospheric pressure. However, it is also possible to carry out under elevated or reduced pressure.

In general, the reduction is carried out using a reducing agent, preferably with a reducing agent suitable for the reduction of the ketone to the hydroxy compound. In this case, in the inert solvent, reduction with a metal hydride or metal hydride complex is particularly suitable if appropriate in the presence of trialkylborane. For example, hydrogenated metals such as lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkylhydridoborohydride or lithium aluminum hydride or diisobutylaluminum hydride (DIBAH) Preference is given to carrying out the reduction using a complex. Very particular preference is given to carrying out the reduction with sodium borohydride or DIBAH in the presence of triethylborane.

Generally, the reducing agent is used in an amount of 4 to 10 moles, preferably 4 to 5 moles per one mole of the compound to be reduced.

In general, the reduction proceeds in the temperature range of -78 ° C to + 50 ° C, preferably -78 ° C to 0 ° C, particularly preferably -78 ° C, in each case depending on the choice of reducing agent and solvent.

Generally, the reduction proceeds at normal pressure, but it is also possible to carry out at elevated or reduced pressure.

In general, the reduction is carried out using a reducing agent, preferably with a reducing agent suitable for the reduction of the ketone to the hydroxy compound. In this case, reduction with a metal hydride or metal hydride complex is particularly suitable in the inert solvent, if appropriate in the presence of trialkylborane. The reduction is, for example, a hydrogenated metal complex such as lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkylhydridoborohydride, diisobutylaluminum hydride or lithium aluminum hydride It is preferably performed using. Very particular preference is given to carrying out the reduction using hydrogenated diisobutylaluminum and sodium borohydride.

Generally, the reducing agent is used in an amount of 1 to 6 moles, preferably 1 to 4 moles per 1 mole of the compound to be reduced.

In general, in the temperature range of -78 ° C to + 50 ° C, preferably -78 ° C to 0 ° C for DIBAH, and for NaBH ₄ , reduction proceeds at 0 ° C to room temperature.

Generally, the reduction proceeds at normal pressure, but it is also possible to carry out at elevated or reduced pressure.

Generally, the protecting group is removed in one of the alcohols and THF, preferably methanol / THF, in the presence of hydrochloric acid or p-toluenesulfonic acid in methanol at a temperature range of 0 ° C. to 50 ° C., preferably at room temperature, at atmospheric pressure.

Examples of induction methods may mention reaction forms such as reduction, hydrogenation, halogenation, Wittig / Grignard reactions, alkylation and amidation.

Suitable bases for each step are conventional strong base compounds. Such bases are preferably organolithium compounds such as, for example, N-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or for example lithium diisopropylamide, sodium amide, potassium amide Or amides such as lithium hexamethylsilylamide, or hydrogenated alkali metals such as sodium or potassium hydride. N-butyllithium, sodium hydride and lithium diisopropylamide are particularly preferably used.

In addition, the base is a conventional inorganic base is suitable. Such bases preferably include alkali metal hydroxides or alkaline earth metal hydroxides, for example sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium carbonate or potassium carbonate or sodium hydrogen carbonate. Sodium hydroxide or potassium hydroxide is particularly preferably used.

Suitable solvents for each reaction step are alcohols such as methanol, ethanol, propanol, butanol or tert-butanol. tert-butanol is preferred.

If appropriate, some reaction steps need to be carried out under a protective gas atmosphere.

Generally, halogenation is carried out in one of the above chlorinated hydrocarbons or toluene.

Suitable halogenating agents are, for example, diethylaminosulfur trifluoride (DAST) or SOCl ₂ .

In general, halogenation proceeds in a temperature range of -78 ° C to + 50 ° C, preferably -78 ° C to 0 ° C.

Generally, halogenation proceeds at normal pressure, but it is also possible to carry out under elevated or reduced pressure.

In this case, an inert organic solvent which does not change under the reaction conditions is suitable as the solvent for the amidation. Such solvents include ethers such as diethyl ether or tetrahydrofuran, dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloro Halogenohydrocarbons such as roethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoramide. It is also possible to use mixtures of these solvents. Particular preference is given to dichloromethane, tetrahydrofuran, acetone or dimethylformamide.

In general, bases that can be used for amidation are inorganic or organic bases. Such bases are preferably alkali metal hydroxides such as sodium or potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as sodium or potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, sodium methoxide, potassium methoxide Seeds, alkali or alkaline earth metal alkoxides such as sodium ethoxide, potassium ethoxide or potassium tert-butoxide, organic amines such as triethylamine (trialkyl- (C ₁ -C ₆ ) amine), or 1,4 With diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine The same heterocycle is included. It is also possible to use alkali metals such as sodium and their hydrides such as sodium hydride as the base. Sodium carbonate, potassium carbonate and triethylamine are preferred.

The base is used in an amount of 1 to 5 moles, preferably 1 to 3 moles per 1 mole of the compound to be amidated.

In general, the amidation is carried out at temperatures of 0 ° C to 150 ° C, preferably of + 20 ° C to + 110 ° C.

Amidation can be carried out at atmospheric pressure, elevated pressure or reduced pressure (eg 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.

As the alkylation solvent, a conventional organic solvent which does not change under the reaction conditions is suitable. Such solvents are preferably ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fraction, or dichloromethane, triclo Halogenohydrocarbons such as romethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoramide, 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 above solvents at temperatures and atmospheric pressures from 0 ° C. to + 150 ° C., preferably from room temperature to + 100 ° C.

Reduction is carried out according to the abovementioned method.

The compounds of formula (II) are in some cases known or in some cases novel compounds, and can be prepared, for example, by the following methods.

First a compound of formula (V) is reacted with an amine of formula (VI) to convert it to a compound of formula (VII), and in a further step the alkoxycarbonyl group CO ₂₃ R ²⁴ is first reduced to the corresponding alkylhydroxyl functional group and finally another alkoxy The carbonyl functional group is reacted to obtain a formyl group.

HNR ² R ³

Wherein A, E, R ² , R ³ and R ²³ have the meanings mentioned above,

R ²⁴ and R ²⁵ are the same or different and represent C ₁ -C ₄ -alkyl.

Suitable solvents for all processes include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fraction, or dichloromethane, Halogenohydrocarbons such as trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoramide, aceto Nitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Acetonitrile and dimethylformamide are preferred.

As the base for each step, conventional strong basic compounds are suitable. Such bases include organolithium compounds such as N-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides such as lithium diisopropylamide, sodium amide, potassium amide or lithium hexamethylsilylamide, or Hydrogenated alkali metals such as sodium hydride or potassium hydride are preferably included.

In general, the base is used in each case in an amount of 1 to 10 moles, preferably 1 to 3 moles, per 1 mole of the compound of formula V.

In general, the reaction proceeds at a temperature from room temperature to + 120 ° C., preferably from 80 ° C. to 120 ° C., depending on the solvent in each case.

In general, the reaction is carried out at atmospheric pressure, but it is also possible to carry out at elevated or reduced pressure.

Compounds of formulas (V) and (VI) are known per se or can be prepared by conventional methods.

Compounds of formula VI are in some cases known or novel and may be prepared as described above.

The compound of formula III is novel in some cases, and the compound of formula VIII is first converted into a compound of formula X by reacting with a compound of formula IX and then reacted with an aldehyde of formula XI The compound can be obtained and finally prepared by reacting with a compound of formula XIII.

D'-CO-CH ₃

E-CO ₂ -R ²⁶

A-CHO

In the formula, D 'represents an aryl group mentioned for D,

R ²⁶ represents C ₁ -C ₄ -alkyl,

A, E, R ²³ , R ² and R ³ have the meanings mentioned above.

In each step, suitable reaction solvents include water or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions. Or halogenohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethyl Phosphoramide, acetonitrile, acetone or nitromethane, or alcohols such as methanol, ethanol or propanol. It is also possible to use mixtures of the solvents mentioned. Toluene is preferred.

In general, the reaction is carried out at atmospheric pressure. However, it is also possible to carry out the process at reduced or elevated pressure (eg in the range from 0.5 to 5 bar).

The compounds of formula (VIII), (IX), (XI) and (XIII) are in some cases known or may be prepared by conventional methods.

The compounds of the formulas (X) and (XII) are in some cases novel and may be prepared as mentioned above.

The compounds of formula (I) according to the invention have a very broad pharmacological action.

The compounds of formula (I) according to the invention have valuable pharmacological properties that are superior to the prior art, in particular they are very effective inhibitors of cholesterol ester transfer protein (CEPT) and stimulate the reverse transfer of cholesterol. The active compounds according to the invention increase HDL cholesterol levels while simultaneously lowering LDL cholesterol levels in the blood. Thus, they can be used to treat lipoprotein hyperemia, hypolipoemia, lipid disorders, hypertriglyceridemia, hyperlipidemia complications or atherosclerosis.

The pharmacological action of the substances according to the invention was determined by the following test.

<CETP Inhibition Test>

Obtaining CETP

CETP was obtained from human plasma in partially purified form by fractional centrifugation and column chromatography and used for testing. To this end, human plasma is adjusted with NaBr to have a density of 1.21 g / ml and centrifuged at 4 ° C. for 18 hours at 50,000 rpm. The bottom fraction (d> 1.21 g / ml) was placed in a Sephadex® Phenyl-Sepharose 4B (Pharmacia) column and washed with 0.15 M NaCl / 0.001 M Tris HCl (pH 7.4). Then eluted with distilled water. The CETP active fractions are collected, dialyzed with 50 mM Na acetate at pH 4.5 and placed in a CM-Sepharose® (Pharmacia) column. Eluted with a straight concentration gradient 0-1 M NaCl. The CETP fractions were combined and dialyzed with 10 mM Tris HCl, pH 7.4, and further purified by chromatography on a Mono Q® column (from Pharmacia).

Obtaining Radiolabeled HDL

50 ml of human clean EDTA plasma were adjusted with NaBr to a density of 1.12 and centrifuged at 4 ° C. with a Ty 65 rotor for 18 hours at 50,000 rpm. Use top layer to get cold LDL. The lower layer was dialyzed three times with 4 l of PDB buffer solution (10 mM Tris HCl, pH 5.4, 0.15 mM NaCl, 1 mM EDTA, 0.02% NaN ₃ ). 20 μl of 3H-cholesterol (Dupont NET-725; 1 μC / μl dissolved in ethanol) was added per 10 ml of retention volume and the mixture was incubated at 37 ° C. under nitrogen for 72 hours.

The batch was then adjusted with NaBr to a density of 1.21 and centrifuged at 20 ° C. with a Ty 65 rotor for 18 hours at 50,000 rpm. The upper layer was recovered and the lipoprotein fractions were purified by gradient centrifugation. To this end, radiolabeled isolated lipoprotein fractions were adjusted to a density of 1.26 using NaBr. Each 4 ml of this solution in a centrifuge tube (SW 40 rotors) (PDB buffer and solution density of NaBr) was covered with a layer of 4 ml of solution of 1.21 and 4.5 ml of solution of 1.063, followed by 24 at 38,000 rpm and 20 ° C. Centrifuged with SW 40 rotor for hours. The intermediate layer containing radiolabeled HDL lying between densities 1.063 and 1.21 was dialyzed three times with 100 times volume PDB at 4 ° C. The residue contains radiolabeled ³ H-CE-HDL, which was adjusted to about 5 × 10 ⁶ cpm per ml for use in testing.

<CETP Exam>

To test CETP activity, the transfer of human HD lipoprotein ^{3 3} H-cholesterol ester to biotinylated LD lipoprotein was measured. The reaction was terminated by the addition of streptavidin-SPA (streptavidin-SPA®) beads (manufactured by Amersham) and the transferred radioactivity was measured directly with a liquid scintillation counter.

In the test batch, 10 μl of HDL- ³ H-cholesterol ester (about 50,000 cpm) was added with 10 μl of CETP (1 mg / ml) and 3 μl of material to be tested (dissolved in 10% DMSO / 1% RSA). Incubation was performed with 10 μl of biotin-LDL (from Amersham) in mM Hepes / 0.15 M NaCl / 0.1% bovine serum albumin / 0.05% NaN ₃ (pH 7.4) at 37 ° C. for 18 hours. Then 200 μl of SPA-streptavidin bead solution (TRKQ 7005) was added and the mixture was further incubated with shaking and measured in a scintillation counter. The control sample used is a corresponding culture containing 10 μl of buffer solution, 10 μl of CETP at 4 ° C. and 10 μl of CETP at 37 ° C.

The transferred activity was graded at a transfer rate of 100% in a control vessel containing CETP at 37 ° C. Substrate concentrations at which this transition was reduced by half are indicated by IC ₅₀ values.

The table below shows IC ₅₀ values (mol / l) for CETP inhibitors.

Example number IC ₅₀ value (mol / l) 6 2.4 × 10 ^-7 9 6 × 10 ^-8 10 6 × 10 ^-7

<In Vitro Activity of Compounds According to the Present Invention>

Indoor breeding Syrian golden hamsters were fasted for 24 hours and anesthetized (0.8 mg of atropine per kg, 0.8 mg of Ketavet® per kg, subcutaneously administered, nembutal per kg after 30 minutes). (Nembutal) 50 mg intraperitoneally) The cannula was then inserted with the jugular vein exposed. Test substance is dissolved in a suitable solvent (typically, Adalat placebo solution: 60 g of glycerol, 100 ml of H ₂ O, PEG-400 to 1000 ml) and administered to the animal via a PE catheter inserted into the jugular vein It was. Control animals received the same volume of solvent without test substance. The vein was then tied and the wound closed. In addition, substances dissolved in DMSO or suspended in 0.5% Tyrose may be administered orally via gavage. Control animals received the same volume of solvent without test substance.

At each time period up to 24 hours post dosing, blood (about 250 μl) was drawn from the animals in the retro-orbital vena cava. After coagulation by incubation at 4 ° C. overnight, the blood was centrifuged at 6000 × g for 10 minutes. CETP activity in the serum thus obtained was measured by modified CETP test. As described in the CETP test above, the transfer of ³ H-cholesterol esters from HD lipoproteins to biotinylated LD lipoproteins was measured.

The reaction was completed by the addition of Streptavidin-SPA ^R beads (manufactured by Amersham) and the transferred radioactivity was measured directly with a liquid scintillation counter.

Test batches were performed as described under the "CETP" test. Only 10 μl of serum of CETP was replaced with 10 μl of the corresponding serum sample. The control sample used is a culture corresponding to the serum of untreated animals.

The metastasized activity in a control batch containing control serum was graded at a metastasis rate of 100%. The concentration of the substance whose transition has been reduced by one half is indicated by the ED ₅₀ value.

In vivo activity of compounds according to the invention

In experiments to determine the activity by oral administration of lipoproteins and triglycerides, test substances dissolved in DMSO and suspended in 0.5% tyros were administered via gavage to orally indoor Syrian golden hamsters. To measure CETP activity, blood (approximately 250 μl) was drawn from the back of the eye before the start of the experiment. The test substance was then administered orally via gavage. Control animals received the same volume of solvent without test substance. Animals were then withdrawn and blood was taken from the vena cava behind the eyes at each time period up to 24 hours after substance administration.

After coagulation by incubation at 4 ° C. overnight, the blood was centrifuged at 6000 × g for 10 minutes. The content of cholesterol and triglycerides in the serum thus obtained was measured with the help of a commercially available enzyme test modification method (cholesterol enzyme 14366 Merck, triglyceride 14364 Merck). Serum was diluted in a suitable manner using physiological saline solution.

100 μl of serum dilution was mixed with 100 μl of test substance in a 96-hole plate and incubated for 10 minutes at room temperature. Subsequently, an optical plate-recording apparatus was used to measure the light density at a wavelength of 492 nM. Triglyceride or cholesterol concentrations contained in the samples were determined with the aid of equally measured standard curves.

After precipitation of the ApoB-containing lipoprotein, the content of HDL cholesterol was measured by reagent mixture (Sigma 352-4 HDL cholesterol reagent) according to the manufacturer's instructions.

In vivo activity in transgenic hCETP mice

Genetically engineered mice bred indoors [Dinchuck, Hart, Gonzalez, Karmann, Schmidt, Wirak; BBA (1995), 1295, 301 were dosed with the substance to be tested. Before starting the experiment, blood was collected from the back of the mouse to determine the amount of cholesterol and triglycerides in the serum. Incubation at 4 ° C. overnight and then centrifugation at 6000 × g yielded the hamster's serum as described above. After 1 week, the blood of mice was drawn to measure lipoproteins and triglycerides. Changes in measured parameters are expressed as% change relative to starting value.

The invention also relates to the combination of a 2-amino-substituted pyridine of formula (I) with a glucosidase and / or amylase inhibitor for the treatment of family history of hyperlipidemia, obesity (fat accumulation) and diabetes mellitus. Glucosidase and / or amylase inhibitors of the present invention include, for example, acarbose, adifosine, bogliboss, migritol, emiglytate, MDL-25637, camigliose (MDL-73945), tenamimi State, AI-3688, trestatin, pradimycin-Q and salvostatin.

Preference is given to combinations of acarbose, miglitol, emiglytate or boligose with one of the above compounds of formula I according to the invention.

In addition, the compounds of the present invention may be combined with cholesterol-lowering bastatin or ApoB-lowering components to treat lipid disorders, hyperlipidemic complications, hypercholesterolemia or hypertriglyceridemia.

The combinations mentioned can be used for the primary or secondary prevention of coronary heart disease (eg myocardial infarction).

Vastatin of the present invention includes, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin. ApoB-lowering agents include, for example, MTB inhibitors.

Preference is given to combinations with cerivastatin or ApoB inhibitors with one of the abovementioned compounds of formula (I) according to the invention.

The novel active compounds may be prepared in conventional formulations such as tablets, tablets, tablets, granules, aerosols, syrups, emulsions, suspensions and solutions by known methods using inert and nontoxic pharmaceutically suitable excipients or solvents. Can be converted to zero. In this relationship, the therapeutically active compound should be present in each case in an amount sufficient to achieve a concentration of about 0.5 to 90% by weight of the total mixture, ie the stated dosage range.

The formulations may, for example, use solvents and / or excipients, where appropriate, emulsifiers and / or dispersants, and in some cases, for example, organic solvents as auxiliary solvents if water is used as a diluent. Prepared by increasing the active compound.

Administration is carried out intravenously, parenterally, sublingually or orally, preferably orally, in conventional manner.

For parenteral administration, solutions of the active compounds can be employed using suitable liquid excipients.

In general, for intravenous administration, an amount of about 0.001 to 1 mg per kg body weight, preferably about 0.01 to 0.5 mg per kg body weight, to achieve an effective result is about 0.01 to per kg body weight for oral administration. It has been proven that daily dosages of 20 mg, preferably 0.1 to 10 mg, are beneficial.

Nevertheless, depending on the body weight or route of administration, if appropriate, it may be necessary to deviate from the stated amounts depending on the individual's behavioral characteristics of the drug, its formulation method, and the time or interval of administration. Thus, in some cases, an amount less than the minimum amount of the above-mentioned amounts may be sufficient, while in other cases, the above-mentioned upper limit should be exceeded. In the case of relatively high doses, it may be desirable to divide each dose into multiples throughout the day.

<Abbreviation used>

CY = cyclohexane

EA = ethyl acetate

PE = petroleum ether

THF = tetrahydrofuran

DAST = dimethylaminosulfur trifluoride

PTS = para-toluenesulfonic acid

PDC = pyridinium dichromate

PE / EA = petroleum ether / ethyl acetate

DIBAH = hydrogenated diisobutylaluminum

HCl = hydrochloric acid

Starting material

<Example 1>

3-ethyl 5-methyl 2-benzylamino-6-cyclopentyl-4- (4-fluoro-phenyl) -pyridine-3,5-dicarboxylate

3-ethyl 5-methyl 2-chloro-6-cyclopentyl-4- (4-fluorophenyl) -pyridine-3,5-dicarboxylate 26 g (64 mmol), benzylamine 14 ml (130 mmol) And 17 g (160 mmol) of sodium carbonate were stirred at reflux for 2 days in 220 ml of acetonitrile. Further 6.9 ml (64 mmol) of benzylamine and 6.8 g (64 mmol) of sodium carbonate were added and the mixture was stirred for 20 more hours under reflux. After cooling to room temperature, it was suction filtered with silica gel and the silica gel was washed with 100 ml of ethyl acetate. After concentration in vacuo, the partially crystallized residue was dissolved in 100 ml of petroleum ether with stirring. The precipitated solid was suction filtered, washed with some petroleum ether and dried in vacuo. The remaining mother liquor was concentrated and chromatographed on silica gel (200 g of silica gel 230-400 mesh, d = 3.5 cm, eluent toluene).

Yield: 25.1 g (82% of theory)

R _f = 0.54 (PE / EA 8: 1)

<Example 2>

Methyl 6-benzylamino-2-cyclopentyl-4- (4-fluoro-phenyl) -5-hydroxymethyl-nicotinate

A solution of 14.8 g (31.1 mmol) of Example 1 was added dropwise to 32.6 ml of a 1.0M solution of LiAlH ₄ in THF over 5 minutes at -40 ° C. under argon and the mixture was allowed to warm to room temperature for 40 minutes. Stirred for 30 minutes, cooled to -15 ° C and 5.0 ml of H ₂ O was added to terminate the reaction. The resulting mixture was suction filtered through diatomaceous earth and the residue was washed with ethyl acetate. The combined organic layers were washed with H ₂ O (twice) and saturated NaCl solution, dried using Na ₂ SO ₄ , filtered and concentrated, and the product was purified by silica gel 60 (petroleum ether / ethyl acetate = 5/1). Chromatography.

Yield: 13.2 g (97% of theory)

R _f = 0.25 (petroleum ether / ethyl acetate = 5/1)

<Example 3>

Methyl 6-benzylamino-2-cyclopentyl-4- (4-fluoro-phenyl) -5- (tetrahydro-pyran-2-yloxymethyl) -nicotinate

779 mg (3.1 mmol) of pyridinium p-toluenesulfonate (PPTS) and 8.8 ml (93 mmol) of 3,4-dihydro-2H-pyran were added to 13.5 g of the compound of Example 2 in 300 ml of anhydrous CH ₂ Cl ₂ ( 31.0 mmol), and the mixture was stirred at rt for 16 h. Dilute with ether and wash with saturated NaCl solution. The organic layer was dried over Na ₂ S0 ₄ , concentrated and the crude product was chromatographed on silica gel 60 (petroleum ether / ethyl acetate = 20/1, then ethyl acetate).

Yield: 9.9 g (59% of theory)

R _f = 0.53 (petroleum ether / ethyl acetate = 5/1)

<Example 4>

[6-benzylamino-2-cyclopentyl-4- (4-fluoro-phenyl) -5- (tetrahydro-pyran-2-yloxy-methyl) -pyridin-3-yl] methanol

23 ml (34.3 mmol) of a hydrogenated diisobutylaluminum (DIBAH) 1.5 M solution in toluene were slowly added dropwise over 10 minutes under argon to a solution of 4.21 g (8.58 mmol) of the compound of Example 3. The mixture was warmed to 0 ° C., stirred at this temperature for 1 hour and 5.7 ml of 1.5 M DIBAH solution was added again. After 1 hour, the mixture was hydrolyzed with 10 ml of water and extracted twice with 300 ml of ethyl acetate with stirring. The gel aqueous solution layer was suction filtered through diatomaceous earth, washed twice with H ₂ O and three times with ethyl acetate. After layer separation, the combined organic layers were washed with saturated NaCl solution, dried over Na ₂ SO ₄ , concentrated and chromatographed with silica gel 60 (CH ₂ Cl ₂ then ethyl acetate).

Yield: 3.5 g (83% of theory)

R _f = 0.31 (petroleum ether / ethyl acetate = 5/1)

Example 5

6-benzylamino-2-cyclopentyl-4- (4-fluoro-phenyl) -5- (tetrahydro-pyran-2-yloxy-methyl) -pyridine-3-carbaldehyde

8.5 g (22.2 mmol) of pyridinium dichromate (PDC) were added to a solution of 3.6 g (7.3 mmol) of the compound of Example 4 in 200 ml of anhydrous CH ₂ Cl ₂ in 6 portions at 0 ° C. over 3 hours, and The mixture was stirred at rt for 30 min. The reaction mixture was added to 50 g of silica gel 60 and the product eluted with CH ₂ Cl ₂ / triethylamine 100: 1. After concentration, the residue was chromatographed on silica gel 60 (petroleum ether / ethyl acetate = 20/1, then 2/1).

Yield: 1.64 g (45% of theory) + 417 mg of recovered starting material (11% of theory)

R _f = 0.50 (petroleum ether / ethyl acetate = 10/1)

<Example 6>

[6-Benzylamino-2-cyclopentyl-4- (4-fluoro-phenyl) -5- (tetrahydro-pyran-2-yloxy-methyl) -pyridin-3-yl]-(4-trifluoro Romethyl-phenyl) -Methanol

32 ml (4.6 mmol) of a freshly prepared, brominated p-trifluoromethyl-phenyl-magnesium 0.144 M solution in THF were added to 800 mg (1.64 mmol) of the compound of Example 5 in dry THF under argon at −20 ° C. . The mixture was stirred for 2 hours at room temperature, 30 ml of 10% NH ₄ Cl solution was added and extracted with ethyl acetate. After washing with H ₂ O and NaCl solution, dried over Na ₂ SO ₄ and concentrated, the residue was chromatographed on silica gel 60 (CH ₂ Cl ₂ then ethyl acetate).

Yield: 559 mg (54% of theory)

R _f = 0.53 (petroleum ether / ethyl acetate = 2/1)

<Example 7>

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

171 μl (1.3 mmol) of diethylaminosulfur trifluoride (DAST) were added to a solution of 549 mg (0.865 mmol) of the compound of Example 6 in anhydrous CH ₂ Cl ₂ at −30 ° C. and the mixture was added for 3 hours. After stirring at this temperature, 2.6 ml (3.89 mmol) of a DIBAH 1.5 M solution in toluene were added at this temperature. The cooling bath was removed and the mixture was stirred for 90 minutes at room temperature and the reaction was terminated by addition of 2 ml of saturated NaCl solution at 0 ° C. This mixture was suction filtered on diatomaceous earth and the residue was washed with H ₂ O, CH ₂ Cl ₂ and ethyl acetate. After separating the layers, the aqueous layer was washed with CH ₂ Cl ₂ , and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. Further purification was performed by chromatography on silica gel 60 (petroleum ether / ethyl acetate = 40/1).

Yield: 482 mg (90% of theory)

R _f = 0.43 (petroleum ether / ethyl acetate = 10/1)

<Example 8>

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

0.36 ml (5.82 mmol) of methyl iodide is added to a solution of 60 mg (0.097 mmol) of the compound of Example 7 and 109 mg (0.97 mmol) of potassium tert-butoxide (KOtBu) in 2 ml of anhydrous DMF, and the mixture is 40 Stir for minutes. 3 ml of saturated NaHCO ₃ solution was added and the mixture was extracted three times with ether, and the combined organic layers were washed with saturated NaCl solution, dried over Na ₂ SO ₄ and concentrated. Further purification was performed by chromatography on silica gel 60 (petroleum ether / ethyl acetate = 40/1).

Yield: 35 mg (57% of theory)

R _f = 0.18 (petroleum ether / ethyl acetate = 10/1)

<Manufacture 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 8 in 2 ml of THF was treated with 0.5 ml of 3M HCl and stirred at room temperature for 90 minutes. 4 ml of saturated NaHCO ₃ solution was added and the mixture was extracted with ethyl acetate (3 times) and the combined organic layers were washed with saturated H ₂ O and NaCl solution, dried over Na ₂ SO ₄ and concentrated. Further purification was performed by chromatography on silica gel 60 (petroleum ether / ethyl acetate = 20/1).

Yield: 24 mg (86% of theory)

R _f = 0.28 (petroleum ether / ethyl acetate = 10/1)

Claims (10)

2-Amino-substituted pyridine of formula I and salts thereof. <Formula I> Wherein A is halogen, hydroxyl, trifluoromethyl, nitro, trifluoromethoxy, or straight or branched chain alkyl, acyl, hydroxyalkyl or alkoxy having up to 7 carbon atoms, or To the same or different groups up to 5 times by a group of NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are the same or different and represent hydrogen, phenyl or straight or branched chain alkyl having up to 6 carbon atoms Optionally substituted aryl of 6 to 10 carbon atoms; D represents aryl of 6 to 10 carbon atoms optionally substituted by nitro, halogen, trifluoromethyl or trifluoromethoxy, or is represented by the formula R ⁶ -L or [Wherein R ⁶ and R ⁷ are the same or different and represent cycloalkyl having 3 to 6 carbon atoms, or aryl having 6 to 10 carbon atoms, or as S, N and / or O To form an optionally benzo-fused, saturated or unsaturated, mono-, non- or tricyclic 5- to 7-membered heterocycle having up to 4 carbon atoms with a heteroatom selected from the group consisting of Here, in the case of nitrogen-containing rings, the ring system is halogen, trifluoromethyl, hydroxyl, nitro, cyano, carboxyl, trifluoromethoxy, straight or branched chain acyl with up to 6 carbon atoms via the N functional group. Optionally having 3 or less heteroatoms in the group consisting of S, N and / or O, by alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl, by aryl of 6 to 10 carbon atoms Optionally substituted by the same or different groups by a 5-7 membered heterocycle of benzo-fused aromatics and / or 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 have from 6 to 6 carbon atoms, some of which may be substituted by the same or different groups up to 2 times by phenyl, halogen, or by straight or branched chain alkyl having up to 4 carbon atoms. represents a 10 aryl, R ¹³ R ¹⁴ are the same or different, or substituted by a group of R ⁴ and R ⁵ has the meaning of a) described above, R ⁶ or R ⁷ is Represents a group of L represents straight or branched chain alkyl or alkenyl of 2 to 10 carbon atoms optionally substituted up to 2 times by hydroxyl, R ⁸ represents hydrogen or halogen, R ⁹ is hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight or branched chain alkoxy having up to 5 carbon atoms or the formula -NR ¹⁵ R ¹⁶ wherein R ¹⁵ and R ¹⁶ The same or different, having the meanings of R ⁴ and R ⁵ mentioned above); or R ⁸ and R ⁹ together form a group of formula = O or = NR ¹⁷ , wherein R ¹⁷ represents hydrogen or straight or branched chain alkyl, alkoxy or acyl of up to 6 carbon atoms Group; E represents cycloalkyl having 3 to 8 carbon atoms, or straight or branched chain alkyl having 8 or less carbon atoms optionally substituted by cycloalkyl or hydroxyl having 3 to 8 carbon atoms, or halogen Or phenyl optionally substituted by trifluoromethyl; R ¹ represents a straight or branched chain alkyl of up to 6 carbon atoms substituted by hydroxyl; R ² and R ³ are the same or different and are hydrogen, phenyl, benzyl, cycloalkyl having 3 to 7 carbon atoms or straight or branched chain alkyl having 6 or less carbon atoms, acyl, or formula -CO-NR ¹⁸ R ¹⁹ Wherein R ¹⁸ and R ¹⁹ are the same or different and represent hydrogen, phenyl, benzyl, or represent straight or branched chain alkyl of up to 6 carbon atoms, or R ² and R ³ together with a nitrogen atom are selected from nitro, cyano, halogen, trifluoromethyl, hydroxyl, carboxyl, straight or branched chain alkoxy or alkoxycarbonyl, phenyl having up to 5 carbon atoms, or Optionally substituted by the same or different groups up to 3 times with a straight or branched chain alkyl of up to 5 carbon atoms which may be partially substituted by hydroxyl, and / or of the formula -NR ²⁰ R ²¹ , wherein R ²⁰ And R ²¹ has the meanings R ¹⁸ and R ¹⁹ mentioned above, which may be the same or different, and no more than four heteroatoms in the group consisting of S, N and / or O And optionally form a benzo-fused, 5-7 membered saturated, partially unsaturated or unsaturated mono- or bicyclic heterocycle. The method of claim 1, A is fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, nitro, trifluoromethoxy, or straight or branched chain alkyl, acyl or alkoxy of up to 6 carbon atoms, or of formula -NR ⁴ R Naph optionally substituted with the same or different groups up to 3 times by groups of ⁵ (wherein R ⁴ and R ⁵ are the same or different and represent hydrogen, phenyl or straight or branched chain alkyl having up to 4 carbon atoms) Butyl or phenyl; D represents phenyl optionally substituted by nitro, fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy, or is represented by the formula R ⁶ -L or [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, benzothiazolyl, phenoxatiin-2-yl, benzoxazolyl, furyl, quinolyl or furin-8-yl, Here, in the case of nitrogen-containing rings, the ring system is fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight or branched with up to 4 carbon atoms via N functional groups. chain acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl, triazolyl, tetrazolyl, benzoxazolyl or thiazolyl optionally substituted by identical or different groups to the phenyl up to three times (or), 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 partly by phenyl, fluorine or chlorine, or by straight or branched chain alkyl of up to 4 carbon atoms Or phenyl substituted with the same or different groups up to 2); or R ⁶ or R ⁷ is Represents a group of L represents straight or branched chain alkyl or alkenyl of 2 to 8 carbon atoms, optionally substituted up to 2 times by hydroxyl, R ⁸ represents hydrogen, fluorine, chlorine or bromine, R ⁹ is hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight or branched alkoxy having up to 4 carbon atoms or a formula -NR ¹⁵ R ¹⁶ (wherein R ¹⁵ And R ¹⁶ are the same or different and have the meanings of R ⁴ and R ⁵ mentioned above; or R ⁸ and R ⁹ together form a group of formula = O or = NR ¹⁷ , wherein R ¹⁷ represents hydrogen or straight or branched chain alkyl, alkoxy or acyl of up to 4 carbon atoms. Group; E represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or up to 6 carbon atoms optionally substituted by cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cycloheptyl, or by hydroxyl A straight or branched chain alkyl of or phenyl optionally substituted by fluorine, chlorine or trifluoromethyl; R ¹ represents straight or branched chain alkyl of up to 5 carbon atoms substituted by hydroxyl; R ² and R ³ are the same or different and represent hydrogen, phenyl, benzyl, cyclopropyl, cyclopentyl, cyclohexyl, or straight or branched chain alkyl of 5 or less carbon atoms, acyl, or formula -CO-NR ¹⁸ R ¹⁹ , wherein R ¹⁸ and R ¹⁹ are the same or different and represent hydrogen, phenyl, benzyl, or represent straight or branched chain alkyl of up to 5 carbon atoms, or R ² and R ³ together with the nitrogen atom are a pyryl, imidazolyl, pyrrolidinyl, morpholine, piperidinyl or piperazinyl ring or Wherein the heterocycle is hydroxyl, trifluoromethyl, fluorine, chlorine, bromine, hydroxyl, carboxyl, methylhydroxyl, or straight or branched chain alkoxy or alkoxycart having up to 4 carbon atoms. A compound of formula I and salts thereof, optionally substituted by carbonyl. The method of claim 1, A is fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, nitro, trifluoromethoxy, or straight or branched chain alkyl, acyl or alkoxy of up to 5 carbon atoms, or of formula -NR ⁴ R Naphthyl or phenyl optionally substituted by a group of ⁵ (wherein R ⁴ and R ⁵ are the same or different and represent hydrogen, phenyl or straight or branched chain alkyl having up to 3 carbon atoms); D represents phenyl optionally substituted by nitro, fluorine, chlorine or bromine, or is of the formula R ⁶ -L or [Wherein R ⁶ and R ⁷ are the same or different and represent cyclopropyl, cyclopentyl or cyclohexyl or phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, phenoxatiin-2 -Yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl or furin-8-yl, Here, in the case of nitrogen-containing rings, the ring system is fluorine, chlorine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight or branched chain acyl with up to 3 carbon atoms via N functional groups. Optionally substituted with the same or different groups up to 3 times by alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl, triazolyl, tetrazolyl, benzothiazolyl or phenyl and are represented by 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 partially up to 2 times with phenyl, fluorine, chlorine, or with straight or branched chain alkyl of up to 3 carbon atoms Substituted with the same or different groups) R ⁶ or R ⁷ is Represents a group of L represents straight or branched chain alkyl or alkenyl of up to 6 carbon atoms optionally substituted up to 2 times by hydroxyl, R ⁸ represents hydrogen or fluorine, R ⁹ is hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, methoxy or the formula -NR ¹⁵ R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are the same or different, Group having the meanings of R ⁴ and R ⁵ mentioned above), or R ⁸ and R ⁹ together form a group of formula = O or = NR ¹⁷ , wherein R ¹⁷ represents hydrogen or straight or branched chain alkyl, alkoxy or acyl of up to 3 carbon atoms Group; E represents cyclopropyl, cyclopentyl or cyclohexyl, or phenyl optionally substituted by fluorine or trifluoromethyl, or straight or branched chain alkyl of up to 4 carbon atoms optionally substituted by hydroxyl; R ¹ represents straight or branched chain alkyl of up to 4 carbon atoms substituted by hydroxyl; R ² and R ³ are the same or different and represent hydrogen, phenyl, benzyl, cyclopropyl, cyclopentyl, or straight or branched chain alkyl, acyl with up to 5 carbon atoms, or formula -CO-NR ¹⁸ R ¹⁹ Wherein R ¹⁸ and R ¹⁹ are the same or different and represent hydrogen, phenyl, benzyl, or represent straight or branched chain alkyl of up to 4 carbon atoms, or R ² and R ³ together with the nitrogen atom are a pyryl, morpholinyl, pyrrolidinyl or piperidinyl ring or formula Wherein the heterocycle is hydroxyl, trifluoromethyl, fluorine, chlorine, bromine, hydroxyl, carboxyl, methylhydroxyl, or straight or branched chain alkoxy or alkoxycar having up to 3 carbon atoms. A compound of formula I and salts thereof, optionally substituted by carbonyl. [A] As a Grignard / Wittig reaction, group D is first introduced into a compound of the following formula (II), in which the substituents are optionally induced by conventional methods, preferably by reduction, and hydroxyl A process for preparing a compound of formula (I) according to claim 1, characterized in that the protecting group is removed in the last step and, where appropriate, all substituents are changed and / or introduced by conventional methods. <Formula II> Wherein A, E, R ² and R ³ have the meanings mentioned above, R ²² has the meaning of R ¹ mentioned above, wherein the hydroxyl functional group is preferably in a form protected by tetrahydropyranyl. A pharmaceutical product comprising at least one 2-amino-substituted pyridine of claim 1 and a pharmaceutically acceptable adjuvant. The agent of claim 5 for the treatment of atherosclerosis. 6. The medicament according to claim 5 for treating lipoprotein hyperemia. Use of the 2-amino-substituted pyridine of claim 1 in the manufacture of a medicament. Use according to claim 8 for the manufacture of a medicament for the treatment of atherosclerosis. Use according to claim 8 for the manufacture of a medicament for the treatment of lipoprotein hyperemia.