3-apatitenepheline or pyrrolidine as antagonists tachykinin, methods for their preparation, intermediate compounds, pharmaceutical composition and method of treatment

 

(57) Abstract:

Describes the new 3-apatitenepheline or pyrrolidine formula I or their pharmaceutically acceptable salts, where R represents a C3-C7cycloalkyl,1-C6alkyl, substituted C3-C7cycloalkyl, or phenyl, possibly substituted OR5where R5is1-C4alkyl; a is CO or SO2; R1represents phenyl, substituted with two halogen substituents; R2represents a group of formula II, where R5, R6, R7is N; X2represents a simple bond; W represents O NSO2NR5R6NS02(C1-C4)alkyl; n is 1; X1represents a simple bond; X represents C1-C4alkylene; m is 0 or 1. New compounds are antagonists of tachykinins. Also describes the methods for their preparation, intermediate compounds, pharmaceutical composition and method of treatment. 6 C. and 9 C.p. f-crystals, 3 PL.

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The invention relates to therapeutic tools, specifically setidentityproviderid N-substituted nitrogenous heterocyclic compounds and methods of producing such heterocycles, promey heterocycles.

In International patent publication number WO 96/05193 described various (azetidin-1-illlil)lactams as antagonists of tachykinins.

These compounds are antagonists of tachykinins, including neurokinin A (NKA), neurokinin IN (N) and substance P acting at the receptor neirokinina-1 (NK1), neirokinina-2 (NK2), neirokinina-3 (NK3person or combination of two or more of them. Heterocycles, therefore, useful for the prevention or treatment of inflammatory diseases such as arthritis, psoriasis, asthma or inflammatory bowel disease, disorders of the Central nervous system (CNS), such as anxiety, depression, dementia or psychosis, gastrointestinal (LCD) disorders such as functional bowel disease, irritable bowel syndrome, gastroesophageal reflex, fecal incontinence, colitis or Crohn's disease, a disease caused by Helicobacter pylori or other urease-positive gram-negative bacteria, disorders of the urinary tract, such as urinary incontinence, hyperreflexia, impotence or cystitis, pulmonary disorders, such as chronic airway obstruction, allergies such as eczema, contact dermatitis, urticaria, assembily day, such as angina or disease Reunaud, proliferative disorders, such as cancer or violation, including the proliferation of fibroblasts, fibrous or collagen diseases, such as scleroderma or tosinopally fasciolosis, reflux sympathetic dystrophy, such as the syndrome of shoulder disorders type of addiction, such as alcoholism, stress-related somatic disorders, peripheral neuropathy, such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, burn, herpetic neuralgia or poligeneticheskie neuralgia, neuropathological disorders, such as Alzheimer's disease or multiple sclerosis, disorders related to immune enhancement or weakening, such as systemic lupus erythematosus, rheumatic "diseases such as fibrositis, vomiting, cough, acute or chronic disease, migraine, offlinecache diseases, such as proliferative retinopathy, influenza or colds.

These derivatives are particularly effective and selective antagonists of tachykinins, including NKA, NKB and substance P acting at receptors NK1NK2and NK3person, or combinations of two or more of them. About the inflammatory bowel disease, disorders of the Central nervous system (CNS), such as fear, depression, dementia or psychosis, gastrointestinal (LCD) disorders such as functional bowel disease, irritable bowel syndrome, gastroesophageal reflex, fecal incontinence, colitis or Crohn's disease, disorders of the urinary tract, such as urinary incontinence or cystitis, pulmonary disorders, such as chronic airway obstruction, allergies such as eczema, contact dermatitis or rhinitis, a hypersensitivity, such as sensitivity to poison ivy, peripheral neuropathy, such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, burn, herpetic neuralgia or poligeneticheskie neuralgia, cough or acute or chronic pain.

The present invention is a compound of the formula:

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and their pharmaceutically acceptable salts, where

R represents a C3-C7cycloalkyl, aryl or C1-C6alkyl, and C1-C6alkyl optionally substituted by fluorine, -COOH, COO(C1-C4)alkyl, C3-C7cycloalkyl, adamantium, aryl or het1and C3-C7cycloalkyl optional sammelalbum, C1-C6alkoxy, hydroxy, fluorine, fluorine (C1-C4) alkyl and fluoro (C1-C4) alkoxy;

A is CO or SO2;

R1represents phenyl, benzyl, naphthyl, thienyl, benzothiazyl or indolin, each of which is optionally substituted by 1 or 2 substituents, each of which is independently selected from C1-C4alkyl, C1-C4alkoxy, halogen and trifloromethyl;

R2represents-CO2H, -CONR3R4, -CONR5(C3-C7cycloalkyl), -NR5(C2- C5alkanoyl), -NR3R4, -NR5CONR5R6, (C3-C7cycloalkyl-C1-C4alkyl) R5N-,

(C3-C7cycloalkyl-C1-C4alkyl)2N-, -NR5COCF3, -NR5SO2CF3, -NR5(SO2-C1-C4alkyl), -NR5SO2NR5R6, -NR5(SO2aryl), N (aryl) (SO2C1-C4alkyl), -OR5, -O(C3-C7cycloalkyl), -SO2NR5R6, het3or a group of the formula:

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or

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R3and R4independently selected from H and C1-C4the alkyl, optionally substituted by hydroxyl, C1-C4and the and het2;

R5and R6independently selected from H, C1-C4the alkyl and C3-C7cycloalkyl - C1-C4of alkyl, and C1-C4alkyl and C3-C7cycloalkyl-C1-C4alkyl optionally substituted by fluorine;

R7represents H, C1-C4alkyl, hydroxy, fluorine (C1-C4alkyl) or phenyl, with phenyl optionally substituted by 1 or 2 substituents, each of which is independently selected from C1-C4of alkyl, fluorine (C1-C4) alkyl, halogen, C1-C4alkoxy and fluorine(C1-C4) alkoxy;

R8represents H, fluorine, hydroxy, C1-C4alkoxy, C2-C5alkanoyl or C2-C5alkanoyloxy;

R9is-NR5R6-NR5COR5, -NR5SO2CF3, -NR5(SO2C1-C4alkyl), -NR5SO2NR5R6, -NR5COO (C1-C4alkyl), -NR5CONR5R6, - NR5(SO2morpholino), - NR5(SO2aryl), -N(aryl) (SO2C1-C4alkyl) or a group of the formula:

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X represents C1-C4alkylen;

X1represents a direct bond or C1-C6alkylen;
CH (C1- C4alkoxy), CHCO2H, CHCO2(C1-C4alkyl), CHONR5R6, CHF, CF2CH(azetidin-1-yl), CH(pyrrolidin-1-yl), CH(piperidine-1-yl), CH(morpholino), CH(benzoxazol-2-yl), CHR9, O, S(O)p, NR5N (C3-C7cycloalkyl), NSO2(C1-C4alkyl), NSO2NR5R6, NSO2CF3, NSO2(morpholino), NSO2(aryl),

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NCONR5R6NCOR5, NCO (aryl) or NCO2(C1-C4alkyl);

W1represents methylene, CO, CH(OH) C(OH)2CH(C1-C4alkoxy), CHCO2H, CHCO2(C1-C4alkyl), CHCONR5R6, CHF, CF2CH(azetidin-1-yl), CH(pyrrolidin-1-yl), CH(piperidine-1-yl), CH(morpholino) or CHR9;

W2is W1, -CH2W1-, -CH2WCH2- or-CH2CH2WCH2-;

m is 0, 1 or 2;

n is 1 or 2 when W is other than methylene and a is 0, 1 or 2 when W is methylene;

p is 0, 1 or 2;

q is 1 or 2;

r is 1, 2, 3 or 4;

the term "aryl", as used in the definition of R, R2, R9and W denotes a naphthyl or phenyl, each of which is optionally substituted C1-C4by alkyl, halogen, -OR5, fluorine (C1-C41"used in the definition of R, denotes thienyl or having a 5 - or 6-membered ring heteroaryl group containing either 1 or 2 heteroatom nitrogen or a nitrogen heteroatom and a heteroatom of oxygen or sulfur, each of which is optionally substituted by 1 or 2 substituents, each of which is independently selected from C1-C4of alkyl, C1-C4alkoxy, halogen, fluorine (C1-C4the alkyl and fluorine (C1-C4alkoxy);

the term "het2"used in the definitions of R3and R4means having a 4-7-membered ring non-aromatic heterocyclic group containing 1 or 2 heteroatoms, each independently selected from nitrogen, oxygen, and S(O)pand this group is optionally C-substituted by 1 or 2 substituents, each of which is independently selected from C1-C4of alkyl, C1-C4alkoxy and fluorine (C1-C4the alkyl, and the nitrogen heteroatom ring is optional as Deputy H, C1-C4alkyl, C2-C5alkanoyl, -CONR5R6or-SO2NR5R6;

the term "het3"used in the definitions of R2denotes optional benzododecinium, N-linked, 5-members is UCA benzododecinium part, 1 or 2 substituents, each of which is independently selected from C1-C4of alkyl, fluorine and fluorine(C1-C4) alkyl.

In the above definitions, the term "halogen" denotes fluorine, chlorine, bromine or iodine and alkyl, alkylene and alkoxygroup containing three or more carbon atoms, or alcoholnye groups containing four or more carbon atoms, can be unbranched or branched chain.

Preferably, when R is aryl, C3-C7cycloalkyl, optionally substituted by fluorine, or C1-C6alkyl, substituted C3-C7cycloalkyl.

More preferably, when R is phenyl, optionally substituted C1-C4alkoxy, C3-C7cycloalkyl, optionally substituted by fluorine, or C1-C6alkyl, substituted C3-C7cycloalkyl.

Very preferably, when R is phenyl, 2-methoxyphenyl, cyclopropyl, cyclohexyl, 4,4-diverticulosis-1-yl or cyclopropylmethyl.

Preferably, when a is CO.

Preferably, when R1represents phenyl, optionally substituted by 1 or 2 halogen substituents.

each of which is independently selected from fluorine and chlorine.

Even more preferably, when R1represents phenyl, 3,4-differenl, 3-chlorophenyl, 4-chlorophenyl or 3,4-dichlorophenyl.

Very preferably, when R1is 3,4-dichlorophenyl.

Preferably, when R2is-CONR3R4, -CONR5-(C3-C7cycloalkyl), -NR3R4, het3or a group of the formula:

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or

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where each of R3and R4independently selected from C1-C4the alkyl and C1-C4of alkyl, substituted hydroxy or C1-C4alkoxy, each of R5and R6independently selected from H, C1-C4the alkyl, optionally substituted by fluorine, and C3-C7cycloalkyl-C1-C4of alkyl, R7is H, hydroxy or phenyl, R8represents hydroxy or C2-C5alkanoyloxy, W is methylene, CH(OH), CHF, CO, CH(C1-C4alkoxy), CHCO2H, CHCO2(C1-C4alkyl), CH(benzoxazol-2-yl), CHNR5R6, CHNR5COR6, CHNR5(SO2C1-C4alkyl), CHNR5COO(C1-C4alkyl), O, S(O)p, NR5, NSO2(C1-C4alkyl), NSO2NR5R6NSO2(morpholino), NCONR

More preferably, when R2is-CONR3R4, - CONR5(C3-C7cycloalkyl), -NR3R4N-linked, 5-membered ring heteroaryl group containing 1 or 2 nitrogen heteroatom, or a group of the formula:

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or

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where each of R3and R4independently selected from methyl and C1-C4of alkyl, substituted hydroxy or methoxy; each of R5and R6independently selected from H, methyl, trifloromethyl and cyclopropylmethyl, R7is H, hydroxy or phenyl, R8represents hydroxy or the atomic charges, W is methylene, CH(OH), CHOOH3, CHF, CO, CHOCH2CH3CHO(CH2)2CH3. CHOC(CH3)3, CHCO2H, CHCO2CH3, CHCO2CH2CH3CH(benzoxazol-2-yl), CHNH2, CHNHCH2(cyclopropyl),

CHNHCOCH3, CHNHSO2CH3, CHNHCO2C(CH3)3, O, S(O)p, NH, NCH3, NCH2(cyclopropyl), NSO2CH3, NSO2NH2, NSO2NHCH3, NSO2N(CH3)2, NSO2(morpholino), NCONH2, NCONHCH3, NCOCH3, NCOCF3, NCO (phenyl) or NCO2C(CH3

Even more preferably, when R2is N-(2-methoxyethyl)-N-methylcarbamoyl, N-cyclohexylcarbonyl, N-(2 - hydroxyethyl)-N-methylamino, N-(2-hydroxy-2-methylpropyl)-N - methylamino, N-(2-methoxyethyl)-N-methylamino, imidazol-1-yl, 3-hydroxypyrrolidine-1-yl, piperidine-1-yl, 2,6-dimethylpiperidin-1-yl, 3-hydroxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4 - methoxypiperidine-1-yl, 4-ethoxypyridine-1-yl, 4-(n - propoxy)piperidine-1-yl, 4-(tert-butoxy)piperidine-1-yl, 4 - carboxypeptidase-1-yl, 4-ethoxycarbonylpyrimidine-1-yl, 4 - ethoxycarbonylpyrimidine-1-yl, 4- (benzoxazol-2-yl) piperidine-1 - yl, 4-aminopiperidin-1-yl, 4-cyclopropylmethyl-aminopiperidin - 1-yl, 4-acetamidophenyl-1-yl, 4-methanesulfonamido-1 - yl, 4-(tert-butoxycarbonylamino)piperidine-1-yl, morpholino, 2 - phenylmorpholine, homomorpholine, thiomorpholine, 1 Osotimehin, 1,1-dioxothiazolidine, piperazine-1-yl, 4-methylpiperazin-1-yl, 4 - cyclopropylamines-1-yl, 4-methanesulfonylaminoethyl-1-yl, 4 - aminosulphonylphenyl-1-yl, 4-methylaminoacetaldehyde-1-yl, 4-dimethylaminocarbonylmethyl-1-yl, 4 - morpholinobutyrophenone-1-yl, 4-carbamoylbiphenyl-1-yl, 4-N - methylcarbamoylmethyl-1-yl, 4-acetylpiperidine-1-yl, 4 - triftoratsetilatsetonom-1-yl, 4-benzomorphan, 3-hydroxy-8-azabicyclo [3,2,1] Oct-8-yl, 3-acetyl-hydroxy-8-azabicyclo[3,2,1]-Oct-8-yl, 4 - foreperiod-1-yl or 4-oxopiperidin-1-yl.

More preferably, when R2is 4-aminopiperidin-1-yl, 4-carboxypeptidase-1-yl, 4-hydroxypiperidine-1-yl, morpholino, 1 Osotimehin, 4-aminosulphonylphenyl-1-yl, 4-methanesulfonylaminoethyl-1-yl, 4-methylaminoacetaldehyde-1-yl, 4-morpholinobutyrophenone-1-yl, 4-foreperiod-1-yl or 4-oxopiperidin-1-yl.

Preferably, when X is ethylene or propylene.

Preferably, when X1is a direct link.

Preferably, when X2is a direct link.

Preferably, when m is 0 or 1.

Pharmaceutically acceptable salts of compounds of formula (I) include acid additive salts and salts of the bases.

Suitable acid additive salts derived from acids which form non-toxic salts and examples are the cleaners containing hydrochloride, hydrobromide, hydroiodide, sulfate, acid sulfate, nitrate, phosphate, secondary acid phosphate, acetate, maleate, fumaric, lactate, tartrate, citrate, gluconate, succinate, banovani derived from reason, which form non-toxic salts and examples are the salts of aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine.

An overview of suitable salts see Berge et.al., J. Pharm. Sci., 66, 1-19(1977).

The compound of formula (I) may contain one or more asymmetric carbon atoms and can therefore exist in two or more stereoisomeric forms. The present invention includes the individual stereoisomers of compounds of formula (I) and mixtures thereof.

Division of diastereoisomers can be achieved by conventional methods, for example by fractional crystallization, chromatography or HPLC stereoisomeric mixtures of compounds of formula (I) or a suitable salt or derivative. An individual enantiomer of the compounds of formula (I) can also be obtained from a corresponding optically pure intermediate or by cleavage, for example, using HPLC of the corresponding racemate using a suitable chiral media or by fractional crystallization of the diastereomeric salts obtained by reaction of the corresponding racemate with a suitable optically active acid or base.

A preferred compound of formula (I) and salts thereof have the stereochemistry, the show is in the ring:

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Preferred examples of compounds of formula (I) are compounds where:

(i) R is phenyl, A is CO, R1is 3,4-dichlorophenyl, R2is morpholino, X is propylene, X1is a direct link and m is 1;

(ii) R is phenyl, A is CO, R1is 3,4-dichlorophenyl, R2is 4-aminosulphonylphenyl-1-yl, X is propylene, X1is a direct link and m is 1;

(iii) R is cyclohexyl, A is CO, R1is 3,4-dichlorophenyl, R2is morpholino, X is propylene, X1is a direct link and m is 1;

(iv) R is cyclohexyl, A is CO, R1is 3,4-dichlorophenyl, R2is 4-aminosulphonylphenyl-1-yl, X is propylene, X1is a direct link and m is 1;

(v) R is cyclohexyl, A is CO, R1is 3,4-dichlorophenyl, R2is morpholino, X is propylene, X1is a direct link and m is 1;

(vi) R is cyclohexyl, A is CO, R1is 3,4-dichlorophenyl, R2predstavljaet) R is phenyl, A represents CO, R1is 3,4-dichlorophenyl, R2is morpholino, X represents ethylene, X1is a direct link and m is 0;

(viii) R is 2-methoxyphenyl, A represents CO, R1is 3,4-dichlorophenyl, R2is morpholino, X represents ethylene, X1is a direct link and m is 0;

(ix) R is phenyl, A is CO, R1is 3,4-dichlorophenyl, R2is morpholino, X represents ethylene, X1is a direct link and m is 1;

(x) R is 2-methoxyphenyl, A represents CO, R1is 3,4-dichlorophenyl, R2is morpholino, X represents ethylene, X1is a direct link and m is 1;

(xi) R is phenyl, A is SO2, R1is 3,4-dichlorophenyl, R2is morpholino, X represents ethylene, X1is a direct link and m is 1;

(xii) R represents cyclopropylmethyl, A represents CO, R1is 3,4-dichlorophenyl, R2is morpholino, X represents ethylene, X1is a direct link and m is 1;

(xiii) R represents cyclopropylmethyl, A represents CO, R1predsedetalem a direct link and m is 1;

or any such connection with the stereochemistry shown above in formula (IA) in position when the connection of the groups X and R1to N-acylated or N-sulfonylamino ring, or pharmaceutically acceptable salt of any of them.

The compounds of formula (I) represented by the invention, can be obtained in the following ways:

1) the compounds of formula (I), where X represents a group (C0-C3alkylen)CH2-, a methylene group, which is attached to the nitrogen atom of azetidine, and R, R1, A, R2X1and m are such as previously defined for compounds of formula (I) can be obtained by reductive amination using as starting materials compounds of the formula:

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where R, A, R1and m are such as previously defined for compounds of formula (I), and compounds of formula:

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or its acid salt additive, where R2and X1such as previously defined for compounds of formula (I). The reaction is preferably carried out in the presence of a suitable acid, for example acetic acid.

The reaction proceeds via the initial formation of an intermediate salt imine formula:

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which can be stable and allocated. The reaction is preferably placed in the compounds of formula (I).

In a typical method, the aldehyde of formula (II) is first subjected to reaction with azetidinol formula (III) in a suitable solvent, for example tetrahydrofuran, and the mixture is then treated with a suitable reducing agent, such as triacetoxyborohydride sodium or cyanoborohydride sodium, in the presence of a suitable acid, for example acetic acid, to obtain the target product. If the source material using an acid additive salt of azetidine formula (III), before adding the reducing agent can be added a suitable acid acceptor, e.g. triethylamine.

The reaction is usually carried out at room temperature.

Source aldehydes of the formula (II) can be obtained, as shown in figure 1 (see end of description), where R, A, R1and m are such as previously defined for compounds of formula (I), and each of Z and Z1represents a suitable leaving group, such as chlorine, bromine, iodine, methanesulfonate, p-toluensulfonate or tripterocalyx, and R-A-Z2is acid RCO2H or its derivatives suitable for the acylation of amines, or connection RSO2Z2suitable for sulfonylamine amines.

Examples Z2include hispanicowned a suitable base, for example sodium hydride, and then alkylate in situ alkylating agent of the formula (V), where Z preferably represents bromine. The reaction is usually carried out in a suitable solvent, for example tetrahydrofuran, at about 0oC for deprotonation and approximately at room temperature for alkylation. The reaction can be carried out also in terms of the transfer phase using a suitable base, for example sodium hydroxide, a suitable catalyst transfer phases, for example chloride, Tetra-n-butylamine, and a suitable solvent, such as cyclohexane, n-pentane or toluene.

Derived derived acetonitrile of formula (VI) is then deprotonated using a suitable base, such as diisopropylamide lithium, and then alkylate in situ a compound of formula (VII), where Z1preferably represents bromine. The reaction is usually carried out in a suitable solvent, for example tetrahydrofuran, at approximately -70oC, heating the mixture to approximately room temperature to complete the reaction. To increase the speed of the reaction after addition of the compounds of formula (VII) can optionally add iodide, Tetra-n-butylamine.

Received from the using Raney Nickel in an atmosphere of hydrogen at atmospheric pressure and room temperature with ammonium solution of ethanol as solvent.

The lactam of formula (IX) then restore using a suitable reducing agent, such as a metal hydride, such as sociallyengaged, in suitable conditions, such as a nitrogen atmosphere, and in a suitable solvent, such as tetrahydrofuran.

Thus obtained cyclic amine (X) is then subjected to reaction with RSO2Z2or acid or acid derivative RCOZ2. In a typical method for A = CO to a mixture of a suitable base, such as triethylamine, Amin (X) and a suitable solvent, such as dichloromethane, add the acid chloride RCOCl. In a typical method for A = SO2to a mixture of a suitable base, such as triethylamine, Amin (X) and a suitable solvent, such as dichloromethane, add sulphonylchloride RSO2Cl.

Received (sulfon)amide of the formula (XI) is then treated with a saturated solution of hydrogen chloride in a suitable C1-C4alcohol, for example methanol, at about room temperature to remove tetrahydropyranol protective group. The removal of the protective group can also be performed using a suitable ion exchange resin, such as amberlyst 15 (trademark), in a suitable solvent, such as emer under oxidizing conditions Svema (oxalicacid, dimethyl sulfoxide, triethylamine and the use of dichloromethane as solvent).

An alternative way to obtain the aldehyde of formula (II) is illustrated in scheme 2 (see the end of the description), where R, A, R1and m are such as previously defined for compounds of formula (I), and R-A-Z2the same as defined for the above Scheme 1.

Source cyanocycline formula (XIII) can be obtained by using common methods.

In a typical method nitrile group Lancelot formula (XIII) restore and cyclist using a suitable system, for example, by catalytic hydrogenation. The reaction is usually carried out in a suitable solvent, for example glacial acetic acid, at room temperature and at elevated pressures and over a suitable catalyst, such as platinum oxide.

Thus obtained lactam (XIV) then restore in a cyclic amine (XV). In the usual method the solution of the lactam (XIV) is added to a suitable restoring the system, such as sociallyengaged in a suitable solvent, such as tetrahydrofuran.

Thus obtained cyclic amine (XV) is then subjected to reaction with R-A-Z2where R-A-Z2such as op is amide (XVI; A = CO), using the linking system, such as N-methylmorpholine/hydrate of 1-hydroxybenzotriazole/hydrochloride 1-(3-dimethylaminopropyl)-3 - ethylcarbodiimide in a suitable solvent such as dichloromethane.

Thus obtained (sulfon)amide (XVI) is then treated with a suitable acid, such as hydrochloric acid in a suitable solvent, for example tetrahydrofuran, at about room temperature to remove acetaldol protective group. The removal of the protective group can also be carried out using amberlyst 15 (TM) in a suitable solvent such as a mixture of acetone/water. Other suitable means for the removal of the protective groups for acetals can be found in "Protective Groups in Organic Synthesis" by TW: Greene and PGM WUTS (2nd end., Wiley Jnterscience).

Another alternative method of producing aldehydes of the formula (II), where m = 1, is illustrated in figure 3 (see end of description), where R1, R3, Z, R, A and Z2such as defined above.

In a typical method, the nitrile of formula (IV) is treated with a suitable base such as sodium hydride, then alkylate in situ a compound of formula (XVII), where Z is as defined before. The compounds of formula (XVII) can be obtained by using common methods. Z, preferred is e, such as N,N-dimethylformamide.

Thus obtained nitrile (XVIII) can then be deprotonate a suitable base, such as tert-piperonyl potassium, and then subjected to reaction with a suitable acrylate ester, such as acrylate. Educated thus essential intermediate product can then hydrolyze in Lancelot (XIX) using suitable gidroliznaya systems, such as 2 N. aqueous sodium hydroxide solution, in suitable conditions, such as stirring at room temperature.

The so formed nitrile (XIX) can then be transformed restoration using a suitable reducing agent, such as sociallyengaged, in a suitable solvent, such as tetrahydrofuran, or by hydrogenation and subsequent recovery educated so amide with borane.

Thus formed piperidine (XX) is then subjected to reaction in a manner similar to the method described for the above transformations (X) ---> (XI) (Scheme 1) and (XV) ---> (XVI) (Scheme 2).

Thus obtained amine derivative (XXI) is then oxidized, for example, by ozonolysis, in a suitable solvent such as methanol, followed by treatment according to the Original azetidine formula (III) can be obtained by using common methods.

2) All the compounds of formula (I), where X, A, X1, R1, R2and m are such as previously defined for compounds of formula (I) can be obtained by reaction of compounds of formula (XXII):

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with the compound of the formula:

R-A-Z2,

where R, A and Z2such as defined above, and the reaction is conducted in a manner similar to methods described previously for the conversion (X) ---> (XI) or, where A represents CO, for the conversion of (XV) ---> (XVI).

Starting materials of the formula (XXII) and R-A-Z2you can get conventional ways, for example by adapting receipts, described in the publication "Advanced Organic Chemistry" by J. March (3rd edn., Wiley interscience) and its references.

3) All the compounds of formula (I), where X, X1, R, A, R1, R2and m are such as defined previously for compounds of formula (I) can be obtained by reaction of the compound of the formula:

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where X, R, A, R1and m are such as defined previously for compounds of formula (I), and Z3represents a suitable leaving group, such as chlorine, bromine, iodine, methanesulfonate, tripterocalyx or p-toluensulfonate, with the compound of the formula:

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where R2and X1such as defined previously for compounds of formula (I).

In a typical method of connecting the eating of the formula (III) in the presence of a suitable acid acceptor, such as triethylamine or potassium carbonate, or combinations thereof, in a suitable solvent, for example acetonitrile, and approximately at the temperature of its phlegmy.

The compound of formula (III) can be obtained in situ from an acid additive salt by use of a molar excess of acid acceptor.

Starting materials of the formula (XXIII) can be obtained by using common methods such as turning hydroxyquinoline group of alcohols of formula (XII), for example, where Z3is methansulfonate, reaction of the alcohol of formula (XII) with methanesulfonamide in the presence of a suitable acid receptor, such as triethylamine.

4) the compounds of formula (I), where R1represents phenyl and X, X1, R, A, R2and m are such as defined previously for compounds of formula (I) can be obtained by the hydrogenolysis of compounds of formula (I), where R1represents phenyl substituted by chlorine, bromine or iodine, X, X1, R, R2and m are such as defined previously for compounds of formula (I).

In a typical method, the hydrogenolysis is carried out in an ammonia ethanol using a suitable catalyst, such as Raney Nickel or preferably palladium on charcoal, at a temperature of about 50o4, (C3-C7cycloalkyl-C1-C4alkyl)HN-,

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or

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R9is-other5W represents NH or CHNHR5, W1is CHNHR5, W2is W1-CH2W1- CH2WCH2- or-CH2CH2WCH2and X, X1X2, R, R1, R5, R6, R7, m and n are such as defined previously for compounds of formula (I) can be obtained by removing the protective group of the compound of the formula:

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where R10represents a group of formula-NZ4R4(C3-C7cycloalkyl-C1-C4alkyl) Z4N-,

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or

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accordingly, R9Ais-NZ4R5, WAis NZ4or CHNZ4R5, W1Ais CHNZ4R5, W2Ais W1A-CH2W1A-, -CH2WACH2- or-CH2CH2WACH2-, and X, X1X2, R, A, R1, R4, R5, R6, R7, m and n are such as defined previously for compounds of formula (I), and Z4represents a suitable protective group, for example tert-butoxycarbonyl (for example, the compound of formula (I), is whether benzyloxycarbonyl).

Suitable protective groups which can be used in this way, together with methods for removing protective groups, well-known specialist in this field, see, for example, Greene et.al., "Protective Groups in Organic Synthesis", Second Edition, 1991, Wiley-Interscience.

In a typical method, where the Z4represents tert-butoxycarbonyl, removing the protective group can be performed using triperoxonane acid in a suitable solvent, for example dichloromethane, at room temperature.

Starting materials of the formula (XXIV) can be obtained by using common methods such as a suitable adaptation of the methods described here to obtain the compounds of formula (I).

6) the compounds of formula (I), where R2represents a group of the formula:

< / BR>
< / BR>
or

< / BR>
where p is 1 or 2, W2represents-CH2S(O)pCH2- or-CH2CH2S(O)pCH2-, and X, X1X2, R, A, R1, R5, R6, R7, m and n are such as previously defined for compounds of formula (I) can be obtained by oxidation of compounds of formula (I), where R represents a group of the formula:

< / BR>
< / BR>
or

< / BR>
that is suitable, W2represents-CH2(S or SO)CH2or CH2CH2(STO compounds of formula (I). The oxidation is conducted at least one molar equivalent of a suitable oxidant, when sulfoxide turn in sulfon, at least two molar equivalents of a suitable oxidant for the conversion of sulfide in sulfon and basically one of the polar equivalent of a suitable oxidant for the conversion of sulfide to sulfoxide.

Suitable oxidizing agents and conditions for this purpose are aqueous solution of hydrogen peroxide in basic conditions (for example, in the presence of potassium carbonate, acetonitrile, and using methanol as solvent) or m-chloroperbenzoic acid in a suitable solvent, for example dichloromethane.

7) the compounds of formula (I), where R2represents a group of the formula:

< / BR>
and X, X1, R, A, R1and m are such as previously defined for compounds of formula (I) can be obtained by removing the protective group of the compound of the formula:

< / BR>
where Z5represents a suitable protective group, for example acetyl (i.e., the compound of formula (I), where R8represents the atomic charges) or tetrahydropyran-2-yl and X, X1, R, A, R1and m are such as previously defined for compounds of formula (I).

Suitable protective groups which magnanni region, see, for example, Greene et.al., "Protective Groups in Organic Synthesis", Second Fdition, 1991, Wiley-Interscience.

In a typical method, where the Z5represents acetyl, removing the protective group can be performed using a water-alcohol solution of a suitable strong base, for example sodium hydroxide. The reaction is usually carried out in aqueous methanol, at about room temperature.

Starting materials of the formula (XXV) can be obtained by using common methods, for example by adaptation of the methods described here to obtain the compounds of formula (I).

8) Compounds of formula (I), where X1represents a direct bond and R2is-NR3R4,(C3-C7cycloalkyl-C1-C4alkyl)R5N-,(C3-C7cycloalkyl-C1-C4alkyl)2N - or a group of the formula:

< / BR>
< / BR>
< / BR>
or

< / BR>
and X, W, W1, R, A, R1, R3, R4R5, R6, R7, R8, R9, m and n are such as previously defined for compounds of formula (I) can be obtained by reaction of the compound of the formula:

< / BR>
where X, R, A, R1and m are such as previously defined for compounds of formula (I), and Z7represents a suitable leaving group, such as methanesulfonyl>C4alkyl) R5NH, (C3-C7cycloalkyl-C1-C4alkyl)2NH,

< / BR>
< / BR>
or

< / BR>
respectively, where W, W1, R3, R4, R5, R6, R7, R8, R9and n are such as previously defined for compounds of formula (I).

In a typical method the reaction is carried out using an excess of amine in a suitable solvent, for example acetonitrile or dichloromethane, and at a temperature of phlegmy solvent. Alternatively, to the reaction mixture, you can add additional suitable acid acceptor such as potassium carbonate.

Source amines can be obtained by using common methods.

Starting materials of the formula (XXVI) can also be obtained by using common methods, for example by reductive amination using as starting materials the compounds of formula (II) and ammonia to obtain the corresponding primary amine, the reaction of the amine with epichlorohydrin or 1,3-dichloropropan-2-I to obtain the corresponding derivative of azetidin-3-ol, followed by vzaimoprevrascheny hydroxyquinoline group to obtain the compounds of formula (XXVI).

9) the compounds of formula (I), X, X1, R, A, R1, R
< / BR>
where X, R, A, R1and m are such as previously defined for compounds of formula (I), the compounds of formula HNR3R4, (C3-C7cycloalkyl-C1-C4alkyl) R5NH, (C3-C7cycloalkyl-C1-C4alkyl)2NH,

< / BR>
< / BR>
< / BR>
or

< / BR>
that is suitable, or its acid salt additive, where W, W1, R3, R4, R5, R6, R7, R8, R9and n are such as previously defined for compounds of formula (I). The reaction is preferably carried out in the presence of a suitable acid, for example acetic acid.

A typical procedure which can be used is described in method (I).

If you use the primary amine, the reaction proceeds through kinowy intermediate product. If you use a secondary amine, the reaction proceeds through an intermediate iminium salt (compare with the compound of the formula (IIIA)). As Eminova and iminium salts can be stable and can be allocated. The reaction is preferably carried out without isolating the intermediate kinoway or iminium salts, in this case, restore it in situ to obtain the compounds of formula (I).

Starting materials of the formula (XXVII) can be obtained by oxidation of the CE is marinated conditions, for example, using chloramine pyridinium or perruthenate of tetrapropylammonium as oxidant.

10) Compounds of formula (I), where R2is morpholino and X, X1, R, A, R1and m are such as previously defined for compounds of formula (I) can be obtained by reaction of compounds of formula (I), where R2represents-NH2and X, X1, R, A, R1and m are such as previously defined for compounds of formula (I) with bis(2-chloration) ether.

In a typical method of the compounds of formula (I), where R2represents-NH2, is subjected to reaction with bis(2-chloration) ether in the presence of a suitable acid acceptor, such as triethylamine and in a suitable solvent, for example dichloromethane.

Some of the original amino derivatives, i.e. derivatives of 3 - aminoacridine, can be obtained by reaction of compounds of formula (XXVI), where Z5represents a suitable leaving group, for example, methanesulfonate-, with a suitable azide such as sodium azide or trimethylsilylmethyl, to obtain the corresponding derivative of 3-azidothymidine and subsequent reduction, for example, using sodium borohydride, to obtain the desired derivative 3-aminoa some amines of the formula (I) derivatives. For example, the compound of formula (I), where R2is

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
or

< / BR>
where W represents NH or CHNHR5, W1is CHNHR5, W2is W1, -CH2W1-, -CH2WCH2- or - CH2CH2WCH2or R9is-other5and X, X1X2, R, A, R1, R5, R6, R7, m and n are such as previously defined for compounds of formula (I), can be turned into

(a) compound of formula (I), where W is NR5or CHNR5R6, W1is CHNR5R6or R9is-other5or an acid additive salt that is suitable, where R5or R6such as previously defined for compounds of formula (I), provided that R5is not H and it has a methylene group linked to the nitrogen atom, by reductive amination of the aldehyde of the formula (C1-C3alkyl)CHO or (C3-C7cycloalkyl - C1-C3alkyl)CHO, and this C1-C3alkyl and C3-C7cycloalkyl-C1-C3alkyl optionally substituted by fluorine. Suitable conditions for the conversion described in method (I);

(b) a compound of formula (I), where W prevset-NR5CONHR6that is suitable, where R5or R6such as defined previously for compounds of formula (I), provided that R6can not be H, the reaction with the isocyanate of the formula:

R6NCO,

where R6such as that previously defined for this method. The reaction is usually carried out using a suitable solvent, for example dichloromethane or tetrahydrofuran;

(C) a compound of formula (I), where W represents the NSO2CF3or CHNR5SO2CF3, W1is CHNR5SO2CF3or R9is-NR5SO2CF3that is suitable, where R5the same as defined for the compounds of formula (I), by reaction with triftormetilfullerenov or triftormetilfullerenov anhydride, optionally in the presence of a suitable acid acceptor, such as triethylamine, pyridine or potassium carbonate. The reaction is usually carried out in a suitable organic solvent, for example dichloromethane or acetonitrile;

(d) compound of formula (I), where W represents the NSO2(C1-C4alkyl), NSO2NR5R6, NSO2(morpholino), NSO2(aryl), CHNR5(SO2C1-C4alkyl) or CHNR5SO2NR5R6, W1the is-NR5(SO2C1-C4alkyl), or-NR5SO2NR5R6that is suitable, where R5and R6such as previously defined for compounds of formula (I), by reaction with C1-C4alkanolammonium or bromide, C1-C4alkanesulfonyl anhydride or a compound of the formula: R5R6NSO2(Cl or Br), (morpholino)SO2(Cl or Br) or (aryl)SO2(Cl or Br), which is suitable, optionally in the presence of a suitable acid acceptor, such as triethylamine. The reaction is usually carried out in a suitable organic solvent, for example dichloromethane, at a temperature of from 0oC to room temperature.

(e) compound of formula (I), where W represents NCOR6or CHNR5COR6, W1is CHNR5COR6or R9is-NR5COR6that is suitable, where R5or R6such as previously defined for compounds of formula (I), provided that R6can not be H, the reaction with the compound of the formula:

R6CO(Cl or Br) or (R6CO)2O,

where R6such as that previously defined for this method, optionally in the presence of a suitable acid acceptor, such as triethylamine. The reaction is usually spending is mperature.

(f) compound of formula (I), where W, W1or R9such as previously defined for method 12 (e) that is suitable, by condensation with the compound of the formula:

R6CO2H,

where R6such as that previously defined for this method. The reaction can be carried out in conventional conditions, for example, using 1,1'-carbonyldiimidazole or 1-hydroxybenzotriazole/1,3-dicyclohexylcarbodimide, for the formation of the activated intermediate products; or

(g) compound of formula (I), where W represents the NSO2NR5R6or CHNR5SO2NR5R6, W1is CHNR5SO2NR5R6or R9is-NR5SO2NR5R6that is suitable, where R5and R6such as previously defined for compounds of formula (I), by reaction with the compound of the formula:

R5R6NSO2NH2.

The reaction is usually carried out at elevated temperature in a suitable solvent, for example 1,4-dioxane.

12) the Compound of formula (I), where R2is

< / BR>
< / BR>
< / BR>
or

< / BR>
where W and W1are CHCO2H, W2is W1, -CH2W1-, -CH2WCH2- or-CH2CH1
are CHCO2(C1-C4alkyl), W2is W1, - CH2W1-, -CH2WCH2or CH2CH2WCH2and X, X1X2, A, R, R1, R2, R5, R6, R7, m and n are such as previously defined for compounds of formula (I). Preferably, when W and W1represent CH2CO2CH3or CH2CO2CH2CH3. The hydrolysis is usually carried out using an aqueous solution of a suitable acid or base, for example mineral acids, such as hydrochloric or sulfuric acid, or bases such as sodium hydroxide or potassium hydroxide, optionally in the presence of a suitable organic co-solvent, for example methanol or ethanol.

13) the Compound of formula (I), where R2is

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
or

< / BR>
where W and W1are CHNR5R6, W2is W1, -CH2W1-, -CH2WCH2- or - CH2CH2WCH2-, R9is-NR5R6and X, X1X2, A, R, R1, R2, R5, R6, R7, m and n are such as previously defined is t

< / BR>
< / BR>
< / BR>
< / BR>
or

< / BR>
where WBand W1Bare CHZ8, W2Bis W1B, - CH2W1B-, -CH2WBCH2- or-CH2CH2WBCH2-, Z8represents a suitable leaving group such as halogen (preferably chlorine or bromine), methansulfonate, tripterocalyx or p-toluensulfonate and X, X1X2, R, A, R1, R5, R6, R7, m and n are such as previously defined for compounds of formula (I) with the compound of the formula:

HNR5R6,

where R5or R6such as previously defined for compounds of formula (I), optionally in the presence of a suitable acid acceptor, such as triethylamine or potassium carbonate. The reaction is usually carried out in a suitable solvent, for example acetonitrile.

14) the Compound of formula (I), where R2is

< / BR>
or

< / BR>
where W and W1are CHNR5R6and X, X1X2, R, A, R1, R5, R6, R7, m and n are such as previously defined for compounds of formula (I) can be obtained by reductive amination using as starting materials the compounds of formula (I), g 7, m and n are such as previously defined for compounds of formula (I), and compounds of formula:

HNR5R6,

where R5and R6such as defined previously for compounds of formula (I). Using conventional reaction conditions such as the conditions described for the method (I). In addition, the formed intermediate Eminova or iminium salt can be stable or allocated. The reaction is preferably carried out without isolating the intermediate product, in this case, restore it in situ to obtain the compounds of formula (I).

15) All the compounds of formula (I) can be obtained by intramolecular cyclization of the compounds of formula:

< / BR>
where X, X1, R, A, R1, R2and m are such as previously defined for compounds of formula (I), and Z9represents a suitable leaving group such as halogen (preferably chlorine or bromine), methane-sulfonyloxy or p-toluensulfonate, optionally in the presence of a suitable acid acceptor, such as triethylamine. The reaction is usually carried out in a suitable solvent, for example dichloromethane.

16) Compounds of formula (I), where A represents CO, can be obtained by intramolecular cyclization of compounds and formula (XXX):

< / BR>
as defined above for the method of 15, moreover, the reaction is carried out by treatment of the parent compound with a suitable base, such as n-utillity.

All of the above reactions and obtain a new source of materials used in the foregoing methods, conventional and appropriate reagents and reaction conditions for their execution or receipt, as well as the methods of isolation of the desired products will be well known to the skilled in the art, from literature precedents and the Examples and Receiving to this invention.

Pharmaceutically acceptable acid additive salt or salt with the base of the compounds of formula (I) can be easily obtained by mixing together solutions of the compounds of formula (I) and the desired acid or base that is suitable. Salt can be precipitated out of solution and collect by filtration or can be distinguished by evaporating the solvent.

Tool compounds of formula (I) and their salts for receptor NK1person can be tested in vitro by testing their ability to inhibit the binding of [3H] -substance P with membranes derived from cell lines M person expressing the receptor NK1man, using a modification of the method described McLean, S. et al., J. Pharm. Exp. Ther., 267, 472-9 (1993), in which cheloveka can be tested in vitro by testing their ability to compete with [3H]- or [125I]NKA (neurokinin A) for binding to membranes derived from ovary cells Chinese hamster expressing the cloned receptor NK1man. In this way the washed cell membrane of Chinese hamster ovary receive, as described for the previous method, where instead they will use cell M. Membranes incubated (90 min, 25oC) with [125I] NKA and with a range of concentrations of the test compounds. Nonspecific binding was determined in the presence of 10 μm NKA.

Antagonistic activity of the compounds of formula (I) for receptor NK2in vitro can be tested by testing their ability to create antagonism contractile action of a selective agonist of the receptor NK2, [Ala8] NKA(4-10)in the pulmonary artery of the rabbit using the method Patacchini and Maggi, Eur. J. Pharmacol., 236, 31-37 (1993).

The compounds of formula (I) and their salts can be tested for the activity of antagonist for receptor NK2in vivo by testing their ability to inhibit bronchostenosis induced [Ala8]NKA(4-10)the shot of Guinea pigs, using the method described by Murai et al., J. Pharm. Exp. Ther., 262, 403-408 (1992) or Metcaife et al., Br. J. Pharmacol., 112, 563P (1994).

the tests their ability to create antagonism contractile action of a selective agonist of the receptor NK3, sectid, in the ileum of Guinea pigs using the method of Maggi et al., Br.J. Pharmacol., 101, 996-1000 (1990).

When applying for a person of compounds of formula (I) and their salts can be introduced as such, but they are usually injected in a mixture with a pharmaceutically acceptable carrier or diluent, selected from the point of view of the intended route of administration and standard pharmaceutical practice. For example, they can be administered orally, including sublingual introduction, in the form of tablets containing such excipients as starch or lactose, or in capsules or Beulah (egg-shaped), as such or in a mixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring tools. They can be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example salts or glucose in sufficient quantity to make the solution isotonic with blood.

For oral and parenteral administration to patients-people level daily dose of the compounds of formula (I) and their salts is from 0.001 to 20, preferred divided doses). Thus tablets or capsules of the compounds will contain from 0.1 to 500, preferably from 50 to 200 mg of active compound for administration once, or twice, or more times for a selected time that is suitable.

The physician in any event will determine the actual dosage which will be most appropriate for the individual patient and which will vary with age, weight and individual susceptibility of the patient. The above doses are examples of ordinary cases; but there may be some instances where applying higher or lower doses, these doses are within the scope of this invention.

Alternatively, the compounds of formula (I) can be entered by inhalation or in the form of a suppository or vaginal suppository or you can apply them tapicerki in the form of a lotion, solution, cream, ointment or powder. An alternative method for percutaneous introduction is the use of a skin patch. For example, you can enter them into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or you can enter them, at concentrations between 1 and 10%, into an ointment consisting of a white wax or white soft paraffin as the base together with such stabilizers and con the tick, as well as the relief of established symptoms of the disease.

Thus, the invention further presents:

i) a pharmaceutical composition comprising a compound of formula (I) or its farmatsevticheskii acceptable salt together with a pharmaceutically acceptable diluent or carrier;

ii) the compound of formula (I) or its farmacevtichesky acceptable salt or composition for use as a drug;

iii) the use of the compounds of formula (I) or its pharmaceutically acceptable salt or composition for the preparation of medicines for treating disease by providing an antagonistic effect on tachykinin acting at receptor

NK1NK2or NK3person or combination of two or more of them;

(iv) use as in (iii), where the disease is an inflammatory disease such as arthritis, psoriasis, asthma or inflammatory bowel disease, a disorder of the Central nervous system (CNS), such as fear, depression, dementia or psychosis, gastrointestinal (LCD) violation, such as functional bowel disease, irritable bowel syndrome, gastroesophageal reflex, fecal incontinence, colitis or Crohn's disease, the infringement of the pKa of the respiratory tract, allergies, such as eczema, contact dermatitis or rhinitis, a hypersensitivity, such as sensitivity to poison ivy, peripheral neuropathy, such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, burn, herpetic neuralgia or poligeneticheskie neuralgia, cough or acute or chronic pain;

v) a method of treatment of human disease by inducing an antagonistic effect on tachykinin acting at the receptor NK1NK2or NK3person or combination of two or more of them, which consists in treating this person an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt or composition;

vi) a method as in (v), where the disease is an inflammatory disease such as arthritis, psoriasis, asthma or inflammatory bowel disease, a disorder of the Central nervous system (CNS), such as fear, depression, dementia or psychosis, gastrointestinal (LCD) violation, such as functional bowel disease, irritable bowel syndrome, gastroesophageal reflex, fecal incontinence, colitis or Crohn's disease, disruption of the urogenital tract, such as urinary incontinence or cystitis, lay rmatic or rhinitis, hypersensitivity, such as sensitivity to poison ivy, peripheral neuropathy, such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, burn, herpetic neuralgia or poligeneticheskie neuralgia, cough or acute or chronic pain.

vii) a compound of the formula (II), (IIIA), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX) or (XXX).

The following examples illustrate the formation of compounds of formula (I).

EXAMPLE 1.

1-Benzoyl-3-(3,4-dichlorophenyl)-3-(3-[3-morpholinomethyl-1-yl] propyl) piperidine

< / BR>
< / BR>
To a solution of aldehyde (see OBTAINING 7) (0,48 r, of 1.23 mmol) dihydrochloride and 3-morpholinoethyl (see 13) (0,291 g, 1,1 mol. EQ.) in tetrahydrofuran (20 ml) under nitrogen atmosphere was added triethylamine (0,38 ml of 2.2 mol. EQ.). Thirty minutes was added triacetoxyborohydride sodium (0,391 g, 1.5 mol. equiv.) then glacial acetic acid (0,07 ml) and the mixture was stirred for eighteen hours. The solvent was removed under reduced pressure and the residue was distributed between 10% aqueous potassium carbonate solution (20 ml) and ethyl acetate (20 ml). The aqueous phase was then extracted again with ethyl acetate (2 x 20 ml) and the combined organic layers costatum was chromatographically using silica gel and elution with a mixture of dichloromethane:methanol (9:1 by volume), getting listed in the title compound (166 mg). RfTLC = 0,25 (silica, dichloromethane:methanol, 9:1 by volume). LRMS m/z = 516 (M+1)+.

Found: C 61,07; H 6,18; N 8,04. C28H35N3O2Cl2= 0.95-1.1 (m), 1.2-1.5 (m), 1.55-1.9 (m), 2.0-2.1 (m), 2.25-2.3 (m), 2.4-2.6 (m), 2.9-3.0 (m), 3.25-3.4 (m), 3.6-3.7 (m), 7.2-7.4 (m).

EXAMPLES 2-8

Compounds of the following General formula

< / BR>
the receipt of which is shown in table 1, was obtained in a manner similar to the method used in EXAMPLE 1, using the appropriate aldehyde (see RECEIVING 7, 8, 9, 36 and 37) and either dihydrochloride 3-morpholinoethyl (13) or bestreferat.ru 3-(4-aminosulphonylphenyl-1-yl)azetidine (GETTING 16).

EXAMPLE 9

1-Benzoyl-3-(3,4-dichlorophenyl)-3-(2-[3-morpholinomethyl-1 - yl] ethyl)piperidine

< / BR>
< / BR>
To a solution of nelfinavir (see GETTING 24) (137 mg, 0.3 mmol) was added dihydrochloride 3-morpholinoethyl (13)

(160 mg, 3 mol. equiv.) the triethylamine (0,125 ml, 3 mol. EQ.) and potassium carbonate (83 mg, 2 mol. EQ.) in acetonitrile (5 ml) and the mixture was heated at the boil under reflux for four hours. The reaction mixture was cooled to room temperature, added water (2 ml) and acetonitrile was removed when it was panixtlahuaca with ethyl acetate (3 x 20 ml). The combined organic layers were then dried using anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was chromatographically using silica gel and a gradient elution with a mixture of dichloromethane:methanol (gradient from 9:1 to 4: 1, by volume), getting mentioned in the title compound (43 mg). Rf= 0,16 (silica, dichloromethane:methanol, 19:1 by volume). LRMS m/z 502 (M+1)+.

1H-NMR (CDCl3): 1.35-1.95 (m, 6H), 2.05-2.15 (m, 2H), 2.25-2.4 (m, 4H), 2.7-2.95 (m, 3H), 3.3-3.6 (m, 5H), 3.65-3.75 (m, 4H), 4.35-4.5 m (M, 1H), 7.2-7.5 (m,8H).

EXAMPLE 10

3-(3,4-Dichlorophenyl-1-(2-methoxybenzoyl)-3-(2-[3-morpholinomethyl - 1-yl] ethyl)piperidine

< / BR>
This compound is obtained by the method similar to the method used in EXAMPLE 9, using nelfinavir received in the RECEIVING 25, dihydrochloride and 3-morpholinoethyl (13).

LRMS (m/z 532 (m+1)+.

1H-NMR (CDCl3): 1.3-2.15 (m, 8H), 2.2-2.4 (m, 5H), 2.7-3.1 (m, 3H), 3.15-4.0 (m, 11H), 4.65-4.7 (m, 1H), 6.8-7.1 (m, 3H), 7.1-7.5 (m, 4H).

EXAMPLE 11

3-(3,4-Dichlorophenyl)-3-(2-[3-morpholinomethyl-1-yl] ethyl)-1 - phenolsulfonephthalein

< / BR>
This compound is obtained by the method similar to the method used in EXAMPLE 9, using nelfinavir, SUB>3
O3S0,1CH2Cl2< / BR>
Calculated: C 57,31; H 6,11; N, 7.68 Per Cent.

1H-NMR(CDCl3): = 1.5-1.9 (m, 6H), 1.95-2.1 (m,1H), 2.15-2.3 (m,5H), 2.7-3.0 (m, 5H), 3.1-3.2 (m,1H), 3.3-3.5 (m,2H), 3.55-3.75 (m, 5H), 7.2-7.3 (m, 1H), 7.35-7.45 (m, 2H), 7.5-7.65 (m, 3H), 7.7-7.8 (m, 2H).

EXAMPLE 12

3(S)-1-Cyclopropylmethyl-3-(3,4-dichlorophenyl)-3-(2-[3- morpholinomethyl-1-yl]ethyl)piperidine

< / BR>
< / BR>
To a solution of the RECEIVE connector 42 (0,319 g, 0.88 mmol), dihydrochloride 3-morpholinoethyl (0.187 g, 1 mol. EQ.) (The RECEIPT. 13) and triethylamine (0,122 ml, 1 mol. EQ.) in tetrahydrofuran (10 ml) was added triacetoxyborohydride sodium (251 mg, of 1.35 mol. EQ.) and glacial acetic acid (0.05 ml, 1 mol. EQ.). The mixture was stirred at room temperature for 64 hours. The mixture was then concentrated to approximately 5 ml and distributed between ethyl acetate (30 ml) and saturated aqueous sodium bicarbonate (20 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified flash chromatography using silica gel and a gradient elution with a mixture of dichloromethane:methanol (gradient from 92:8 to 9:1 by volume), getting mentioned in the title compound (220 mg). RfTLC = 0,2 (silica, methanol:dichloromethane, 8:92 the SUB>O20,25 CH2Cl2< / BR>
Calculated: C 60,45; H 7,3; N, 8.38% As.

1H-NMR (CDCl3) : 0.1-0.2 (m, 2H),0.5-0.55 (m,2H), 0.85-0.95 (m,1H), 1.35-2.3 (m,14H), 2.65-2.8 (m,2H), 2.85-2.95 (m,1H), 3.2-4.4 (m,10H), 7.2-7.4 (m,3H).

EXAMPLE 13

3(S)-1-Cyclopropylmethyl-3-(3,4-dichlorophenyl)-3-(2-[3- { 4-methanesulfonyl-piperazine-1-yl}azetidin-1-yl]ethyl)piperidine

< / BR>
< / BR>
To a solution of the RECEIVE connector 42 (0.31 g, 0.88 mmol), bestreferat.ru 3- (4-methanesulfonylaminoethyl-1-yl) azetidine (0.39 g, 1 mol. EQ.) (GETTING 46) and triethylamine (0,122 ml, 1 mol. EQ.) in tetrahydrofuran (10 ml) was added triacetoxyborohydride sodium (186 mg, 1 mol. EQ.) and glacial acetic acid (0,053 ml of 1.05 mol. EQ.). The mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated to approximately 3 ml and distributed between ethyl acetate (30 ml) and saturated aqueous sodium bicarbonate (30 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure, obtaining a residue that was purified flash chromatography using silica gel and elution with a mixture of dichloromethane:methanol (10:1 by volume), getting mentioned in the title compound (375 mg). RfTLC = 0,35 (silicon dioxide, dihormati the S 0,25 CH2Cl2Calculated: C 54,63; H 6,72; N 9,70%.

1H-NMR (CDCl3) : 0.05-0.15 (m,2H), 0.45-0.55 (m,2H), 0.9-1.0 (m,1H), 1.4-2.4 2.7-3.0 (m,6H), 3.2-4.4 (m.10H), 7.2-7.4 (m,3H).

EXAMPLE 14

3(R)-3-(3-[3-(4-Aminosulphonylphenyl-1-yl)azetidin-1-yl] - propyl)-1-benzoyl-3-(3,4-dichlorophenyl)piperidine

< / BR>
< / BR>
A mixture of the RECEIVE connector 54 (190 mg, 0,404 mmol), bestreferat.ru 1-aminosulfonyl-4-(azetidin-3-yl)piperazine (GETTING 16) (542 mg, 3 mol. EQ. ), potassium carbonate (334 mg, 6 mol. EQ.) triethylamine (0,335 ml, 6 mol. EQ. ) in acetonitrile (15 ml) was heated at the boil under reflux for 8 hours.

The reaction mixture was cooled to room temperature, was added dichloromethane (50 ml) and the mixture was washed with water (100 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure, obtaining the remainder, which was chromatographically on silica gel with a gradient elution with a mixture utilizat:methanol (gradient from 9:1 to 3:2 by volume), getting mentioned in the title compound (19 mg). LRMS (m/z 515 (m-SO2NH2)+.

1H-NMR (CDCl3) : 1.6-1.9(m, 5H), 2.1-2.2 (m,1H), 2.25-2.45 (m,8H), 2.7-2.8 (m, 2H). 2.9-3.0 (m, 1H), 3.2-3.3 (m,7H), 3.35-3.5 (m,6H), 4.3-4.4 (m,1H), 7.25-7.5 (m,5H).

Following Receipt of the illustration is of 1

2-(3,4-Dichlorophenyl)Gex-5-enitel

< / BR>
To a solution of sodium hydride (14.8 g, 370,4 mmol, 60% dispersion in mineral oil) in dimethylformamide (150 ml) at 0oC in nitrogen atmosphere was added a solution of 3,4-dichlorobenzonitrile (68,9 g, 1 mol. EQ.) in dimethylformamide (300 ml) and the mixture was stirred for three hours. Then the solution was added 4 brobot-1-ene (50 g, 1 mol. EQ.) in dimethylformamide (100 ml) and the mixture was stirred at room temperature for one hour, then heated to 60oC for five hours.

The reaction mixture was then cooled and added to water (1 l). The mixture was then extracted with ethyl acetate (2 x 500 ml). The combined organic layers were washed with water (2 x 1 l), dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was then purified column chromatography using silica gel and a gradient elution with a mixture of ethyl acetate: hexane (gradient from 1:19 to 1:6 by volume), receiving specified in the header (connection (51,5 g). RfTLC = 0,47 (silica, hexane: ethyl acetate, 6:1 by volume).

1H-NMR (CDCl3): = 1.85-2.1 (m, 2H), 2.2-2.3 (m, 2H), 3.75-3.8 (m, 1H), 5.05-5.1 (m, 2H), 5.7-5.3 (m, 1H), 7.15-7.2 (m, 1H), 7.4-7.45 (m, 2H).

GETTING 2

4-Cyano-4-(3,4-SUP>oC in an atmosphere of nitrogen was added tert-piperonyl potassium (1.5 g, 0,06 mol. EQ. ) and acrylate (25,4 ml, 1,11 mol. EQ.) and the mixture was stirred for one hour. Then added an aqueous solution of sodium hydroxide (2 n, 150 ml) and the mixture was stirred at room temperature for seventy minutes.

Then added methyl tert-butyl ether (300 ml) and the mixture was acidified to pH 1 with aqueous 2 n hydrochloric acid. The solution then was extracted with methyl tert-butyl ether (2 x 300 ml) and the combined organic layers were then dried over anhydrous magnesium sulfate and filtered. Removal of the solvent under reduced pressure gave specified in the header connection (68,12 g), which was used in the next stage without further purification.

1H-NMR (CDCl3): = 1.8-2.6 (m, 9H), 4.9-5.0 (m, 2H), 5.65 - 5.75 (m, 1H), 7.2-7.25 (m, 1H), 7.45-7.5 (m, 2H).

GETTING 3

3-(But-1-EN-4-yl)-3-(3.4-dichlorophenyl)piperidine

< / BR>
< / BR>
To a solution of sociallyengaged (16.6 g, 2 mol. EQ.) in tetrahydrofuran (300 ml) at 0oC in nitrogen atmosphere was slowly added a solution of the RECEIVE connector 2 (68,12 g) in tetrahydrofuran (300 ml) and the reaction mixture was stirred for two hours.

Then gently dobavlyali methyl tert butyl ether (300 ml). Organic washing liquid is then combined with the filtrate, dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was then chromatographically using silica gel and a gradient elution with a mixture of methanol: ethyl acetate (gradient from 1:19 to 2:5 by volume), getting mentioned in the title compound in the form of a mixture with recyclebank aminosterol (19.6 g), which was used in the next stage without further purification.

GETTING 4

3-(But-1-EN-4-yl)-1-benzoyl-3-(3,4-dichlorophenyl)piperidine.

< / BR>
To a solution of the product OBTAIN 3 (of 6.02 g) in dichloromethane (70 ml) at 0oC in an atmosphere of nitrogen was added benzoyl chloride (9,37 ml, 4 mol. EQ.) and triethylamine (13,8 ml of 5 mol. EQ.) and the mixture was stirred for 45 minutes.

Then add dichloromethane (50 ml) and the mixture was washed with 2 N. aqueous solution of hydrochloric acid (h ml). The organic phase is then dried over anhydrous magnesium sulfate and filtered. The solvent is removed under reduced pressure. Then add 4% solution of sodium hydroxide in methanol (100 ml) and the mixture is stirred at room temperature for 50 minutes. Then add dichloromethane (200 ml), the mixture is washed with water under pressure, receiving the remainder. Chromatography using silica gel and a gradient elution with a mixture of ethyl acetate: hexane (eluent from 1:4 to 3:5, by volume) gave specified in the header connection (with 3.27 g). RfTLC = 0,87 (silica, hexane:ethyl acetate, 3:5 by volume).

LRMS m/z 388 (m+1)+.

1H-NMR (CDCl3): = 1.3-2.2 (m, 8H), 3.1-3.5 (m, 3H), 1.5 - 1.7 (m, 1H), 4.85-4.95 (m, 2H), 5.55-5.7 (m, 1H), 7.2-7.55 (m, 8H).

GETTING 5

3-(But-1-EN-4-yl)-1-cyclohexanol-3-(3,4-dichlorophenyl)piperidine

< / BR>
This compound was obtained in the same manner as described in OBTAINING 4, using cyclohexanediamine instead of benzoyl chloride.

1H-NMR (CDCl3): 1.1-1.9 (m, 19H), 2.05-2.15 (m, 1H), 2.35-2.5 (m, 1H), 3.1-3.3 (m, 2H), 3.5-3.65 (m, 1H), 4.45-4.5 (m, 1H), 4.8-4.9 (m, 2H), 5.55-5.7 (m, 1H), 7.1-7.15 (m, 1H), 7.3-7.4 (m, 2H).

GETTING 6

3- (But-1-EN-4-yl)-1-cyclopropanol-3-(3,4-dichlorophenyl)piperidine

< / BR>
This compound was obtained in the same manner as described in OBTAINING 4, using cyclopropylamine instead of benzoyl chloride.

LRMS m/z 352 (m+1)+.

1H-NMR (CDCl3): = 0.65-1.1 (m, 4H), 1.4-2.15 (m, 8H), 3.15-3.45 (m, 2H). 3.7-3.9 (m, 2H), 4.35-4.45 (m, 1H), 4.8-4.95 (m, 2H), 5.55-5.7 (m, 1H), 7.1-7.4 (m, 3H).

GETTING 7

1-Benzoyl-3-(3,4-dichlorophenyl)-3-(2-formylated)piperidine
the value of ten minutes was barbotirovany ozone at 50 ml/min (used amps 1.5 amps for generating ozone from oxygen). After this current was reduced to zero through the reaction mixture for ten minutes was barbotirovany oxygen at a speed of 5 ml/min oxygen Flow was then stopped and through the reaction mixture for twelve minutes was barbotirovany nitrogen. After this time, was added dropwise a solution of dimethyl sulfide (6.4 ml, 14 mol. EQ.) in methanol (15 ml) and the reaction mixture was allowed to warm to room temperature for eighteen hours. The solvent was then removed under reduced pressure and the reaction mixture was distributed between ethyl acetate (20 ml) and water (15 ml). The organic layer was separated and the aqueous portion further extracted with ethyl acetate (2 x 20 ml). The organic layers were then combined, dried with magnesium sulfate, filtered and the solvent evaporated under reduced pressure, obtaining specified in the header connection (3,18 g) which was used without further purification.

1H-NMR (CDCl3): = 1.3-2.1 (m, 6H), 3.15-3.25 (m. 4H), 3.35-3.55 (m, 2H), 7.2-7.45 (m, 8H), 9.6 (s. br., 1H).

GET 8, 9

Compounds of General formula:

< / BR>
received a manner similar to the method used in OBTAINING 7, with the use of compounds of MAKING 5 and 6, respectively (table. 2)

RECEIVE 10

1-Diphenylmethylene) was stirred at room temperature for five days and then was heated at 40oC for two days. The solvent was then removed under reduced pressure, the residue was dissolved in isopropyl alcohol (500 ml) and the solution was heated at the boil under reflux for six hours. The solution was cooled to room temperature and the precipitate was separated by filtration. This solid portion was distributed between dichloromethane (400 ml) and saturated aqueous sodium bicarbonate (500 ml). The aqueous phase was extracted with dichloromethane (2 x 400 ml) and the combined organic phases were dried over magnesium sulfate. The solution is then filtered and the solvent removed from the filtrate under reduced pressure, obtaining mentioned in the title compound (86 g) in the form of a crystalline substance.

1H-NMR (CDCl3): = 1.8-2.3 (s,br,1H), 2.85-2.9 (m, 2H), 3.5 - 3.55 (m, 2H), 4.35 (s, 1H), 4.4-4.5 (m, 1H), 7.15-7.4 (m, 10H).

RECEIPT 11

1-Diphenylmethyl-3-methanesulfonanilide

< / BR>
To a solution of 1-diphenylethylamine-3-ol (see 10) (65.9 g, 275,7 mmol) in dry dichloromethane (700 ml) at 0oC in an atmosphere of nitrogen was added triethylamine (57 ml of 1.2 mol. EQ.). Five minutes were added methanesulfonamide (25.6 ml of 1.5 mol. EQ.) and the mixture was stirred for one hour. Then added water (300 ml) and the mixture was extracted with di and the solvent was removed from the filtrate under reduced pressure. The residue was chromatographically using silica gel and elution with a mixture of methanol:dichloromethane (1:49 by volume), receiving specified in the header connection (73,4 g) as a solid.

1H-NMR (CDCl3): =2.95 (s,3H), 3.15-3.25(m,2H), 3.6 - 3.65(m,2H), 4.4(s, 1H), 5.05-5.15(m,1H), 7.15-7.4(m,10H).

GETTING 12

1-Diphenylmethyl-3-morpholinomethyl

< / BR>
A solution of 1-diphenylmethyl-3-methanesulfonanilide (see 11) (24,46 g, 7,72 mmol), potassium carbonate (32 g, 3 mol. EQ.) and research (7,34 ml of 1.09 mol. EQ.) in acetonitrile (200 ml) was heated at the boil under reflux for four hours. The solution is then cooled to room temperature, added water (50 ml) and the mixture was concentrated under reduced pressure. The residue was distributed between ethyl acetate (400 ml) and water (400 ml) and the organic phase was separated and washed with water (2 x 400 ml). The organic phase was dried over magnesium sulfate, filtered and the solvent removed from the filtrate under reduced pressure. The residue was then chromatographically using silica gel and elution with a mixture of hexane:diethyl ether (1:1 by volume), getting mentioned in the title compound (16.5 g).

1H-NMR (CDCl3): = 2.25-2.3 (m,4H), 2.85-3.05 (m,3H), 3.35-3.4 (m,2H), 3.7-3.75 (m,4H), 4.45 the Tyl-3-morpholinoethyl (see OBTAINING 12) (08,6 g, 60,4 mmol), palladium hydroxide (2 g), ethanol (200 ml) and 1 N. aqueous solution of hydrochloric acid (52 ml) was stirred in hydrogen atmosphere at 345 kPa (50 psi) for three hours. The catalyst was then removed by filtration and the filtrate evaporated to dryness. Adding to the residue dichloromethane (100 ml) and rubbing gave a solid product, which was recrystallize from methanol, getting mentioned in the title compound (10.2 g) as a crystalline solid. LRMS m/z 179 (M+1)+. (Note. Monohydrochloride used instead dihydrochloride in some reactions, can be obtained similarly, using one molar equivalent of hydrogen chloride).

GETTING 14

1-(tert-Butoxycarbonyl)-3-(piperazine-1-yl)azetidin

< / BR>
Piperazine (149,2 g, 8 mol. EQ.) was heated to melting and then added 1-(tert-butoxycarbonyl)-3 - methanesulfonanilide (see Publication of international patent application N WO93/19059) (54,5 g, 217 mmol). The mixture was heated at 115oC within twenty-four hours. The reaction mixture was cooled and the excess piperazine was removed under reduced pressure. The residue was purified column flash chromatography on silica gel using is="ptx2">

LRMS m/z= 242 (m+1)+.

1H-NMR (CDCl3): = 1.4 (m, 9H), 2.5-2.6 (m, 4H), 3.1-3.25 (m, 5H), 3.7-3.8 (m, 2H), 3.9-3.95 (m, 2H), 4.6 (br. s, 1H).

RECEIVE 15

3-(4-Aminosulphonylphenyl-1-(tert-butoxycarbonyl)azetidin

< / BR>
The solution of the RECEIVE connector 14 (50 g, to 132.6 mmol) and sulphonamide (88 g of 6.9 mol. EQ.) in 1,4-dioxane (1300 ml) was heated at the boil under reflux for fifty-five hours. The solution was cooled and the solvent was removed under reduced pressure. The residue was purified column flash chromatography on silica gel using methanol: dichloromethane (5: 95 by volume) as eluent, obtaining mentioned in the title compound (50 g).

1H-NMR (CDCl3): = 1.45 (s, 9H), 2.4-2.5 (m, 4H), 3.1-3.2 (m, 1H), 3.25.3.3 (m, 4H), 3.75-3.8 (m, 2H), 3.85-3.9 (m, 2H), 4.3 (br, s, 2H).

GETTING 16

Bestrefiratecom 3-(4-aminosulphonylphenyl-1-yl)azetidine

< / BR>
To a solution of the RECEIVE connector 15 (364 mg, to 1.14 mmol) in dichloromethane (6 ml) under nitrogen atmosphere at 0oC was slowly added triperoxonane acid (3 ml, 35 mol. EQ. ) and the reaction mixture was allowed to warm to room temperature for two hours. The solvent was then removed under reduced pressure and the residue was subjected to azeotropic distillation with DIH (379 mg), which was used without further purification.

1H-NMR (CDCl3): = 2.4-2.6 (m, 4H), 2.95-3.15 (m, 4H), 3.35-3.5 (m, 1H), 3.8-4.1 (m, 4H), 6.6-6.8 (m, 2H), 8.6-8.85 (m, 3H).

GETTING 17

2-(3,4-Dichlorophenyl)-4-(tetrahydropyran-2-yloxy)Botanical

< / BR>
To a mixture of 60% (mass. /mass.) dispersion of sodium hydride in oil (19,24 g of 1.05 mol. EQ.) in dry tetrahydrofuran (450 ml) at 0oC in nitrogen atmosphere is added dropwise, in the course of forty minutes, the solution was added 3,4-dichlorobenzonitrile (89,5 g, 1 mol. EQ.) in dry tetrahydrofuran (450 ml). Through additional forty minutes was added a solution of 2-prematureejaculation (100 g, 1 mol. EQ.) in tetrahydrofuran (100 ml) and the mixture was allowed to warm to room temperature and was stirred for fourteen hours. Added a 30% aqueous solution of sodium chloride (500 ml) and the mixture was extracted with diethyl ether (2 x 400 ml). The organic layers were combined and washed with water (2 x 400 ml), dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was then chromatographically using silica gel and a gradient elution with a mixture of diethyl ether:hexane (gradient from 1:9 to 1:1, by volume), getting mentioned in the title compound (51 g). RfTLC = 0,55 (silicon dioxide, methyl-Tret.05-2.3 (m, 2H), 2.4-2.65 (m, 2H), 2.8-2.95 (m, 2H), 4.0-4.1 (m, 1H), 4.5-4.6 (m, 1H), 7.2-7.25 (m, 1H), 7.25-7.5 (m, 2H).

GETTING 18

Ethyl 4-cyano-4(3,4-dichlorophenyl)-6-(tetrahydropyran-2 - yloxy)hexanoate

< / BR>
To a solution of Diisopropylamine (15 ml, of 0.77 mol. EQ.) in tetrahydrofuran (80 ml) at -78oC in nitrogen atmosphere was added n-utility (77,3 ml of 2.5 M solution in hexane, 1,4 mol. EQ.) and the solution is then allowed to warm to room temperature for two hours. The solution was cooled to -78oC and slowly added to the solution of the RECEIVE connector 17 (43.9 g, 138 mmol) in tetrahydrofuran (180 ml). The resulting solution was allowed to warm to room temperature for two hours. The solution then was cooled to -78oC and was added dropwise a solution of ethyl 3-bromopropionate (22,36 ml of 1.3 mol. EQ.) in tetrahydrofuran (70 ml). Then added iodide, Tetra-n-butylamine (50 g, 1 mol. equiv.) the reaction mixture was allowed to warm to room temperature and was stirred over fourteen hours. Then added water (10 ml) and the solution was concentrated under reduced pressure. Was added water (400 ml) and brine (400 ml) and the mixture was extracted with ethyl acetate (2 x 500 ml). The combined organic layers were washed with water (2 x 300 ml), dried over magnesium sulfate and the solvent galalxy (1:1 by volume) gave specified in the title compound (35 g). RfTCX = 0,30 (silica, diethyl ether:hexane, 1:1 by volume).

1H-NMR (CDCl3): = 1.25 (t, 3H), 1.35-1.8 (m, 6H), 2.0-2.55 (m, 6H), 3.3-3.45 (m. 2H), 3.65-3.8 (m, 2H), 4.0-4.1 (m, 2H), 4.4 - 4.5 (m, 1H), 7.2-7.55 (m, 3H).

GETTING 19

5-(3,4-Dichlorophenyl)-5-(2-[tetrahydrofuran-2-yloxy]-2(1H)- piperidin

< / BR>
The RECEIVE connector 18 (18.7 g, 45,2 mmol) was dissolved in a saturated ammoniacal solution of ethanol (500 ml) containing Raney Nickel (3.5 g). The mixture was stirred in hydrogen atmosphere at atmospheric pressure for seven hours. The catalyst was then removed by filtration, the ethanol was removed under reduced pressure and the residue was chromatographically using silica gel and elution first with diethyl ether and then with a mixture of methanol:dichloromethane (1: 9 by volume), getting mentioned in the title compound (10.4 g). RfTLC (silica, methanol: dichloromethane, 1:9 by volume).

LRMS m/z = 372 (m+1)+.

1H-NMR (CDCl3): = 1.4-1.8 (m, 6H), 1.9-2.1 (m, 5H), 2.3-2.45 (m, 1H), 3.0-3.2 (m, 1H), 3.35-3.85 (m, 4H), 4.35-4.4 (m, 1H), 6.05 (s,br.,1H), 7.15-7.45 (m, 3H).

20 and 21

3-(3,4-Dichlorophenyl)-3-(2-hydroxyethyl)piperidine (20) and 3-(3,4-dichlorophenyl)-3-(2-[tetrahydropyran-2-yloxy] ethyl)piperidine (Getting 21)

< / BR>
< / BR>
To a solution of 5-(3,4-dichloro the P>C in an atmosphere of nitrogen was added dropwise a solution of the complex of borane-dimethyl sulfide (2,36 ml, 5 mol. EQ., 10 M solution). The solution is then slowly heated to room temperature and then was heated at the boil under reflux for two hours. The solution was cooled to room temperature and the solvent was then removed under reduced pressure. The remainder is then distributed between dichloromethane (30 ml) and saturated aqueous sodium bicarbonate (30 ml). The aqueous phase was extracted with an additional portion of dichloromethane (30 ml) and the combined organic layers were dried using anhydrous magnesium sulfate. The solution is then filtered and the solvent was removed under reduced pressure. The residue was purified column chromatography using silica and elution with a mixture of methanol: dichloromethane (1:19 by volume), receiving the first alcohol (20) in the form of a complex of borane-dimethyl sulphide and the second protected alcohol (21) (132 mg). The fractions containing the complex of borane (20) and evaporated under reduced pressure, the residue was dissolved in methanol (10 ml) and 2 N. aqueous hydrochloric acid (10 ml) and the mixture was heated at the boil under reflux for one hour. The solution is then cooled to room temperature the R> LRMS m/z 274 (m+1)+;

1H-NMR (CDCl3): = 1.45-2.0 (m, 6H), 2.3 (s, br.,2H), 2.7-2.8 (m. 1H), 2.85-2.95 (m, 1H), 3.1 (s, br., 2H), 3.35-3.55 (m, 2H), 7.1-7.2 (m, 1H), 7.35-7.4 (m, 2H).

Spectral data for (21):

LRMS m/z 358(m+1)+;1H-NMR (CDCl3): 1.4-2.1 (m, 12H), 2.8 - 3.6 (m, 8H), 3.65-3.85 (m, 1H), 4.35 (s, br., 1H), 7.15-7.2 (m, 1H), 7.35-7.5 (m, 2H).

GETTING 22

1-benzoyl-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidine

< / BR>
To a solution of the RECEIVE connector 20 (150 mg, 0.55 mmol) in dichloromethane (5 ml) at 0oC in an atmosphere of nitrogen was added triethylamine (0,114 ml of 1.5 mol. EQ. ) and benzoyl chloride (0,076 ml of 1.2 mol. EQ.) and the mixture was stirred at room temperature for one hour. Was added water (30 ml) and saturated aqueous sodium bicarbonate solution (30 ml) and the mixture was extracted with dichloromethane (3 x 40 ml). The combined organic layers were then dried using anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure, obtaining mentioned in the title compound (187 mg), which was used without further purification. RfTLC = 0,34 (silica, dichloromethane/methanol, 19:1 by volume).

LRMS 378 m/z (m+1)+.

1H-NMR (CDCl3): = 1.4-2.3 (m, 7H), 3.25-4.3 (m, 6H), 7.15-7.6 (m, 8H).

23

1-(2-Methoxybenzoyl)-3-(3,4-daliparthy in OBTAINING 22, using the compound obtained in the Obtaining 20, and 2-methoxybenzoate instead of benzoyl chloride. The compound was purified column chromatography (silica, gradient elution with a mixture of dichloromethane: methanol gradient from 49:1 to 24:1 by volume).

LRMS 410 m/z(m+1)+.

1H-NMR(CDCl3): = 1.35-2.2 (m, 8H), 3.1-4.5 (m, 8H), 6.8-7.1 (m, 2H), 7.2-7.55 (m, 5H).

GETTING 24

1-Benzoyl-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl) piperidine

< / BR>
To a solution of the RECEIVE connector 22 (170 mg, 0.45 mmol) in dichloromethane (4 ml) under nitrogen atmosphere was added triethylamine (0,094 ml of 1.5 mol. EQ.) and the solution was cooled to 0oC. Then was added methanesulfonamide (0,042 ml of 1.2 mol. EQ. ) and the mixture was stirred for one hour. Was added water (20 ml) and the aqueous phase was extracted with dichloromethane (20 ml). The combined organic layers were then dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was then chromatographically using silica and elution with dichloromethane, getting mentioned in the title compound (145 mg). RfTLC = 0,39 (silicon dioxide, a mixture of dichloromethane:methanol, 19:1 by volume).

LRMS 456 m/z (m+1)+.

1

RECEIVE 25

1-(2-Methoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2 - methanesulfonylaminoethyl)piperidine

< / BR>
This compound was obtained in a manner similar to the method used in OBTAINING 24, using the compound described in 23.

LRMS 486 m/z (m+1)+.

1H-NMR (CDCl3): = 1.4-2.4 (m, 6H), 2.9-4.6 (m, 12H), 6.75-7.6 (7H).

GETTING 27

1-(Phenylsulfonyl)-3-(3,4-dichlorophenyl)-3-([tetrahydropyran-2 - yloxy] ethyl)piperidine

< / BR>
To a solution of the RECEIVE connector 21 (123 mg, 0.34 mmol) in dichloromethane (3 ml) at 0oC in an atmosphere of nitrogen was added tri ethylamine (0.06 ml, 1,5 mol. EQ. and benzosulphochloride (0,07 ml of 1.2 mol. EQ.). The reaction mixture was stirred for one hour. Then added water (10 ml) and saturated aqueous sodium bicarbonate (10 ml) and the mixture was extracted with dichloromethane (3 x 10 ml). The combined organic layers were then dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure, obtaining a resin, which was chromatographically using silica gel and elution with dichloromethane, getting mentioned in the title compound (131 mg). RfTLC = 0,92 (silica, dichloromethane:methanol, 19:1 by volume).

LRMS m/z 515 (m+Nm, 1H), 4.3-4.4 (m, 1H), 7.3-7.8 (m, 8H).

GETTING 28

1-(Phenylsulfonyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidine

< / BR>
To a saturated solution of hydrogen chloride in methanol (5 ml) at room temperature was added a RECEIVE connector 27 (125 mg) and the mixture was stirred at room temperature for two hours. The solvent was then removed under reduced pressure. Then was added a saturated aqueous solution of sodium bicarbonate (30 ml) and the aqueous phase was extracted with ethyl acetate (3 x 30 ml). The combined organic phases are then dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure, obtaining mentioned in the title compound (155 mg), which was used without further purification. RfTLC (silica, dichloromethane:methanol, 19:1 by volume).

LRMS m/z 414 (m+1)+.

1H-NMR (CDCl3): = 1.45-2.5 (m, 12H), 2.55-2.65 (m, 2H), 2.95-3.1 (m, 1H), 3.3 - 3.55 (m, 3H), 3.7-3.8 (m, 1H), 3.9-4.05 (m, 1H), 4.3-4.4 (m, 1H), 7.3-7.8 (m, 8H).

GETTING 29

Ethyl 3-cyano-3-(3,4-dichlorophenyl)-5-(tetrahydropyran-2-yloxy pentanoate

< / BR>
To a solution of Diisopropylamine (25,9 ml, 1 mol. EQ.) in tetrahydrofuran (200 ml) at -78oC in nitrogen atmosphere was added n-utility (73,9 ml of 2.5 M solution, 1 mol. EQ is henyl)-4-(tetrahydropyran-2-yloxy) Botanical

(GETTING 17) (58 g, 158 mmol) in tetrahydrofuran (200 ml) and the solution was stirred for one hour. Then was added a solution of ethyl 2-bromoacetate (20.5 ml, 1 mol. EQ.) in tetrahydrofuran (50 ml) and the reaction mixture was heated at the boil under reflux for two hours. Then added water (10 ml) and the solution was concentrated under reduced pressure. Was added water (300 ml) and brine (300 ml) and the mixture was extracted with ethyl acetate (2 x 300 ml). The combined organic layers were washed with water (2 x 300 ml), dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. Chromatography using silica gel and a gradient elution with a mixture of diethyl ether:hexane (gradient from 4:1 to 1:1 by volume) gave specified in the header of the connection.

LRMS m/z 417 (m+NH4)+.

1H-NMR (CDCl3): = 0.85-0.9 (m, 1H), 1.1-1.75 (m, 10H), 2.1-2.3 (m, 1H), 2.35-2.45 (m, 1H), 2.95-3.3 (m, 2H), 3.4-3.55 (m, 1H), 3.7-3.8 (m, 1H), 4.05-4.15 (m, 2H), 4.45 (s, br., 1H), 7.3-7.55 (m, 3H).

30

4-(3,4-Dichlorophenyl)-4-(2-[tetrahydropyran-2-yloxy]ethyl)-2(1H)- pyrrolidone

< / BR>
The RECEIVE connector 29 (9.0 g, to 22.5 mmol) was dissolved in a saturated ammoniacal solution of ethanol (100 ml) containing Raney Nickel (1.0 g). The mixture peremeci the hydrogen within fourteen hours. Then add the next portion of Raney Nickel (0.2 g) and the reaction mixture was stirred in hydrogen atmosphere at 345 kPa (50 psi) and 50oC over the next three hours. The catalyst was removed by filtration, the ethanol was removed under reduced pressure and the residue was chromatographically using silica gel and a gradient elution with a mixture of methanol:dichloromethane (gradient from 1: 19 to 1:9 by volume), getting mentioned in the title compound (6.0 g).

LRMS m/z 358 (m+1)+.

1H-NMR (CDCl3): = 1.4-1.8 (m, 6H), 2.05-2.2 (m, 2H), 2.7-2.75 (m, 2H), 3.1-3.2 (m, 1H), 3.4-3.5 (m, 1H), 3.55-3.7 (m, 4H), 4.4 (s,br., 1H),5.9(s, br., 1H), 7.0-7.05 (m, 1H), 7.25-7.4 (m, 2H).

GETTING 31

3-(3,4-Dichlorophenyl)-3-(2-[tetrahydropyran-2-yloxy]ethyl) pyrrolidin

< / BR>
To a solution of sociallyengaged (100 mg, 2 mol. EQ.) in dry diethyl ether (20 ml) at 0oC in nitrogen atmosphere was added a solution of compound 30 (0.5 g, 1.4 mmol) in diethyl ether (20 ml) and the mixture was stirred for 24 hours. Then add the next portion of sociallyengaged (50 mg, 1 mol. EQ.) and the reaction mixture was stirred for additional 2 hours. Was added water (0.1 ml), then 15% aqueous sodium hydroxide solution (0.1 ml) and water (0.3 ml). The hard part was removed by filtration. Filtri elution with a mixture of dichloromethane:methanol: ammonia (94: 5:1 by volume) gave specified in the title compound (200 mg). RfTLC = 0,42 (silica, dichloromethane:methanol:ammonia, 90:9:1 by volume).

1H-NMR (CDCl3): = 1.45-1.85 (m, 6H), 1.9-2.25 (m, 6H), 2.95-3.2 (m, 4H), 3.2-3.65 (m, 2H), 3.7-3.8 (m, 1H), 4.35-4.45 (m, 1H), 7.1-7.4 (m, 3H).

GETTING 32

1-Benzoyl-3-(3,4-dichlorophenyl)-3-(2-[tetrahydropyran-2-yloxy] ethyl)pyrrolidin

< / BR>
To a solution of the RECEIVE connector 31 (1.4 g, 4,06 mmol) in dichloromethane (20 ml) was added triethylamine (0,57 ml, 1 mol. EQ.). The solution then was cooled to 0oC. was added dropwise a benzoyl chloride (0,47 ml, 1 mol. EQ.) and the solution was stirred at 0oC for 30 minutes and then at room temperature for 1 hour. The crude reaction mixture was washed with water (50 ml) and then saturated aqueous sodium bicarbonate (50 ml). The organic layer was dried using anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure, obtaining oil. Chromatography using silica gel and a gradient elution with a mixture of methanol:dichloromethane (gradient from 1:19 to 1:9 by volume) gave specified in the title compound (1.5 g).

LRMS m/z 448 (m+1)+.

1H-NMR (CDCl3): = 1.25-2.4 (m, 10H), 3.0-4.4 (m, 9H), 6.9-7.6 (m, 8H).

RECEIVE 33

1-(2-Methoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-[tetrahydro the WMD in OBTAINING 32, using the compound obtained in the OBTAINING 31, and 2-methoxybenzaldehyde instead of benzoyl chloride.

1H-NMR (CDCl3): = 1.2-2.25 (m, 10H), 3.05-4.45 (m, 11H), 6.9-7.45 (m, 7H).

GETTING 34

1-Benzoyl-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidin

< / BR>
The solution of the RECEIVE connector 32 (1.5 g, to 3.34 mmol) in methanol saturated with hydrogen chloride (50 ml) was stirred at room temperature for one hour. The solvent was then removed under reduced pressure, obtaining mentioned in the title compound, which was used without further purification. RfTLC = 0,61 (silicon dioxide, a mixture of dichloromethane:methanol, 9:1 by volume).

LRMS m/z 364 (m+1)+.

1H-NMR (CDCl3): = 1.9-2.4 (m, br., 4H), 3.3-4.1 (m, br., 6H), 5.5-5.9 (m, br., 2H), 7.0-7.6 (m, br., 7H).

RECEIVE 35

1-(2-Methoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl) pyrrolidin

< / BR>
This compound was obtained in a manner similar to the method used in OBTAINING 34, using the compound obtained in the OBTAINING 33.

LRMS m/z 394 (m+1)+.

1H-NMR (CDCl3): =1.85-2.3 (m, 4H), 3.15-3.65 (m, 4H), 3.8-4.0 (m, 6H), 6.9-7.45 (m, 7H).

GETTING 36

1-Benzoyl-3-(3,4-dichlorophenyl)-3-(formylmethyl)pyrrolidin

< / BR>
It races sulfoxide (0,23 ml, 2,4 mol. EQ. ) and the solution was stirred at -78oC for forty-five minutes. Solution was added to the RECEIVE connector 34 (0.5 g, 1.37 mmol) in dichloromethane (10 ml) and the reaction mixture was stirred at -78oC for 1.75 hours. Was added triethylamine (0.95 ml, 5 mol. EQ.) and the reaction mixture was left to warm to room temperature and was stirred for one hour. The mixture was washed with a saturated aqueous solution of sodium carbonate (50 ml) and dried over magnesium sulfate. The solution was filtered and the solvent was removed under reduced pressure. The residue was purified by chromatography using silica and elution with a mixture of ethyl acetate:methanol (19:1 by volume), getting mentioned in the title compound (300 mg).

LRMS 362 m/z (m+1)+.

1H-NMR (CDCl3): = 2.25-2.45 (m), 2.65-2.9 (m), 3.4-4.1 (m), 9.45-9.6 (m).

GETTING 37

1-(2-Methoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(formylmethyl) pyrrolidin

< / BR>
This compound was obtained in a manner similar to the method used in OBTAINING 36, using the compound obtained in the OBTAINING 35.

LRMS m/z 392 (m+1)+.

1H-NMR (CDCl3): =2.15-2.35 (m,2H), 2.7 - 2.95 (m,2H), 3.15-3.7 (m,3H), 3.75-3.9 (m,3H), 3.95-4.1 (m, 1H), 6.9-7.5 (m, 7H), 9.45-9.55 (m, 1H).

Polycentrality lithium in tetrahydrofuran (4,69 l) under nitrogen atmosphere is added dropwise, within 45 minutes, 5oC was added a solution of 3,4-dichlorobenzonitrile (750 g, 4,28 mol) in tetrahydrofuran (750 ml). The reaction mixture was stirred for 2 hours. The reaction mixture was again cooled again to 5oC and added dropwise, in the course of fifty minutes, the solution was added 2-methyl bromide-1,3 - dioxolane (782 g) in tetrahydrofuran (780 ml). In parts was added iodide, Tetra-n-butylamine (75 g) and the mixture was allowed to warm to room temperature and was stirred for 14 hours. The reaction mixture was then cooled to 5oC and was added dropwise a solution of hexamethyldisilazide lithium in tetrahydrofuran (1.0 M, 4,69 l). The mixture was stirred for 5 hours at room temperature. The solution was cooled to 5oC and added dropwise over 50 minutes, the solution was added ethyl 3-bromopropionate (840,5 g) in tetrahydrofuran (840 ml). The reaction mixture was stirred for 14 hours. The reaction mixture was cooled to 5oC was added a 1.5 M aqueous solution of sodium hydroxide (4,25 l, containing 255 g of sodium hydroxide and the mixture was extracted with ethyl acetate (2 x 3 l). The combined organic layers were washed with water (2 x 5 l). The aqueous phases were combined and acidified to pH 1 using 5 N. aqueous solution of hydrochloric acid and then extrem pressure to a concentration of approximately 3 ml/g based on theoretical yield of the product. Added dichloromethane (50 ml) and the solution was washed with water (100 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure, obtaining mentioned in the title compound (390 g) which was used without further purification. RfTLC = 0,28 (silica, hexane:ethyl acetate, 2:3 by volume).

1H-NMR (CDCl3): = 1.25-4.4 (m,17H), 7.25-7.55 (m, 8H).

The above experimental method was then repeated with similar quantities.

To the combined organic solutions of both reactions was added (S)-(-)-alpha-methylbenzylamine (1.13 kg) and the mixture was stirred for 14 hours. The thick slurry is then stirred with cooling in an ice bath for 2 hours, filtered, the solid part was washed with ethyl acetate (2 x 1 l) and then dried under reduced pressure at 35oC, receiving 1,85 kg of material. Part of the material (1.34 kg) was dissolved in a mixture of butanone (2 l) and water (503 ml) and was heated at the boil under reflux. Added the following portion of butanone (4,7 l) and the solution was let to cool slowly to room temperature over night. The resulting solid portion was separated by filtration, washed with butanone (2 x 1 l) and dried at first recrystallization from a mixture of butanone/water gave specified in the procurement of the compound in the form of salt (S)-(-)-alpha-methylbenzylamine with enantiomeric excess of 99.8 per cent. To a stirred solution of this salt in ethyl acetate and water were added 5 N. aqueous solution of hydrochloric acid to achieve a pH of 1. The mixture was stirred for further 30 minutes, the layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water and the solvent was removed by evaporation under reduced pressure, obtaining specified in the header of the connection.

1H-NMR (CDCl3): = 2.05-2.35 (m, 4H), 2.4-2.65 (m, 2H), 3.7 - 4.0 (m, 4H), 4.75-4.85 (m, 1 H), 7.25-7.55 (m, 3H), 9.9 (s, br., 1 H acid).

GETTING 39

5(S)-5-(3,4-Dichlorophenyl)-5-(1,3-dioxolane-2-ylmethyl)-2- (1H)-piperidin

< / BR>
To a solution of the RECEIVE connector 38 (13.5 g, to 39.22 mmol) in glacial acetic acid (130 ml) was added platinum oxide (1,21 g) and the mixture was stirred in hydrogen atmosphere at a pressure of 414 kPa (60 psi) and at room temperature for 17 hours. The catalyst was removed by filtration and added to the next portion of the oxide of platinum (1,21 g). The reaction mixture was then stirred in an atmosphere of hydrogen at 414 kPa (60 psi) and at room temperature for 48 hours. The catalyst was removed by filtration and the solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (80 ml) and washed with saturated aqueous bicay solid product was stirred in hexane solution (20 ml) and ethyl acetate (20 ml) for 2 hours at 0oC and then filtered, obtaining specified in the header connection (8,15 g).

1H-NMR (CDCl3): = 1.85-1.95 (m, 1H), 2.0-2.25 (m, 4H), 2.35-2.4 (m, 1H), 3.45-3.55 (m, 1H), 3.65-3.75 (m, 2H), 3.8-3.9 (m, 3H), 4.35-4.4 (m, 1H), 6.15 (s, br., 1H), 7.2-7.45 (m, 3H) ppm.

RECEIVE 40

3(S)-3-(3,4-Dichlorophenyl)-3-(1,3-dioxolane-2-ylmethyl)piperidine

< / BR>
To a stirred solution of sociallyengaged (12,7 ml of 1 M solution in tetrahydrofuran, (2,1 mol. EQ. ) in tetrahydrofuran (60 ml) under nitrogen atmosphere was added 5(S)-5-(3,4-dichlorophenyl)-5- (1,3-dioxolane-2-ylmethyl)-2(1H)-piperidine (2 g, the 6.06 mmol) (OBTAINING 39) in three portions and the mixture was heated at the boil under reflux for sixteen hours.

Dropwise, in the course of twenty minutes, was added water (0,48 ml) and then aqueous sodium hydroxide solution (of 0.48 ml, 15% solution, mass. /mass.). Five minutes were added water (2 x 0,48 ml) and the mixture was stirred for thirty minutes.

The mixture was filtered and the solvent removed from the filtrate under reduced pressure and the residue was distributed between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (100 ml). The organic layer was dried over anhydrous magnesium sulfate, getting an oil, which was then subjected to flash column-chromatography with and the giving (1.3 g).

1H-NMR (CDCl3): = 1.4-1.5 (m, 1H), 1.55-1.7 (m, 1H), 1.8 - 1.9 (m, 1H), 1.95-2.0 (m, 2H), 2.05-2.1 (m, 1H), 2.3 (s, br., 1H), 2.8-2.9 (m, 2H), 3.0-3.1 (m, IH), 3.3-3.35 (m, IH), 3.6-3.7 (m, 2H), 3.8-3.9 (m, 2H), 4.3-4.4 (m, IH), 7.2-7.3 (m, 1H), 7.4-7.5 (m, 2H).

GETTING 41

3(S)-1-Cyclopropylmethyl-3-(3,4-dichlorophenyl)-3-(1,3-dioxolane - 2-yl)methyl)piperidine

< / BR>
To a solution of the RECEIVE connector 40 (0.65 g, of 2.06 mmol) in dichloromethane (20 ml) at room temperature under nitrogen atmosphere was added cyclopropylalanine acid (206 mg, 1 mol. equiv.) M - methylmorpholin (0,23 ml, 1 mol. EQ. ), hydrate of 1 - hydroxybenzotriazole (0,316 g, 1 mol. EQ.) and the hydrochloride of 1-(3 - dimethylaminopropyl)-3-ethylcarbodiimide (0,546 g, 1,4 mol. EQ.). The mixture was stirred for sixteen hours. The mixture was then poured into ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate solution and the organic phase was separated and dried over anhydrous magnesium sulfate. The solution was filtered, the solvent was removed under reduced pressure and the residue was chromatographically using silica gel and elution with a mixture of ethyl acetate:hexane (1:1 by volume), getting mentioned in the title compound (0.7 g). RfTCX = 0,25 (silicon dioxide, a mixture of etelaat:hexane, 1:1 by volume).

LRMS m/z = 398 (m+1)+.

1H-NMR (CDCl3): = 0.05-0.2 (m, 2H), 0.4-0.5 (m, 2H), 0.85-0.95 is Il)formylmethionine

< / BR>
To a solution of the RECEIVE connector 41 (0.7 g, of 1.76 mmol) in tetrahydrofuran (10 ml) was added hydrochloric acid (10 ml, 5 n solution) and the mixture was stirred at room temperature for 5 hours. The mixture is then distributed between ethyl acetate (30 ml) and saturated aqueous sodium bicarbonate (30 ml) and the organic phase was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, obtaining specified in the header connection (0,62 g) which was used without further purification.

1H-NMR (CDCl3): a = 0.1-0.2 (m, 2H), 0.5-0.6 (m, 2H), 0.9-1.0 (m, 1H), 1.6-2.3 (m, 6H), 2.65-2.7 (m, 2H), 3.4-3.5 (m, 2H), 3.8, (d, 1H), 4.05 (d, 1H), 7.3-7.5 (m, 3H), 9.5 (s, 1H).

GETTING 43

1-(tert-Butoxycarbonyl)-3-(1-piperazinil)azetidin

< / BR>
Piperazine (23,69 g, 8 mol. EQ.) melted and added 1- (tert-butoxycarbonyl)-3-methanesulfonanilide (see Publication of International Patent Application N WO93/19059 (8,64 g, to 34.4 mmol). The mixture was heated at 120oC for 15 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature and the excess piperazine was removed under reduced pressure. The residue was then chromatographically on silica gel using gradient elution (methanol: dichloromethane, the gradient of the Sabbath.">

1H-NMR (d6-DMSO): = 1.35 (s, 9H), 2.4-2.5 (m, 4H), 3.0-3.1 (m, 5H), 3.2-4.2 (m, br., 5H).

GETTING 44

1-(tert-Butoxycarbonyl)-3-(4-methylsulfonylmethane-1 - yl)azetidin

< / BR>
To a solution of the RECEIVE connector 43 (8.06 g, is 21.3 mmol) in dichloromethane (160 ml) was added triethylamine (13.4 ml). The solution was kept under nitrogen atmosphere and cooled to 0oC. is added dropwise, within 30 minutes, was added methanesulfonamide (the 5.25 ml, to 7.77 g, 3 mol. EQ.). The reaction mixture was allowed to warm to room temperature for 2.5 hours and then was stirred for a further 18 hours. The reaction mixture was washed with water (3 x 50 ml) and then brine (2 x 30 ml). The organic layer was dried using anhydrous magnesium sulfate. The mixture is then filtered and the solvent removed from the filtrate under reduced pressure. The residue was chromatographically on silica gel, elwira a mixture of concentrated aqueous ammonia:methanol:dichloromethane (1:10:89 by volume). The product of this phase chromatography then again chromatographically on a column of silica gel with elution with a mixture of methanol:ethyl acetate (1:10 by volume), getting mentioned in the title compound (0.9 g). RfTLC or = 0.6 (silica, concentrated aqueous ammonia: methanol:dichloromethane, 1:10:89 at the 3 (m, 4H), 3.75 - 3.8 (m, 2H), 3.9-4.0 (m, 2H).

45

3-(3,4-Dichlorophenyl)-3-(2-methanesulfonylaminoethyl)-1 - phenolsulfonephthalein

< / BR>
To a solution of the RECEIVE connector 28 (109 mg, 0.29 mmol) in dichloromethane (4 ml) under nitrogen atmosphere at 0oC was added methanesulfonamide (0,026 ml of 1.2 mol. EQ.). The reaction mixture was stirred at room temperature for one hour. Was added water (30 ml) and saturated aqueous sodium bicarbonate solution (30 ml) and the mixture was extracted with dichloromethane (3 x 40 ml). The combined organic layers were then dried using anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. This gave specified in the title compound (106 mg) in the form of a resin, which was used without further purification. RfTLC = 0,89 (silica, methanol: dichloromethane, 1:19 by volume).

GETTING 46

Bestrefiratecom-3-(4-methylsulfonylmethane-1-yl)azetidine

< / BR>
To a solution of the RECEIVE connector 44 (1.4 g, 5.8 mmol) in dichloromethane (10 ml) at 0oC in an atmosphere of nitrogen was added dropwise triperoxonane acid (5 ml). The mixture was then allowed to warm to room temperature and was stirred for one hour. The mixture was concentrated under reduced is aluca specified in the header of the connection.

LRMS m/z 220 (m + 1)+.

1H-NMR (d6-DMSO): = 2.4-2.5 (m, 2H), 2.9 (s, 3H), 3.1-3.2 (m, 4H), 3.3-3.5 (m, 1H), 3.8-4.0 (m, 4H), 8.7-8.9 (m, 3H).

GETTING 47

2-(3,4-Dichlorophenyl)Penta-4-enitel

< / BR>
To a stirred solution of 3,4-dichlorobenzonitrile (800 g, 4.3 mol) in cyclohexane (16 l) at room temperature was carefully added to an aqueous solution of sodium hydroxide (1600 g of sodium hydroxide in 8 l of water). This addition caused an increase in the reaction temperature to 50oC. Then was added allylbromide (572 g, 1,1 mol. EQ.) and the hydrate of Tetra chloride-and-butylamine (40 g 0,03 mol. EQ.) and the reaction mixture was stirred for one hour at 50oC. the Aqueous phase was removed and the organic layer was washed with water (10 l). The organic phase was filtered through silica gel (1 kg) under reduced pressure, obtaining a yellow solution. From the filtrate under reduced pressure, the solvent was removed, getting mentioned in the title compound as oil (960 g) with a purity of 70%, which was used without further purification. RfTLC = 0,71 (silica, diethyl ether: hexane, 1:1 by volume).

LRMS m/z = 226 (m+1)+.

1H-NMR (CDCl3): = 2.6-2.75 (m, 2H), 3.85 (t, 1H), 5.1-5.25 (m, 2H), 5.7-5.9 (m, 1H), 7.2-7.25 (m, 1H), 7.5-7.55 (m, 2H).

GETTING 48

4-Qi g) of sodium hydride in oil in tetrahydrofuran (17 l) in nitrogen atmosphere at 10oC was added dropwise, within three hours, a solution of 3-bromopropane acid (806.5 g) in tetrahydrofuran (6 l). The reaction mixture was allowed to warm to room temperature for 22 hours. The reaction mixture was then cooled to -10oC. Simultaneously dropwise over two hours in a nitrogen atmosphere at -10oC the solution of the RECEIVE connector 47 (1633,5 g) in tetrahydrofuran (2.5 l) was added to a stirred suspension of 60% (wt./mass.) dispersion of sodium hydride in oil (221 g) in tetrahydrofuran (2.5 l). When you are finished adding the second reaction mixture was allowed to warm to room temperature for eighteen hours. The reaction mixture was then cooled to -10oC and Coulibaly in the above-mentioned mixture of the sodium salt of 3-bromopropane acid for 3 hours. The reaction mixture then was heated at 50oC for five hours. The reaction mixture was then cooled, poured into water (8 l) and podslushivaet to a pH of 9.3 by using an aqueous solution of sodium bicarbonate. This mixture was washed with dichloromethane (5 x 2.5 l) and the aqueous portion was acidified to a pH of 1.0 using concentrated hydrochloric acid. The aqueous solution was extracted with dichloromethane (4 x 2.5 l) and the organic layers were combined, dried with use the yellow oil. This oil is then triturated with hexane (1.5 l), receiving specified in the title compound in the form of solid cream color (1153,3 g) which was used without any further purification. RfTLC = 0,42 (silica, methanol: dichloromethane, 1:9 by volume).

LRMS m/z = 316 (m+NH4)+.

1H-NMR (CDCl3): = 2.15-2.8 (m, 6H), 5.1-5.25 (m, 2H), 5.55-5.7 (m, 1H), 7.2 - 7.25 (m, 1H), 7.5-7.55 (m, 2H) ppm.

GETTING 49

Sol (R)-(+)-1-(1-naphthyl)ethylamine and 4(S)-4-cyano-4-(3,4 - dichlorophenyl)hept-6-ene acid

To a solution of the RECEIVE connector 48 (16 g) in ethyl acetate (50 ml) was added (R)-(+)-1-(naphtyl)ethylamine (4.8 g). The solution was stirred for thirty minutes at room temperature and then the solvent was removed under reduced pressure, collecting the resin. The resin was partially dissolved in a mixture of hexane:diethyl ether (4:1 by volume, 150 ml) and the walls of the flask scratched to induce crystallization. Formed by the white product was separated by filtration and recrystallize three times from ethyl acetate, getting mentioned in the title compound (4.9 g). So pl. 153-154oC.

[]25589-7.1o(C = 0.0012).

1H-NMR (CDCl3): = 1.6 (d, 3H),2.0-2.2 (m. 2H), 2.25-2.5 (m, 2H), 2.5-2.7 (m, 2H), 3.8-4.1 (s, br, 3H), 5.0-5.2 (m, 3H), 5.5-5.7 (m, 1H), 7.15-7.slot

To a stirred solution of compound RECEIVING 49 (5.5 g) in dichloromethane (100 ml) was added 1 N. aqueous solution of hydrochloric acid (100 ml). The aqueous layer was then removed and the organic portion washed with 1 N. aqueous solution of hydrochloric acid (70 ml). The organic layer was dried using anhydrous magnesium sulfate, filtered and the filtrate evaporated to dryness under reduced pressure, obtaining mentioned in the title compound (3.6 g).

LRMS m/z = 316 (m+NH4)+.

1H-NMR (CDCl3): = 2.15-2.8 (m, 6H), 5.1-5.25 (m, 2H), 5.55-5.7 (m, 1H), 7.2-7.25 (m, 1H), 7.5 - 7.55 (m, 2H).

GETTING 51

3(S)-3-(3,4-Dichlorophenyl)-3-arylpiperazine

< / BR>
To a mixture of sociallyengaged (867 mg, 2 mol. EQ.) in tetrahydrofuran (30 ml) at 0oC in an atmosphere of nitrogen was added dropwise a solution of 4(S)-4-cyano-4-(3,4-dichlorophenyl)hept-6-envoy acid (3.4 g, 11,41 mol) (RECEIVE 50) in tetrahydrofuran (30 ml). The mixture was stirred for two hours. Caution was added water (20 ml), then aqueous sodium hydroxide solution (2 x 20 ml). The solid portion was separated by filtration and the filter cake washed with tert-butyl methyl ether (100 ml). The organic phase is then dried over anhydrous magnesium sulfate and filtered. The solvent adelaidenow elution (ethyl acetate:methanol, the gradient: 98: 2, 19: 1, 9:1 by volume), receiving (a) specified in the title compound, which was contaminated (C) (S)-4-(aminomethyl)-4- (3,4-dichlorophenyl)hept-6-EN-1-I (2.55 g), which was used without further purification.

LRMS m/z 270 (M+1)+.

GET 52

3(S)-1-Benzoyl-3-(3,4-dichlorophenyl)-3-arylpiperazine

< / BR>
To a solution of compound (GETTING 51) (2,55 r) in dichloromethane (70 ml) at 0oC in an atmosphere of nitrogen was added triethylamine (3.9 ml) and benzoyl chloride (1,43 ml). The mixture was stirred for 15 minutes. Added dichloromethane (50 ml), the solution was washed with hydrochloric acid (2 ad, 2 x 200 ml) and the organic phase was dried over anhydrous magnesium sulfate. The solution was filtered and the solvent was removed under reduced pressure, obtaining the remainder, which was chromatographically on silica gel with a gradient elution with a mixture of solvents hexane: ethyl acetate (gradient from 9:1 to 1:4 by volume). This product (2,02 g) was then mixed with 2% sodium hydroxide solution in methanol (60 ml) for one hour. Added dichloromethane (60 ml), the mixture was washed with water (100 ml) and the organic phase was dried over anhydrous magnesium sulfate. The solution was filtered and the solvent was removed under reduced pressure, getting the balance is about 2:3 by volume), getting listed in the title compound (1.24 g).

LRMS m/z 374 (M+1)+.

RfTLC = 0,59 (silica, hexane:ethyl acetate 1:1 by volume).

1H-NMR (CDCl3) : 1.35-1.7 (m. 2H), 1.8-1.9 (m, 2H), 2.1-2.2 (m, 1H), 2.3 - 2.5 (m, 2H), 3.2-3.8 (m, 2H), 4.5-4.6 (m, 1H), 4.9-5.1 (m, 2H), 5.4-5.5 (m, 1H), 7.2-7.6 (m, 8H).

GETTING 53

3(S)-Benzoyl-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidine

< / BR>
To 9-borzillo[3.3.1]nonane (representing 22.06 ml, 0.5 M solution in tetrahydrofuran) solution was added to the RECEIVE connector 52 (825 mg, 2.21 mmol) in tetrahydrofuran (15 ml). The mixture was stirred at room temperature for 90 minutes. Then added an aqueous solution of sodium hydroxide (3,7 ml, 3 M solution) and ethanol (7 ml) and the mixture was cooled in a bath of ice and water. Then was added dropwise hydrogen peroxide (3,7 ml, 30% wt./mass. aqueous solution) and the solution was stirred for one hour.

Added ethyl acetate (50 ml) and the solution was washed with water (2 x 50 ml) and the organic phase was dried over anhydrous magnesium sulfate. The solution was filtered and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (20 ml) and the solution was cooled in an ice bath. Was added triethylamine (1.5 ml, 5 mol. EQ.) and benzoyl chloride (0,65 ml, 2.5 mol. EQ.) and the mixture re is (2 x 50 ml, 2 M solution). The organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure.

The residue was mixed with 4% sodium hydroxide solution in methanol (50 ml) for one hour. Added dichloromethane (60 ml) and the mixture was washed with water (100 ml). The organic phase was dried over anhydrous magnesium sulfate. The solution was filtered and the solvent was removed under reduced pressure, obtaining the remainder, which was chromatographically on silica gel with gradient elution by the mixture hexane: ethyl acetate (gradient from 4:1 to 1:3 by volume), getting mentioned in the title compound (320 mg).

LRMS m/z = 392 (M+1)+.

RfTCX = 0,22 (silica, hexane:ethyl acetate, 2: 3 by volume).

1H-NMR (CDCl3): 1.1-1.3 (m, 1H), 1.4-1.55 (m, 2H), 1.6-1.95 (m, 6H), 2.1-2.2 (m, 1H), 3.3-3.85 (m, 4H), 4.25-4.35 (m, 1H), 7.25-7.5 (m, 8H).

GETTING 54

3(R)-1-Benzoyl-3-(3,4 dichlorophenyl)-3-(3-methanesulfonylaminoethyl) piperidine

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To a solution of the RECEIVE connector 53 (320 mg, 0.82 mol) in dichloromethane (10 ml) under nitrogen atmosphere, cooled in a bath of ice and water was added triethylamine (0,34 ml, 3 mol. EQ.) and methansulfonate (0,096 ml of 1.5 mol. EQ.). The mixture was stirred for fifteen minutes.anhydrous magnesium sulfate, was filtered and the solvent was removed under reduced pressure, obtaining mentioned in the title compound (390 mg), which was used without further purification. RfTLC = 0,28 (silica, hexane:ethyl acetate, 2:3 by volume).

1H NMR (CDCl3): 1,25-4,4 (m, 17H), 7,25-of 7.55 (m, 8H).

The example of the pharmaceutical composition.

Tablets direct compression.

COMPOSITION mg/tablet

Active ingredient - 50,00

Microcrystalline cellulose Ph Eur 50,00

Lactose Ph Eur - 121,76

Nitrocresols NF - 2,00

Magnesium stearate Ph Eur 2,00

The active ingredient is sifted and mixed with other components. The resulting mixture is pressed into tablets using a rotary tablet press press (Manestry Betapress), equipped with a 6 mm normal concave punches. The resulting tablets can be coated with a film of a suitable film-forming material.

PHARMACOLOGICAL DATA

Representative sampling of the compounds of the examples were tested in vitro for their ability to inhibit the binding of [3H]-substance P with membranes obtained from the cell line IM9 person expressing the receptor NK1man (Method A), on their affinity to the receptor NK2the man who ovary cells Chinese hamster, expressing the cloned receptor NK2man (Method B), on their ability to create antagonism contractile action of a selective agonist of the receptor NK2, [Ala8]NKA(4-10)in the pulmonary artery of the rabbit (Method C) and on their ability to create antagonism contractile action of a selective agonist of the receptor NK3sentida in the ileum of Guinea pigs (method D) by the methods described on pages 40-41 description.

The results are shown in table 3.

It should be noted that the compounds according to the invention is suitable as antagonists of receptors tachykinin acting at the receptor neirokinina-1 person (NK1), neirokinina-2 (NK2or neirokinina-3 (NK3).

In the prior art (Pharmacological Research, 36(2), 153-169(1997)) it is known that in the development of such painful conditions like inflammatory disease, such as arthritis, psoriasis, asthma or inflammatory bowel disease (see Can. J. Physiol Pharmacol, 73(7), 843-847(1995) and Br.J.Pharmcol, 120, 1263-73(1997)), a disorder of the Central nervous system (CNS), such as fear, depression, dementia or psychosis (see Regulatory Peptides, 46,9-19(1993)), gastrointestinal (LCD) violation, such as a functional disease of cichecki is a (see Cell Tissue Res, 286(3), 281-292(1996)), violation of the urinary tract, such as urinary incontinence, hyperreflexia or cystitis (see Br. J Pharmacol, 115, 875-882 (1995)), pulmonary violation, such as chronic airway obstruction (see Arch Int Pharmacodyn Ther, 329(1), 205-219 (1995) and Eur Respir J, 6(5), 735-742 (1993)), allergies, such as eczema, contact dermatitis or rhinitis, a hypersensitivity, such as sensitivity to poison ivy (see J Pharmacol Exp Ther, 262(2), 646-653 (1992)), peripheral neuropathy, such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, burn, herpetic neuralgia or poligeneticheskie neuralgia (CM. J Neurosci, 14 (6), 3672-3687(1994)), cough (see Eur J Pharmacol, 250(1), 169-171(1993)) or acute or chronic pain (see Br J Pharmacol, 120, 1263-1273 (1997), involved a PC-receptors, in the treatment of such diseases therapeutic effect from the use of antagonists of these receptors. Because of the claimed compounds exhibit antagonistic activity against NK1NK2and NK3receptors, they can be used in the treatment of these diseases. Thus, it is the confirmation of the possibility of the use of the compounds according to the invention in the treatment of diseases, which shows the antagonistic effect on takenin-3 (NK3or a combination of two or more of them.

1. 3-Apatitenepheline or pyrrolidine formula I

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or their pharmaceutically acceptable salt,

where R represents a C3-C7cycloalkyl, C1-C6alkyl, substituted C3-C7cycloalkyl, or phenyl, possibly substituted OR5where R5represents C1-C4alkyl;

A is CO or SO2;

R1represents phenyl, substituted with two halogen substituents;

R2represents a group of the formula

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where R5, R6, R7represents H;

X2represents a simple bond;

W represents O, NSO2NR5R6, NSO2(C1-C4) alkyl;

n = 1;

X1represents a simple bond;

X represents C1-C4alkylen;

m is 0 or 1.

2. The compound or salt according to p. 1, where R represents phenyl, C3-C7cycloalkyl or C1-C6alkyl, substituted C3-C7cycloalkyl.

3. The compound or salt according to any one of the preceding paragraphs, where A is CO.

4. The compound or salt according to any one of the preceding paragraphs, where R2is , SO2(C1-C4) alkyl, NSO2NR5R6;

n = 1;

5. The compound or salt according to any one of the preceding paragraphs, where X represents ethylene or propylene.

6. The compound or salt according to any one of the preceding paragraphs, which has the stereochemistry shown in formula IA

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7. The compound or salt according to any one of the preceding paragraphs, where (i) R is phenyl; A is CO; R1is 3,4-dichlorophenyl; R2is morpholino; X is propylene; X1represents a simple bond and m is 1;

(ii) R is phenyl; A is CO; R1is 3,4-dichlorophenyl; R2is 4-aminosulphonylphenyl-1-yl; X is propylene; X1represents a simple bond and m is 1;

(iii) R is cyclohexyl; A is CO; R1is 3,4-dichlorophenyl; R2is morpholino; X is propylene; X1represents a simple bond and m is 1;

(iv) R is cyclohexyl; A is CO; R1is 3,4-dichlorophenyl; R2is 4-aminosulphonylphenyl-1-yl; X is propylene; X1represents a simple bond and m is 1;

(v) R, RETA; X is propylene; X1represents a simple bond and m is 1;

(vi) R is cyclopropyl; A represents CO, R1is 3,4-dichlorophenyl; R2is 4-aminosulphonylphenyl-1-yl; X is propylene; X1represents a simple bond and m is 1;

(vii) R is phenyl; A is CO; R1is 3,4-dichlorophenyl; R2is morpholino; X is ethylene; X1represents a simple bond and m is 0;

(viii) R is 2-methoxyphenyl; A is CO; R1is 3,4-dichlorophenyl; R2is morpholino, X is ethylene; X1represents a simple bond and m is 0;

(ix) R is phenyl; A is CO; R1is 3,4-dichlorophenyl; R2is morpholino; X is ethylene; X1represents a simple bond and m is 1;

(x) R is 2-methoxyphenyl; A is CO; R1is 3,4-dichlorophenyl; R2is morpholino; X is ethylene; X1represents a simple bond and m is 1;

(xi) R is phenyl; A is SO2; R1is 3,4-dichlorophenyl; R2is morpholino; X represents the ethyl1is 3,4-dichlorophenyl; R2is morpholino; X is ethylene; X1represents a simple bond and m is 1;

(xiii) R represents cyclopropylmethyl; A is CO; R1is 3,4-dichlorophenyl; R2is 4-methanesulfonylaminoethyl-1-yl; X is ethylene; X1represents a simple bond and m is 1 or

(xiv) R is phenyl; A is CO; R1is 3,4-dichlorophenyl; R2is 4-aminosulphonylphenyl-1-yl; X is propylene; X1represents a simple bond and m is 1.

8. The compound or salt according to any one of paragraphs.1 to 7 for use as a medicinal product with the activity of the receptor antagonist NK1, NR2or NK3or a combination of two or more of them.

9. Pharmaceutical composition having the activity of a receptor antagonist NK1NK2or NK3containing the compound or salt according to any one of the preceding paragraphs and a pharmaceutically acceptable diluent or carrier.

10. The composition according to p. 9 for use as a medicinal product with the activity of the receptor antagonist NK1, NRora shows an antagonistic effect on tachykinin, acting at the receptor neirokinina-1 person (NK1), neirokinina-2 (NK2or neirokinina-3 (NK3or a combination of two or more of them, by introducing an effective amount of a compound or salt according to any one of paragraphs.1 to 7 or the composition of p. 9.

12. The method according to p. 11, where the disease is an inflammatory disease such as arthritis, psoriasis, asthma or inflammatory bowel disease, a disorder of the Central nervous system (CNS), such as fear, depression, dementia or psychosis, gastrointestinal (LCD) violation, such as functional bowel disease, irritable bowel syndrome, gastroesophageal reflex, fecal incontinence, colitis or Crohn's disease, disruption of the urogenital tract, such as urinary incontinence, hyperreflexia or cystitis, pulmonary violation, such as chronic airway obstruction, allergies, such as eczema, contact dermatitis or rhinitis, a hypersensitivity, such as sensitivity to poison ivy, peripheral neuropathy, such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, burn, herpetic neuralgia or poligeneticheskie neuralgia, cough or acute or XP is whether the formula XXIII

< / BR>
where X, R, A, R1and m such as defined in paragraph 1, and Z3is methansulfonate.

14. A method of obtaining a compound or salt according to any one of paragraphs.1 to 7, where X represents a group (C0-C3alkylen)CH2-, a methylene group which is connected to the nitrogen atom of azetidine, and R, R1, A, R2X1and m such as defined in paragraph 1, including reductive amination using as starting materials the compounds of formula II

< / BR>
where R, A, R1and m are such as previously defined for compounds of formula I,

and the compounds of formula III

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or its acid salt additive, where R2and X1such, as defined in paragraph 1.

15. A method of obtaining a compound or salt according to any one of paragraphs.1 to 7, characterized in that when X, X1, R, A, R1, R2and m such as defined in paragraph 1, involves the reaction of compounds of formula XXIII

< / BR>
where X, R, A, R1and m such as defined in paragraph 1 and Z3is methansulfonate,

with the compound of the formula III

< / BR>
where R2and X1such, as defined in paragraph 1.

 

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