RU2278856C2 - Derivatives of piperidine and method for their preparing - Google Patents

Abstract

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I):

in free form or as a salt wherein Ar¹ means phenyl substituted with one or some halogen atoms; Ar² means phenyl or naphthyl that can be unsubstituted or substituted with one or some substitutes chosen from the group comprising halogen atom, cyano-, hydroxy-, nitro-group, (C₁-C₈)-alkyl, (C₁-C₈)-halogenalkyl, (C₁-C₈)-alkoxy-group or (C₁-C₈)-alkoxycarbonyl; R¹ means hydrogen atom or (C₁-C₈)-alkyl optionally substituted with hydroxy-,(C₁-C₈)-alkoxy-, acyloxy-group, -N(R²)R³, halogen atom, carboxy-group, (C₁-C₈)-alkoxycarbonyl, -CON(R⁴)R⁵ or monovalence cyclic organic group; each among R² and R³ and independently of one another means hydrogen atom or (C₁-C₈)-alkyl, or R² means hydrogen atom and R³ means acyl or -SO₂R⁶, or R and R³ in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; each among R⁴ and R⁵ and independently of one another means hydrogen atom or (C₁-C₈)-alkyl, or R⁴ and R in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; R⁶ means (C₁-C₈)-alkyl, (C₁-C₈)-halogenalkyl or phenyl optionally substituted with (C₁-C₈)-alkyl; n means 1, 2, 3 or 4 under condition that when Ar¹ means para-chlorophenyl and R¹ means hydrogen atom then Ar² doesn't mean phenyl or para-nitrophenyl. Compounds of the formula (I) possess the inhibitory CCR-3 activity and can be used in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

7 cl, 47 ex

Description

The invention relates to organic compounds, their preparation and use as pharmaceutical agents.

One of the objects of the invention are compounds of the formula

in free form or in salt form, where

Ar ¹ is phenyl substituted with one or more halogen atoms,

Ar ² is phenyl or naphthyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, cyano, hydroxy, nitro, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, C ₁ -C ₈ alkoxy or C ₁ -C ₈ alkoxycarbonyl,

R ¹ is hydrogen or C ₁ -C ₈ alkyl optionally substituted with hydroxy, C ₁ -C ₈ alkoxy, acyloxy, -N (R ² ) R ³ , halogen, carboxy, C ₁ -C ₈ alkoxycarbonyl, -CON ( R ⁴ ) R ⁵ or a monovalent cyclic organic group,

R ² and R ³ each independently of one another is hydrogen or C ₁ -C ₈ alkyl, or R ² is hydrogen and R ³ is acyl or —SO ₂ R ⁶ , or R ² and R ³ together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocyclic group,

R ⁴ and R ⁵ each independently of one another is hydrogen or C ₁ -C ₈ alkyl, or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group,

R ⁶ is C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl or phenyl optionally substituted with C ₁ -C ₈ alkyl, and

n is 1, 2, 3 or 4,

with the proviso that when Ar ¹ is para-chorphenyl and R ¹ is hydrogen, then Ar ^{2 is} not phenyl or para-nitrophenyl.

The concepts that are used in the present description have the following meanings:

"C ₁ -C ₈ alkyl" in the context of the present description refers to C ₁ -C ₈ straight or branched chain alkyl, which may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, straight or branched chain pentyl, straight or branched chain hexyl, straight or branched chain heptyl or straight or branched octyl. Preferably, C ₁ -C ₈ alkyl is C ₁ -C ₄ alkyl.

"C ₁ -C ₈ alkoxy" in the context of the present description refers to a C ₁ -C ₈ alkoxy group with a straight or branched chain, which may mean, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy , tert-butoxy, straight or branched chain pentoxy, straight or branched hexyloxy, straight or branched heptyloxy, or straight or branched octyloxy. Preferably C ₁ -C ₈ alkoxy is C ₁ -C ₄ alkoxy.

"C ₁ -C ₈ haloalkyl" in the context of the present description means C ₁ -C ₈ alkyl, as defined above, substituted by one or more halogen atoms, preferably one, two or three halogen atoms.

"Acyl" in the context of the present description means alkylcarbonyl, for example C ₁ -C ₈ alkylcarbonyl, where C ₁ -C ₈ alkyl may be one of the above C ₁ -C ₈ alkyl groups, optionally substituted with one or more halogen atoms; cycloalkylcarbonyl, for example C ₃ -C ₈ cycloalkylcarbonyl, where C ₃ -C ₈ cycloalkyl may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; 5- or 6-membered heterocyclylcarbonyl ring having one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, such as furylcarbonyl or pyridylcarbonyl; arylcarbonyl, for example C ₆ -C ₁₀ arylcarbonyl, such as benzoyl; or aralkylcarbonyl, for example C ₆ -C ₁₀ aryl-C ₁ -C ₄ alkylcarbonyl, such as benzylcarbonyl or phenylethylcarbonyl. Preferably, the acyl is C ₁ -C ₄ alkylcarbonyl.

"Acyloxy" in the context of the present description means alkylcarbonyloxy, for example C ₁ -C ₈ alkylcarbonyloxy, where C ₁ -C ₈ alkyl may be one of the above C ₁ -C ₈ alkyl groups optionally substituted with one or more halogen atoms; cycloalkylcarbonyloxy, for example C ₃ -C ₈ cycloalkylcarbonyloxy, where C ₃ -C ₈ cycloalkyl may be, for example, cyclopropyl, cyclobutyl, cyclopetyl, cyclohexyl, cycloheptyl or cyclooctyl; A 5- or 6-membered heterocyclylcarbonyloxy group having in the ring one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, such as furylcarbonyloxy or pyridylcarbonyloxy; an arylcarbonyloxy, for example a C ₆ -C ₁₀ arylcarbonyloxy group such as benzoyloxy; or an aralkylcarbonyloxy group, for example a C ₆ -C ₁₀ aryl-C ₁ -C ₄ alkylcarbonyloxy group, such as benzylcarbonyloxy or phenylethylcarbonyloxy. Preferably, the acyloxy is C ₁ -C ₄ alkylcarbonyloxy.

"Halogen" in the context of the present description refers to fluorine, chlorine, bromine or iodine; preferably fluorine, chlorine or bromine.

In Ar ^{1, the} phenyl group may be substituted with one, two or three, preferably one or two halogen atoms, which are preferably selected from fluorine and chlorine atoms. When one halogen atom is present as a substituent, it is preferably in the para position relative to said carbonyl group. When two or three halogen atoms are present as substituents, preferably one of them is in the para position relative to said carbonyl group and at least one of the others is in the ortho position relative to said carbonyl group.

If Ar ² is substituted phenyl, then it can, for example, be substituted with one, two, three, four or five, preferably one, two or three, of the above substituents. Ar ² may, for example, be a monosubstituted phenyl, the substituent of which is preferably halogen, cyano, nitro or a C ₁ -C ₄ alkoxy group, which is preferably in the ortho or meta position relative to the indicated —CH═CH group. In another embodiment, Ar ² may be, for example, disubstituted phenyl, the substituents of which are preferably selected from the group consisting of halogen, cyano, hydroxy, nitro, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl and C ₁ -C ₄ haloalkyl, particularly preferred substituents are two halogen atoms (the same or different halogen atoms), two C ₁ -C ₄ alkoxy groups, two C ₁ -C ₄ alkyl groups, two C ₁ -C ₄ haloalkyl groups, one halogen and one cyano group, one halogen and one C ₁ -C ₄ alkoxy group, one halogen and one nitro group, one halogen and one hydroxyechinenone igruppa one halogen and one C ₁ -C ₄ -haloalkyl, one cyano and one C ₁ -C ₄ alkoxy group, a hydroxy group and a C ₁ -C ₄ alkyl or one hydroxy and one C ₁ -C ₄ alkoxy. In another embodiment, Ar ² may be, for example, trisubstituted phenyl, the substituents of which are preferably selected from the group consisting of halogen, hydroxy, C ₁ -C ₄ alkoxy and C ₁ -C ₄ alkoxycarbonyl, particularly preferably the substituents are three halogen atoms (identical atoms or two or three different halogen atoms) or two C ₁ -C ₄ alkoxy groups and one halogen, hydroxy or C ₁ -C ₄ alkoxycarbonyl. In yet another embodiment, Ar ² may mean, for example, pentasubstituted phenyl, the substituents of which are preferably halogen atoms, especially fluorine. Particularly preferred Ar ² groups are cyanophenyl, especially meta-cyanophenyl, and disubstituted phenyl, one of the substituents of which is a C ₁ -C ₄ alkoxy group, preferably located in the ortho position relative to the —CH═CH group, and the second substituent, preferably in the para position relative to the C ₁ -C ₄ alkoxy group, is C ₁ -C ₄ alkoxy, halogen, cyano or C ₁ -C ₄ alkyl.

R ¹ , which is optionally substituted C ₁ -C ₈ alkyl, is preferably optionally substituted C ₁ -C ₄ alkyl, especially C ₁ -C ₄ alkyl or substituted methyl or ethyl. When R ^{1 is} substituted with a cyclic organic group, the latter may represent a carbocyclic or heterocyclic group, for example a C ₃ -C ₁₅ carbocyclic group or a 5-7 membered heterocyclic group bearing one or more, preferably one, two or three ring heteroatoms selected from a group comprising nitrogen, oxygen and sulfur. A C ₃ -C ₁₅ carbocyclic group may, for example, mean a cycloaliphatic group having 3-8 carbon atoms, preferably C ₅ or C ₆ cycloalkyl, such as cyclopentyl, methylcyclopentyl or cyclohexyl. In another embodiment, a C ₃ -C ₁₅ carbocyclic group may denote, for example, a C ₁ -C ₈ aromatic group, such as phenyl, which may be unsubstituted or substituted with C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, halogen, cyano , —CON (R ⁴ ) R ⁵ , —SO ₂ N (R ⁴ ) R ^5, or C ₁ -C ₈ alkylsulfonylamino group, wherein R ⁴ and R ⁵ are as defined above. A heterocyclic group may carry one nitrogen, oxygen or sulfur atom in the ring or may carry two nitrogen atoms or one oxygen atom and one or two nitrogen atoms, or one sulfur atom and one or two nitrogen atoms. The heterocyclic group is preferably a heterocyclic aromatic group, especially a 5- or 6-membered heterocyclic group, such as furyl, imidazolyl, thiazolyl or pyridyl. In the most preferred compounds, R ¹ is C ₁ -C ₄ alkyl substituted with a hydroxy group, phenyl, or a 5- or 6-membered heterocyclic aromatic group containing one or two ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

Preferred compounds of formula I in free or salt form are those in which

Ar ¹ is phenyl substituted with fluorine or chlorine in the para position relative to the specified carbonyl group and optionally further substituted with halogen in the ortho position relative to the specified carbonyl group,

Ar ² is phenyl monosubstituted with a substituent selected from the group consisting of halogen, cyano, nitro and C ₁ -C ₄ alkoxy, phenyl substituted with two identical or different substituents selected from the group consisting of halogen, cyano, hydroxy, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl and nitro, or phenyl substituted with three identical or different substituents selected from the group consisting of halogen, hydroxy, C ₁ -C ₄ alkoxy and C ₁ -C ₄ alkoxycarbonyl,

R ¹ is hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkyl substituted with hydroxy, C ₃ -C ₈ cycloalkyl, phenyl, phenyl, substituted with C ₁ -C ₄ alkylsulfonylamino, or a 5- or 6-membered heterocyclic aromatic a group carrying one or more ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and

n is 1 or 2.

Also preferred compounds of formula I in free or salt form are those in which

Ar ¹ is phenyl substituted with fluorine or chlorine in the para position relative to said carbonyl group,

Ar ² is phenyl substituted in the ortho position relative to the indicated —CH═CH— group with a C ₁ -C ₄ alkoxy group and substituted in the para position with respect to the C ₁ -C ₄ alkoxy group by a cyano group, halogen or a C ₁ -C ₄ alkoxy group,

R ¹ is C ₁ -C ₄ alkyl substituted with a hydroxy group, phenyl, phenyl substituted with a C ₁ -C ₄ alkylsulfonylamino group, or a 5- or 6-membered heterocyclic aromatic group containing one or two ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and

n is 1.

The compounds represented by the formula have the ability to form acid addition salts, especially pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable acid addition salts of a compound of the formula include salts of inorganic acids, for example, hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example, aliphatic monocarboxylic acids, such as formic acid, acetic acid, trifluoroacetic acid, propionic acid and butyric acid, aliphatic hydroxy acids, such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids, such as maleic acid or succinic acid, aromatic carboxylic acids such as benzoic acid, para-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids from, such as ortho-hydroxybenzoic acid, para-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid or 3-hydroxy-naphthalene-2-carboxylic acid, and sulfonic acids such as methanesulfonic acid or benzenesulfonic acid. These salts can be obtained from compounds of the formula using known salt formation processes.

Compounds of the formula that contain acidic, for example, carboxyl groups, can also form salts with bases, especially with pharmaceutically acceptable bases, which are well known in the art; such salts may include metal salts, especially alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonia salts or pharmaceutically acceptable organic amines or heterocyclic bases, such as ethanolamines, benzylamines or pyridines. These salts can be obtained from compounds of formula I using known salt formation processes.

When R ¹ has a value other than hydrogen, the carbon atom to which R ^{1 is} attached in the formula is asymmetric, in which case the compounds exist as individual optically active isomeric forms or mixtures thereof, for example, as racemic or diastereoisomeric mixtures. The scope of the invention covers both individual optically active R and S isomers and mixtures thereof, for example racemic or diastereoisomeric mixtures.

Specific preferred compounds of the invention are those described in the examples, in particular in examples 4, 9, 10, 15, 18, 19, 20, 21, 23, 24, 25, 28, 29, 30, 37, 38, 40, 42, 43, 44 and 45.

The invention also relates to a method for producing compounds of the formula, comprising

(I) (A) the interaction of the compounds of formula

with a compound of the formula

or an amide-forming derivative thereof, wherein Ar ¹ , Ar ² , R ¹ and n are as defined above, or

(B) reacting a compound of formula III or an amide derivative thereof with a compound of formula

where Ar ¹ , R ¹ and n are as defined above and Z is a solid phase substrate chemically bonded to said nitrogen atom and the cleavage of the product formed from the substrate by replacing Z with hydrogen; and

(Ii) isolating the product in free or salt form.

According to process variant (A), the compound of formula II may be in free form or in salt form. Option (A) of the method can be carried out using known methods, for example, by reacting a compound of formula II with an acid halide, in particular with an acid chloride of formula III, using known amide formation processes. Typically, a compound of formula II in free or salt form is reacted with a free carboxylic acid of formula III, for example, by known processes such as reacting in the presence of a tertiary amine and a peptide binding agent such as the phosphonium salt tetrafluoroborate 2- (1H -benzotriazol-1-yl) -1,1,3,3-tetraamethyluronium or diisopropylcarbodiimide; this reaction is carried out in an inert organic solvent, for example, in a halogenated hydrocarbon such as dichloromethane; as a rule, the reaction temperature is from 0 to 40 ° C, preferably represents the ambient temperature.

According to another embodiment of method variant (A), a compound of formula II, preferably in salt form, is reacted with an amide-forming acid derivative of formula III, which is a thioether of formula

where Ar ² has the above meanings. The reaction can be carried out using known processes or similarly to the methods described in the examples. It can be carried out in the presence of a tertiary base such as N-methylmorpholine. The reaction is usually carried out in an organic solvent, preferably an alcohol, such as ethanol. The reaction temperature may be, for example, from 30 to 60 ° C., typically from 40 to 50 ° C.

Option (B) of the method can be carried out using known methods, for example, by reacting a compound bound to a substrate with a free acid under known conditions of a peptide combination, for example, in the presence of a tertiary amine and the above peptide binding agent. The reaction can be carried out in an inert organic solvent such as dimethylformamide (DMF). Acceptable reaction temperature is from 0 to 40 ° C., For example, 15-25 ° C. The product can be cleaved from the substrate by a known method, for example, treatment with trifluoroacetic acid in the case when the N atom is bonded to CH _{2 of the} benzyl group in Z.

The compounds of formula III are either commercially available or can be prepared by known methods. Compounds of formula III A can be prepared by reacting an acid of formula III with 2,2'-dibenzothiazolyl disulfide in the presence of triphenylphosphine and a tertiary base such as N-methylmorpholine, for example, according to the methods described in the examples.

Compounds of formula II can be prepared by reacting a compound of formula

with a compound of the formula

where Ar ¹ , R ¹ and n are as defined above, provided that when R ¹ contains a reactive functional group, such as a hydroxy group, the reactive group may be present in protected form, for example, the hydroxy group is protected as a tert-butoxy group, R ⁷ is hydrogen or an amino protecting group, e.g. tert-butoxycarbonyl group, and X is halogen, and if R ⁷ is a protecting group by replacement of R ¹ in the product by hydrogen, and if R ¹ in the product contains a protected functional group by replacement of protecting groups by hydrogen. If R ⁷ is hydrogen, the reaction between the compound of formula V and the salt of the compound of formula VI can be carried out according to the processes described in US 4,559,349. If R is a protective group, the reaction between compounds of formulas V and VI can be carried out by known methods, for example, in the presence of tertiary an organic base such as triethylamine or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), typically in an inert solvent, for example, in a polar solvent such as dimethylformamide, the reaction is usually carried out with 0-40 ° C, prefer at ambient temperature. The replacement of the protective group R ^{7 with} hydrogen can be carried out using known methods; for example, if R ⁷ is tert-butoxycarbonyl, treatment with a carboxylic acid such as trifluoroacetic acid. The replacement of the protective group with R ¹ can be carried out using known methods, for example, when R ¹ contains a hydroxy group protected by an ether group, such as a tert-butoxy group, by treating HBr in a carboxylic acid such as acetic acid; when R ⁷ is a protecting group, this treatment also leads to the replacement of R ^{7 with} hydrogen. The compounds of formulas V and VI are known or can be obtained by known methods.

If the description refers to protected functional groups or protective groups, it is assumed that the protective groups can be selected depending on the nature of the functional group, for example, as described in "Protective Groups in Organic Synthesis", TWGreene and PGMWuts, John Wiley & Sons Inc, 2nd ed., 1991, which also describes methods used to replace the protecting groups with hydrogen.

Compounds of formula II can also be prepared by reacting a compound of formula V with a compound of formula

where R ¹ , R ⁷ and n are as defined above, and with a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, for example, using known reductive amination processes, typically in an inert organic solvent, such as an ether such as tetrahydrofuran (THF ), the reaction temperature, as a rule, is from 0 to 40 ° C, and if R ⁷ denotes a protective group by replacing it with hydrogen. The compounds of formula VII are known or can be obtained using known processes.

Compounds of formula II in which R ¹ is hydroxymethyl can also be prepared by reacting a compound of formula V with (R) -4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester of the formula

and a reducing agent, such as sodium triacetoxyborohydride, for example, under the conditions described above for the interaction of the compounds of formulas V and VII, and the interaction of the product with a reagent that can cleave the oxazolidine ring, and replacing the nitrogen-bound ether group with hydrogen, for example hydrogen chloride, in ethanol or dioxane, as described in the examples below, in this case, the compound of formula II is obtained in the form of a hydrochloride. The reaction product of compounds of formulas V and VIIa, for example, can be treated with an optically active acid, such as di-O, O-benzoyl-L-tartaric acid, before cleavage of the oxazolidine ring, for example, to improve enantiomeric purity. The compound of formula VIIa can be obtained according to the method described by A.D. Campbell et al., Synthesis 1707-1709 (1998) or G.Ageno et al., Tetrahedron 51, 8121-8134 (1995).

Compounds of formula II in which R is C ₁ -C ₈ alkoxymethyl or acyloxymethyl can be prepared by the corresponding esterification or acylation of compounds of formula II in which R ¹ is hydroxymethyl.

Compounds of formula IV can be prepared by reacting a compound of formula V with a compound of formula

where R ¹ , Z and n have the above meanings, for example, using known processes, such as reaction in an inert organic solvent, such as DMF, in the presence of a tertiary amine, usually at a temperature of from 40 to 60 ° C. Compounds of formula VIII can be prepared by reacting a compound of formula

where R ¹ , Z and n have the above meanings, with iodine, for example, using known processes, such as the interaction in an inert organic solvent, such as a mixture of THF and acetonitrile, in the presence of triarylphosphine and imidazole, usually at a temperature of from 10 up to 40 ° C. Compounds of formula IX can be prepared by reacting a compound of formula

where R ¹ and n have the above meanings, with a solid phase substrate Z that carries a group, such as an aldehyde group, which reacts with an amino group. Such solid phase substrates, including modified resins, especially modified polystyrene resins, are commercially available. Compounds of formula X are known or may be prepared by known methods.

The compounds of formula I in free form can be converted into a salt by conventional methods, and vice versa, compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent that is used for crystallization. The compounds of formula I can be isolated from the reaction mixtures and purified by conventional methods. Isomers, such as enantiomers, can be obtained by the conventional method, for example, by fractional crystallization or asymmetric synthesis, from starting materials that are suitably asymmetrically substituted, for example, from optically active materials.

The compounds of formula I in free form or in the form of a pharmaceutically acceptable salt, hereinafter referred to as the agents of the invention, can be used as pharmaceutical agents. Thus, the invention also relates to a compound of formula I in free form or in the form of a pharmaceutically acceptable salt, intended for use as a pharmaceutical agent. The agents of the invention act as antagonists of the CCR-3 receptor, thereby inhibiting the inflammation and infiltration and activation of inflammatory cells, especially eosinophils, and inhibiting an allergic reaction. The inhibitory activity of the agents of the invention can be demonstrated by the following assay:

CCR-3 Binding Assay

Using this analysis, the effect of the agents of the invention on the binding of human eotaxin to human CCR-3 is evaluated. Recombinant cells expressing human CCR-3 are immobilized using agglutinin from wheat seedlings (PAP) polyvinyltoluiden (PVT) SPA granules (Amersham) through specific binding between PAP and carbohydrate residues of glycoproteins on the cell surface. [ ¹²⁵ I] labeled human eotaxin (Amersham) specifically binds to CCR-3 receptors, bringing the human [ ¹²⁵ I] eotaxin into close contact with SPA granules. Alpha particles emitted by human [ ¹²⁵ I] -otoxin excite due to their close arrangement of the fluorophore in the granules and cause the emission of light. Free human [ ¹²⁵ I] -eotaxin in solution does not have close contact with the scintillator and therefore does not cause light emission. Therefore, the number of outbreaks is a measure of the extent to which a test compound inhibits the binding of eotaxin to CCR-3.

Preparation of assay buffer: 5.96 g of HEPES and 7.0 g of sodium chloride are dissolved in distilled water and 1 M aqueous solution of CaCl ₃ (1 ml) and 1 M aqueous solution of MgCl ₂ (5 ml) are added. The pH was adjusted to 7.6 with NaOH and the final solution volume was adjusted to 1 L with distilled water. Then, 5 g of bovine serum albumin and 0.1 g of sodium azide are dissolved in the solution, and the resulting buffer is stored at 4 ° C. On the day of use, a tablet containing a mixture of protease inhibitors such as Complete ™ (Boehringer) is added to 50 ml of buffer.

Preparation of homogenization buffer: Tris base (2.42 g) is dissolved in distilled water, the pH of the solution is adjusted to 7.6 with hydrochloric acid, and the solution is diluted with distilled water to a final volume of 1 liter. The resulting buffer was stored at 4 ° C. On the day of use, a tablet containing a mixture of Complete ™ type protease inhibitors is added to 50 ml of buffer.

Membrane production: Confluent rat basophilic leukemia (RBL-2H3) cells stably expressing CCR-3 are isolated from tissue culture flasks using an enzyme-free cell dissociation buffer and resuspended in phosphate buffered saline. Cells are centrifuged (800 × g, 5 min), debris is resuspended in ice-cold homogenization buffer using 1 ml of homogenization buffer per 1 g of cells, and incubated on ice for 30 minutes. Cells are homogenized on ice by 10 strokes in a glass mortar and pestle. The homogenate is centrifuged (800 g, 5 min, 4 ° C), the supernatant is again centrifuged (48000 × g, 30 min, 4 ° C) and the debris is redissolved in a homogenization buffer containing 10 vol. % glycerol. The protein content in the membrane preparation was evaluated by the Bradford method (Anal. Biochem., 72: 248 (1976)) and aliquots were quickly frozen and stored at -80 ° C.

The analysis is carried out in a final volume of 250 μl per well of an Optiplate plate (Canberra Packard). 50 μl of test compound solutions in assay buffer containing 5% DMSO (concentration from 0.01 nM to 10 μM) was added to certain wells of an Optiplate plate. To determine total binding, 50 μl of assay buffer containing 5% DMSO was added to certain other wells. To determine non-specific binding, 50 μl of 100 nM human eotaxin (R&D Systems) was added to other selected wells in an assay buffer containing 5% DMSO. 50 μl of human [ ¹²⁵ I] -eotaxin (Amersham) were added to all wells in assay buffer containing 5% DMSO at a concentration of 250 pM (obtaining a final concentration of 50 pM per well), 50 μl of PPA-PVT SPA granules in the analysis buffer (obtaining a final concentration of 1.0 mg of granules per well) and 100 μl of the membrane preparation at a concentration of 100 μg of protein in the analysis buffer (receiving a final concentration of 10 μg of protein per well). The plate is then incubated for 4 hours at room temperature. The tablet is sealed with TopSeal-S (Canberra Packard) according to the manufacturer's instructions. The resulting flashes are counted using a Canberra Packard TopCount device, and each well is counted for 1 min. From the concentration inhibition graphs, the concentration of the test compound at which binding is inhibited by 50% (IC ₅₀ ) is calculated in the usual manner.

For the compounds of the examples below, using the above analysis, it was found that the IC ₅₀ values are less than 1 μM. For example, for the compounds of examples 1, 2, 4, 7, 9, 13, 20, 23, 25, 28, 30, 38, 40, 43 and 44, the IC ₅₀ (nM) values are 125, 68, 13, 15, 5, 26, 8, 10, 11, 2, 13, 14, 6, 22, and 25, respectively.

For most of the compounds of the examples, a selective effect was found with respect to inhibition of binding to CCR-3 compared to inhibition of binding to alpha-1 adrenergic receptor. The inhibitory effect of the agents of the invention on binding to the alpha-1 adrenergic receptor can be demonstrated by the following assay:

The cerebral cortex of male Sprague-Dawley rats (175-200 g) was cut off and homogenized in 10 volumes of ice-cold 0.32 M sucrose solution (containing 1 mM MgCl ₂ dihydrate and 1 mM K ₂ NRA ₄ ) in a glass / Teflon homogenizer. The membranes are centrifuged at 1000 × g for 15 min, the debris is discarded and centrifugation is repeated. The supernatants are combined and centrifuged at 18,000 × g for 15 minutes. Debris is subjected to osmotic shock in 10 volumes of water and kept on ice for 30 minutes. The suspension is centrifuged at 39000 × g for 20 minutes, resuspended in Krebs-Henseleit buffer, pH 7.4 (1.17 mm MgSO ₄ (anhydrous) 4.69 mm KCl, 0.7 mm K ₂ HPO ₄ (anhydrous), 0.11 M NaCl, 11 mm D-glucose and 25 mm NaHCO ₃ ) containing 20 mm Tris, and incubated for 2 days at -20 ° C. Then the membranes are thawed at 20-23 ° C, washed three times with Krebs-Henseleit buffer by centrifugation at 18000 × g for 15 min, kept overnight at 4 ° C and washed again three times. The final debris is resuspended in the same buffer using a glass / Teflon homogenizer at a rate of 125 ml / 100 membranes. A sample was taken to determine the protein concentration (using Bradford analysis using gamma globulin as a standard) and the remaining aliquots were stored at -80 ° C.

In the resulting membranes, radioligand binding is analyzed. The assay is performed in triplicate using 96-well plates containing [ ¹²⁵ I] -HEAT (Amersham) (40 pM, K _d : 58.9 + 18.7 pM), unlabeled test compound and membrane (57.1 μg / ml). receiving a final volume of 250 μl (assay buffer containing 50 mM Tris base and 0.9% (w / v) NaCl, pH 7.4). The plates were incubated at 37 ° C. for 60 minutes, followed by rapid vacuum filtration using Whatman GF / C 96-well filter plates. Each plate was then washed three times with 10 ml of ice-cold assay buffer using a Brandel cell harvester (Gaithersburg, Maryland). After drying the plates for 3 hours at 50 ° C, 40 μl of Microscint 20 scintillation liquid was added to each well, the plates were incubated at room temperature for another 20 minutes and the radioactivity retained was quantified using a Packard Topcount NXT scintillation counter.

The stock solutions of the test compounds are first dissolved in 100% DMSO and diluted with the assay buffer to the required concentrations, bringing the concentration of DMSO to 1 vol.%.

From the concentration inhibition curves, the concentration of the test compound at which 50% inhibition is observed (IC ₅₀ ) is calculated in the usual manner.

Using this analysis, it was found that for the compounds of examples 1, 2, 4, 7, 9, 13, 20, 23, 25, 28, 30, 38, 40, 43, and 44, the IC ₅₀ values (nM) are 210, 221 , 94, 48, 58, 53, 89, 131, 387, 72, 121, 1519, 215, 356 and 331.

Given their ability to inhibit binding to CCR-3, the agents of the invention can be used to treat conditions mediated by CCR-3, especially inflammatory or allergic conditions. According to the invention, the treatment may be symptomatic or prophylactic.

Thus, the agents of the invention can be used to treat inflammatory or obstructive diseases of the respiratory tract, which leads, for example, to reduced tissue damage, bronchial hyperreactivity, to remodeling or to reduce the development of the disease. Inflammatory or obstructive airway diseases that can be treated according to the present invention include asthma, regardless of its type or genesis, including both hereditary (non-allergic) bronchial asthma and acquired (allergic) bronchial asthma, mild asthma, moderate asthma severity, severe asthma, bronchial asthma caused by physical activity, asthma, occupational asthma and asthma caused by a bacterial or viral infection. The term "treatment of asthma" also refers to the treatment of patients less than 4 or 5 years old who have symptoms of stridor and who are diagnosed or can be diagnosed with a child suffering from stridor, i.e. patients belonging to the category of patients of great medical importance, which are often called asthmatics with initial or early stage of asthma. (For simplicity, this particular asthmatic condition is called "Stridor Syndrome").

The effectiveness of prophylactic treatment of asthma can be identified by reducing the frequency or severity of symptomatic seizures, such as acute asthma attacks or bronchostenosis attacks, improving lung function, or reducing increased airway reactivity. In addition, it can be evaluated by the decrease in the frequency of use of other means of symptomatic treatment, i.e. treatments designed to limit or eliminate symptomatic seizures if they occur, such as the frequency of use of anti-inflammatory drugs (such as corticosteroids) or bronchodilators. Prophylactic efficacy against asthma is most evident for patients prone to the so-called "morning immersion." "Morning diving" is an asthmatic syndrome that affects a certain percentage of asthmatics, characterized by an asthma attack, for example, between about 4 and 6 in the morning, i.e. in a period of time quite remote from the time when any symptomatic treatment of asthma was previously performed.

Other inflammatory or obstructive diseases or conditions of the respiratory tract that the present invention can be used to treat include acute lung injury (ALP), adult respiratory distress syndrome (RDSV), chronic obstructive pulmonary or respiratory disease (COPD or COPD), including including chronic bronchitis or associated shortness of breath, emphysema, as well as exacerbation of airway hyperresponsiveness due to treatment using other drugs, in particular treatment using the use of other drugs administered by inhalation. The invention can also be used to treat bronchitis of any type or genesis, for example, acute, arachidoid, catarrhal, croupous, chronic or purulent tuberculous bronchitis. Other inflammatory or obstructive respiratory diseases for the treatment of which the present invention can be used include pneumoconiosis (an inflammatory, usually occupational, lung disease, often accompanied by obstruction of the respiratory tract, which may be chronic or acute, and which is associated with continuous inhalation of dust) of any type genesis, including, for example, aluminosis, anthracosis, asbestosis, chalycosis, poultry, siderosis, silicosis, tobaccoosis and byssinosis.

Given their anti-inflammatory activity, especially with respect to inhibiting eosinophil activation, the agents of the invention can also be used to treat eosinophil-related diseases, for example, eosinophilia, in particular eosinophil-mediated respiratory tract diseases (for example, including pathological infiltration of pulmonary tissue eosinophils), including including hypereosinophilia, since they affect the airways and / or lungs, as well as, for example, for the treatment of eosinophil-related disorders respiratory tract infections that result from or that accompany Leffler's syndrome, eosinophilic pneumonia, parasitic (in particular, caused by Metazoa representatives) invasion (including tropical eosinophilia), bronchopulmonary aspergillosis, nodose polyarteritis (including Churg-Strauss syndrome), granulosa-eosinophilia eosinophils diseases affecting the drug-sensitive airways.

The agents of the invention can also be used to treat inflammatory or allergic skin conditions, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, exudative erythema, herpetiform hepatitis, sclerodema, vitiligo, hypersensitive angiitis, urticaria, bullous pemphigoid, systems of red pemphigoid, systems congenital bullous epidermolysis and other inflammatory or allergic skin conditions.

The agents of the invention can also be used to treat other diseases or conditions, especially diseases or conditions that have an inflammatory component, for example, for the treatment of diseases and conditions of the eyes, such as conjunctivitis, dry keratoconjunctivitis and spring conjunctivitis, nasal diseases, including allergic rhinitis, for example atrophic chronic or seasonal rhinitis, inflammatory diseases of the gastrointestinal tract, for example inflammatory bowel disease, such as ulcerative colitis and disease Crohn's disease, bone and joint diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and systemic sclerosis, and other diseases such as atherosclerosis, multiple sclerosis, diabetes (type I), severe pseudoparalytic myasthenia gravis, hyper-IgE syndrome and acute and chronic allograft rejection, for example, after transplantation of a heart, kidney, liver, lung, or bone marrow.

The ability of the agents of the invention to inhibit inflammatory conditions, for example in inflammatory diseases of the respiratory tract, can be demonstrated by modeling in animals, for example mice or rats, inflammation of the respiratory tract or other inflammatory conditions, for example according to the methods described by Szarka et al., J. Immmunol . Methods, 202: 49-57 (1997); Renzi et al., Am. Rev. Respir. Dis., 148: 932-939 (1993); Tsuyuki et al., J. Clin. Invest., 96: 2924-2931 (1995); and Cernadas et al. Am. J. Respir. CellMol. Biol. 20: 1-8 (1999).

The agents of the invention can also be used as auxiliary therapeutic agents in combination with anti-inflammatory, bronchodilator or antihistamine drugs, especially for the treatment of the above obstructive or inflammatory diseases of the respiratory tract, for example, as potentiators to enhance the therapeutic activity of such drugs or as a means to reduce the required doses or possible side effects of such drugs. The agent of the invention can be mixed with another drug to form a fixed pharmaceutical composition, or it can be administered individually before, at the same time, or after administration of another drug. Such anti-inflammatory drugs include steroids, especially glucocorticosteroids such as budesonide, beclamethasone, fluticasone, cyclesonide or mometasone, LTB4 antagonists (leukotriene B4), such as those described in US Pat. such as cabergoline, bromocriptine, ropinerol and 4-hydroxy-7- [2 - [[2 - [[3- (2-phenylethoxy) propyl] sulfonyl] ethyl] amino] ethyl] -2 (3H) -benzothiazolone and its pharmaceutically acceptable salts (e.g. commercially available hydrochloride salt) Viozan® company AstraZeneca), and PDE4 inhibitors such as Ariflo® (GlaxoSmith Kline), roflumilate (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 ( Schering-Plow) and PD189659 (Parke-Davis). Such bronchodilator drugs include anticholinergic or antimuscarinic agents, in particular ipratropium bromide, oxytropium bromide and tiotropium bromide, and beta-2-adrenergic agonists such as salbutamol, terbutaline, salmeterol, and especially formoterol, and also pharmaceutically acceptable, and also pharmaceutically acceptable compounds of formula I (in free form or in the form of a salt or solvate) described in international patent application PCT WO 00/75114, which is incorporated herein by reference, preferably compounds from rivedennyh examples herein, especially a compound of formula

and its pharmaceutically acceptable salts. Antihistamines that can be used for co-therapy include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride. Combinations of the agents of the invention and steroids, beta-2 agonists, PDE4 inhibitors or LTD4 antagonists can be used, for example, for the treatment of COPD or, especially, asthma. Combinations of the agents of the invention and anticholinergic or antimuscarinic agents, PDE4 inhibitors, or dopamine receptor agonists can be used, for example, for the treatment of asthma or, especially, COPD.

Other valuable combinations of the anti-inflammatory drug agents of the invention are combinations with other chemokine receptor antagonists, for example CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR- 8, CCR-9 and CCR-10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, in particular with CCR-5 antagonists, such as Schering-Plow SC-351125, SCH-55700 and SCH-D antagonists, with antagonists of the company Takeda, such as chloride N - [[4 - [[6,7-dihydro-2- (4-methylphenyl) -5H-benzocyclohepten-8-yl] carbonyl] amino] phenyl] methyl] tetrahydro-N, N- dimethyl-2H-pyran-4-ammonium (TAK-770), and with the CCR-5 antagonists described in p tent US 6166037 (particularly in paragraphs 18 and 19 claims), in WO 00/66558 (in particular, claim 8) and WO 00/66559 (particularly claim 9 in the invention).

According to the foregoing, the invention also provides a method of treating a condition mediated by CCR-3, for example, an inflammatory or allergic condition, in particular an obstructive or inflammatory disease of the respiratory tract, which comprises administering to a patient, especially a person in need of such treatment, an effective amount of the compound described above of formula I in free form or in the form of a pharmaceutically acceptable salt thereof. Another object of the invention is the use of the above-described compounds of formula I in free form or in the form of a pharmaceutically acceptable salt for the preparation of a medicament for the treatment of a mediated CCR-3 condition, for example, for the treatment of an inflammatory or allergic condition, especially an obstructive or inflammatory disease respiratory tract.

The agents of the invention may be administered by any suitable route, for example, orally, for example, in the form of a tablet or capsule; parenterally, for example, intravenously; by inhalation, especially in the treatment of obstructive or inflammatory diseases of the respiratory tract; intranasally, for example, in the treatment of allergic rhinitis; locally on the skin, for example, in the treatment of atopic dermatitis, or rectally, for example, in the treatment of inflammatory bowel disease.

Another object of the invention is a pharmaceutical composition comprising a compound of formula I in free form or in the form of a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable diluent or carrier. The composition may contain an additional therapeutic agent, for example, the anti-inflammatory or bronchodilator drug described above. Such compositions can be prepared using conventional diluents or excipients and methods known in the art of preparing galenic forms. Thus, forms for oral administration may be tablets and capsules. Topical compositions may be creams, ointments, gels, or transdermal administration systems, for example, plaques. Compositions for inhalation may be an aerosol or other sprayable composition or composition based on dry powder.

Thus, an object of the invention is (A) an agent according to the invention, which can be administered by inhalation, for example, in the form of an aerosol or other sprayable composition or particles suitable for inhalation, for example, in finely divided form; (B) a medication intended for inhalation, comprising an agent of the invention in a form suitable for inhalation; (B) a pharmaceutical product comprising such an agent of the invention in a form suitable for inhalation in combination with an inhalation device; and (D) an inhalation device containing such an agent of the invention in a form suitable for inhalation.

Doses of the agents of the invention used in the practice of the invention should naturally vary depending, for example, on the particular condition being treated, the expected effect and route of administration. In general, suitable daily dosages for administration by inhalation are from about 0.01 to 30 mg / kg, and suitable daily doses for oral administration are from about 0.01 to 100 mg / kg.

Below the invention is illustrated by examples.

Examples 1-47

The compounds of formula I, which are also represented by the formula

and options for methods for their preparation are shown in the following table, and the methods themselves are described below. Ra 'is H in all examples except Example 12, where it is F. The table also shows mass spectrometry data ([MH] ⁺ ) and, if salt is obtained in the example, salt-forming acid is indicated

Example No. Ra Rb Rc Rd Re Rf Rg M / c Salt form Method one F N H CN H H H 406.1 CF ₃ CO ₃ N AT 2 F

H CN H H H 496.8 - B 3 F

H CN H H H 448.5 ^- B four F

OCH ₂ CH ₃ H H Br H 593.3 - B 5 F H H CN OCH ₃ H H 436.2 CF ₃ CO ₃ N AT 6 F H OCH ₃ H H OCH ₃ H 441.3 CF ₃ CO ₃ N AT 7 F H OCH ₃ H H Br H 491.2 CF ₃ CO ₃ N AT 8 F

H CN H H H 497.4 CF ₃ CO ₃ N BUT 9 F

OCH ₃ H H Br H 580.2 - BUT 10 F N OH N N Cl N 431.7 CF ₃ CO ₂ N AT eleven F N OCH ₃ N N F N 429.0 CF ₃ CO ₂ N AT 12 F N OCH ₃ N N Br N 508.6 CF ₃ CO ₂ N AT 13 Cl N OCH ₃ N N Br N 506.7 CF ₃ CO ₂ N AT fourteen F N OCH ₃ N N CN N 436.0 CF ₃ CO ₂ N AT fifteen F N OCH ₃ N N Cl N 445.2 CF ₃ CO ₂ N AT 16 F N OCH ₂ CH ₃ N N Cl N 459.3 CF ₃ CO ₂ N AT 17 F N O (CH ₂ ) ₂ CH ₃ N N Cl N 473.3 CF ₃ CO ₂ N AT eighteen F N

N N Cl N 473.3 CF ₃ CO ₂ N AT 19 F N O (CH ₂ ) ₂ CH ₃ N N Br N 519.2 CF ₃ CO ₂ N AT twenty F N

N N Br N 519.2 CF ₃ CO ₂ N AT 21 F N OCH ₃ N N CH ₃ N 425.3 CF ₃ CO ₂ N AT 22 F N

N N CH ₃ N 453.3 CF ₃ CO ₂ N AT 23 F

H N N CN N 486.4 - BUT 24 F

OCH ₃ N N OCH ₃ N 521.4 - BUT 25 F

OCH ₃ N N Br N 521.2 - B 26 F

N N N CN N 503.4 - BUT 27 F

OCH ₃ N N OCH ₃ N 624.4 - G, A 28 F

OCH ₃ N N CN N 516.5 - BUT 29th F

OCH ₃ N N Br N 571.1 - BUT thirty F

OCH ₃ N n CN N 516.6 - B 31 F

OCH ₃ N n CN N 516.5 - BUT 32 F N N N CH ₃ N n 395.4 CF ₃ CO ₂ N AT 33 F N F F F F F 471.3 CF ₃ CO ₂ N AT 34 F N N CF ₃ N CF ₃ N 517.4 CF ₃ CO ₂ N AT 35 F N N NO ₂ N N N 426.3 CF ₃ CO ₂ N AT 36 F N n UNSD ₃ OCH ₃ N OCH ₃ 499.9 CF ₃ CO ₂ N AT 37 F

OCH ₃ N N CN N 466.1 - E 38 C1

OCH ₃ N N CN N 482.2 - D 39 F

N N N CN N 420.5 - B 40 Cl

OCH ₃ N N Cl N 491.1 CF ₃ CO ₂ N B 41 Cl N OCH ₃ N N CN N 452.0 CF ₃ CO ₂ N B 42 F

OCH ₃ N N Br N 533.3 - 43 Cl

OCH ₃ N N Br N 537.0 - D 44 F

OCH ₃ N N CN N 527.6 - BUT 45 F

OCH ₃ N N CN N 480.5 - E 46 Cl

OCH ₃ N N CN N 482

F 47 Cl

OCH ₃ N N CN N 482 - F

Method a

Preparation of ((R) -2-hydroxy-1-pyridin-3-ylmethylethyl) carbamic acid tert-butyl ester.

To a solution of (R) -2-tert-butoxycarbonylamino-3-pyridin-3-yl-propionic acid (0.9 g, 3.37 mmol) in dimethoxyethane (18 ml) was added N-methylmorpholine (0.44 ml, 4.04 mmol) and isobutyl chloroformate (0.48 ml, 3.71 mmol). The reaction mixture was stirred at ambient temperature for 20 minutes and then filtered. The filtrate was treated with an aqueous solution of sodium borohydride (25 ml, 10.11 mmol) and the reaction mixture was immediately diluted with water (200 ml). Stirring is continued for 1 h at ambient temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic phase is separated, dried over magnesium sulfate and evaporated. The crude product is purified by flash chromatography on silica gel (eluting with EtOAc) to give tert-butyl ester of ((R) -2-hydroxy-1-pyridin-3-ylmethylethyl) carbamic acid. [MN] ⁺ 253.5.

Preparation of ((R) -2-bromo-1-pyridin-3-ylmethylethyl) carbamic acid tert-butyl ester.

To a solution of ((R) -2-hydroxy-1-pyridin-3-ylmethylethyl) carbamic acid tert-butyl ester (0.43 g, 1.70 mmol) in dichloromethane (10 ml), carbon tetrabromide (0.33 g 2.04 mmol) and triphenylphosphine (0.23 g, 1.70 mmol). The reaction mixture was stirred at ambient temperature for 2 hours, filtered and the filtrate was partitioned between ethyl acetate and hydrochloric acid (1 M). The aqueous phase is separated, neutralized with saturated sodium bicarbonate solution and extracted with dichloromethane. The dichloromethane layer was dried over magnesium sulfate and evaporated to give ((R) -2-bromo-1-pyridin-3-ylmethylethyl) carbamic acid tert-butyl ester ¹ H-NMR (400 MHz, CDCl ₃ ) (1.29 (s 9H), 3.05 (dd, J 14.3, 9.8, 1H), 3.18 (dd, J 14.3 4.9, 1H), 3.51 (d, J 4.9, 2H), 4.07-4.16 (m, 1H), 7.84 (dd J 7.9, 5.9, 1H), 8.35 (d, J 7.9, 1H), 8.65 (d, J 5.4, 1H); 8.86 (s, 1H).

Preparation of {(R) -2- [4- (4-fluorobenzoyl) piperidin-1-yl] -1-pyridin-3-ylmethylethyl} carbamic acid tert-butyl ester

(4-Fluorophenyl) piperidin-4-ylmethanone (0.15 g, 0.73 mmol) is added to a solution containing ((R) -2-bromo-1-pyridin-3-ylmethylethyl) carbamic acid tert-butyl ester ( 0.21 g, 0.66 mmol) and 1.8 diazabicyclo [5.4.0] undec-7-ene (0.12 ml, 0.79 mmol) in dimethylformamide (3 ml). The reaction mixture was stirred at ambient temperature for 24 hours before partitioning between ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate and evaporated. The crude product was dried by flash chromatography on silica gel (eluting with 97: 3, dichloromethane: methanol) to give tert-butyl ether {(R) -2- [4- (4-fluorobenzoyl) piperidin-1-yl] -1 -pyridin-3-ylmethylethyl} carbamic acid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ1.36 (s. 9H), 1.68-1.85 (br m, 4H), 2.00-2.38 (br m, 4H), 2, 78-2.91 (m, 4H), 3.05-3.19 (m 1H), 3.81-3.93 (m, 1H), 7.05 (t, J 8.8, 2H), 7.12-7.18 (m, 1H), 7.48 (d, J 7.9, 1H), 7.85-7.93 (dd, J 8.8 5.4, 2H), 8, 36 (d, J 1.5, 1H); 8.40 (dd, J 4.9 1.5, 1H).

Preparation of [1 - ((R) -2-amino-3-pyridin-3-ylpropyl) piperidin-4-yl] - (4-fluorophenyl) methanone

To a solution of {(R) -2- [4- (4-fluorobenzoyl) piperidin-1-yl] -1-pyridin-3-ylmethylethyl} carbamic acid (0.149 g, 0.34 mmole) in dichloromethane ( 2 ml) trifluoroacetic acid (0.5 ml) was added and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was evaporated and the residue was dissolved in hydrochloric acid (1M), the solution was alkalinized with sodium hydroxide solution (4M) and the residue was extracted with dichloromethane . The dichloromethane layer was dried over magnesium sulfate and evaporated to give [1 - ((R) -2-amino-3-pyridin-3-ylpropyl) piperidin-4-yl] - (4-fluorophenyl) methanone. H-NMR (400 MHz, CDCl ₃ ) δ 1.63-1.85 (m, 4H), 1.88-2.00 (m, 1H), 2.08-2.32 (m, 5H), 2 50 (dd, J 13.5, 7.9, 1H), 2.67 (dd, J 13.5, 4.9, 1H), 2.78-2.98 (m, 2H), 3, 04-3.20 (m, 2H), 7.04 (t, J 8.8, 2H), 7.17 (dd, J 6.9, 4.9, 1H), 7.48 (d, J 7.9, 1H), 7.88 (dd, J 8.8, 5.4, 2H), 8.33-8.45 (m, 2H).

Preparation of (E) -3- (3-cyanophenyl) -N - {(R) -2- [4- (4-fluorobenzoyl) piperidin-1-yl] -1-pyridin-3-ylmethylethyl} acrylamide.

To a solution of (E) -3- (4-cyanophenyl) acrylic acid (0.022 g, 0.126 mmol) in dichloromethane (1 ml), triethylamine (0.016 ml, 0.126 mmol) and hexafluorophosphate (benzotriazo-1-yloxy) tripyrrolidinephosphonium (0, 06 g, 0.116 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes and then a solution of 1 - ((R) -2-amino-3-pyridin-3-ylpropyl) piperidin-4-yl] - (4-fluorophenyl) methanone (0.036 g) was added. , 0.105 mmol) in dichloromethane (1 ml). Stirring is continued for another 1.5 hours, then the reaction mixture is filtered. The filtrate was evaporated and the crude product was purified by flash chromatography on silica gel (dichloromethane: methanol: acetic acid, 10: 0.5: 0.05) to obtain (E) -3- (3-cyanophenyl) -N - {(R) - 2- [4- (4-fluorobenzoyl) piperidin-1-yl] -1-pyridin-3-ylmethylethyl} acrylamide [MH] ⁺ 497.4.

Method b

Preparation of {(R) -1-benzyl-2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl} carbamic acid tert-butyl ester

A solution containing ((R) -1-benzyl-2-oxoethyl) carbamic acid tert-butyl ester (0.5 g, 2.0 mmol), (4-fluorophenyl) piperidin-4-ylmethanone (0.414 g, 2, 0 mmol) and sodium triacetoxyborohydride (0.638 g, 3.0 mmol) in tetrahydrofuran (20 ml), stirred at ambient temperature for 24 hours. The solvent was evaporated and the residue was redissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The dichloromethane layer was dried over magnesium sulfate and evaporated. The crude product is purified by flash chromatography on silica gel (elution with ethyl acetate: hexane 3: 1) to give tert-butyl ether [(R) -1-benzyl-2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl} carbamic acid [MH] ⁺ 441.3.

Preparation of [1 - ((R) -2-amino-3-phenylpropyl) piperidin-4-yl] (4-fluorophenyl) methanone.

Solution of {(R) -1-benzyl-2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl} carbamic acid (1.12 g, 2.54 mmole) and trifluoroacetic acid solution (3 ml) in dichloromethane (6 ml) was stirred at ambient temperature for 3 hours. The solvent was evaporated and the residue was dissolved in hydrochloric acid (2M), washed with ethyl acetate and made basic with sodium hydroxide solution (4M) to pH 8-9. The suspension was extracted with dichloromethane, the dichloromethane layer was dried over magnesium sulfate and the solvent was evaporated, yielding [1 - ((R) -2-amino-3-phenylpropyl) piperidin-4-yl] (4-fluorophenyl) methanone. [MN] ⁺ 341.7.

Preparation of (E) -N - {(R) -1-benzyl-2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl} -3- (3-cyanophenyl) acrylamide

To a solution of (E) -3- (4-cyanophenyl) acrylic acid (0.042 g, 0.242 mmol) in dichloromethane (1 ml), triethylamine (0.046 ml, 0.331 mmol) and hexafluorophosphate (benzotriazo-1-yloxy) tripyrrolidinophosphonium (0.126 g 0.242 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes and then a solution of [1 - ((R) -2-amino-3-phenylpropyl) piperidin-4-yl] (4-fluorophenyl) methanone (0.075 g, 0.220 mmol) was added. in dichloromethane (1 ml). Stirring is continued for another 3 hours, then the reaction mixture is diluted with dichloromethane (25 ml) and washed with saturated sodium bicarbonate solution and saturated brine. The dichloromethane layer was dried over magnesium sulfate and the solvent was evaporated. The crude product is purified by flash chromatography on silica gel (elution with ethyl acetate: hexane, 5: 1) to give (E) -N - {(R) -1-benzyl-2- [4- (4-fluorobenzoyl) piperidin-1- yl] ethyl} -3- (3-cyanophenyl) acrylamide [MH] ⁺ 496.8.

Method B

Preparation of (E) -3- (5-bromo-2-methoxyphenyl) -N- {2- [4- (4-chlorobenzoyl) piperidin-1-yl] ethyl} acrylamide.

To a suspension containing 2- (formyl-3-methoxyphenoxy) ethyl polystyrene (AMEVA) resin (Novabiochem) (6.85 g, 3.33 mmol) in a mixture of methanol / dichloromethane (60 ml, 1: 1 v / v), 2-aminoethanol and sodium triacetoxyborohydride (4.00 g, 18.85 mmol) are added and the mixture is shaken for 16 hours at 20 ° C, then filtered. The resin is washed with methanol, DMF and dichloromethane, then dried under vacuum. A THF / acetonitrile mixture (50 ml, 1: 1 v / v) was added to the dried resin, followed by iodine (4.80 g, 18.85 mmol), imidazole (1.28 g, 18.85 mmol) and triphenylphosphine ( 4.90 g, 18.85 mmol). The resulting suspension was shaken for 18 hours at 20 ° C, then filtered. The resin is washed with THF and dried under vacuum. To a freshly prepared resin (0.50 g, 0.35 mmol), a solution of hydrochloride (4-chlorophenyl) piperidin-4-ylmethanone (0.18 g, 0.70 mmol) dissolved in DMF (2 ml) and diisopropylethylamine (0 , 36 g, 2.8 mmol). The mixture was kept at 50 ° C. for 16 hours and then filtered. The resin is washed with DMF. To the washed resin was added (E) -3- (5-bromo-2-methoxyphenyl) acrylic acid (0.27 g, 1.05 mmol), 2- (1H-benzotriazol-1-yl) -1.1 tetrafluoroborate, 3,3-tetramethyluronium (0.34 g, 1.05 mmol), diisopropylethylamine (0.29 g, 1.05 mmol) and DMF (4 ml) and the mixture was shaken at 20 ° C for 16 hours, then washed with DMF and methanol, after which, to isolate the product from the resin, it is treated with a mixture of trifluoroacetic acid / dichloromethane (6 ml, 1: 1 v / v) at 20 ° C for 1 h. The resulting mixture is filtered and the filtrate is evaporated under vacuum, obtaining the desired product, [ MH] ⁺ 506.7.

Method g

Preparation of {(R) -1- (4-aminobenzyl) -2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl} carbamic acid tert-butyl ester

To a solution of [(R) -2- [4- (4-fluorobenzoyl) piperidin-1-yl] -1- (4-nitrobenzyl) ethyl] carbamic acid tert-butyl ester (1.41 g, 2.90 mmol) in acetic acid (11 ml), cooled to 0 ° C, add an aqueous solution of calcium chloride (4 ml, 0.47 M) and powdered zinc (3.9 g, 59.6 mmol). The reaction mixture was stirred at 0 ° C. for 35 minutes and then filtered through a celite plug. The filtrate was evaporated and the residue was dissolved in water and extracted with dichloromethane. The dichloromethane layer was evaporated and the residue was dissolved in water and made basic with an aqueous solution of sodium bicarbonate and extracted with dichloromethane. The dichloromethane layer was dried over magnesium sulfate and evaporated to give tert-butyl ether {(R) -1- (4-aminobenzyl) -2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl} carbamic acid, [MH ] ⁺ 456.5.

Preparation of [(R) -2- [4- (4-fluorobenzoyl) piperidin-1-yl] -1- (4-methanesulfonylaminobenzyl) ethyl] carbamic acid tert-butyl ester

To a solution of tert-butyl ester {(R) -1- (4-aminobenzyl) -2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl} carbamic acid (1.19 g, 2.61 mmol) in dichloromethane (15 ml), cooled to 0 ° C., triethylamine (0.37 ml, 2.65 mmol) and methanesulfonyl chloride (0.192 ml, 2.49 mmol) are added. The reaction mixture was allowed to warm to ambient temperature, stirring for 1 h, then washed with water and brine, dried over magnesium sulfate and evaporated. The crude product is purified by flash chromatography on silica gel (elution in a gradient of ethyl acetate: hexane 6: 4 to 1: 0) to give tert-butyl ether [(R) -2- [4- (4-fluorobenzoyl) piperidin1-yl] - 1- (4-methanesulfonylaminobenzyl) ethyl] carbamic acid, [MH] ⁺ 534.7.

Method D

Preparation of (S) -4- [4- (4-chlorobenzoyl) piperidin-1-ylmethyl] -2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester

To a solution of (R) -4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (0.5 g, 2.18 mmol) in tetrahydrofuran (15 ml) was added (4-chlorophenyl) piperidin-4 -ylmethanone (0.49 g, 2.18 mmol) and sodium triacetoxyborohydride (0.69 g, 3.27 mmol) and the reaction mixture was stirred for 3.5 hours at ambient temperature. The solvent was evaporated and the residue was partitioned between ethyl acetate (50 ml) and saturated sodium bicarbonate solution (50 ml). The ethyl acetate layer was dried over magnesium sulfate and evaporated. The crude product is purified by flash chromatography on silica gel (elution with ethyl acetate: hexane, 1: 1) to give tert-butyl ether (S) -4- [4- (4-chlorobenzoyl) piperidin-1-ylmethyl] -2,2-dimethyloxazolidine -3-carboxylic acid, [MH] 437.2.

Preparation of [1 - ((S) -2-amino-3-hydroxypropyl) piperidin-4-yl] (4-chlorophenyl) methanone hydrochloride.

(S) -4- [4- (4-chlorobenzoyl) piperidin-1-methylmethyl] -2,2-dimethyloxazolidine-3-carboxylic acid threot-butyl ester (0.68 g, 1.55 mmol) is added to the chloride solution hydrogen in ethanol (5 ml, 5.5 M). The reaction mixture was stirred at ambient temperature for 1 h, then evaporated to dryness to give [1 - ((S) -2-amino-3-hydroxypropyl) piperidin-4-yl] (4-chlorophenyl) methanone hydrochloride, [MH] ⁺ 297.0.

Preparation of (E) -3- (5-cyan-2-methoxyphenyl) acrylic acid

To a suspension of palladium (II) acetate (0.77 g, 3.42 mmol) in N, N-dimethylacetamide (375 ml) in a nitrogen atmosphere, tetraethylammonium chloride (19.36 g, 114.5 mmol), dicyclohexylmethylamine (35, 1 g, 174.5 mmol) and 3-bromo-4-methoxybenzonitrile (25.51 g, 118.0 mmol). The suspension is heated to 100-105 ° C, after which tert-butyl acrylate (14.82 g, 114.5 mmol) is added slowly over 45 minutes. After stirring for another 30-60 minutes at 100 ° C, the solution was cooled to room temperature and diluted with TBME (375 ml). The resulting biphasic mixture was stirred vigorously for 10 minutes. The upper phase (TBME) is washed successively with water (100 ml), 10% aqueous citric acid solution (100 ml) and 25% aqueous NaCl solution (100 ml). The combined aqueous phases were extracted with TBME (100 ml). After the addition of activated carbon (0.4 g), the combined TBME phases were vigorously stirred for 10 minutes and filtered. Anhydrous Na ₂ SO ₄ (10 g) was added and the resulting suspension was stirred for another 10 minutes and filtered. The filtrate was concentrated to a volume of 50-70 ml under reduced pressure for 25-30 minutes, added at room temperature to anhydrous trifluoroacetic acid (150 ml). The resulting solution was stirred at room temperature for 60 minutes (the resulting precipitate was cooled to 0-5 ° C in an ice bath and diluted with ethyl acetate (410 ml). After vigorous stirring at 0 ° C for another 60 minutes, the suspension was filtered. The residue was dried under vacuum at 45-50 ° C, obtaining (E) -3- (5-cyan-2-methoxyphenyl) acrylic acid as a crystalline solid, _mp 252-253 ° C. MC (ES): [M-H] ^- 202.

Preparation of (E) -N - {(S) -2- [4- (4-chlorobenzoyl) piperidin-1-yl] -1-hydroxymethylethyl} -3- (5-cyan-2-methoxyphenyl) acrylamide.

To a solution containing (E) -3- (5-cyan-2-methoxyphenyl) acrylic acid (0.31 g, 1.55 mol), triethylamine (0.2 ml, 1.55 mmol) and tetrafluoroborate 2- ( 1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium (0.49 g, 1.55 mmol) in dichloromethane (5 ml), a solution of hydrochloride [1 - ((S) -2-amino -3-hydroxypropyl) piperidin-4-yl] (4-chlorophenyl) methanone and triethylamine (0.4 ml, 3.1 mmol) in dichloromethane (5 ml) and the reaction mixture was stirred at ambient temperature for 1 h. Reaction the mixture was diluted with dichloromethane (20 ml), washed successively with saturated bicarbonate solution atria (25 mL) and brine (25 mL), then dried over magnesium sulfate. The solvent was evaporated and the crude residue was purified by flash chromatography on silica gel (methanol: dichloromethane 5:95) to give (E) -N - {(S) -2- [4- (4-chlorobenzoyl) piperidin-1-yl] -1 -hydroxymethylethyl} -3- (5-cyan-2-methoxyphenyl) acrylamide, [MH] ⁺ 482.2.

Method E

Preparation of (S) -4- [4- (4-fluorobenzoyl) piperidin-1-ylmethyl] -2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester

To a solution of (4-fluorophenyl) piperidin-4-ylmethanone (3.5 g, 17 mmol) in anhydrous tetrahydrofuran (50 ml) is added tert-butyl ether (R) -4-formyl-2,2-dimethyloxazolidine-3-carbon acids (3.9 g, 17 mmol) and sodium triacetoxyborohydride (5.4 g, 25 mmol) and the reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was filtered and the solvent was evaporated, yielding a white solid. The solid is dissolved in dichloromethane (50 ml) and washed with saturated sodium bicarbonate solution (50 ml), water (2x 50 ml) and brine (50 ml). The organic phase was dried over magnesium sulfate and evaporated to give the desired product, [MH] ⁺ 420.9.

Preparation of [1 - ((S) -2-amino-3-hydroxypropyl) piperidin-4-yl] - (4-fluorophenyl) methanone hydrochloride.

To a suspension of (S) -4- [4- (4-fluorobenzoyl) piperidin-1-ylmethyl] -2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (4.9 g, 11.7 mmol) in ethanol (25 ml) add hydrogen chloride in dioxane (25 ml, 4 M). The resulting clear solution was stirred for 4 hours at ambient temperature, and a white precipitate formed. The reaction mixture was cooled to 0 ° C and the precipitate was filtered to obtain the desired product, [MH] ⁺ 281.6.

Preparation of (E) -N - {(S) -2- [4- (4-fluorobenzoyl) piperidin-1-yl] -1-hydroxymethylethyl} -3- (5-cyan-2-methoxyphenyl) acrylamide.

To a solution of [1 - ((S) -2-amino-3-hydroxypropyl) piperidin-4-yl] - (4-fluorophenyl) methanone hydrochloride (1.8 g, 5.7 mmol) and diisopropylethylamine (2.0 ml , 11.4 mmol) in dichloromethane (45 ml) add (E) -3- (5-cyan-2-methoxyphenyl) acrylic acid (1.1 g, 5.7 mmol), and then 2- (1H-) tetrafluoroborate benzotriazol-1-yl) -1,1,3,3-tetramethyluronium (1.83 g, 5.7 mmol). The reaction mixture was stirred at ambient temperature for 4.5 hours, then filtered and the filtrate washed with water (50 ml), saturated sodium bicarbonate solution (50 ml), water (50 ml) and brine (50 ml). The organic phase is dried over magnesium sulfate, the solvent is evaporated and the residue is purified by flash chromatography on silica gel (elution in a dichloromethane: methanol gradient from 98: 2 to 92: 8) to obtain the desired product, [MH] ⁺ 466.1.

Method G

Preparation of (S) -4- [4- (4-chlorobenzoyl) piperidin-1-ylmethyl] -2,2-dimethyloxazolidine-3-carboxylic acid dibenzoyl-L-tartrate (dibasic).

To a cooled (0 ° C) suspension of sodium borohydride (2.40 g, 63.55 mmol) in anhydrous toluene (50 ml), acetic acid (11.45 g, 189.9 mmol) was added in an inert gas atmosphere over 1 h. . Stirring is continued at ambient temperature for 5 hours until the evolution of hydrogen ceases (suspension 1). In another flask, 4- (4-chlorobenzoyl) piperidine hydrochloride (prepared by reacting N-formyl-4- (4-chlorobenzoyl) piperidine and acetyl chloride) (5.51 g, 21.18 mmol) was suspended in anhydrous toluene (20 ml) at room temperature. Triethylamine (2.57 g, 25.42 mmol) was added and a toluene solution (55 ml) of (R) -4-formyl-2,2-dimethyloxazolidine-3-carboxylic tert-butyl ether was added dropwise over 45 minutes with stirring acid (5.59 g, 24.36 mmol). Stirring is continued for another 20 minutes, then suspension 1 is added slowly with stirring over 60 minutes. The resulting suspension is stirred at ambient temperature until, according to TLC, uptake of the starting products ceases (14 hours), then slowly added to the solution NaHCO ₃ (25 g, 297.6 mmol) in water (120 ml). The resulting emulsion is stirred at 20 ° C for 60 minutes, the aqueous phase of the mixture is separated and the organic phase is washed twice in succession using 20 ml of a 10% aqueous solution of NaHCO ₃ and water. After adjusting the pH of the combined aqueous phases to 9.5 with solid Na ₂ CO _{3, the} aqueous phases were extracted with toluene (2 × 25 ml). Celite (0.5 g) was added to the combined organic phases, after which they were filtered and evaporated to dryness to give a free base, which was then dissolved in isopropanol (35 ml) and kept at reflux. A solution of di-O, O-benzoyl-L-tartaric acid (4.0 g, 10.6 mmol) in isopropanol (10 ml) was added dropwise. After stirring at 79-81 ° C for 20 min, the mixture is cooled, diluted with methyl tert-butyl ether (TBME) and the product is crystallized at 0 ° C, filtered, washed with cold (0 ° C) with a mixture of TBME: isopropanol, 1: 2 (15 ml) and chilled (0 ° C) TBME (3 × 5 ml) and dried under vacuum. After recrystallization of the dried product from isopropanol and subsequent drying under vacuum, the title product is obtained as a crystalline solid, _mp 174 ° C.

MS (ES +): [M} ⁺ 437.

Preparation of [1 - ((S) -2-amino-3-hydroxypropyl) piperidin-4-yl] (4-chlorophenyl) methanone dihydrochloride

(S) -4- [4- (4-chlorobenzoyl) piperidin-1-ylmethyl] -2,2-dimethyloxazolidine-3-carboxylic acid dibenzoyl-L-tartrate (dibasic) (4.0 g, 3 , 2 mmol) are suspended in n-butyl acetate (40 ml). Aqueous (32%) hydrochloric acid (2.18 g, 19.2 mmol) was added and the mixture was stirred at ambient temperature until, according to TLC, the uptake of the starting products ceased (2 h). The suspension was stirred in an ice bath for another 3 hours and filtered. The solid product is washed with cold (0 ° C) n-butyl acetate (2 × 5 ml) and dried under vacuum at 45-50 ° C to obtain the title product as colorless crystals _mp 232-237 ° C. MS (ES +): [MH] ⁺ 297.

Preparation of (E) -3- (5-cyano-2-methoxyphenyl) thioacrylic acid S-benzothiazol-2-yl ester

A suspension containing 2,2'-dibenzothiazolyl disulfide (4.0 g, 12.0 mmol) and triphenylphosphine (3.15 g, 12.0 mmol) in CH ₂ Cl ₂ (60 ml) was stirred vigorously at 25 ° C. within 30 minutes After cooling to 0 ° C, (E) -3- (5-cyano-2-methoxyphenyl) acrylic acid (obtained according to method D) (2.24 g, 11.0 mmol) is added in an ice bath, and then N-methylmorpholine (1.21 ml, 11.0 mmol). The suspension is stirred vigorously and allowed to warm to room temperature overnight. After stirring for 24 hours at room temperature, the precipitate formed is filtered at 0 ° C and washed with cold (0 ° C) CH ₂ Cl ₂ (10 ml). After drying under vacuum at 35 ° C, the title product is obtained in the form of a crystalline powder, _mp 183-185 ° C. MS (EI): [M] ⁺ 352.

Preparation of (E) -N - {(S) -1- [4- (4-chlorobenzoyl) piperidin-1-ylmethyl] -2-hydroxyethyl} -3- (5-cyan-2- methoxyphenyl) acrylamide

To a suspension of [1 - ((S) -2-amino-3-hydroxypropyl) piperidin-4-yl] - (4-chlorophenyl) methanone (9.24 g, 25.0 mmol) in ethanol (250 ml) was added N-methylmorpholine (2.53 g, 25.0 mmol). The suspension is stirred at 45 ° C. for 30 minutes, then (E) -3- (5-cyano-2-methoxyphenyl) thioacrylic acid S-benzothiazol-2-yl ester (4.40 g, 12.5 mmol) is added. the suspension was diluted with ethanol (20 ml) and stirring was continued at 45 ° C for 3 hours. An additional portion of thioether (2.64 g, 7.5 mmol) was added and the suspension was stirred for another 4 hours at 45 ° C. The last portion of thioether (1.76 g, 5.0 mmol) was added and, after stirring for another 3 hours, another portion of N-methylmorpholine (1.26 g, 12.46 mmol) was added and stirring was continued overnight, then added the last portion of N-methylmorpholine (1.26 g, 12.46 mmol). The suspension was immediately filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (250 ml) and washed successively with 10% aqueous Na ₂ CO ₃ (2 × 100 ml) and 10% aqueous NaCl (4 × 100 ml). The organic phase is stirred with celite (1 g), filtered and evaporated to dryness. The residue was dried in vacuo and dissolved in ethanol (130 ml). Under stirring at 35 ° C, a solution of L-tartaric acid (4.5 g, 30.0 mmol) in ethanol (100 ml) was added, and the resulting suspension was stirred at 50-55 ° C until a clear solution was obtained. After turbidity associated with the formation of crystals, the suspension is slowly cooled to 0 ° C and stirred in an ice bath for another 45 minutes, then the precipitate is filtered, washed with cold (0 ° C) ethanol (20 ml) and recrystallized from ethanol, obtaining specified in product title, _mp 90-120 ° C (decomposition). MS (ES +): [MH] ⁺ 482.

Preparation of (E) -N - {(S) -1- [4- (4-chlorobenzoyl) piperidin-1-ylmethyl] -2-hydroxyethyl} -3- (5-cyan-2-methoxyphenyl) acrylamide

10% aqueous Na ₂ CO ₃ (100 ml) was added with stirring at room temperature to a suspension of (E) -N - {(S) -1- [4- (4-chlorobenzoyl) piperidine semi- (L) -tartrate -1-ylmethyl] -2-hydroxyethyl} -3- (5-cyan-2-methoxyphenyl) acrylamide (6.32 g, 10.0 mmol) in CH ₂ Cl ₂ (150 ml) and water (50 ml). After stirring at ambient temperature for 30 minutes, the phases were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (100 ml). The combined CH ₂ Cl ₂ phases were extracted with 10% aqueous NaCl (2 × 100 ml), stirred with celite (500 mg) and filtered after evaporation under reduced pressure to obtain a colorless foam. After adding butyl acetate (200 ml), a clear solution forms, which is heated to 80 ° C and allowed to slowly cool to room temperature. After dilution with TBME (150 ml), the suspension is cooled to 0 ° C, the precipitated crystals are filtered off, washed with cold (0 ° C) 1: 1 butyl acetate / TBME mixture and dried under vacuum at 45-50 ° C, obtaining ( E) -N - {(S) -1- [4- (4-chlorobenzoyl) piperidin-1-ylmethyl] -2-hydroxyethyl} -3- (5-cyan-2-methoxyphenyl) acrylamide, _mp 162-163 ° C. MS (EI): [MH] ⁺ 482.

Claims (7)

1. Derivatives of piperidine of the formula

in free form or in salt form, where Ar ¹ denotes phenyl substituted by one or more halogen atoms, Ar ² is phenyl or naphthyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, cyano, hydroxy, nitro, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, C ₁ -C ₈ alkoxy or C ₁ -C ₈ alkoxycarbonyl, R ¹ is hydrogen or C ₁ -C ₈ alkyl optionally substituted with hydroxy, C ₁ -C ₈ alkoxy, acyloxy, -N (R ² ) R ³ , halogen, carboxy, C ₁ -C ₈ alkoxycarbonyl, -CON ( R ⁴ ) R ⁵ or a monovalent cyclic organic group, R ² and R ^{3 are} each independently hydrogen or C ₁ -C ₈ alkyl, or R ² is hydrogen and R ³ is acyl or —SO ₂ R ⁶ , or R ² and R ³ together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocyclic group, R ⁴ and R ⁵ each independently of one another is hydrogen or C ₁ -C ₈ alkyl, or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group, R ⁶ is C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl or phenyl optionally substituted with C ₁ -C ₈ alkyl, and n is 1, 2, 3 or 4, provided that when Ar ¹ is parachlorophenyl and R ¹ is hydrogen, then Ar ^{2 is} not phenyl or paranitrophenyl. 2. The compound according to claim 1, where Ar ² denotes monosubstituted phenyl, the substituent of which is halogen, cyano, nitro or C ₁ -C ₄ alkoxygroup; or disubstituted phenyl, the substituents of which are selected from the group consisting of halogen, cyano, hydroxy, nitro, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl and C ₁ -C ₄ haloalkyl; or trisubstituted phenyl, the substituents of which are selected from the group consisting of halogen, hydroxy, C ₁ -C ₄ alkoxy and C ₁ -C ₄ alkoxycarbonyl; or pentasubstituted phenyl, the substituents of which are halogen atoms. 3. The compound according to claim 1, where R ¹ denotes C ₁ -C ₄ alkyl, optionally substituted with hydroxy, C ₁ -C ₈ alkoxy, acyloxy, halogen, carboxy, C ₁ -C ₈ alkoxycarbonyl, -CON (R ⁴ ) R ⁵ or a monovalent cyclic organic group. 4. The compound according to claim 1, where Ar ¹ is phenyl substituted with fluorine or chlorine in the para position relative to the specified carbonyl group and optionally further substituted with halogen in the ortho position relative to the specified carbonyl group, Ar ² is phenyl monosubstituted with a substituent selected from the group consisting of halogen, cyano, nitro and C ₁ -C ₄ alkoxy, phenyl substituted with two substituents, which may be the same or different, selected from the group consisting of halogen, cyano, hydroxy, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl and nitro or phenyl substituted with three substituents, which may be the same or different, selected from the group consisting of halogen, hydroxy, C ₁ -C ₄ alkoxy and C ₁ -C ₄ alkoxycarbonyl, R ¹ is hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkyl substituted with a hydroxy group, C ₃ -C ₈ cycloalkyl, phenyl, phenyl, substituted with a C ₁ -C ₄ alkylsulfonylamino group, or a 5- or 6-membered heterocyclic aromatic a group carrying one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and n is 1 or 2. 5. The compound according to claim 1, where Ar ¹ is phenyl substituted with fluorine or chlorine in the para position relative to said carbonyl group, Ar ² is phenyl substituted in the ortho position relative to the indicated —CH═CH group with a C ₁ -C ₄ alkoxy group and in the para position relative to the C ₁ -C ₄ alkoxy group by a cyano group, halogen or a C ₁ -C ₄ alkoxy group, R ¹ is C ₁ -C ₄ alkyl substituted with a hydroxy group, phenyl, phenyl substituted with a C ₁ -C ₄ alkylsulfonylamino group or a 5- or 6-membered heterocyclic aromatic group carrying one or two ring heteroatoms selected from nitrogen, oxygen and sulfur , and n is 1. 6. The compound according to claim 1 of the formula

in free form or in salt form, where Ra 'is hydrogen and Ra, Rb, Rc, Rd, Re, Rg and Rf have the meanings indicated in the following table Ra Rb Rc Rd Re Rf Rg F N N CN H H H F

N CN H H H F

N CN H H H F

OCH ₂ CH ₃ H H Br H F N N CN OCH ₃ H H F N OCH ₃ H H OCH ₃ H F N OCH ₃ H H Br H F

N CN H H H F

OCH ₃ H H Br H F N IT H H Cl H F N OCH ₃ H H F H Cl N OCH ₃ H H Br H F N OCH ₃ H H CN H F N OCH ₃ H H Cl H F N OCH ₂ CH ₃ H H Cl H F N O (CH ₂ ) ₂ CH ₃ H H Cl H F N

H H Cl H F N O (CH ₂ ) ₂ CH ₃ H H Br H F N

H H Br H F N OCH ₃ H H CH ₃ H F N

H H CH ₃ H F

H N N CN N F

OCH ₃ N N OCH ₃ N F

OCH ₃ N N Br N F

H N N CN N F

OCH ₃ N N OCH ₃ N F

OCH ₃ N N CN N F

OCH ₃ N N Br N F

OCH ₃ N N CN N F

OCH ₃ N N CN N F H N N CH ₃ N N F H F F F F F F H N CF ₃ N CF ₃ N F H N NO ₂ N N N F H N UNSD ₃ OCH ₃ N OCH ₃ F

OCH ₃ N N CN N Cl

OCH ₃ N N CN N F

N N N CN N Cl

OCH ₃ N N Cl N Cl H OCH ₃ N N CN N F

OCH ₃ N N Br N Cl

OCH ₃ N N Br N F

OCH ₃ N N CN N F

OCH ₃ N N CN N or where Ra and Ra 'are fluoro, Rb, Rd, Re and Rg are hydrogen, Rc is methoxy and Rf is bromo. 7. A method for producing compounds of formula I, comprising reacting a compound of formula

with a compound of the formula

or with its amide derivative, where Ar ¹ , Ar ² , R ¹ and n have the meanings indicated in claim 1, followed by isolation of the target product in free form or in salt form.