Piperidine compounds, pharmaceutical composition containing therein and its application

FIELD: chemistry.

SUBSTANCE: invention relates to piperidine compounds of formula and their pharmaceutically acceptable salts, based on them pharmaceutical composition, treatment method with therein application and therein application for treatment of gastrointestinal diseases. In formula (I) m represents integer number 1 or 2; n represents integer number from 0 to 2, A is selected from phenyl group and benzimidazole group, where phenyl group is substituted with one or more groups, independently selected from C1-C6 linear or branched alkyl group, C1-C6 linear or branched alkoxygroup, aminogroup and halogen, and benzimidazole group is substituted with one or more groups, independently selected from C1-C6 linear or branched alkyl group, C1-C6 linear or branched alkoxygroup, C3-C7 cyclic alkyl group, aminogroup, halogen and oxogroup; X represents hydroxyl or OCONR1R2, where R1 and R2 are independently selected from hydrogen and C1-C6 linear or branched alkyl group, or R1 and R2 form 5-7-membered heterocyclic ring or 3,5-dimethylpiperidine ring, together with nitrogen atom, to which they are attached, and B is selected from phenyl group, phenoxygroup, thienyl group and naphthyl group, where phenyl group, phenoxygroup, thienyl group or naphthyl group is substituted with one or more groups, independently selected from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, phenyl, C1-C6 linear or branched alkyl group and C1-C6 linear or branched alkoxygroup.

EFFECT: obtaining novel compounds.

25 cl, 3 tbl, 163 ex

 

TECHNICAL AREA

The present invention relates in General to piperidinium the compound and its pharmaceutically acceptable salts, pharmaceutical compositions containing an effective amount of racemic or enantiomerically enriched been the analogs of piperidine compounds for the treatment of gastrointestinal diseases and to a method of treatment of gastrointestinal diseases in a mammal. More specifically, the present invention relates to racemic or enantiomerically enriched O-carbamoyl and hydroxyl piperidinium compounds and their pharmaceutically acceptable salts, which are suitable for the treatment of irritable bowel syndrome (IBS), disorders of motor function of the stomach and visceral pain.

PRIOR art

Many reports indicated that piperidine compounds are effectively used for the treatment of various gastrointestinal disorders, especially irritable bowel syndrome (IBS) and disorders of motor function of the stomach.

For example, CIS-4-amino-5-chloro-N-[1-[3-(4-pertenece)-propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide (common name: cisapride (Cisapride)) was widely used in the clinic as an amplifier peristalsis of the gastrointestinal tract or gastrointestinal prokinetics agent, and other piperidino connection would and described in numerous patent documents (WO 2005/092882, WO 1999/055674, WO 2005/021539, WO 04/026868, WO 04/094418, WO 99/02494) as a therapeutic drug for the treatment of gastrointestinal diseases.

Continued active research and attempts to create, naprawianie to use been the analogs of piperidine compounds for the treatment of gastrointestinal diseases.

SUMMARY of the INVENTION

In some embodiments proposed piperidino connection and/or its pharmaceutically acceptable salt, pharmaceutical composition containing an effective amount piperidinol compounds and/or pharmaceutically acceptable salts, for the treatment of gastrointestinal diseases, as well as a method of treating diseases in a mammal, such as irritable bowel syndrome (IBS), impaired motor function of the stomach and/or visceral pain.

In some embodiments the method of treating disorders in a mammal by introducing an effective amount of racemic or enantiomerically enriched piperidinol compounds represented by following structural formula (I), in particular compounds represented by following structural formulas (IV) and (V), and a pharmaceutically acceptable carrier to a mammal in need of treatment of irritable bowel syndrome (IBS) or impairment of motor function of the stomach.

In some embodiments the application piperidino connection and/or its pharmaceutically acceptable salts for the prevention and/or treatment of gastrointestinal diseases such as irritable bowel syndrome (IBS), impaired motor function of the stomach, constipation and/or visceral pain, in a mammal.

In some embodiments the application piperidino connection and/or its pharmaceutically acceptable salts in the manufacture of pharmaceutical compositions for the prevention and/or treatment of gastrointestinal diseases such as irritable bowel syndrome (IBS), impaired motor function of the stomach, constipation and/or visceral pain, in a mammal.

DETAILED description of the INVENTION

A more complete understanding of the invention and many of its inherent advantages will be apparent in the form of better understanding with reference to the following detailed description.

In one embodiment of the proposed piperidino the connection represented by the following structural formula (I)and its pharmaceutically acceptable salts

Where m represents the integer 1 or 2;

n is an integer from 0 to 2, preferably 0;

A is selected from the group consisting of a phenyl group and a benzimidazole group, where the phenyl group which may be substituted by one or more identical or different groups, independently selected from the group consisting of hydrogen, C1-C6 linear or branched alkyl groups, C1-C6 linear or branched alkoxygroup, amino and halogen, and benzimidazole group may be substituted by one or more identical or different groups independently selected from the group consisting of hydrogen, C1-C6 linear or branched alkyl groups, C1-C6 linear or branched alkoxygroup, C3-C7 cyclic alkyl group, amino group, halogen and carbonyl group;

X represents a hydroxy or OCONR1R2where R1and R2may be the same or different and independently selected from the group consisting of hydrogen, C1-C6 linear or branched alkyl group, benzyl group and a 5-7 membered cyclic or heterocyclic compounds which may be substituted by one or more identical or different groups independently selected from the group consisting of C1-C6 alkyl, or Ri and R2 may form a 5-7-membered heterocyclic ring together with the nitrogen atom to which they are attached; and

In selected from the group consisting of phenyl groups, fenoxaprop, thienyl groups and naftilos group, where the phenyl group, fenoxaprop, thienyl group or naftalina group may be substituted by one or more identical or different group is AMI, independently selected from the group consisting of hydrogen, halogen, nitro, cyano, methanesulfonyl, trifloromethyl, triptoreline, deformedarse, phenyl, C1-C6 linear or branched alkyl groups and C1-C6 linear or branched alkoxygroup.

In the definition of substituents the alkyl group may be selected from the group consisting of methyl, ethyl, linear or branched propyl, linear or branched butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and benzyl. Halogen selected from fluorine atoms, chlorine, bromine and iodine.

In one embodiment A Deputy in the structural formula (I) may represent a phenyl group which may be substituted by one or more identical or different groups independently selected from the group consisting of hydrogen, halogen, amino, C1-C6 linear or branched alkyl groups or C1-C6 linear and branched alkoxygroup.

Deputy A can be represented by the structural formula (II):

where R3represents a substituted or unsubstituted C1-C6 linear or branched alkyl.

When A Deputy in the structural formula (I) has the structural formula (II), piperidine compound represented by the following structural formula (IV):

where m n, X, B and R3are as defined above.

Examples of compounds having the chemical formula (IV)may include 4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzamide;

4-amino-5-chloro-N-[[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-yl]-methyl]-2-methoxybenzamide: hydrochloride;

4-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-were)ethyl]piperidine-4-yl]methyl]-2-methoxybenzamide: hydrochloride;

4-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-methoxyphenyl)ethyl]piperidine-4-yl]methyl]-2-methoxybenzamide: hydrochloride;

4-amino-5-chloro-N-[[1-[2-(4-chlorophenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide: hydrochloride;

4-amino-5-chloro-N-[[1-[2-(3,4-dichlorophenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide: hydrochloride;

4-amino-5-chloro-N-[[1-[2-hydroxy-2-[4-(trifluoromethyl)phenyl]ethyl]-piperidine-4-yl]methyl]-2-methoxybenzamide : hydrochloride;

4-amino-5-chloro-N-[[1-[2-(3,4-differenl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide: hydrochloride;

[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-phenylethyl]carbamate:hydrochloride;

[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)ethyl]carbamate:hydrochloride;

[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(3,4-dichlorophenyl)ethyl]carbamate:hydrochloride;

[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]Pipa is one-1-yl]-1-(3,4-differenl)stil]carbamate:hydrochloride;

[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-[4-(trifluoromethyl)phenyl]ethyl]carbamate:hydrochloride;

4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide:hydrochloride;

4-amino-5-chloro-N-[[1-[3-(4-forfinal)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide: hydrochloride;

4-amino-5-chloro-N-[[1-[3-(3,4-dichlorophenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide : hydrochloride;

4-amino-5-chloro-N-[[1-(3-hydroxy-3-thiophene-2-ylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide: hydrochloride;

4-amino-5-chloro-N-[[1-[4-(4-forfinal)-3-hydroxybutyl]piperidine-4-yl]methyl]-2-methoxybenzamide: hydrochloride;

4-amino-5-chloro-N-[[1-[5-(4-forfinal)-3-hydroxyphenyl]piperidine-4-yl]methyl]-2-methoxybenzamide:hydrochloride;

[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-chlorophenyl)propyl]carbamate:hydrochloride;

[4-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)butane-2-yl]carbamate:hydrochloride;

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-5-(4-forfinal)pentane-3-yl]carbamate:hydrochloride;

4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]-methyl]-2-methoxybenzamide:hydrochloride;

4-amino-5-chloro-N-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide : hydrochloride;

4-amino-5-chloro-N-[[1-[2-hydroxy-3-[4-(is riformati)phenoxy]propyl]-piperidine-4-yl]methyl]-2-methoxybenzamide:hydrochloride;

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]carbamate:hydrochloride;

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(4-pertenece)propan-2-yl] - for 3,5-dimethylpiperidin-1-carboxylate hydrochloride;

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(4-methoxyphenoxy)propan-2-yl]carbamate:hydrochloride;

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(2,3-dichlorophenoxy)propan-2-yl]azepin-1-carboxylate: hydrochloride;

4-amino-5-chloro-N-[[1-[(2S)-2-hydroxy-2-phenylethyl]piperidine-4-yl]-methyl]-2-methoxybenzamide;

4-amino-5-chloro-M-[[1-[(2R)-2-hydroxy-2-phenylethyl]piperidine-4-yl]-methyl]-2-methoxybenzamide;

4-amino-5-chloro-N-[[1-[3-(4-chlorophenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;

[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)propyl]carbamate;

(R)-[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)propyl]carbamate;

(S)-[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)propyl]carbamate;

4-amino-5-chloro-N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidine-4-yl]methyl]-2-methoxybenzamide;

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]piperidine-1-carboxylate; and

4-amino-5-chloro-N-[[1-[3-(2,5-dichlorophenoxy)-2-hydrox is propyl]-piperidine-4-yl]methyl]-2-methoxybenzamide.

In another embodiment A Deputy can be a benzimidazole group which may be substituted by one or more identical or different groups independently selected from the group consisting of hydrogen, C1-C6 linear or branched alkyl groups, C1-C6 linear or branched alkoxygroup, NW-C7 cyclic alkyl group, amino group, halogen and carbonyl group.

Deputy A in structural formula (I) is represented by structural formula (III):

where R4represents a C1-C6 linear or branched alkyl group or a C3-C7 cyclic alkyl which may be substituted or unsubstituted.

When A Deputy in the structural formula (I) has the structural formula (III), piperidine compound represented by the following structural formula (V):

Examples of compounds having the chemical formula (V)may include [1-(2-methylphenoxy)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-yl]propan-2-yl]carbamate;

N-[[1-[2-hydroxy-3-(4-nitrophenoxy)propyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamid: hydrochloride;

N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamid:hydrochloride;

N-[[1-[3-(4-pertenece)-2-hydroc propyl]piperidine-4-yl]methyl]-3-methyl-2-oxopentanoate-1-carboxamid: hydrochloride;

3-ethyl-N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamid:hydrochloride;

[1-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl) - amino]-methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]carbamate: hydrochloride;

[1-(4-pertenece)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-yl]propan-2-yl]carbamate: hydrochloride;

[1-(4-methoxyphenoxy)-3-[4-[[(3-methyl-2-oxopentanoate-1-carbonyl)-amino]methyl]piperidine-1-s-1-yl]propan-2-yl]carbamate: hydrochloride;

[1-[4-[[(3-ethyl-2-oxopentanoate-1-carbonyl)amino]methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]carbamate: hydrochloride;

[1-(4-chlorophenoxy)-3-[4-[[(3-ethyl-2-oxopentanoate-1-carbonyl)-amino]methyl]piperidine-1-yl]propan-2-yl]carbamate: hydrochloride;

3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamid:hydrochloride;

3-cyclopropyl-N-[[1-[3-(4-forfinal)-3-hydroxypropyl]piperidine-1-s-4-yl]methyl]-2-oxopentanoate-1-carboxamid:hydrochloride;

[3-[4-[[(3-cyclopropyl-2-oxopentanoate-1-carbonyl)amino]methyl]-piperidine-1-s-1-yl]-1-phenylpropyl]carbamate: hydrochloride;

[1-(4-forfinal)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-s-1-yl]propyl]carbamate: hydrochloride;

[1-(4-methoxyphenyl)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-s-1-yl]party who drank]carbamate: hydrochloride;

M-[[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamid:hydrochloride;

[1-(4-forfinal)-2-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-s-1-yl]ethyl]carbamate: hydrochloride;

[[2-[4-[[(3-cyclopropyl-2-oxopentanoate-1-carbonyl)amino]methyl]-piperidine-1-s-1-yl]-1-(3-methoxyphenyl)ethyl]carbamate:hydrochloride;

[1-[4-[[(3-methyl-2-oxopentanoate-1-carbonyl)amino]methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]carbamate;

N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide; and

[3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]-piperidine-1-yl]-1-phenylpropyl]carbamate.

In accordance with one embodiment of the present invention, the compound represented by structural formula (I)and its pharmaceutically acceptable salts can be obtained according to the following stages, starting with aminosteroid compounds represented by the following General structural formula (VI):

where A, B, m and n are such as described above.

The method of obtaining On-carbamoyl compounds represented by the following General structural formula (VII):

where A, B, R1, R2, m and n are such as described above, are described in detail below.

On-carbamoyl connection, presented the General structural formula (VII), produced by interaction of amerosport represented by the General structural formula (VI)with 1,1'-carbonyl diimidazol (CDI) and then with an amine base represented by the following General structural formula (VIII):

where R1 and R2 are, as described above.

This procedure is summarized as shown in Reaction scheme I below.

Reaction scheme I

The reaction conditions described in Reaction scheme I, are disclosed in detail below. For the conversion of compound (VI) to the compound (VII) the concentration of the original substance (VI) is about 0.005 to 0.1 mol, with the number of 1,1'-carbonyldiimidazole (CDI), ranging from about 2.0 to 3.0 equivalents. This reaction is preferably carried out at a temperature from 10 to 30°C. Without purification the intermediate connection handle from 1 to 1000 equivalents of amine base represented by the General structural formula (VIII), at a temperature of from 10 to 30°C To produce compounds of General structural formula (VII). For this carbamylcholine can be used solvents, representing ethers, such as diethyl ether and tetrahydrofuran, a solvent, which represents a halogenated hydrocarbon such as dichloromethane and chloroform, or a mixture.

In Reaction scheme I Npredictable an acid, which are capable of forming pharmaceutically acceptable salt with the basic nitrogen atom. Specific examples of the acid used to obtain the compound (IX) from compound (VII)include hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, citric acid, malonic acid, salicylic acid, malic acid, fumaric acid, oxalic acid, succinic acid, tartaric acid, lactic acid, gluconic acid, ascorbic acid, maleic acid, aspartic acid, benzosulfimide acid, methanesulfonate acid, econsultancy acid, hydroxyethanesulfonic acid, hydroxyethanesulfonic acid and the like. Additional acid may be found in "Pharmaceutical Salts", J. Pharm. Sci., 1977; 66 (1): 1-19. This obtaining is carried out in a reaction medium, an example of which can serve as the solvent, representing a simple ether, such as tetrahydrofuran, an alcohol solvent such as methanol, hard-ester solvent such as ethyl acetate, a solvent, which represents a halogenated hydrocarbon, and mixtures thereof. The solvent, which represents a simple ether, is recommended as an added solution including ethyl ether, propyl ether, isopropyl ether, butyl ether and isobutyl ether. The concentration of C is unity (VII) is of the order of from about 0.01 to 5 mol.

Piperidine compounds of structural formula (I), with all possible isomeric forms, such as racemic, enantiomeric and diastereoisomeric forms, and pharmaceutically acceptable salts joining with inorganic and/or organic acids or with inorganic and/or organic bases of the compounds of structural formula (I), can be used to produce pharmaceuticals for the prevention and/or treatment of gastrointestinal diseases such as irritable bowel syndrome (IBS), impaired motor function of the stomach and/or visceral pain.

The method of obtaining amino-alcohol benzamide compounds represented by the following structural formula (X)

where B, m and n are as described above, are described in detail below.

Amino-alcohol benzamide compounds represented by the General structural formula (X), get through interaction peridynamic represented by the General structural formula (XI), with alkylhalogenide represented by the following General structural formula (XII), the epoxide represented by the following General structural formula (XIII), or Amida Weinraub represented by the following General structural formula (XIV):

where m represents the integer 1 or 2, Z represents a halogen, and B is as defined above;

,

where n is an integer from 0 to 2, preferably 0, and B is as defined above; and

,

where n is an integer from 0 to 2, preferably 0, and B is as defined above.

This procedure is summarized as shown in Reaction scheme II below.

Reaction scheme II

Stage II-1

Stage II-2

Stage II-3

Stage II-1

At this stage the target piperidine compound of structural formula (XV) are obtained by alkylation of compounds of structural formula (XI) with alkylhalogenide (XII) and recovery of the resulting ketone. Details of the reaction conditions described for Stage II-1, are the following. For the conversion of compound (XI) to compound (XV) the concentration of the original substance (XI) is approximately 0.005 to 0.1 mol, with the amount of compound (XII-1), ranging from approximately 1.1 to 3.0 equivalents, and the base, such as potassium carbonate, cesium carbonate and triethylamine, ranging from approximately 1.5 to 5.0 equival now. This reaction is preferably carried out at a temperature from 20 to 80°C. Without purification the intermediate ketone is treated with from 1.0 to 10.0 equivalents NaBH4at a temperature of from 0 to 30°C with obtaining compounds of General structural formula (XV).

For alternative transformations of the compound (XI) to compound (XV), where alkylhalogenide represented by structural formula (XII-2), the concentration of the original substance (XI) is approximately 0.005 to 0.1 mol, with the amount of compound (XII-2), ranging from approximately 1.1 to 3.0 equivalents, and the base, such as potassium carbonate, cesium carbonate and triethylamine, ranging from approximately 1.5 to 5.0 equivalents. This reaction is preferably carried out at a temperature from 20 to 80°C. For this reaction can be used a solvent, representing a simple ether, such as diethyl ether and tetrahydrofuran, a solvent, which represents a halogenated hydrocarbon such as dichloromethane and chloroform, an alcohol solvent such as methanol, ethanol and isopropanol, or acetonitrile.

Stage II-2

At this stage piperidine compound (XVI) are obtained by reaction of the disclosure epoxy rings.

Details of the reaction conditions described for Stage 11-2, are as follows. For prevrasheniya compound (XI) to compound (XVI) the initial concentration is about substance (XI) is approximately 0.005 to 0.1 mol, with the amount of compound (XIII), ranging from approximately 1.1 to 3.0 equivalents. This reaction is preferably carried out at a temperature from 20 to 80°C. For this reaction can be used a solvent, representing a simple ether, such as diethyl ether and tetrahydrofuran, a solvent, which represents a halogenated hydrocarbon such as dichloromethane and chloroform, an alcohol solvent such as methanol, ethanol and isopropanol, or acetonitrile.

Stage II-3

At this stage piperidine compound (XVIII) are obtained by reaction of a combination of compounds of structural formula (XI) with the compound representing amide Weinraub, structural formulas (XIV) and restore the obtained ketone compounds of structural formula (XVII). Details of the reaction conditions described for Stage II-3 are as follows. For the conversion of compounds (XI) to compound (XVIII) the concentration of the amide Weinraub (XIV) is about 0.005 to 0.1 mol, the amount of bromide vinylmania, ranging from approximately 1.1 to 2.0 equivalents. Then, the resulting intermediate compound is treated piperidinium compound represented by the General formula (XI), and the excess water at a temperature of from 0 to 30°C with obtaining compounds of General structural formula (XVII). Without purification the intermediate ke the traditional connection handle from 1.0 to 10.0 equivalents NaBH 4at a temperature of from 0 to 30°C with obtaining compounds of General structural formula (XVIII). For this reaction can be used a solvent, representing a simple ether, such as diethyl ether and tetrahydrofuran, a solvent, which represents a halogenated hydrocarbon such as dichloromethane and chloroform, an alcohol solvent such as methanol, ethanol and isopropanol, or acetonitrile.

The method of obtaining amino-alcohol benzimidazole compounds represented by the following General structural formula (XIX), will be described in detail below.

here B, R4, m, and n are as defined above.

Amino-alcohol-benzimidazole compounds represented by the General structural formula (XIX), get through interaction piperidino benzimidazole represented by the General structural formula (XX), with alkylhalogenide represented by the following General structural formula (XII), or the epoxide represented by the following General structural formula (XIII):

where m represents the integer 1 or 2, Z represents a halogen, and B is as defined above; and

where n is an integer from 0 to 2, and is therefore, completeline above.

This procedure is summarized as shown in Reaction scheme III below.

Reaction scheme III

Stage II1-1

Stage III-2

Stage III-1

At this stage piperidine compound of structural formula (XXI) are obtained by alkylation of compounds of structural formula (XX) using alkylhalogenide and recovery. The reaction can be carried out under the same conditions as described for Stage 11-1.

Stage III-2

At this stage piperidine compound of structural formula (XXII) are obtained by reaction of the disclosure epoxy ring. The reaction can be carried out in the same conditions as described for Stage II-2.

It should be noted that the stereochemistry of the product (I, IV or V) depends on the stereochemistry of the original substance (XII or XIII); the original substance (XII or XIII) as (S)-enantiomer gives only product in the form of (S)-enantiomer, and the original substance (XII or XIII) as (R)-enantiomer gives only product in the form of (R)-enantiomer.

Based on therapeutic activities of new been the analogs of piperidine compounds, as shown in the following examples, in another embodiment of the proposed pharmaceutical composition comprising as an active ingredient piperidine compounds represented by structural formula (I), cha is in the surrounding area connection represented by structural formulas (IV) and (V).

In another embodiment of the proposed pharmaceutical composition comprising an effective amount been the analogs of piperidine compounds represented by structural formula (I), in particular compounds represented by structural formulas (IV) and (V), for the treatment of disorders of the gastrointestinal tract, such as irritable bowel syndrome (IBS), motility disorders of the gastrointestinal tract (e.g., impaired motor function of the stomach, constipation, visceral pain, and the like.

In another embodiment, a method for treatment of disorders of the gastrointestinal tract, such as irritable bowel syndrome (IBS), motility disorders of the gastrointestinal tract (e.g., impaired motor function of the stomach, constipation and visceral pain, in a mammal, comprising introducing the composition of the compounds of structural formulas (I) to a mammal in need of therapy for disorders of the gastrointestinal tract.

Compounds of structural formula (I) useful in the treatment of IBS, especially IBS with constipation, constipation and other gastro-intestinal disorders associated with motility disorders of the gastrointestinal tract, because they can enhance the motility of the gastrointestinal tract.

In addition, the compounds of structural formula (I)are useful in reducing visceral pain, caused by IBS and/or other gastrointestinal disorders, because they can reduce visceral pain and discomfort associated with IBS and the like.

Compounds of structural formula (I) can be administered orally or parenterally, by themselves or in combination with conventional pharmaceutical carriers. Acceptable solid carriers can include one or more substances which may also act as corrigentov, lubricating agents, solubilization, suspendida agents, fillers, moving substances, substances that facilitate pressing, binding agents, agents, providing raspadaemost tablets, or encapsulating materials. In powders, the carrier can be a finely ground solid material, which is mixed with finely ground active ingredient. In tablets, the active ingredient in appropriate proportions mixed with carrier having the necessary compression properties, and presents in the desired shape of the required size. The powders and tablets can contain up to 99% of active ingredient.

Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinyle alidon, low melting waxes and ion exchange resins. Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.

The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilization, emulsifiers, buffering agents, preservatives, sweeteners, corrigentov, suspendresume agents, thickeners, dyes, viscosity regulators, stabilizers or regulators osmosis. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing the above additives, such as cellulose derivatives, preferably a solution of sodium carboxymethyl cellulose), alcohols (including monohydroxy alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and peanut butter).

Carrier for parenteral administration may also be a fatty acid ester, such as etiloleat and isopropylmyristate. Sterile compositions in liquid form for parenteral administration are sterile liquid media. Liquid headlight is asepticheskie composition, which are sterile solutions or suspensions, can be introduced through, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.

Oral administration may be in the form of compositions in liquid or solid form. Preferably, pharmaceutical compositions containing these compounds, presented in a standard dosage form, for example in the form of tablets or capsules. In this form, the composition is divided into unit doses containing appropriate quantities of the active ingredients. Standard dosage form can be a packaged composition, for example Packed powders, vials, ampoules, prefilled syringes or sachets containing liquids. Alternative standard dosage form may represent, for example, the capsule or tablet, or it can represent the appropriate number of any such compositions in Packed form. Used therapeutically effective dosage can vary or be adjusted carrying the introduction of the doctor, and in General ranges from 0.5 mg to 750 mg, in accordance with the specific(and) condition(s)subject(s) of treatment, and the size, age and type of response of the patient

Compounds of structural formula (I) can be administered to the patient in a dosage of from 0.7 to 7000 mg per day. For a normal adult humans weighing approximately 70 kg, the quantity entered is a daily dose of from 0.01 to 100 mg per 1 kg of body weight. Specific applied dose, however, may vary depending on the needs of the patient, severity of the patient's condition and activity of the connection. Determination of optimum dosages for a particular situation should be done in a clinical setting and is within the competence of the specialist in this field.

In another embodiment of the application piperidino connection and/or its pharmaceutically acceptable salt in the prevention and/or treatment of gastrointestinal diseases such as irritable bowel syndrome (IBS), impaired motor function of the stomach, constipation and/or visceral pain, in a mammal. In yet another embodiment of the application piperidino connection and/or its pharmaceutically acceptable salts in the manufacture of pharmaceutical compositions for the prevention and/or treatment of gastrointestinal diseases such as irritable bowel syndrome (IBS), impaired motor function of the stomach, constipation and/or visceral pain, in a mammal.

A better understanding of the present invention may be to the by in the light of the following examples, which are presented as illustrations and are not intended to limit the present invention.

EXAMPLE 1

4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

A mixture of 4-amino-5-chloro-2-methoxy-N-(piperidine-4-yl)methyl)benzamide (5.0 mmol), 2-bromoacetophenone (6.0 mmol) and potassium carbonate (7.6 mmol) was stirred in 15 ml of acetonitrile for 2 hours the solution is then concentrated in a rotary evaporator and diluted with ethyl acetate. This mixture is then washed with brine and the organic layer was dried and purified column chromatography. It was dissolved in ethanol (10 ml) was added borohydride sodium (10.0 mmol) at 0°C and stirred at 25°C for 2 h the solution was concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine, dried and concentrated in vacuum. The residue was purified column chromatography. The obtained 4-amino-5-chloro-N-((1-(2-hydroxy-2-phenylethyl)piperidine-4-yl)methyl)-2-methoxybenzamide was dissolved in methylene chloride (MC) and the solution was treated with a solution of HCl in diethyl ether. The precipitate was filtered to obtain specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.4-7.2 (m, 5H), 6.35 (s, 1H), 4.95 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4-3.3 (m, 3H), 3.0 (m, 1H), 2.6 (t, 2H), 2.4 (m, 1H), 2.2 (m, 1H), 1.9-1.6 (m, 3H), 1.6-1.4 (m, 2H).

POR WHAT MEASURES 2

4-amino-5-chloro-N-[[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 1, using as reagent of 2-bromo-4'-forfatteren instead of 2-bromoacetophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.15 (m, 2H), 7.1-6.95 (m, 2H), 6.35 (s, 1H), 4.9 (m, 1H), 4.4 (s, 2H), 3.9 (m, 3H), 3.4-3.2 (m, 3H), 3.1-2.9 (m, 1H), 2.6-2.3 (m, 3H), 2.3-2.1 (m, 1H), 1.9-1.7 (m, 3H), 1.6-1.4 (m, 2H).

EXAMPLE 3

4-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-were)ethyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 1, using as reagent of 2-bromo-4'-methylacetophenone instead of 2-bromoacetophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.3-7.1 (m, 4H), 6.35 (s, 1H), 4.9 (m, 1H), 4.4 (s, 2H), 3.9 (m, 3H), 3.5-3.3 (m, 3H), 3.3-3.1 (m, 1H), 2.7 (m, 2H), 2.6-2.5 (m, 1H), 2.4 (m, 4H), 1.9-1.7 (m, 3H), 1.6-1.5 (m, 2H).

EXAMPLE 4

4-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-methoxyphenyl)ethyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 1, using as reagent of 2-bromo-4'-methoxyacetophenone instead of 2-bromoacetophenone, obtaining specified in the connection header.

1H NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.2 (m, 2H), 6.95-6.85 (m, 2H), 6.35 (s, 1H), 4.9 (m, 1H), 4.4 (s, 2H), 3.9 (m, 3H), 3.8 (s, 3H), 3.4-3.2 (m, 3H), 3.1-3.0 (, 1H), 2.6 (m, 2H), 2.5 (m, 1H), 2.3-2.1 (m, 1H), 1.9-1.7 (m, 3H), 1.6-1.4 (m, 2H).

EXAMPLE 5

4-amino-5-chloro-N-[[1-[2-(4-cyanophenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 1, using as reagent of 2-bromo-4'-cyanoacetate instead of 2-bromoacetophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.65 (m, 2H), 7.55 (m, 2H), 6.35 (s, 1H), 4.9 (m, 1H), 4.45 (s, 2H), 3.9 (m, 3H), 3.4 (m, 2H), 3.2 (m, 1H), 2.95 (m, 1H), 2.7-2.33 (m, 3H), 2.2 (m, 1H), 1.9-1.7 (m, 3H), 1.6-1.4 (m, 2H).

EXAMPLE 6

4-amino-5-chloro-N-[[1-[2-(4-chlorophenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 1, using as reagent of 2-bromo-4'-chloroacetophenone instead of 2-bromoacetophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (m, 1H), 7.8 (m, 1H), 7.3 (m, 4H), 6.35 (s, 1H), 4.8 (t, 1H), 4.4 (s, 2H), 3.9 (s, MN), 3.4-3.2 (m, 3H), 3.05-2.9 (m, 1H), 2.6-2.3 (m, 3H), 2.2 (m, 1H), 1.9-1.6 (m, 3H), 1.6-1.4 (m, 2H).

EXAMPLE 7

4-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-phenylphenyl)ethyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 1, using as reagent of 2-bromo-4'-phenylacetophenone instead of 2-bromoacetophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (m, 1H), 7.85 (m, 1H), 7.6-7.3 (m, N), 6.35 (s, 1H), 5.3(m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.8-3.4 (m, 4H), 3.2-3.0 (m, 2H), 3.0-2.7 (m, 2H), 2.4-1.6 (m, 3H), 1.6-1.4 (m, 2H).

EXAMPLE 8

4-amino-5-chloro-N-[[1-[2-hydroxy-2-(2-methoxyphenyl)ethyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 1, using as reagent of 2-bromo-2'-methoxyacetophenone instead of 2-bromoacetophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (m, 1H), 7.85 (m, 1H), 7.6 (m, 1H), 7.3 (m, 1H), 7.0 (m, 1H), 6.9 (m, 1H), 6.35 (s, 1H), 5.25 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.8 (s, 3H), 3.6 (m, 2H), 3.1-3.0 (m, 2H), 2.9-2.7 (m, 4H), 1.9-1.7 (m, 3H), 1.7-1.4 (m, 2H).

EXAMPLE 9

4-amino-5-chloro-N-[[1-[2-hydroxy-2-(3-methoxyphenyl)ethyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 1, using as reagent of 2-bromo-3'-methoxyacetophenone instead of 2-bromoacetophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (m, 1H), 7.85 (t, 1H), 7.3-7.2 (m, 1H),7.0-6.9 (m, 2H), 6.85 (m, 1H), 6.35 (s, 1H), 4.8 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.8 (s, 3H), 3.4-3.2 (m, 3H), 3.0 (m, 1H), 2.6 (m, 2H), 2.4 (m, 1H), 2.2 (m, 1H), 1.9-1.6 (m, 3H), 1.6-1.4 (m, 2H).

EXAMPLE 10

4-amino-5-chloro-N-[[1-[2-(3,4-dichlorophenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 1, using as reagent of 2-bromo-3',4'-dichloroacetophenone instead of 2-bromoacetophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.5 (s, 1H), 7.45 (m, 1H), 7.2 (m, 1H), 6.35 (s, 1H), 4.8 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4 (m, 2H), 3.3-3.2 (m, 1H), 3.0 (m, 1H), 2.6-2.3 (m, 3H), 2.2 (m, 1H), 1.9-1.6 (m, 3H), 1.6-1.3 (m, 2H).

EXAMPLE 11

4-amino-5-chloro-N-[[1-[2-(2,4-differenl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 1, using as reagent of 2-bromo-2',4'-defloration instead of 2-bromoacetophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.85 (m, 1H), 7.65 (m, 1H), 7.0-6.7 (m, 2H), 6.35 (s, 1H), 5.3 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.5 (m, 1H), 3.4 (m, 2H), 3.2 (m, 2H), 2.9-2.2 (m, 4H), 2.7-2.4 (m, 2H), 2.0-1.8 (m, 3H), 1.8-1.6 (m, 2H).

EXAMPLE 12

4-amino-N-[[1-[2-(4-tert-butylphenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-5-chloro-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 1, using as reagent of 2-bromo-4'-tert-butylacetophenone instead of 2-bromoacetophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.45-7.3 (m, 4H), 6.35 (s, 1H), 4.8 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4-3.2 (m, 3H), 3.0 (m, 1H), 2.6 (m, 2H), 2.4 (m, 1H), 2.15 (m, 1H), 1.9-1.6 (m, 3H), 1.55 (m, 2H), 1.3 (s, N).

EXAMPLE 13

4-amino-5-chloro-N-[[1-[2-(2-chlorophenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 1, using as reagent of 2-bromo-2'-chloroacetophenone the place of 2-bromoacetophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.85 (m, 1H), 7.75 (m, 1H), 7.3 (m, 3H), 6.35 (s, 1H), 5.3 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4 (m, 3H), 3.05 (m, 1H), 2.85 (m, 1H), 2.5 (m, 2H), 2.3 (m, 1H), 1.9-1.7 (m, 3H), 1.6 (m, 2H).

EXAMPLE 14

4-amino-5-chloro-N-[[1-[2-(2,4-dimetilfenil)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 1, using as reagent of 2-bromo-2',4'-dimethylacetophenone instead of 2-bromoacetophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.45 (m, 1H), 7.05 (m, 1H), 6.95 (m, 1H), 6.35 (m, 1H), 5.05 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4-3.3 (m, MN), 3.0 (m, 1H), 2.6-2.4 (m, 3H), 2.35 (m, 6N), 2.2 (m, 1H), 1.9-1.6 (m, 3H), 1.55 (m, 2H).

EXAMPLE 15

4-amino-5-chloro-N-[[1-[2-(2,5-acid)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 1, using as reagent of 2-bromo-2',5'-dimethoxyacetophenone instead of 2-bromoacetophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.2 (m, 1H), 6.8 (s, 2H), 6.35 (m, 1H), 5.2 (m, 1H), 4.45 (s, 2H), 3.9 (s, 3H), 3.8 (m, 6N), 3.35 (m, 2H), 3.0 (m, 1H), 2.8 (m, 1H), 2.55 (m, 2H), 2.2 (m, 1H), 1.9-1.7 (m, 3H), 1.5 (m, 2H).

EXAMPLE 16

4-amino-5-chloro-N-[[1-[2-[4-(deformedarse)phenyl]-2-hydroxyethyl]-piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure in which the example 1, using as reagent of 2-bromo-4'-(deformedarse)acetophenone instead of 2-bromoacetophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.4 (m, 2H), 7.1 (m, 2H), 6.35 (m, 1H), 4.85 (m, 1H), 4.45 (s, 2H), 3.9 (s, 3H), 3.4-3.2 (m, 3H), 3.0 (m, 1H), 2.7-2.4 (m, 3H), 2.2 (m, 1H), 1.9-1.7 (m, 3H), 1.5 (m, 2H).

EXAMPLE 17

4-amino-5-chloro-N-[[1-[2-(3,4-differenl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 1, using as reagent of 2-bromo-3',4'-defloration instead of 2-bromoacetophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.3-7.1 (m, 3H), 6.35 (m, 1H), 4.85 (m, 1H), 4.45 (s, 2H), 3.9 (s, 3H), 3.5-3.2 (m, 3H), 3.0 (m, 1H), 2.7-2.4 (m, 3H), 2.2 (m, 1H), 1.9-1.7 (m, 3H), 1.5 (m, 2H).

EXAMPLE 18

4-amino-5-chloro-N-[[1-[2-hydroxy-2-[4-(trifluoromethyl)phenyl]ethyl]-piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 1, using as reagent of 2-bromo-4'-(trifluoromethyl)acetophenone instead of 2-bromoacetophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.6 (m, 2H), 7.5 (m, 2H), 6.35 (m, 1H), 4.9 (m, 1H), 4.45 (s, 2H), 3.9 (s, 3H), 3.4 (m, 2H), 3.3 (m, 1H), 3.0 (m, 1H), 2.7-2.3 (m, 3H), 2.2 (m, 1H), 1.9-1.7 (m, 3H), 1.5 (m, 2H).

EXAMPLE 19

4-amino-5-chloro-N-[[1-[2-(2,4-dichlorophenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide; g is drochloric

Followed the procedure given in Example 1, using as reagent of 2-bromo-2',4'-dichloroacetophenone instead of 2-bromoacetophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.65 (m, 2H), 7.35 (m, 2H), 6.35 (m, 1H), 5.25 (m, 1H), 4.45 (s, 2H), 3.9 (s, 3H), 3.4 (m, 2H), 3.0 (m, 1H), 2.8 (m, 1H), 2.6-2.2 (m, 3H), 1.9-1.7 (m, 3H), 1.5 (m, 2H).

EXAMPLE 20

4-amino-5-chloro-N-[[1-[(28)-2-hydroxy-2-phenylethyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

A mixture of 4-amino-5-chloro-2-methoxy-N-(piperidine-4-yl)methyl)-benzamide (5.0 mmol), (C)-styreneoxide (6.0 mmol) was boiled under reflux in 30 ml of isopropanol for 4 hours the solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture is then washed with brine and the organic layer was dried and purified column chromatography.

The obtained 4-amino-5-chloro-N-[[1-[(28)-2-hydroxy-2-phenylethyl]piperidine-4-yl]methyl]-2-methoxybenzamide was dissolved in MC and the solution was treated with a solution of HCl in diethyl ether. The precipitate was filtered to obtain specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (m, 1H), 8.0-7.9 (br, 1H), 7.5-7.3 (m, 5H), 6.35 (s, 1H), 5.45 (br, 1H), 4.4 (s, 2H), 3.9 (s, MN), 3.5-2.7 (m, 6N), 2.2-2.0 (m, 2H), 1.9-1.4 (m, 5H).

EXAMPLE 21

4-amino-5-chloro-N-[[1-[(2R)-2-hydroxy-2-phenylethyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Consequently the and procedure, shown in Example 20, using as reagent (R)-styreneoxide instead of (S)-styreneoxide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (m, 1H), 8.0-7.9 (br, 1H), 7.5-7.3 (m, 5H), 6.35 (s, 1H), 5.2 (br, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.5-2.7 (m, 6N), 2.2-2.0 (m, 2H), 1.9-1.4 (m, 5H).

EXAMPLE 22

[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-phenylethyl]carbamate; hydrochloride

4-Amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzamide (1.5 mmol) from Example 1 at 0°C was dissolved in 10 ml of THF and was added 1,1'-carbonyldiimidazole (12 mmol). The reaction mixture was stirred at room temperature for 2 h, then was added an excess of ammonium hydroxide (3 ml) at room temperature. After 2 h stirring at room temperature for completion of the reaction was added water. The organic layer was extracted 3 times with dichloromethane, was dried and concentrated in vacuum. The resulting carbamate was dissolved in MC and the solution was treated with a solution of HCl in diethyl ether. The precipitate was filtered to obtain specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.2 (m, 5H), 6.35 (s, 1H), 5.9 (m, 1H), 4.7 (m, 2H), 4.4 (s, 2H), 3.9 (m, 3H), 3.3 (m, 2H), 3.1-2.8 (m, 3H), 2.6-2.5 (m, 1H), 2.2-2.0 (m, 2H), 1.8-1.3 (m, 5H).

EXAMPLE 23

[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)ethyl]carb is at; hydrochloride

Followed the procedure given in Example 22, using as reagent 4-amino-5-chloro-N-[[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide of Example 2 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.2 (m, 2H), 7.15-7.0 (m, 2H), 6.35 (s, 1H), 5.9-5.8 (m, 1H), 5.1-4.8 (br, 2H), 4.4 (s, 2H), 3.9 (m, 3H), 3.4 (m, 2H), 3.3-3.0 (m, 3H), 2.8-2.6 (m, 2H), 2.5-2.3 (m, 2H), 1.9-1.5 (m, 5H).

EXAMPLE 24

[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-were)ethyl]carbamate; hydrochloride

Followed the procedure given in Example 22, using as reagent 4-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-were)-ethyl]piperidine-4-yl]methyl]-2-methoxybenzamide of Example 3 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzamide,

obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.3-7.1 (m, 4H), 6.35 (s, 1H), 5.9-5.8 (m, 1H), 4.9 (m, 2H), 4.4 (s, 2H), 3.9 (m, 3H), 3.4 (m, 2H), 3.2-2.9 (m, 3H), 2.6 (m, 1H), 2.35 (s, 3H), 2.3-2.1 (m, 2H), 1.9-1.5 (m, 5H).

EXAMPLE 25

[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-cyanophenyl)ethyl]carbamate; hydrochloride

Followed the procedure given in Example 22, using as reagent 4-amino-5-chloro-N-[[1-[2-(4-CANopen the l)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide of Example 5 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.7 (m, 2H), 7.5 (m, 2H), 6.35 (s, 1H), 5.9-5.8 (m, 1H), 5.0-4.8 (br, 2H), 4.4 (s, 2H), 3.9 (m, 3H), 3.4 (m, 2H), 3.1-2.9 (m, 3H), 2.7-2.6 (m, 1H), 2.4-2.2 (m, 2H), 1.9-1.7 (m, 3H), 1.5 (m, 2H).

EXAMPLE 26

[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-phenylphenyl)ethyl]carbamate; hydrochloride

Followed the procedure given in Example 22, using as reagent 4-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-phenylphenyl)ethyl]piperidine-4-yl]methyl]-2-methoxybenzamide of Example 7 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (DMSO-d6, 200 MHz) δ 10.2 (br, 1H), 8.05 (s, 1H), 7.7 (m, 5H), 7.5-7.3 (m, 4H), 6.9-6.8 (m, 2H), 6.5 (s, 1H), 6.05 (m, 1H), 3.9 (s, 3H), 3.6 (m, 2H), 3.4 (m, 3H), 3.2 (m, 1H), 3.0 (m, 2H), 1.9-1.4 (m, 5H).

EXAMPLE 27

[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(3-methoxyphenyl)ethyl]carbamate; hydrochloride

Followed the procedure given in Example 22, using as reagent 4-amino-5-chloro-N-[[1-[2-hydroxy-2-(3-methoxyphenyl)ethyl]piperidine-4-yl]methyl]-2-methoxybenzamide from Example 9 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (DMSO-d6, 200 MHz)δ10.1 (br, 1H), 8.05 (s, 1H), 7.65 (m, 1H), 7.4-7.3 (m, 1H), 7.0-6. (m, 5H), 6.5 (s, 1H), 6.0 (m, 1H), 3.9 (s, 3H), 3.85 (s, 3H), 3.6 (m, 2H), 3.4 (m, 3H), 3.2 (m, 1H), 3.0 (m, 2H), 1.9-1.4 (m, 5H).

EXAMPLE 28

[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(3,4-dichlorophenyl)ethyl]carbamate; hydrochloride

Followed the procedure given in Example 22, using as reagent 4-amino-5-chloro-N-[[1-[2-(3,4-dichlorophenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide from Example 10 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.85 (m, 1H), 7.5 (m, 2H), 7.3 (m, 1H), 6.35 (s, 1H), 5.95 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4 (m, 2H), 3.3-3.0 (m, 3H), 2.7 (m, 1H), 2.6-2.3 (m, 2H), 1.9-1.6 (m, 5H).

EXAMPLE 29

[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(2-chlorophenyl)ethyl]carbamate; hydrochloride

Followed the procedure given in Example 22, using as reagent 4-amino-5-chloro-N-[[1-[2-(2-chlorophenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide from Example 13 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.5-7.2 (m, 4H), 6.35 (m, 1H), 6.3 (m, 1H), 5.1 (m, 2H), 4.45 (s, 2H), 3.9 (s, 3H), 3.4-3.2 (m, 3H), 3.0 (m, 1H), 2.9 (m, 1H), 2.7 (m, 1H), 2.3 (m, 2H), 1.9-1.6 (m, 3H), 1.55 (m, 2H).

EXAMPLE 30

[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methylpiperidin-1-yl]-1-(2,4-dimetilfenil)ethyl]carbamate; hydrochloride

Followed the procedure given in Example 22, using as reagent 4-amino-5-chloro-N-[[1-[2-(2,4-dimetilfenil)-2-hydroxyethyl]-piperidine-4-yl]methyl]-2-methoxybenzamide from Example 14 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzo-amide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.05 (m, 1H), 7.0 (m, 2H), 6.35 (s, 1H), 6.1 (m, 1H), 4.9 (br, 2H), 4.45 (s, 2H), 3.9 (s, MN), 3.4 (m, 2H), 3.2 (m, 1H), 3.05-2.9 (m, 2H), 2.6 (m, 2H), 2.5-2.1 (m, 7H), 1.9-1.5 (m, 5H).

EXAMPLE 31

[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(2,5-acid)ethyl]carbamate; hydrochloride

Followed the procedure given in Example 22, using as reagent 4-amino-5-chloro-N-[[1-[2-(2,5-acid)-2-hydroxyethyl]-piperidine-4-yl]methyl]-2-methoxybenzamide from Example 15 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzo-amide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 6.95 (s, 1H), 6.8 (s, 2H), 6.35 (s, 1H), 6.3 (m, 1H), 4.95 (br, 2H), 4.45 (s, 2H), 3.9 (s, 3H), 3.8 (d, 6N), 3.4-3.2 (m, 3H), 3.0 (m, 1H), 2.9 (m, 1H), 2.7 (m, 1H), 2.4-2.2 (m, 2H), 1.9-1.7 (m, 3H), 1.5 (m, 2H).

EXAMPLE 32

[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-[4-(deformedarse)phenyl]ethyl]carbamate; hydrochloride

Followed the procedure given in Example 22, using the image quality is as reagent 4-amino-5-chloro-N-[[1-[2-[4-(deformedarse)phenyl]-2-hydroxyethyl]-piperidine-4-yl]methyl]-2-methoxybenzamide from Example 16 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzo-amide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.4 (m, 2H), 7.15 (m, 2H), 6.65 (s, 1H), 6.35 (s, 1H), 5.9 (m, 1H), 5.1-4.8 (br, 2H), 4.45 (s, 2H), 3.9 (s, 3H), 3.4-3.2 (m, 2H), 3.3-3.0 (m, 3H), 2.7 (m, 1H), 2.5-2.2 (m, 2H), 1.9-1.5 (m, 5H).

EXAMPLE 33

[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(3,4-differenl)ethyl]carbamate; hydrochloride

Followed the procedure given in Example 22, using as reagent 4-amino-5-chloro-N-[[1-[2-(3,4-differenl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide from Example 17 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.3-7.0 (m, 3H), 6.35 (s, 1H), 5.8 (m, 1H), 5.1-4.8 (br, 2H), 4.4 (s, 2H), 3.9 (s, 3H), 3.35 (m, 2H), 3.2-2.9 (m, 2H), 2.6 (m, N), 2.4-2.1 (m, 3H), 1.9-1.4 (m, 5H).

EXAMPLE 34

[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-[4-(trifluoromethyl)phenyl]ethyl]carbamate; hydrochloride

Followed the procedure given in Example 22, using as reagent 4-amino-5-chloro-N-[[1-[2-hydroxy-2-[4-(trifluoromethyl)phenyl]ethyl]-piperidine-4-yl]methyl]-2-methoxybenzamide from Example 18 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzo-amide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.65 (m, 2 is), 7.5 (m, 2H), 6.35 (s, 1H), 5.9 (m, 1H), 5.1-4.8 (br, 2H), 4.4 (s, 2H), 3.9 (s, 3H), 3.35 (m, 2H), 3.2-2.9 (m, 3H), 2.6 (m, N), 2.4-2.1 (m, 2H), 1.9-1.4 (m, 5H).

EXAMPLE 35

[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(2,4-dichlorophenyl)ethyl]carbamate; hydrochloride

Followed the procedure given in Example 22, using as reagent 4-amino-5-chloro-N-[[1-[2-(2,4-dichlorophenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide from Example 19 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.5-7.2 (m, 3H), 6.35 (s, 1H), 6.2 (m, 1H), 5.1-4.8 (br, 2H), 4.4 (s, 2H), 3.9 (s, 3H), 3.35 (m, 2H), 3.2 (m, 1H), 3.0 (m, 1H), 2.8 (m, 1H), 2.65 (m, 1H), 2.35 (m, 2H), 1.9-1.4 (m, 5H).

EXAMPLE 36

4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

A mixture of 4-amino-5-chloro-2-methoxy-N-(piperidine-4-yl)methyl)benzamide (5.0 mmol), 3-chloropropiophenone (6.0 mmol), potassium carbonate (7.6 mmol) and potassium iodide (7.6 mmol) was boiled under reflux in 15 ml of acetonitrile for 12 h the solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture is then washed with brine and the organic layer was dried and purified column chromatography. It was dissolved in ethanol (10 ml) and at 0°C was added borohydride sodium (10.0 mmol) and peremeci the Ali at 25°C for 2 hours This solution was concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine, dried and concentrated in vacuum. The residue was purified column chromatography. The obtained 4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide was dissolved in MC and the solution was treated with a solution of HCl in diethyl ether. The precipitate was filtered to obtain specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.4-7.2 (m, 5H), 6.35 (s, 1H), 4.95 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4-3.1 (m, 4H), 2.75 (m, 2H), 2.3-1.7 (m, 7H), 1.5 (m, 2H).

EXAMPLE 37

4-amino-5-chloro-N-[[1-[3-(4-forfinal)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure described in Example 36, using as reagent 3-chloro-4'-forpromotion instead of 3 chloropropiophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.3 (m, 2H), 7.1-7.0 (m, 2H), 6.35 (s, 1H), 4.9 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4-3.1 (m, 4H), 2.9-2.7 (m, 2H), 2.4-2.0 (m, 2H), 1.9-1.7 (m, 5H), 1.7-1.5 (m, 2H).

EXAMPLE 38

4-amino-5-chloro-N-[[1-[3-(4-chlorophenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure described in Example 36, using as reagent 3-chloro-4'-chloropropiophenone instead of 3 chloropropiophenone, obtaining specified in the header is connected to the I.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.4-7.35 (m, 2H), 7.1-6.9 (m, 2H), 6.35 (s, 1H), 4.9 (m, 1H), 4.4 (s, 2H), 3.9 (s, MN), 3.4 (m, 2H), 3.3-3.1 (m, 2H), 2.8-2.6 (m, 2H), 2.3-1.7 (m, 7H), 1.5 (m, 2H).

EXAMPLE 39

4-amino-5-chloro-N-[[1-[3-hydroxy-3-(4-were)propyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure described in Example 36, using as reagent 3-chloro-4'-methylpropiophenone instead of 3 chloropropiophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (m, 1H), 7.85 (m, 1H), 7.3 (m, 2H), 7.2 (m, 2H), 6.35 (s, 1H), 4.95 (t, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4 (m, 2H), 3.2 (m, 2H), 2.8-2.7 (m, 2H), 2.4 (s, 3H), 2.2 (m, 1H), 2.05-1.7 (m, 6N), 1.4-1.2 (m, 2H).

EXAMPLE 40

4-amino-5-chloro-N-[[1-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure described in Example 36, using as reagent 3-chloro-4'-methoxypropiophenone instead of 3 chloropropiophenone, obtaining specified in the connection header.

1H-NMR (CDCl3) 200 MHz) δ 8.15 (m, 1H), 7.85 (t, 1H), 7.3 (m, 2H), 6.9 (m, 2H), 6.35 (s, 1H), 4.95 (t, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.8 (s, 3H), 3.4 (m, 2H), 3.3-3.1 (m, 2H), 2.8-2.6 (m, 2H), 2.2 (m, 1H), 2.2-1.7 (m, 6N), 1.6-1.4 (m, 2H).

EXAMPLE 41

4-amino-5-chloro-N-[[1-[3-(2-chlorophenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

A mixture of 2-chlorbenzoyl acid (5 mmol) and 1,1'-carbonyldiimidazole was stirred in 30 ml of THF (tetrahydrofuran) for 30 the minutes and the hydrochloride was added N,O-dimethylhydroxylamine (6.5 mmol) and triethylamine (5 mmol). After 12 h stirring to complete the reaction at room temperature was added water. The organic layer was extracted 2 times with ethyl acetate and the organic layer washed with 5%HCl solution and brine, dried and concentrated in vacuum. The crude product was dissolved in THF (30 ml) and at 0°C was added a 1 M solution of bromide vinylmania (5.5 mmol) in THF. After 10 minutes of stirring the mixture was heated to room temperature and was stirred for 1 h, and then were added 4-amino-5-chloro-2-methoxy-N-(piperidine-4-yl)methyl)benzamide (7.5 mmol) and water (7.5 ml) at room temperature. After 30 minutes stirring at room temperature was added water and ethyl acetate and the organic layer was washed with brine, dried and concentrated in vacuum. The residue was purified column chromatography. It was dissolved in ethanol (10 ml) and at 0°C was added borohydride sodium (10.0 mmol) and stirred at 25°C for 2 h the solution was concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine, dried and concentrated in vacuum. The obtained 4-amino-5-chloro-N-[[1-[3-(2-chlorophenyl)-3-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide was dissolved in MC and the solution was treated with a solution of HCl in diethyl ether. The precipitate was filtered to obtain specified in the connection header.

1H-NMR (CDCl3 , 200 MHz) δ 8.05 (s, 1H), 7.8 (m, 1H), 7.7 (m, 1H), 7.4-7.1 (m, 3H), 5.3 (s, 1H), 4.5 (s, 2H), 3.9 (s, 3H), 3.35 (m, 2H), 3.1 (m, 2H), 2.6 (m, 2H), 2.2-1.6 (m, 7H), 1.5-1.3 (m, 2H).

EXAMPLE 42

4-amino-5-chloro-N - [[1-[3-(3-chlorophenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure described in Example 41, using as reagent 3-chlorobenzoyl acid instead of 2-chlorbenzoyl acid, obtaining specified in the connection header.

1H-NMR (CDCl,200 MHz) δ 8.05 (s, 1H), 7.8 (m, 1H), 7.4 (s, 1H), 7.3-7.1 (m, 3H), 6.3 (s, 1H), 4.9 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.35 (m, 2H), 3.1 (m, 2H), 2.6 (m, 2H), 2.1-1.9 (m, 1H), 1.9-1.5 (m, 6N), 1.5-1.3 (m, 2H).

EXAMPLE 43

4-amino-5-chloro-N-[[1-[3-(2-forfinal)-3-hydroxypropyl]piperidin-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure described in Example 41, using as reagent 2-fermenting acid instead of 2-chlorbenzoyl acid, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.05 (s, 1H), 7.8 (m, 1H), 7.6 (m, 1H), 7.2 (m, 2H), 6.95 (m, 1H), 6.3 (s, 1H), 5.2 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.3 (m, 2H), 3.1 (m, 2H), 2.6 (m, 2H), 2.2-1.5 (m, 7H), 1.5-1.1 (m, 2H).

EXAMPLE 44

4-amino-5-chloro-N-[[1-[3-(3-forfinal)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure described in Example 41, using as reagent 3-fermenting acid instead of 2-chlorbenzoyl acid, obtaining specified in the header connect the Oia.

1H-NMR (CDCl3, 200 MHz) δ 8.05 (s, 1H), 7.8 (m, 1H), 7.3 (m, 1H), 7.1 (m, 2H), 6.9 (m, 1H), 6.3 (s, 1H), 4.9 (m, 1H), 4.6 (s, 2H), 3.9 (s, 3H), 3.3 (m, 2H), 3.1 (m, 2H), 2.6 (m, 2H), 2.2-1.5 (m, 7H), 1.5-1.2 (m, 2H).

EXAMPLE 45

4-amino-5-chloro-N-[[1-[3-(2,3-dichlorophenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure described in Example 41, using as reagent 2,3-dichlorobenzoyl acid instead of 2-chlorbenzoyl acid, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.6 (m, 1H), 7.3 (m, 4H), 6.35 (s, 1H), 5.2 (m, 1H), 4.5 (m, 2H), 3.9 (s, 3H), 3.35 (m, 2H), 3.1 (m, 2H), 2.8-2.5 (m, 2H), 2.2-1.6 (m, 7H), 1.4 (m, 2H).

EXAMPLE 46

4-amino-5-chloro-N-[[1-[3-(2,4-dichlorophenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure described in Example 41, using as reagent 2,4-dichlorobenzoyl acid instead of 2-chlorbenzoyl acid, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.6 (m, 1H), 7.4-7.2 (m, 2H), 6.35 (s, 1H), 5.3 (m, 1H), 4.5 (s, 2H), 3.9 (s, 3H), 3.35 (m, 2H), 3.1 (m, 2H), 2.8-2.5 (m, 2H), 2.2-1.6 (m, 7H), 1.4 (m, 2H).

EXAMPLE 47

4-amino-5-chloro-N-[[1-[3-(3,4-dichlorophenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure described in Example 41, using as reagent 3,4-dichlorobenzoyl acid instead of 2-chlorbenzoyl acid, with what rucenim specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.5-7.3 (m, 2H), 7.2 (m, 1H), 6.35 (s, 1H), 4.95 (m, 1H), 4.5 (s, 2H), 3.9 (s, 3H), 3.35 (m, 2H), 3.2 (m, 2H), 2.8-2.6 (m, 2H), 2.2-1.6 (m, 7H), 1.5 (m, 2H,).

EXAMPLE 48

4-amino-5-chloro-N-[[1-[3-(4-isopropylphenyl)-3-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure described in Example 41, using as reagent 4-isopropylbenzoic acid instead of 2-chlorbenzoyl acid, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.3-7.15 (m, 4H), 7.2 (m, 2H), 6.3 (s, 1H), 4.9 (m, 1H), 4.5 (s, 2H), 3.9 (s, 3H), 3.35 (m, 2H), 3.2 (m, 2H), 2.9 (m, 1H), 2.6 (m, 2H), 2.2-1.6 (m, 7H), 1.4 (m, 2H), 1.3 (m, 6N).

EXAMPLE 49

4-amino-5-chloro-N-[[1-[3-(3-methoxyphenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure described in Example 41, using as reagent 3-methoxybenzoic acid instead of 2-chlorbenzoyl acid, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.3-7.2 (m, 1H), 6.9 (m, 2H), 6.8 (m, 1H), 6.3 (s, 1H), 5.7 (br, 1H), 4.9 (m, 1H), 4.55 (s, 2H), 3.9 (s, 3H), 3.85 (s, 3H), 3.3 (m, 2H), 3.1 (m, 2H), 2.65 (m, 2H), 2.1 (m, 2H), 2.0 (m, 1H), 1.9-1.6 (m, 3H), 1.45 (m, 2H).

EXAMPLE 50

4-amino-5-chloro-N-[[1-(3-hydroxy-3-thiophene-2-ylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure described in Example 41, using as reagent 2-thiencarbazone the acid instead of 2-chlorbenzoyl acid, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.3-7.2 (m, 1H), 6.9 (m, 2H), 6.8 (m, 1H), 6.3 (s, 1H), 5.2 (m, 1H), 4.9 (br, 1H), 4.55 (s, 2H), 3.9 (s, 3H), 3.35 (m, 2H), 3.2 (m, 2H), 2.7 (m, 2H), 2.2 (m, 1H), 2.1 (m, 3H), 1.9-1.6 (m, 3H), 1.45 (m, 2H).

EXAMPLE 51

4-amino-5-chloro-N-[[1-[4-(4-forfinal)-3-hydroxybutyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure described in Example 41, using as reagent 4-florfenicol acid instead of 2-chlorbenzoyl acid, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.2 (m, 2H), 7.0 (m, 2H), 6.3 (s, 1H), 4.4 (s, 2H), 4.0 (m, 1H), 3.9 (s, 3H), 3.3 (m, 2H), 3.0 (m, 1H), 2.9-2.6 (m, 4H), 2.3-1.3 (m, 11N).

EXAMPLE 52

4-amino-5-chloro-N-[[1-[5-(4-forfinal)-3-hydroxyphenyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure described in Example 41, using as reagent 3-(4-forfinal)propionic acid instead of 2-chlorbenzoyl acid, obtaining specified in the connection header.

1H-NMR (CDCI3) 200 MHz) δ 8.1 (s, 1H), 7.75 (m, 1H), 7.15 (m, 2H), 7.0 (m, 2H), 6.3 (s, 1H),4.4 (s, 2H), 3.85 (s, 3H), 3.8 (m, 4H), 3.3 (m, H), 3.2 (m, 1H), 3.0-2.6 (m, 6N), 2.1 (m, 1H), 2.0-1.6 (m, 4H), 1.6-1.3 (m, 2H).

EXAMPLE 53

[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-phenylpropyl]carbamate; hydrochloride

4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzyl is d (1.5 mmol) from Example 34 at 0°C was dissolved in 10 ml of THF and was added 1,1'-carbonyldiimidazole (12 mmol). The reaction mixture was stirred at room temperature for 4 h, then was added an excess of ammonium hydroxide (3 ml) at 0°C. After 2 h stirring at room temperature for completion of the reaction was added water. The organic layer was extracted 3 times with dichloromethane, was dried and concentrated in vacuum. The resulting carbamate was dissolved in dichloromethane and the solution was treated with a solution of HCI in diethyl ether. The precipitate was filtered to obtain specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.75 (m, 1H), 7.4-7.3 (m, 5H), 6.3 (s, 1H), 5.7 (m, 1H), 4.6 (m, 2H), 4.4 (s, 2H), 3.9 (s, 3H), 3.35 (m, 2H), 2.9 (m, 2H), 2.4-2.3 (m, 2H), 2.0-1.8 (m, 2H), 1.8-1.5 (m, 3H), 1.4-1.2 (m, 2H).

EXAMPLE 54

[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)propyl]carbamate; hydrochloride

Followed the procedure described in Example 53, using as reagent 4-amino-5-chloro-N-[[1-[3-(4-forfinal)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide from Example 35 instead of 4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.2 (m, 2H), 7.1-7.0 (m, 2H), 6.35 (s, 1H), 5.7 (m, 1H), 4.6 (m, 2H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4-3.2 (m, 2H), 3.0-2.8 (m, 2H), 2.4-2.1 (m, 4H), 2.0-1.5 (m, 5H), 1.5-1.3 (m, 2H).

EXAMPLE 55

[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)am is but]methyl]piperidine-1-yl]-1-(4-chlorophenyl)propyl]carbamate; hydrochloride

Followed the procedure described in Example 53, using as reagent 4-amino-5-chloro-N-[[1-[3-(4-chlorophenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide from Example 36 instead of 4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.4-7.2 (t, 2H), 7.1-7.0 (m, 2H), 6.35 (s, 1H), 5.7 (m, 1H), 4.7 (m, 2H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4 (m, 2H), 3.1-2.9 (m, 2H), 2.4 (m, 2H), 2.3-1.6 (m, 7H), 1.5-1.3 (m, 2H).

EXAMPLE 56

[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(2-chlorophenyl)propyl]carbamate; hydrochloride

Followed the procedure described in Example 53, using as reagent 4-amino-5-chloro-N-[[1-[3-(2-chlorophenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide from Example 39 instead of 4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.5-7.1 (m, 4H), 6.3 (s, 1H), 6.05 (m, 1H), 5.0 (m, 2H), 4.5 (m, 2H), 3.9 (s, 3H), 3.3 (m, 2H), 3.0 (m, 2H), 2.55 (m, 2H),2.1 (m, 2H), 1.8-1.2 (m, 5H), 0.9 (m, 2H).

EXAMPLE 57

[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(2-forfinal)propyl]carbamate; hydrochloride

Followed the procedure described in Example 53, using as reagent 4-amino-5-chloro-N-[[1-[3-(2-forfinal)-3-guide the oksipropil]piperidine-4-yl]methyl]-2-methoxybenzamide from Example 41 instead of 4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.4-6.9 (m, 4H), 6.3 (s, 1H), 5.95 (m, 1H), 5.0 (s, 2H), 4.5 (m, 2H), 3.85 (s, MN), 3.3 (m, 2H), 2.95 (m, 2H), 2.45 (m, 2H), 2.1 (m, 2H), 1.8-1.2 (m, 5H), 0.9 (m, 2H).

EXAMPLE 58

[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(3-forfinal)propyl]carbamate; hydrochloride

Followed the procedure described in Example 53, using as reagent 4-amino-5-chloro-N-[[1-[3-(3-forfinal)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide from Example 42 instead of 4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.3 (m, 1H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.65 (m, 1H), 4.9 (s, 2H), 4.5 (s, 2H), 3.85 (s, 3H), 3.3 (m, 2H), 2.9 (m, 2H), 2.35 (m, 2H), 2.2-1.8 (m, 2H), 1.8-1.2 (m, 5H), 0.9 (m, 2H).

EXAMPLE 59

[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(2,3-dichlorophenyl)propyl]carbamate; hydrochloride

Followed the procedure described in Example 53, using as reagent 4-amino-5-chloro-N-[[1-[3-(2,3-dichlorophenyl)-3-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide from Example 43 instead of 4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.15 (m, 3H), 6.3 (s, 1H), 6.05(m, 1H), 5.05 (m, 2H), 4.5 (s, 2H), 3.9 (s, 3H), 3.3 (m, 2H), 2.95 (m, 2H), 2.5 (m, 2H), 2.1-1.8 (m, 4H), 1.8-1.5 (m, 3H), 1.3 (m, 2H).

EXAMPLE 60

[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(2,4-dichlorophenyl)propyl]carbamate; hydrochloride

Followed the procedure described in Example 53, using as reagent 4-amino-5-chloro-N-[[1-[3-(2,4-dichlorophenyl)-3-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide from Example 44 instead of 4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.15 (m, 3H), 6.3 (s, 1H), 6.05 (m, 1H), 5.05 (br, 2H), 4.5 (s, 2H), 3.9 (s, 3H), 3.35 (m, 2H), 3.05 (m, 2H), 2.6 (m, 2H), 2.1-1.8 (m, 4H), 1.8-1.5 (m, 3H), 1.3 (m, 2H).

EXAMPLE 61

[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(3,4-dichlorophenyl)propyl]carbamate; hydrochloride

Followed the procedure described in Example 53, using as reagent 4-amino-5-chloro-N-[[1-[3-(3,4-dichlorophenyl)-3-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide from Example 45 instead of 4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.45 (m, 2H), 7.2 (m, 1H), 6.3 (s, 1H), 5.6 (m, 1H), 4.95 (br, 2H), 4.45 (s, 2H), 3.9 (s, 3H), 3.53 (m, 2H), 2.9 (m, 2H), 2.3 (m, 4H), 2.2-1.5 (m, 5H), 1.3 (m, 2H).

EXAMPLE 62

[3-[4-[[(4-amino-5-chloro-2-label benzoyl)amino]methyl]piperidine-1-yl]-1-(4-isopropylphenyl)propyl]carbamate; hydrochloride

Followed the procedure described in Example 53, using as reagent 4-amino-5-chloro-N-[[1-[3-(4-isopropylphenyl)-3-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide from Example 46 instead of 4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.3-7.1 (m, 4H), 6.3 (s, 1H), 5.65 (s, 1H), 4.95 (s, 2H), 4.5 (s, 2H), 3.85 (s, 3H), 3.3 (m, 2H), 3.1-2.8 (m, 3H), 2.4 (m, 2H), 2.2-1.8 (m, 4H), 1.8-1.5 (m, 3H), 1.4-1.2 (m, 8H).

EXAMPLE 63

[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(3-methoxyphenyl)propyl]carbamate; hydrochloride

Followed the procedure described in Example 53, using as reagent 4-amino-5-chloro-N-[[1-[3-(3-methoxyphenyl)-3-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide from Example 47 instead of 4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.25 (m, 1H), 6.9 (m, 3H), 6.3 (s, 1H), 5.7 (m, 1H), 4.9 (s, 2H), 4.55 (s, 2H), 3.9 (s, 3H), 3.8 (s, 3H), 3.35 (m, 2H), 2.95 (m, 2H), 2.4 (m, 2H), 2.2-1.9 (m, 4H), 1.8-1.5 (m, 3H), 1.45-1.2 (m, 2H).

EXAMPLE 64

[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-thiophene-2-ylpropyl]carbamate; hydrochloride

Followed the procedure described in Example 53, using as reagent 4-amino-chloro-N-[[1-(3-hydroxy-3-thiophene-2-ylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide from Example 48 instead of 4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.3 (m, 1H), 7.1-6.9 (m, 2H), 6.35 (s, 1H), 4.75 (s, 2H), 4.4 (s, 2H), 3.9 (s, 3H), 3.35 (m, 2H), 3.1 (m, 2H), 2.55 (m, 1H), 2.5-2.0 (m, 5H), 1.9-1.2 (m, 5H).

EXAMPLE 65

[4-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)butane-2-yl]carbamate; hydrochloride

Followed the procedure described in Example 53, using as reagent 4-amino-5-chloro-N-[[1-[4-(4-forfinal)-3-hydroxybutyl]piperidine-4-yl]methyl]-2-methoxybenzamide from Example 51 instead of 4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.75 (m, 1H), 7.15 (m, 2H), 7.0 (m, 2H), 6.3 (s, 1H), 4.9 (m, 1H), 4.8 (s, 2H), 4.5 (s, 2H), 3.85 (s, 3H), 3.3 (m, 2H), 2.9-2.8 (m, 4H), 2.4 (m, 2H), 1.9 (m, 2H), 1.8-1.5 (m, 5H), 1.3 (m, 2H).

EXAMPLE 66

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidin-1-yl]-5-(4-forfinal)pentane-3-yl]carbamate hydrochloride

Followed the procedure described in Example 53, using as reagent 4-amino-5-chloro-N-[[1-[5-(4-forfinal)-3-hydroxyphenyl]piperidine-4-yl]methyl]-2-methoxybenzamide from Example 52 instead of 4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.75 (m, 1H), 7.15 (m, 2H), 6.95 (m, 2H), 6.3 (s, 1H), 4.8 m, 1H), 4.75 (s, 2H), 4.45 (s, 2H), 3.85 (s, 3H), 3.35 (m, 2H), 2.95 (m, 2H), 2.65 (m, 2H), 2.4 (m, 2H), 2.0-1.5 (m, N), 1.3 (m, 2H).

EXAMPLE 67

(8)-4-amino-5-chloro-N-[[1-[3-(4-forfinal)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

A solution of 3-chloro-4'-forpromotion (5.4 mmol) was slowly added 1.6 M solution of (-)-chlorodiisopinocampheylborane in hexane (8.1 mmol) at -25°C. This reaction mixture was stirred at room temperature for 16 hours After 16 h stirring at -25°C for completion of the reaction was added MeOH, and then it was washed with brine and the organic layer was dried and concentrated in vacuum. The crude product was dissolved in 20 ml of acetonitrile and 25°C was added 4-amino-5-chloro-2-methoxy-N-[(piperidine-4-yl)methyl]benzamide (3.6 mmol), potassium carbonate (5.4 mmol) and potassium iodide (5.4 mmol). The reaction mixture is boiled under reflux for 12 h the solution was then concentrated on a rotary evaporator and diluted with ethyl acetate, washed with brine, the resulting organic layer was dried and purified column chromatography. The obtained (S)-4-amino-5-chloro-N-[[1-[3-(4-forfinal)-3-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide was dissolved in MC and the solution was treated with a solution of HCl in diethyl ether. The precipitate was filtered to obtain specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.3 (m, 2H), 7.1-7.0 (m, 2H), 6.35 (s, 1H), 4.9 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4-3.1 (m, 4H), 2.9-2.7 (m, 2H), 2.4-2.0 (m, 2H), 1.9-1.7 (m, 5H), 1.7-1.5 (m, 2H).

EXAMPLE 68

(S)-[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)propyl]carbamate; hydrochloride

(S)-4-amino-5-chloro-N-[[1-[3-(4-forfinal)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide (1.5 mmol) from Example 62 was dissolved in 10 ml of THF and was added 1,1'-carbonyldiimidazole (12 mmol) at 0°C. the Reaction mixture was stirred at room temperature for 4 h, then at 0°C was added an excess of ammonium hydroxide (3 ml). After 2 h stirring at room temperature was added water to complete the reaction. The organic layer was extracted 3 times with dichloromethane, was dried and concentrated in vacuum. The obtained (S)-[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)propyl]-carbamate was dissolved in MC and the solution was treated with a solution of HCl in diethyl ether. The precipitate was filtered to obtain specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.2 (m, 2H), 7.1-7.0 (m, 2H), 6.3 (s, 1H), 5.7 (m, 1H), 4.6 (m, 2H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4-3.1 (m, 4H), 2.8-2.6 (m, 2H), 2.3-2.0 (m, 2H), 2.0-1.6 (m, 5H), 1.5-1.3 (m, 2H).

EXAMPLE 69

(R)-4-amino-5-chloro-N-[[1-[3-(4-forfinal)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 7, using as reagent (+)-chlorodiisopinocampheylborane instead of (-)-chlorodiisopinocampheylborane, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.4-7.3 (m, 2H), 7.1-7.0 (m, 2H), 6.35 (s, 1H), 4.9 (m, 1H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4-3.1 (m, 4H), 2.9-2.7 (m, 2H), 2.4-2.0 (m, 2H), 1.9-1.7 (m, 5H), 1.7-1.5 (m, 2H).

EXAMPLE 70

(R)-[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)propyl]carbamate; hydrochloride

Followed the procedure described in Example 68, using as reagent (R)-4-amino-5-chloro-N-[[1-[3-(4-forfinal)-3-hydroxypropyl]-piperidine-4-yl]-methyl]-2-methoxybenzamide instead of (3)-4-amino-5-chloro-N-[[1-[3-(4-forfinal)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (m, 1H), 7.8 (m, 1H), 7.4-7.3 (m, 4H), 6.35 (s, 1H), 4.9 (m, 2H), 4.4 (s, 2H), 3.9 (s, 3H), 3.4 (m, 2H), 3.3-3.1 (m, 2H), 2.7 (m, 2H), 2.2 (m, 1H), 2.1-1.6 (m, 6N), 1.5-1.3 (m, 2H).

EXAMPLE 71

4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

A mixture of 4-amino-5-chloro-2-methoxy-N-[(piperidine-4-yl)methyl]benzamide (3 mmol) and 1,2-epoxy-3-phenoxypropane (3 mmol) was boiled under reflux in 10 ml of isopropanol for 3 hours the solution was concentrated on a rotary evaporator and the mixture was purified column chromatography. The obtained 4-amino-5-chloro-N-((1-(2-hydrox the-3-phenoxypropan)-piperidine-4-yl)methyl)-2-methoxybenzamide was dissolved in MC and the solution was treated with a solution of HCl in diethyl ether. The precipitate was filtered to obtain specified in the connection header.

1H NMR (DMSO (dimethylsulfoxid), 200 MHz), ppm (δ): (in the form of HCl salt) 9.75 (br, 1H), 8.0 (m, 1H), 7.66 (s, 1H), 7.30 (m, 2H), 6.96 (m, 3H), 6.48 (s, 1H), 5.96 (s, 2H), 4.35 (m, 1H), 3.95 (m, 2H), 3.83 (m, 3H), 3.54 (m, 2H), 3.17 (m, 4H), 3.0 (m, 2H), 1.9-1.5 (m, 5H).

EXAMPLE 72

4-amino-5-chloro-N-[[1-[3-(4-pertenece)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 71, using as reagent 4-ferverishly ether instead of 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H NMR (DMSO, 500 MHz), ppm (δ): (HCl salt form) 9.3 (m, 1H), 8.0 (s, 1H), 7.67 (s, 1H), 7.13 (m, 2H), 6.96 (m, 2H), 6.48 (s, 1H), 5.93 (s, 2H), 4.3 (m, 1H), 3.92 (s, 2H), 3.83 (s, 3H), 3.55 (m, 2H), 3.3-3.2 (m, 4H), 3.0 (m, 2H), 1.77 (m, 3H), 1.6 (m, 1H), 1.5 (m, 1H).

EXAMPLE 73

4-amino-5-chloro-N-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 71, using as reagent 4-chlorophenylglycine ether instead of 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (in the form of a free amine) 7.9 (m, 1H), 7.65 (s, 1H), 7.3 (m, 2H), 6.95 (m, 2H), 6.46 (s, 1H), 5.93 (s, 2H), 4.85 (m, 1H), 4.0-3.8 (m, 5H), 3.3-3.1 (m, 4H), 2.9 (m, 2H), 2.4 (m, 1H), 2.0 (m, 2H), 1.7-1.4 (m, 3H), 1.2 (m, 2H).

EXAMPLE 74

4-amino-5-chloro-N-[[1-[2-hydroxy-3-(4-methoxyphenol the si)propyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 71, using as reagent glycidyl-4-methoxyphenacyl ether instead of 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H NMR (DMSO, 500 MHz), ppm (δ): (HCl salt form) 9.4 (m, 1H), 8.00 (m, 1H), 7.67 (s, 1H), 6.86 (m, 4H), 6.48 (m, 1H), 5.91 (m, 2H), 4.29 (m, 1H), 3.9 (m, 2H), 3.83 (s, 3H), 3.52 (m, 2H), 3.21 (m, 4H), 2.90 (m, 2H), 1.75 (m, 3H), 1.56 (m, 1H), 1.47 (m, 1H).

EXAMPLE 75

4-amino-5-chloro-N-[[1-[3-(2,3-dichlorophenoxy)-2-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 71, using as reagent 2,3-dichlorophenylisocyanate ether instead of 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7,9-7.85 (m, 1H), 7.25 (s, 1H), 7.20-7.05 (m, 2H), 6.95 (m, 1H), 6.35 (s, 1H), 4.4 (m, 2H), 4.2 (m, 1H), 4.05 (m, 2H), 3.9 (s, 3H), 3.3 (m, 2H), 3.1 (m, 1H), 3.0 (m, 1H), 2.7 (m, 2H), 2.4 (m, 1H), 2.2 (m, 1H), 1.97-1.8 (m, 3H), 1.6-1.4 (m, 2H).

EXAMPLE 76

4-amino-5-chloro-N-[[1-[3-(2,4-dichlorophenoxy)-2-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 71, using as reagent 2,4-dichlorophenylisocyanate ether instead of 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7,9-7.85 (m, 1H), 7.4 (s, 1H), 7.20 (m, 1H), 6.9 (m, 1H), 6.35 (s, 1H), 4.4 (m, 2H), 4.2 (m, 1H), 4.05(m, 2H), 3.9 (s, 3H), 3.4 (m, 2H), 3.1 (m, 1H), 2.9 (m, 1H), 2.65 (m, 2H), 2.4 (m, 1H), 2.1 (m, 1H), 1.9-1.65 (t, 3H), 1.6-1.25 (m, 2H).

EXAMPLE 77

4-amino-5-chloro-N-[[1-[3-(2,5-dichlorophenoxy)-2-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 71, using as reagent 2,5-dichlorophenylisocyanate ether instead of 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.3 (m, 1H), 6.95 (m, 2H), 6.3 (s, 1H), 4.4 (s, 2H), 4.2 (m, 1H), 4.0 (m, 2H), 3.9 (s, 3H), 3.4 (t, 2H), 3.1 (m, 1H), 2.9 (m, 1H), 2.6 (t, 2H), 2.4 (m, 1H), 2.1 (m, 1H), 1.9-1.8 (m, 3H), 1.5-1.3 (m, 2H).

EXAMPLE 78

4-amino-5-chloro-N-[[1-[3-(2,6-dichlorophenoxy)-2-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 71, using as reagent 2,6-dichlorophenylisocyanate ether instead of 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.8 (m, 1H), 8.1 (s, 1H), 7.3 (2H), 7.0 (t, 1H), 6.35 (s, 1H), 4.4 (s, 2H), 4.2 (s, 1H), 4.1 (t, 2H), 3.95 (s, 3H), 3.4 (t, 2H), 3.15 (m, 1H), 3.0 (m, 1H), 2.75 (m, 2H), 2.4 (m, 1H), 2.2 (m, 1H), 1.8 (m, 3H), 1.6-1.3 (m, 2H).

EXAMPLE 79

4-amino-5-chloro-N-[[1-[3-(3,4-dichlorophenoxy)-2-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 71, using as reagent 3,4-dichlorophenylisocyanate ether instead of 1,2-epoxy-C-f is oxypropane, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (m, 1H), 7.8 (m, 1H), 7.4-7.3 (m, 1H), 7.1 (m, 1H), 6.9 (m, 1H), 6.3 (m, 1H), 4.4 (s, 2H), 4.1 (m, 1H), 4.0-3.9 (m, 5H), 3.4 (m, 2H), 3.1 (m, 1H), 2.9 (m, 1H), 2.6 (m, 2H), 2.4 (m, 1H), 2.2-2.05 (m, 1H), 1.9-1.6 (m, 3H), 1.5-1.3 (m, 2H).

EXAMPLE 80

4-amino-5-chloro-N-[[1-[3-(2-chlorophenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 71, using as reagent 2-chlorophenylglycine ether instead of 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (m, 1H), 7.8 (t, 1H), 7.4-7.2 (m, 2H), 7.0-6.9 (m, 2H), 6.9-6.8 (m, 1H), 6.4 (s, 1H), 4.5-4.4 (m, 2H), 4.3-4.1 (m, 3H), 3.9 (m, 3H), 3.4 (m, 2H), 3.1 (m, 1H0), 2.9 (m, 1H), 2.6 (m, 2H), 2.4 (m, 1H), 2.1 (m, 1H) and 1.9-1.6 (m, 3H), 1.5-1.3 (m, 2H).

EXAMPLE 81

4-amino-5-chloro-N-[[1-[3-(4-methylphenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 71, using as reagent glycidyl-4-methylphenylene ether instead of 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (m, 1H), 7.8 (t, 1H), 7.1 (m, 2H), 6.8 (m, 2H), 6.4 (s, 1H), 4.4 (m, 2H), 4.1 (m, 1H), 4.0-3.9 (m, 5H), 3.4 (m, 2H), 3.1 (m, 1H), 2.9 (m, 1H), 2.6 (m, 2H), 2.3 (m, 4H), 2.1 (m, 1H), 1.9-1.6 (m, 3H), 1.4 (m, 2H).

EXAMPLE 82

4-amino-5-chloro-N-[[1-[3-(3,4-divergence)-2-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide; g is drochloric

Followed the procedure given in Example 71, using as reagent 3,4-differentially ether instead of 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.2-7.0 (m, 1H), 6.9-6.6 (m, 2H), 6.35 (s, 1H), 4.4 (s, 2H), 4.1 (m, 1H), 3.9 (m, 5H), 3.4 (m, 2H), 3.1-2.9 (m, 2H), 2.6 (m, 2H), 2.4 (m, 1H), 2.1 (m, 1H), 1.9-1.6 (m, 3H), 1.5-1.3 (m, 2H).

EXAMPLE 83

4-amino-5-chloro-N-[[1-[2-hydroxy-3-[4-(trifluoromethyl)phenoxy]propyl]-piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 71, using as reagent glycidyl-4-cryptomaterial ether instead of 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.75 (m, 1H), 7.6-7.5 (m, 2H), 7.0 (m, 2H), 6.3 (s, 1H), 4.4 (s, 2H), 4.2-4.0 (m, 3H), 3.9 (s, 3H), 3.35 (m, 2H), 3.1 (m, 1H), 2.9 (m, 1H), 2.5 (m, 2H), 2.35 (m, 1H), 2.1 (m, 1H), 1.9-1.6 (m, 3H), 1.5-1.3 (m, 2H).

EXAMPLE 84

4-amino-5-chloro-N-[[1-[2-hydroxy-3-(4-phenyleneoxy)propyl]piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 71, using as reagent glycidyl-4-phenylphenolate ether instead of 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.75 (m, 1H), 7.5-6.9 (m, N), 6.3 (s, 1H), 5.7 (m, 1H), 4.6 (m, 2H), 4.4 (s, 2H), 3.9 (s, 3H), 3.35 (m, 2H), 2.9 (m, 2H), 2.4-2.3 (m, 2H), 2.0-1.8 (m, 2H), 1.8-15 (m, MN), 1.4-1.2 (m, 2H).

EXAMPLE 85

4-amino-5-chloro-N-[[1-(2-hydroxy-3-naphthalene-2-roxiprin)piperidine-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 71, using as reagent 2-(naphthalene-2-intoximeter)-oxiran instead of 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8 (m, 1H), 7.6-7.3 (m, 5H), 7.0 (m, 2H), 6.3 (s, 1H), 4.4 (s, 2H), 4.3 (m, 1H), 4.1-4.0 (m, 2H), 3.9 (s, 3H), 3.3 (m, 1H), 3.1 (m, 1H), 2.7 (m, 2H), 2.5 (m, 1H), 2.35 (m, 1H), 1.9-1.6 (m, 3H), 1.6-1.4 (m, 2H).

EXAMPLE 86

4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenylpropyl)piperidine-1-s-4-yl]methyl]-2-methoxybenzamide; hydrochloride

Followed the procedure given in Example 71, using as reagent (2,3-epoxypropyl)benzene instead of 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.3 (m, 5H), 6.35 (s, 1H), 4.45 (s, 2H), 4.0 (m, 1H), 3.95 (s, 3H), 3.35 (m, 2H), 3.05 (m, 1H), 2.9 (m, 2H), 2.7 (m, 1H), 2.5-2.3 (m, 3H), 2.0 (m, 1H), 1.8-1.6 (m, 3H), 1.4 (m, 2H).

EXAMPLE 87

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]carbamate; hydrochloride

4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]-methyl]-2-methoxybenzamide (1 mmol) at 0°C was dissolved in 10 ml of THF and was added 1,1'-carbonyldiimidazole (1.5 mmol). The reaction mixture was stirred at room temperature in accordance with the s 2 h, then added an excess of ammonium hydroxide (3 ml) at room temperature. After 2 h stirring at room temperature for completion of the reaction was added water. The organic layer was extracted 3 times with dichloromethane, was dried and concentrated in vacuum. The resulting carbamate was dissolved in MC and the solution was treated with a solution of HCl in diethyl ether. The precipitate was filtered to obtain specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 8.0 (m, 1H), 7.66 (s, 1H), 7.29 (m, 2H), 6.96 (m, 2H), 6.90 (m, 1H), 6.48 (s, 1H), 5.98 (s, 2H), 5.35 (m, 1H), 4.15 (m, 2H), 3.83 (s, 3H), 3.3-2.1 (m, 6H), 3.0 (m, 2H), 1.78 (m, 3H), 1.5 (m, 2H).

EXAMPLE 88

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]piperidine-1-carboxylate; hydrochloride

Specified in the title compound was obtained by the method described in Example 87, except that used piperidine (2 mmol) instead of ammonium hydroxide.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.95 (m, 1H), 8.05 (m, 1H), 7.66 (s, 1H), 7.31 (m, 2H), 6.96 (t, 3H), 6.48 (s, 1H), 6.0 (br, 2H), 5.4 (m, 1H), 4.2 (m, 2H), 3.83 (s, 3H), 3.7-3.4 (m, 6N), 3.18 (m, 4H), 3.0 (m, 2H), 1.77 (m, 3H), 1.7-1.3 (m, 8H).

EXAMPLE 89

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(4-pertenece)propan-2-yl] - for 3,5-dimethylpiperidin-1-carboxylate; hydrochloride

4-amino-5-chloro-N-[[1-[3-(4-pertenece)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-methox benzamide (1 mmol) at 0°C was dissolved in 10 ml of THF and was added 1,1'-carbonyldiimidazole (1.5 mmol). The reaction mixture was stirred at room temperature for 2 h, then was added 3,5-dimethylpiperidin (2 mmol) at room temperature. After 2 h stirring at room temperature for completion of the reaction was added water. The organic layer was extracted 3 times with dichloromethane, was dried and concentrated in vacuum. The resulting carbamate was dissolved in MC and the solution was treated with a solution of HCl in diethyl ether. The precipitate was filtered to obtain specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (in salt form HCI) 8.0 (s, 1H), 7.66 (s, 1H), 7.09 (m, 2H), 7.01 (m, 2H), 6.48 (s, 1H), 5.96 (s, 2H), 5.35 (br, 1H), 4.17 (s, 2H), 4.0-3.8 (m, 7H), 3.46 (t, 2H), 3.18 (m, 4H), 3.0 (m, 2H), 2.22 (m, 2H), 1.9-1.3 (m, 7H), 0.81 (m, 6N).

EXAMPLE 90

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(4-chlorophenoxy)propan-2-yl] - for 3,5-dimethylpiperidin-1-carboxylate; hydrochloride

Specified in the title compound was obtained by the method described in Example 89, except that as the starting substances used 4-amino-5-chloro-N-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide instead of 4-amino-5-chloro-N-[[1-[3-(4-pertenece)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 10.1 (br, 1H), 8.0 (m, 1H), 7.66 (s, 1H), 7.34 (m, 2H), 7.00 (m, 2H), 6.48 (s, 1H), 5.96 (s, 2H), 5.35 (m, 1H), 4.2 (m, 2H), 4.0-3.7 (m, 7H), 3.6-3.4 (m, 2H), 3.18 (m, 4H), 3.0 (m, 2H), 2.2 (m, 2H), 1.9-1.2 (m, 7H), 0.9-0.6 (m, 6N).

EXAMPLE 91

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(4-methoxyphenoxy)propan-2-yl]carbamate; hydrochloride

Followed the procedure in Example 87, using as reagent 4-amino-5-chloro-N-[[1-[3-(4-methoxyphenoxy)-2-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide from Example 74 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-methoxybenzo-amide, obtaining specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.95 (m, 1H), 8.0 (m, 1H), 7.66 (s, 1H), 6.88 (m, 6N), 6.48 (s, 1H), 5.35 (m, 1H), 4.07 (m, 2H), 3.83 (s, 3H),3.69 (s, 3H), 3.6 (m, 2H), 3.25 (m, 5H),3.0 (m, 2H), 2.0-1.5 (m, 5H).

EXAMPLE 92

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(2,3-dichlorophenoxy)propan-2-yl]carbamate; hydrochloride

Followed the procedure in Example 87, using as reagent 4-amino-5-chloro-N-[[1-[3-(2,3-dichlorophenoxy)-2-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide from Example 75 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-methoxybenzo-amide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.3 (m, 1H), 7.1 (m, 1H), 6.9 (m, 1H), 6.35 (s, 1H), 5.3 (m, 1H), 4.4 (m, 2H), 4.3 (m, 2H), 3.95 (m, 3H), 3.8 (m, 2H), 3.4 (m, 2H), 3.1 (m, 1H), 2.9 (m, 1H), 2.3-2.2 (m, 2H), 1.9-1.3 (m, 5H).

EXAMPLE 93

[1-[4-[[(4-amino-5-chlorine is-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(2,3-dichlorophenoxy)propan-2-yl]pyrrolidin-1-carboxylate; hydrochloride

4-amino-5-chloro-N-[[1-[3-(2,3-dichlorophenoxy)-2-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide (1 mmol) at 0°C was dissolved in 10 ml of THF and was added 1,1'-carbonyldiimidazole (1.5 mmol). The reaction mixture was stirred at room temperature for 2 h, then was added pyrrolidine (2 mmol) at room temperature. After 2 h stirring at room temperature for completion of the reaction was added water. The organic layer was extracted 3 times with dichloromethane, was dried and concentrated in vacuum. The resulting carbamate was dissolved in MC and the solution was treated with a solution of HCl in diethyl ether. The precipitate was filtered to obtain specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.9 (m, 1H), 7.2-7.1 (m, 2H), 7.0-6.9 (m, 1H), 6.4 (s, 1H), 5.6 (m, 1H), 4.5-4.3 (m, 2H), 3.9 (m, 3H), 3.6 (m, 1H), 3.55-3.3 (m, 5H), 2.8 (m, 2H), 2.55 (m, 3H), 2.1 (m, 1H), 2.0-1.8 (m, 7H), 1.4-1.2 (m, 2H).

EXAMPLE 94

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(2,3-dichlorophenoxy)propan-2-yl]piperidine-1-carboxylate; hydrochloride

Specified in the title compound was obtained by the method described in Example 93, except that used the piperidine instead of pyrrolidine.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.3 (s, 1H), 7.2-7.1 (m, 2H), 7.0 (m, 1H), 6.4 (s, 1H), 5.6 (m, 1H), 4.5 (m, 1H), 4.3 (m, 1H), 3.9 (m, 3H), 33.6 (m, 1H), 3.5-3.3 (m, 5H), 2.9-2.7 (m, 2H), 2.5 (m, 4H), 2.2-1.9 (m, 4H), 1.8-1.5 (m, 7H).

EXAMPLE 95

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(2,3-dichlorophenoxy)propan-2-yl]azepin-1-carboxylate; hydrochloride

Specified in the title compound was obtained by the method described in Example 93, except that used hexamethylenamine instead of pyrrolidine.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.9 (m, 1H), 7.3 (m, 1H), 7.2-7.1 (m, 2H), 7.0-6.9 (m, 1H), 6.4 (s, 1H), 5.6 (m, 1H), 4.5 (m, 1H), 4.35 (m, 1H), 4.2-4.0 (m, 2H), 3.95 (s, 3H), 3.7-3.3 (m, 6N), 2.8 (m, 2H), 2.7-2.4 (m, 4H), 2.2-1.8 (m, 4H), 1.8-1.5 (m, N).

EXAMPLE 96

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(2,4-dichlorphenoxy)propan-2-yl]carbamate; hydrochloride

Followed the procedure in Example 87, using as reagent 4-amino-5-chloro-N-[[1-[3-(2,4-dichlorophenoxy)-2-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide from Example 76 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-methoxybenzo-amide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (m, 1H), 7.9 (m, 1H), 7.4 (m, 1H), 7.1 (m, 1H), 6.9 (m, 1H), 6.35 (m, 1H), 5.2 (m, 1H), 4.8 (m, 2H), 4.4 (m, 2H), 4.2 (m, 2H), 3.9 (m, 3H), 3.4 (m, 2H), 3.0 (m, 2H), 2.75 (m, 2H), 2.2 (m, 2H), 1.9-1.5 (m, 3H), 1.5-1.3 (m, 2H).

EXAMPLE 97

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(2,5-dichlorophenoxy)propan-2-yl]carbamate; hydrochloride

Followed the procedure in Example 87, using as reagent amino-5-chloro-N-[[1-[3-(2,5-dichlorophenoxy)-2-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide from Example 77 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-methoxybenzo-amide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (m, 1H), 7.8 (m, 1H), 7.3 (m, 1H), 7.0-6.9 (m, 2H), 6.3 (m, 1H), 5.2 (m, 1H), 4.8 (m, 2H), 4.4 (m, 2H), 4.3-4.1 (m, 2H), 3.9 (m, 3H), 3.3 (m, 2H), 3.0 (m, 2H), 2.7 (m, 2H), 2.2 (m, 2H), 1.9-1.6 (m, 3H), 1.4-1.3 (m, 2H).

EXAMPLE 98

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(2,6-dichlorophenoxy)propan-2-yl]carbamate; hydrochloride

Followed the procedure in Example 87, using as reagent 4-amino-5-chloro-N-[[1-[3-(2,6-dichlorophenoxy)-2-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide from Example 78 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-methoxybenzo-amide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (m, 1H), 7.9 (m, 1H), 7.4 (m, 1H), 7.05 (m, 1H), 6.8 (m, 1H), 6.4 (m, 1H), 5.2 (m, 1H), 4.8 (s, 2H), 4.4 (s, 2H), 4.2 (m, 2H), 3.9 (m, 3H), 3.4 (m, 2H), 3.0 (m, 2H), 2.8 (m, 2H), 2.1 (m, 2H), 1.8-1.5 (m, 3H), 1.4-1.2 (m, 2H).

EXAMPLE 99

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(3,4-dichlorophenoxy)propan-2-yl]carbamate; hydrochloride

Followed the procedure in Example 87, using as reagent 4-amino-5-chloro-N-[[1-[3-(3,4-dichlorophenoxy)-2-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide from Example 79 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-methoxybenzo-amide, obtaining specified in the connection header.

1 3, 200 MHz) δ 8.1 (s, 1H), 7.9 (m, 1H), 7.4-7.3 (m, 1H), 7.1 (m, 1H), 6.9 (m, 1H), 6.35 (s, 1H), 5.2 (m, 1H), 4.8 (m, 2H), 4.4 (m, 2H), 4.2-4.0 (m, 2H), 3.95 (s, 3H), 3.35 (m, 2H), 3.1-2.9 (m, 2H), 2.6 (m, 2H), 2.2-2.1 (m, 2H), 1.8-1.5 (m, 3H), 1.4-1.2 (m, 3H).

EXAMPLE 100

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-[4-(trifluoromethyl)phenoxy]propan-2-yl]carbamate; hydrochloride

Followed the procedure in Example 87, using as reagent 4-amino-5-chloro-N-[[1-[2-hydroxy-3-[4-(trifluoromethyl)phenoxy]-propyl]piperidine-4-yl]methyl]-2-methoxybenzamide from Example 83 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.75 (m, 1H), 7.7-7.5 (m, 2H), 7.0 (m, 2H), 6.3 (s, 1H), 5.2 (m, 1H), 4.7 (m, 2H), 4.4 (s, 2H), 4.2 (m, 2H), 3.9 (s, 3H), 3.35 (m, 2H), 2.9 (m, 2H), 2.7-2.6 (m, 2H), 2.2-2.05 (m, 2H), 1.85 (m, 2H), 1.7 (m, 1H), 1.4-1.2 (m, 2H).

EXAMPLE 101

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(4-phenyleneoxy)propan-2-yl]carbamate; hydrochloride

Followed the procedure in Example 87, using as reagent 4-amino-5-chloro-N-[[1-[2-hydroxy-3-(4-phenyleneoxy)propyl]-piperidine-4-yl]methyl]-2-methoxybenzamide from Example 84 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-methoxybenzo-amide, obtaining specified in the header connection.

1H-NMR (CDCl3, 200 MHz) δ 8.15 (s, 1H), 7.8-7.7 (m, 5H) 7.5-7.1 (m, 5H), 6.3 (s, 1H), 5.25 (m, 1H), 4.7 (m, 2H), 4.4-4.2 (m, 4H), 3.9 (s, 3H), 3.35 (m, 2H), 3.1-2.9 (m, 2H), 2.7 (m, 2H), 2.2-2.1 (m, 2H), 1.8-1.5 (m, 3H), 1.4-1.2 (m, 2H).

EXAMPLE 102

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-naphthalene-2-aloxiprin-2-yl]carbamate; hydrochloride

Followed the procedure in Example 87, using as reagent 4-amino-5-chloro-N-[[1-(2-hydroxy-3-naphthalene-2-roxiprin)-piperidine-4-yl]methyl]-2-methoxybenzamide from Example 85 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-methoxybenzo-amide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) 6 8.15 (s, 1H), 7.8 (m, 1H), 7.6-7.3 (m, 5H), 7.0 (m, 2H), 6.3 (s, 1H), 5.25 (m, 1H), 4.9-4.7 (br, 2H), 4.4 (s, 2H), 4.2 (m, 2H), 3.9 (s, 3H), 3.4-3.3 (m, 2H), 3.2-3.1 (m, 2H), 2.9-2.8 (m, 2H), 2.4-2.15 (m, 2H), 1.9-1.6 (m, 3H), 1.6-1.4 (m, 2H).

EXAMPLE 103

[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-phenylpropane-2-yl]carbamate; hydrochloride

Followed the procedure in Example 87, using as reagent 4-amino-5-chloro-N-[[1-(2-hydroxy-Z-phenyl propyl)piperidine-1-s-4-yl]methyl]-2-methoxy-benzamide from Example 86 instead of 4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-methoxybenzamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.1 (s, 1H), 7.8 (m, 1H), 7.3-7.1 (m, 5H), 6.3 (s, 1H), 5.1 (m, 1H), 4.95 (s, 2H), 4.6 (s, 2H), 4.0 (m, 1H), 3.85 (s, 3H), 3.35 (m, 2H), 3.0-2.6 (m, 4H), 2.5-2.2 (m, 2H), 2.1-1.9 m, 2H), 1.8-1.5 (m, 3H), 1.3 (m, 2H).

EXAMPLE 104

N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide; hydrochloride

A mixture of piperidine-4-ylmethyl)-amide 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (3 mmol) and 1,2-epoxy-C-phenoxypropane (3 mmol) was boiled under reflux in 10 ml of isopropanol for 3 hours the solution was concentrated on a rotary evaporator and the mixture was purified column chromatography. Obtained N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide was dissolved in MC and the solution was treated with a solution of HCl in diethyl ether. The precipitate was filtered to obtain specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (in the form of a free amine) 8.83 (m, 1H), 8.05 (m, 1H), 7.44 (m, 1H), 7.4-7.1 (m, 4H),6.93 (m, 3H), 4.84 (m, 1H), 4.67 (m, 1H), 3.88 (m, 2H), 3.22 (m, 2H),2.92 (m, 2H), 2.4 (m, 2H), 1.99 (m, 2H), 1.64 (m, 3H), 1.48 (m, 6N), 1.22 (m, 2H).

EXAMPLE 105

N-[[1-[2-hydroxy-3-(4-nitrophenoxy)propyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide; hydrochloride

Followed the procedure given in Example 104, using as reagent glycidyl-4-nitrophenyloctyl ether instead of 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) 9.0 (m, 1H), 8.35-8.2 (m, 3H), 7.2 (m, 3H), 7.0 (m, 2H), 4.75 (m, 1H), 4.2-4.05(m, MN), 3.4 (t, 2H), 3.1 (m, 1H), 2.9 (m, 1H), 2.55 (m, 2H), 2.4 (m, 1H), 2.05 (m, 1H), 1.85 (m, 2H), 1.7 (m, 1H), 1.6 (d, 6N), 1.4 (m, 2H).

EXAMPLE 106

N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide; hydrochloride

Followed the procedure given in Example 104, using as reagent glycidyl-4-methoxyphenacyl ether instead of 1,2-epoxy-C-phenoxypropane, obtaining specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (in the form of a free amine) 8.83 (m, 1H), 8.07 (m, 1H), 7.44 (m, 1H), 7.15 (m, 2H),6.85 (m, 4H), 4.78 (m, 1H), 4.66 (m, 1H), 3.91-3.77 (m, 2H), 3.68 (s, 3H), 3.22 (m, 2H), 2.87 (m, 2H),2.36 (m, 2H), 1.96 (m, 2H), 1.60 (m, 2H), 1.48 (m, 7H), 1.23 (m, 2H).

EXAMPLE 107

N-[[1-[3-(4-pertenece)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide; hydrochloride

Followed the procedure given in Example 104, using as reagent 4-ferverishly ether instead of 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.65 (m, 1H), 8.88 (m, 1H), 8.07 (m, 1H), 7.45 (m, 1H), 7.16 (m, 4H), 6.96 (m, 2H), 5.96 (m, 1H), 4.67 (m, 1H), 4.34 (m, 1H), 3.94 (m, 2H), 3.56 (m, 2H), 3.26 (m, 4H), 2.99 (m, 2H), 1.86 (m, 3H), 1.7-1.4 (m, 8H).

EXAMPLE 108

N-[[1-[2-hydroxy-3-(2-methylphenoxy)propyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide; hydrochloride

Followed the procedure given in Example 104, using ka is estwe of this reagent glycidyl-2-methylphenylene ether instead of 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.3 (m, 1H), 8.87 (m, 1H), 8.07 (m, 1H), 7.45 (m, 1H), 7.18 (m, 5H), 6.90 (m, 2H), 5.94 (m, 1H), 4.7 (m, 1H), 4.35 (m, 1H), 3.95 (m, 2H), 3.59 (m, 2H), 3.4-2.8 (m, 6N), 2.18 (s, 3H), 1.87 (m, 3H), 1.7-1.4 (m, 8H).

EXAMPLE 109

N-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide; hydrochloride

Followed the procedure given in Example 104, using as reagent 4-chlorophenylglycine ether instead of 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.5 (m, 1H), 8.87 (m, 1H), 8.07 (m, 1H), 7.5-6.9 (m, 6N), 5.97 (m, 1H), 4.67 (m, 1H), 4.35 (m, 1H), 3.96 (m, 2H), 3.55 (m, 2H), 3.27 (m, 4H), 2.99 (m, 2H), 1.87 (m, 3H), 1.7-1.4 (m, 8H).

EXAMPLE 110

N-[[1-[3-(4-tert-butylphenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide; hydrochloride

Followed the procedure given in Example 104, using as reagent 4-tert-butyleneglycol ether instead of 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.32 (m, 1H), 8.87 (m, 1H), 8.07 (m, 1H), 7.45 (m, 1H), 7.29 (m, 1H), 7.19 (m, 2H), 6.87 (m, 2H), 5.95 (m, 1H), 4.65 (m, 1H), 4.29 (m, 1H), 3.93 (m, 2H), 3.54 (m, 2H), 3.5-3.1 (m, 4H), 2.99 (m, 2H), 1.87 (m, 3H), 1.7-1.47 (m, 8H), 1.25 (s, N).

EXAMPLE 111

N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl-3-methyl-2-oxopentanoate-1-carboxamide; hydrochloride

Followed the procedure given in Example 104, using as reagent (piperidine-4-ylmethyl)-amide 3-methyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid instead of (piperidine-4-ylmethyl)-amide 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid, to obtain specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.3 (m, 1H), 8.83 (m, 1H), 8.03 (m, 1H), 7.29-7.16 (m,5H), 6.97 (m, 3H), 5.98 (m, 1H), 4.30 (m, 1H), 3.96 (m, 2H), 3.61 (m, 2H), 3.5-3.1 (m, 5H), 2.93 (m, 2H), 2.6 (m, 2H), 1.87 (m, 3H), 1.6 (m, 2H).

EXAMPLE 112

N-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-3-methyl-2-oxopentanoate-1-carboxamide; hydrochloride

Followed the procedure given in Example 104, using as reagents (piperidine-4-ylmethyl)-amide 3-methyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 4-chlorophenylglycine ester instead of (piperidine-4-ylmethyl)-amide 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.6 (m, 1H), 8.82 (m, 1H), 8.02 (m, 1H), 7.4-6.9 (m, 7H), 5.98 (m, 1H), 4.35 (m, 1H), 3.95 (m, 2H), 3.54 (m, 2H), 3.4-2.9 (m, N), 1.87 (m, 3H), 1.63 (m, 2H).

EXAMPLE 113

N-[[1-[3-(4-tert-butylphenoxy)-2-hydroxypropyl]piperidine-4-yl]-methyl]-3-methyl-2-oxopentanoate-1-carboxamide; hydrochloride

Followed the procedure in the ore 104, using as reagents (piperidine-4-ylmethyl)-amide 3-methyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 4-tert-butyleneglycol ester instead of (piperidine-4-ylmethyl)-amide 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 1,2-epoxy-C-phenoxypropane, obtaining specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.64 (m, 1H), 8.82 (m, 1H), 8.02 (m, 1H), 7.4-7.12 (m, 5H), 6.87 (m, 2H), 5.95 (m, 1H), 4.34 (m, 1H), 3.93 (m, 2H), 3.58 (m, 2H), 3.5-3.1 (m, 7H), 3.0 (m, 2H), 1.87 (m, 3H), 1.53 (m, 2H), 1.25 (s, N).

EXAMPLE 114

N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidine-4-yl]methyl]-3-methyl-2-oxopentanoate-1-carboxamide; hydrochloride

Followed the procedure given in Example 104, using as reagents (piperidine-4-ylmethyl)-amide 3-methyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and glycidyl-4-methoxyphenacyl ester instead of (piperidine-4-ylmethyl)-amide 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.45 (m, 1H), 8.82 (m, 1H), 8.02 (m, 1H), 7.35-7.1 (m, 3H), 6.88 (m, 4H), 5.95 (m, 1H), 4.29 (m, 1H), 3.89 (m, 2H),3.69 (s, 3H), 3.6-3.1 (m, 7H), 2.99 (m, 4H), 1.87 (m, 3H), 1.6 (m, 2H).

EXAMPLE 115

N-[[1-[3-(4-pertenece)-2-hydroxypropyl]piperidine-4-yl]methyl]-3-methyl-2-oxopentanoate-1-carboxamide; hydrochloride

Followed the procedure is e, shown in Example 104, using as reagents (piperidine-4-ylmethyl)-amide 3-methyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 4-ferverishly ester instead of (piperidine-4-ylmethyl)-amide 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 1,2-epoxy-C-phenoxypropane, obtaining specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.5 (m, 1H), 8.82 (m, 1H), 8.02 (m, 1H), 7.35-7.05 (m, 5H), 6.98 (m, 2H), 5.94 (m, 1H), 4.32 (m, 1H), 3.94 (m, 2H), 3.55 (m, 2H), 3.5-3.1 (m, 7H), 2.98 (m, 2H), 1.87 (m, 3H), 1.6 (m, 2H).

EXAMPLE 116

3-ethyl-N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide; hydrochloride

Followed the procedure given in Example 104, using as reagent (piperidine-4-ylmethyl)-amide 3-ethyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid instead of (piperidine-4-ylmethyl)-amide 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid, to obtain specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.95 (m, 1H), 8.25 (m, 1H), 7.4-7.15 (m, 3H), 7.1-6.9 (m, 5H), 4.1 (m, 2H), 4.0 (m, 2H), 3.55 (m, 1H), 3.4 (t, 2H), 3.1 (m, 1H), 3.0 (m, 1H), 2.6 (m, 2H), 2.4 (m, 1H), 2.1 (m, 1H), 1.9-1.6 (m, 3H), 1.5-1.3 (m, 5H).

EXAMPLE 117

3-ethyl-N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide; hydrochloride

Followed the procedure given in Example 104, using as reactants (piperidin-4-ylmethyl)-amide 3-ethyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and glycidyl-4-methoxyphenacyl ester instead of (piperidine-4-ylmethyl)-amide 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 1,2-epoxy-3-phenoxypropane, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.95 (m, 1H), 8.2 (m , 1H), 7.3-7.0 (m, 3H), 6.8 (m, 4H), 4.25 (m, 1H), 4.0 (m, 4H), 3.8 (s, 3H), 3.5-3.3 (m, 4H), 2.9 (m, 2H), 2.6 (m, 1H), 2.4 (m, 1H), 1.9 (m, 2H), 1.8-1.6 (m, 3H), 1.4 (t, 3H).

EXAMPLE 118

3-ethyl-N-[[1-[2-hydroxy-3-(2-methylphenoxy)propyl]piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide; hydrochloride

Followed the procedure given in Example 104, using as reagents (piperidine-4-ylmethyl)-amide 3-ethyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and glycidyl-2-methylphenacyl ester instead of (piperidine-4-ylmethyl)-amide 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 1,2-epoxy-C-phenoxypropane, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.95 (m, 1H), 8.25 (m, 1H), 7.3-7.0 (m, 6N), 6.85 (m, 2H), 4.3-3.9 to (m, 5H), 3.4 (m, 2H), 3.2 (m, 1H), 3.05 (m, 1H), 2.65 (m, 2H), 2.4 (m, 1H), 2.3 (s, 3H), 2.15 (m, 1H), 1.85 (m, 2H), 1.75 (m, 1H), 1.6-1.3 (m, 5H).

EXAMPLE 119

N-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-3-ethyl-2-oxopentanoate-1-carboxamide; hydrochloride

Followed the procedure given in Example 104, using as reagents (piperidine-4-ylmethyl)-amide 3-ethyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 4-chlorophenylglycine ester instead of (piperidine-4-ylmethyl)-amide 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 1,2-epoxy-C-phenoxypropane, with what rucenim specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.95 (m, 1H), 8.25 (m, 1H), 7.2-7.0 (m, 4H), 7.05 (m, 1H), 6.9 (m, 2H), 4.2 (m, 1H), 4.0 (m, 4H), 3.4 (m, 2H), 3.2 (m, 1H), 3.05 (m, 1H), 2.65 (m, 2H), 2.4 (m, 1H), 2.0-1.7 (m, 3H), 1.6-1.3 (m, 5H).

EXAMPLE 120

[1-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]-piperidine-1-yl]-3-phenoxypropan-2-yl]carbamate: hydrochloride

N-[[1-(2-Hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide (1 mmol) at 0°C was dissolved in 10 ml of THF and was added 1,1'-carbonyldiimidazole (1.5 mmol). The reaction mixture was stirred at room temperature for 2 h, then was added an excess of ammonium hydroxide (3 ml) at room temperature. After 2 h stirring at room temperature for completion of the reaction was added water. The organic layer was extracted 3 times with dichloromethane, was dried and concentrated in vacuum. The resulting carbamate was dissolved in MC and the solution was treated with a solution of HCI in diethyl ether. The precipitate was filtered to obtain specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 10.2 (m, 1H), 8.88 (m, 1H), 8.07 (m, 1H), 7.6-6.8 (m, 10H), 5.34 (m, 1H), 4.66 (m, 1H), 4.15 (m, 2H), 3.55 (m, 2H), 3.26 (m, 4H),3.04 (m, 2H), 1.85 (m, 3H), 1.59 (m, 2H), 1.48 (m, 6N).

EXAMPLE 121

[1-(4-methoxyphenoxy)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-yl]propan-2-yl]carbamate; hydrochloride

Followed the procedure is Oh in Example 120, using as reagent N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide from Example 106 instead of N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide, to obtain specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.7 (m, 1H), 8.80 (m, 1H), 8.07 (m, 1H), 7.45 (m, 1H),7.18 (m, 2H), 6.88 (m, 4H), 5.28 (m, 1H), 4.65 (m, 1H), 4.07 (s, 2H), 3.69 (s, 3H), 3.58 (m, 2H), 3.5-3.2 (m, 2H), 3.03 (m, 4H), 1.86 (m, 3H), 1.49 (m, 8H).

EXAMPLE 122

[1-(4-pertenece)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-yl]propan-2-yl]carbamate; hydrochloride

Followed the procedure described in Example 120, using as reagent N-[[1-[3-(4-pertenece)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide from Example 107 instead of N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide, obtaining specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.5 (m, 1H), 8.88 (m, 1H), 8.07 (m, 1H), 7.45 (m, 1H), 7.16 (m, 4H), 7.0-6.8 (m, 4H), 5.31 (m, 1H), 4.66 (m, 1H), 4.11 (m, 2H), 3.60 (m, 2H), 3.5-3.2 (m, 4H), 3.00 (m, 2H), 1.87 (m, 3H), 1.7-1.4 (m, 8H).

EXAMPLE 123

[1-(2-methylphenoxy)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-yl]propan-2-yl]carbamate; hydrochloride

Followed the procedure is Oh in Example 120, using as reagent N-[[1-[2-hydroxy-3-(2-methylphenoxy)propyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide from Example 108 instead of N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide, to obtain specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.8 (m, 1H), 8.88 (m, 1H), 8.04 (m, 1H), 7.45 (m, 1H), 7.18 (m, 5H), 6.90 (m, 4H), 5.35 (m, 1H), 4.7 (m, 1H), 4.15 (m, 2H), 3.56 (m, 2H), 3.4-2.9 (m, 6N), 2.18 (s, 3H), 1.86 (m, 3H), 1.7-1.4 (m, 8H).

EXAMPLE 124

[1-(4-chlorophenoxy)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-yl]propan-2-yl]carbamate; hydrochloride

Followed the procedure described in Example 120, using as reagent N-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide from Example 109 instead of N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide, obtaining specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.35 (m, 1H), 8.88 (m, 1H), 8.07 (m, 1H), 7.5-6.9 (m, N), 5.3 (m, 1H), 4.65 (m, 1H), 4.13 (m, 2H), 3.60 (m, 2H), 3.0 (m, 4H),2.84 (m, 2H), 1.87 (m, 3H), 1.7-1.1 (m, 8H).

EXAMPLE 125

[1-(4-tert-butylphenoxy)-3-[4-[[(3-methyl-2-oxopentanoate-1-carbonyl)amino]methyl]piperidine-1-yl]propan-2-yl]carbamate; hydrochloride

Followed the procedure described in Example 120, using the quality of the reagent N-[[1-[3-(4-tert-butylphenoxy)-2-hydroxypropyl]piperidine-4-yl]-methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide from Example 110 instead of N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide, obtaining specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (in salt form HCI) 9.64 (m, 1H), 8.82 (m, 1H), 8.02 (m, 1H), 7.3-7.1 (m, 5H), 6.87 (m, 4H), 5.35 (m, 1H), 4.1 (m, 2H), 3.58 (m, 2H), 3.5-3.1 (m, 7H), 3.0 (m, 2H), 1.87 (m, 3H), 1.53 (m, 2H), 1.25 (s, N).

EXAMPLE 126

[1-[4-[[(3-methyl-2-oxopentanoate-1-carbonyl)amino]methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]carbamate; hydrochloride

Followed the procedure described in Example 120, using as reagent N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-3-methyl-2-oxopentanoate-1-carboxamide from Example 111 instead of N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide, to obtain specified in the connection header.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.3 (m, 1H), 8.83 (m, 1H), 8.02 (m, 1H), 7.4-6.8 (m, 8H), 5.31 (m, 1H), 4.12 (m, 2H), 3.61 (m, 2H), 3.5-2.81 (m, 7H), 2.4-2.1 (m, 2H), 1.81 (m, 3H), 1.52 (m, 2H).

EXAMPLE 127

[1-(4-chlorophenoxy)-3-[4-[[(3-methyl-2-oxopentanoate-1-carbonyl)-amino]methyl]piperidine-1-yl]propan-2-yl]carbamate; hydrochloride

Followed the procedure described in Example 120, using as reagent N-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-3-methyl-2-oxopentanoate-1-carboxamide from Example 112 instead of N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide, to obtain specified in the header connection.

1 H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.5 (m, 1H), 8.83 (m, 1H), 8.02 (m, 1H), 7.4-6.9 (m, 7H), 6.87 (m, 2H), 5.3 (m, 1H), 4.14 (m, 2H),3.6 (m, 2H), 3.4-3.1 (m, 5H), 3.0 (m, 4H), 1.87 (m, 3H), 1.63 (m, 2H).

EXAMPLE 128

[1-(4-tert-butylphenoxy)-3-[4-[[(3-methyl-2-oxopentanoate-1-carbonyl)amino]methyl]piperidine-1-yl]propan-2-yl]carbamate; hydrochloride

Followed the procedure described in Example 120, using as reagent N-[[1-[3-(4-tert-butylphenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-3-methyl-2-oxopentanoate-1-carboxamide from Example 113 instead of N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide, to obtain the specified in the connection header.

1H-NMR (DMSO-d6, 200 MHz, HCl form) δ 9.64 (m, 1H), 8.82 (m, 1H), 8.02 (m, 1H), 7.3-7.1 (m, 5H), 6.87 (m, 4H), 5.35 (m, 1H), 4.1 (m, 2H), 3.58 (m, 2H), 3.5-3.1 (m, 7H), 3.0 (m, 2H), 1.87 (m, 3H), 1.53 (m, 2H), 1.25 (s, N).

EXAMPLE 129

[1-(4-methoxyphenoxy)-3-[4-[[(3-methyl-2-oxopentanoate-1-carbonyl)-amino]methyl]piperidine-1-s-1-yl]propan-2-yl]carbamate; hydrochloride

Followed the procedure described in Example 120, using as reagent N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidine-4-yl]methyl]-3-methyl-2-oxopentanoate-1-carboxamide from Example 114 instead of N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide, to obtain specified in the title compound.

1H NMR (DMSO, 200 MHz), ppm (δ): (the HCl salt form) 9.65 (m, 1H), 8.82 (m, 1H), 8.02 (m, 1H), 7.35-7.1 (m, 3H), 6.88 (m, 6N), 5.35 (m, 1H), 4.06 (m, 2H), 3.69 (s, 3H), 3.6-3.1 (m, 7H), 3.04 (m, 4H), 1.87 (m, 3H), 1.6 (m, 2H).

EXAMPLE 130

[1-(4-pertenece)-3-[4-[[(3-methyl-2-oxopentanoate-1-carbonyl)-amino]methyl]piperidine-1-yl]propan-2-yl]carbamate; hydrochloride

Followed the procedure described in Example 120, using as reagent N-[[1-[3-(4-pertenece)-2-hydroxypropyl]piperidine-4-yl]methyl]-3-methyl-2-oxopentanoate-1-carboxamide from Example 115 instead of N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide, to obtain specified in the header connection.

1H NMR (DMSO, 200 MHz), ppm (δ): (HCl salt form) 9.45 (m, 1H), 8.83 (m, 1H), 8.02 (m, 1H), 7.35-7.05 (m, 5H), 6.99 (m, 2H),6.88 (m, 2H), 5.35 (m, 1H), 4.11 (m, 2H), 3.60 (m, 2H), 3.5-3.1 (m, 7H), 3.04 (m, 2H), 1.87 (m, 3H), 1.49 (m, 2H).

EXAMPLE 131

[1-[4-[[(3-ethyl-2-oxopentanoate-1-carbonyl)amino]methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]carbamate; hydrochloride

Followed the procedure described in Example 120, using as reagent 3-ethyl-M-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide from Example 116 instead of N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide, to obtain specified in the connection header.

1H-NMR (CDC3, 200 MHz) δ 8.9 (m, 1H), 8.25 (m, 1H), 7.4-6.9 (m, 8H), 5.3 (s, 2H), 5.2 (m, 1H), 4.15 (m, 2H), 4.0 (m, 2H), 3.35 (t, 2H), 3.0 (m, 2H), 2.65 (m, 2H, 2.1 (m, 2H), 1.75 (m, 2H), 1.6 (m, 1H), 1.5-1.2 (m, 5H).

EXAMPLE 132

[1-[4-[[(3-ethyl-2-oxopentanoate-1-carbonyl)amino]methyl]piperidine-1-s-1-yl]-3-(4-methoxyphenoxy)propan-2-yl]carbamate; hydrochloride

Followed the procedure described in Example 120, using as reagent 3-ethyl-N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide from Example 117 instead of N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide, to obtain specified in the title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.9 (m, 1H), 8.25 (m, 1H), 7.2 (m, 2H), 7.05 (m, 1H), 6.85 (m, 4H), 5.15 (m, 1H), 5.0 (s, 2H), 4.15 (m, 2H), 4.0 (m, 2H), 3.8 (s, 3H), 3.35 (t, 2H), 3.0 (m, 2H), 2.65 (m, 2H), 2.1 (m, 2H), 1.75 (m, 2H), 1.6 (m, 1H), 1.5-1.2 (m, 5H).

EXAMPLE 133

[1-[4-[[(3-ethyl-2-oxopentanoate-1-carbonyl)amino]methyl]piperidine-1-yl]-3-(2-methylphenoxy)propan-2-yl]carbamate; hydrochloride

Followed the procedure described in Example 120, using as reagent 3-ethyl-N-[[1-[2-hydroxy-3-(2-methylphenoxy)propyl]piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide from Example 118 instead of N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide, to obtain specified in the title compound.

1H-NMR (CDCl3, 200 MHz) δ 8.9 (m, 1H), 8.25 (m, 1H), 7.3-7.0 (m, 5H), 6.85 (m, 2H), 5.25 (m, 1H), 5.05 (s, 2H), 4.15 (m, 2H), 4.0 (m, 2H), 3.35 (t, 2H), 3.0 (m, 2H), 2.7 (d, 2H), 2.2 (s, 3H), 2.1 (m, 2H), 1.8 (m, 2H), 1.6 (m, 1H), 1.5-1.2 (m, 5H).

EXAMPLE 134

[1-(4-chlorophenoxy)-3-[4-[[(3-ethyl-2-oxopentanoate-1-carbonyl)-amino]methyl]piperidine-1-yl]propan-2-yl]carbamate; hydrochloride

Followed the procedure described in Example 120, using as reagent N-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-3-ethyl-2-oxopentanoate-1-carboxamide from Example 119 instead of N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide, to obtain specified in the header connection.

1H-NMR (CDCl3, 200 MHz) δ 8.9 (m, 1H), 8.25 (m, 1H), 7.3-7.0 (m, 5H), 6.9 (m, 2H), 5.2 (m, 1H), 5.0 (s, 2H), 4.15 (m, 2H), 4.0 (m, 2H), 3.35 (t, 2H), 2.95 (m, 2H), 2.6 (d, 2H), 2.1 (m, 2H), 1.75 (m, 2H), 1.6 (m, 1H), 1.5-1.2 (m, 5H).

EXAMPLE 135

3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide; hydrochloride

A mixture of piperidine-4-ylmethyl)-amide 3-cyclopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (5.0 mmol), 3-chloropropiophenone (6.0 mmol), potassium carbonate (7.6 mmol) and potassium iodide (7.6 mmol) was boiled under reflux in 15 ml of acetonitrile for 12 h the solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture is then washed with brine and the organic layer was dried and purified column chromatography. It was dissolved in ethanol (10 ml) and at 0°C was added borohydride soda is I (10.0 mmol) and stirred at 25°C for 2 hours This solution was concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine, dried and concentrated in vacuum. The residue was purified column chromatography. The obtained 3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide was dissolved in MC and the solution was treated with a solution of HCI in diethyl ether. The precipitate was filtered to obtain specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.95 (m, 1H), 8.35 (m, 1H), 7.5-7.1 (m, N), 4.95 (m, 1H), 3.35-3.1 (m, 4H), 2.9 (m, 1H), 2.7 (m, 2H), 2.2 (m, 1H), 2.1-1.6 (m, 5H), 1.5 (m, 2H), 1.3-1.0 (m, 5H).

EXAMPLE 136

N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide; hydrochloride

Followed the procedure described in Example 135, using as reagent (piperidine-4-ylmethyl)-amide 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid instead of (piperidine-4-ylmethyl)-amide 3-cyclopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid, to obtain specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 9.0 (m, 1H), 8.25 (m, 1H), 7.5-7.1 (m, N), 4.95 (m, 1H), 4.75 (m, 1H), 3.35 (m, 2H), 3.15 (m, 2H), 2.8-2.55 (m, 2H), 2.1 (m, 1H), 1.9 (m, 4H), 1.8-1.4 (m, 10H).

EXAMPLE 137

N-[[1-[3-(4-forfinal)-3-hydroxypropyl]piperidine-1-s-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide; hydrochloride

Followed the procedure is e, Example 135 using as reagents (piperidine-4-ylmethyl)-amide 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 3-chloro-4'-forpromotion instead (piperidine-4-ylmethyl)-amide 3-cyclopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 3-chloropropiophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 500 MHz) δ 9.00 (m, 1H), 8.28 (s, 1H), 7.36 (m, 2H), 7.20 (m, 3H), 7.03 (m, 2H), 4.95 (m, 1H), 4.72 (m, 1H), 3.37 (m, 2H), 3.35 (m, 1H), 3.22 (m, 1H), 2.81 (m, 1H), 2.71 (m, 1H), 2.28 (m, 1H), 2.11 (m, 1H), 1.93 (m, 4H), 1.79 (m, 1H), 1.58 (m, 8H).

EXAMPLE 138

3-cyclopropyl-N-[[1-[3-(4-forfinal)-3-hydroxypropyl]piperidine-1-s-4-yl]methyl]-2-oxopentanoate-1-carboxamide; hydrochloride

Followed the procedure described in Example 135, using as reagent 3-chloro-4'-forpromotion instead of 3 chloropropiophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 500 MHz) δ 9.00 (m, 1H), 8.20 (s, 1H), 7.36 (m, 2H), 7.20 (m, 3H), 7.05 (m, 2H), 4.96 (m, 1H), 3.37 (m, 3H), 3.30 (m, 1H), 2.92 (m, 2H), 2.80 (m, 1H), 2.35 (m, 1H), 2.2 (m, 1H), 1.96 (m, 2H), 1.79 (m, 2H), 1.65 (m, 3H), 1.20 (m, 2H), 1.05 (m, 2H).

EXAMPLE 139

N-[[1-[3-(4-chlorophenyl)-3-hydroxypropyl]piperidine-1-s-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide; hydrochloride

Followed the procedure described in Example 135 using as reagents (piperidine-4-ylmethyl)-amide 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 3-chloro-4'-chloropropiophenone instead (piperidine-4-ylmethyl)-amide 3-cyclopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 3-chloropropiophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 500 MHz) δ 9.00 (m, 1H), 8.27 (m, 1H), 7.33 (m, 4H), 7.18 (m, 3H), 4.96 (m, 1H), 4.72 (m, 1H), 3.37 (m, 3H), 3.25 (m, 1H), 2.87-2.70 (m, 2H), 2.40 (m, 1H),2.13 (m, 1H), 1.95 (m, 5H), 1.78 (m, 2H),1.58 (m, 6N).

EXAMPLE 140

N-[[1-[3-(4-chlorophenyl)-3-hydroxypropyl]piperidine-1-s-4-yl]methyl]-3-cyclopropyl-2-oxopentanoate-1-carboxamide; hydrochloride

Followed the procedure described in Example 135, using as reagent 3-chloro-4'-chloropropiophenone instead of 3 chloropropiophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 500 MHz) 5 8.94 (m, 1H), 8.20 (m, 1H), 7.33-7.19 (m, 7H), 4.96 (m, 1H), 3.37 (m, 3H), 3.26 (m, 1H), 2.91 (m, 2H), 2.81 (m, 1H), 2.32 (m, 1H), 2.15 (m, 1H), 1.95 (m, 4H), 1.77 (m, 2H), 1.62 (m, 3H), 1.18 (m, 2H), 1.05 (m, 2H).

EXAMPLE 141

N -[[1-[3-hydroxy-3-(4-were)propyl]piperidine-1-s-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide; hydrochloride

Followed the procedure described in Example 135 using as reagents (piperidine-4-ylmethyl)-amide 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 3-chloro-4'-methylpropiophenone instead (piperidine-4-ylmethyl)-amide 3-cyclopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 3-chloropropiophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 500 MHz) δ 9.01 (m, 1H), 8.26 (m, 1H), 7.37-7.15 (m, 7H), 4.95 (m, 1H), 4.75 (m, 1H), 3.38 (m, 4H), 2.90 (m, 2H), 2.36 (s, 3H), 2.10-1.65 (m, 9H), 1.60 (m, 6H).

WHEN THE EP 142

3-cyclopropyl-N-[[1-[3-hydroxy-3-(4-were)propyl]piperidine-1-s-4-yl]methyl]-2-oxopentanoate-1-carboxamide; hydrochloride

Followed the procedure described in Example 135, using as reagent 3-chloro-4'-methylpropiophenone instead of 3 chloropropiophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 500 MHz) δ 8.95 (m, 1H), 8.20 (m, 1H), 7.42-7.13 (m, 7H), 4.75 (m, 1H), 3.42-3.20 (m, 4H), 2.90 (m, 1H), 2.81 (m, 2H), 2.32 (m, 3H), 2.18 (m, 1H), 1.95 (m, 3H), 1.80 (m, 2H), 1.65 (m, 3H), 1.20 (m, 2H), 1.06 (m, 2H).

EXAMPLE 143

N-[[1-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperidine-1-s-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide; hydrochloride

Followed the procedure described in Example 135 using as reagents (piperidine-4-ylmethyl)-amide 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 3-chloro-4'-methoxypropiophenone instead (piperidine-4-ylmethyl)-amide 3-cyclopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 3-chloropropiophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 9.05 (m, 1H), 8.25 (m, 1H), 7.35 (m, 3H), 7.2 (m, 3H), 6.9 (m, 2H), 6.85 (m, 1H), 5.0 (m, 1H), 4.7 (m, 1H), 3.85 (s, 3H), 3.7 (m, 1H), 3.5 (m, 1H), 3.4 (m, 2H), 3.25 (m, 2H), 3.0 (m, 3H), 2.65 (m, 2H), 2.3 (m, 2H), 2.1 (m, 2H), 1.6 (m, 6N).

EXAMPLE 144

3-cyclopropyl-N-[[1-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperidine-1-s-4-yl]methyl]-2-oxopentanoate-1-carboxamide; hydrochloride

Followed the procedure p is evidenoe in Example 135, using as reagent 3-chloro-4'-methoxypropiophenone instead of 3 chloropropiophenone, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.95 (m, 1H), 8.2 (m, 1H), 7.4-7.2 (m, 5H), 6.9 (m, 2H), 4.9 (m, 1H), 3.8 (s, 3H), 3.35 (m, 2H), 3.2 (m, 2H), 2.9 (m, 1H), 2.75 (m, 2H), 2.3-2.0 (m, 2H), 1.9 (m, 4H), 1.7 (m, 1H), 1.55 (m, 2H), 1.2-1.0 (m, 4H).

EXAMPLE 145

[3-[4-[[(3-cyclopropyl-2-oxopentanoate-1-carbonyl)amino]methyl]-piperidine-1-s-1-yl]-1-phenylpropyl]carbamate; hydrochloride

3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide (1 mmol) at 0°C was dissolved in 10 ml of THF and was added 1,1'-carbonyldiimidazole (1.5 mmol). The reaction mixture was stirred at room temperature for 2 h, then was added an excess of ammonium hydroxide (3 ml) at room temperature. After 2 h stirring at room temperature for completion of the reaction was added water. The organic layer was extracted 3 times with dichloromethane, was dried and concentrated in vacuum. The resulting carbamate was dissolved in MC and the solution was treated with a solution of HCl in diethyl ether. The precipitate was filtered to obtain specified in the connection header.

1H-NMR (CDCb, 200 MHz) δ 9.00 (m, 1H), 8.20 (m, 1H), 7.31-7.18 (m, 8H), 5.71 (m, 1H), 4.73 (br, 2H), 3.35 (m, 2H), 3.12 (br, 2H), 2.90 (m, 2H), 2.80 (m, 1H), 2.30 (m, 2H), 2.07 (m, 2H), 1.86 (m, 2H), 1.75 (m, 1H), 1.60 (m, 2H), 1.20 (m, 2H), 1.05 (m, 2H).

EXAMPLE 146

[3-[4-[[(2-oxo-3-ropan-2-Evenimentul-1-carbonyl)amino]methyl]-piperidine-1-yl]-1-phenylpropyl]carbamate; hydrochloride

Followed the procedure outlined in Example 145, using as reagent N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide from Example 136 instead of 3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide, to obtain specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 9.0 (m, 1H), 8.3 (m, 1H), 7.8 (m, 1H), 7.4-7.1 (m, N), 5.75 (m, 1H), 4.8-4.6 (m, 3H), 3.35 (m, 2H), 3.1 (m, 2H), 2.55 (m, 3H), 2.4-2.0 (m, 5H), 1.9-1.6 (m, 4H), 1.5 (m, 6N).

EXAMPLE 147

[1-(4-forfinal)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)-amino]methyl]piperidine-1-s-1-yl]propyl]carbamate; hydrochloride

Followed the procedure outlined in Example 145, using as reagent N-[[1-[3-(4-forfinal)-3-hydroxypropyl]piperidine-1-s-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide from Example 137 instead of 3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 500 MHz) δ 9.00 (m, 1H), 8.25 (s, 1H), 7.36 (m, 2H), 7.20 (m, 3H), 7.05 (m, 2H), 5.69 (m, 1H), 4.72 (m, 1H), 3.36 (m, 2H), 3.20 (m, 2H), 2.65 (m, 2H), 2.3 (m, 2H), 1.93 (m, 3H), 1.79 (m, 2H), 1.65 (m, 2H), 1.58 (m, 6N).

EXAMPLE 148

[3-[4-[[(3-cyclopropyl-2-oxopentanoate-1-carbonyl)amino]methyl]-piperidine-1-s-1-yl]-1-(4-forfinal)propyl]carbamate; hydrochloride

Followed the procedure resulted is authorized in Example 145, using as reagent 3-cyclopropyl-N-[[1-[3-(4-forfinal)-3-hydroxypropyl]piperidine-1-s-4-yl]methyl]-2-oxopentanoate-1-carboxamide from Example 138 instead of 3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide, to obtain specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.89 (m, 1H), 8.20 (m, 1H), 7.35-7.19 (m, 5H), 7.03 (m, 2H), 5.68 (m, 1H), 4.78 (br, 2H), 3.33 (m, 2H), 3.03 (m, 2H), 2.90 (m, 1H), 2.47 (m, 2H), 2.20 (m, 1H), 2.06 (m, 3H), 1.81 (m, 2H), 1.65 (m, 1H), 1.45 (m, 2H), 1.17 (m, 2H), 1.05 (m, 2H).

EXAMPLE 149

[1-(4-chlorophenyl)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)-amino]methyl]piperidine-1-s-1-yl]propyl]carbamate; hydrochloride

Followed the procedure outlined in Example 145, using as reagent N-[[1-[3-(4-chlorophenyl)-3-hydroxypropyl]piperidine-1-s-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide from Example 139 instead of 3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.98 (m, 1H), 8.26 (m, 1H), 7.34-7.17 (m, 7H), 5.67 (m, 1H), 4.72 (m, 3H), 3.35 (m, 2H), 3.06 (m, 2H), 2.50 (m, 2H), 2.25 (m, 1H), 2.12 (m, 1H), 2.05 (m, 2H), 1.85 (m, 2H), 1.80 (m, 1H), 1.58 (m, 6N), 1.28 (m, 2H).

EXAMPLE 150

[1-(4-chlorophenyl)-3-[4-[[(3-cyclopropyl-2-oxopentanoate-1-carbonyl)-amino]methyl]piperidine-1-s-1-yl]propyl]carbamate; hydrochloride

Followed procedure given Primera 145, using as reagent N-[[1-[3-(4-chlorophenyl)-3-hydroxypropyl]piperidine-1-s-4-yl]methyl]-3-cyclopropyl-2-oxopentanoate-1-carboxamide from Example 140 instead of 3-cyclopropyl-M-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide, to obtain specified in the connection header.

1H-NMR (CDCl3, 500 MHz) δ 8.93 (m, 1H), 8.19 (m, 1H), 7.35-7.20 (m, 7H), 5.68 (m, 1H), 4.78 (m, 2H), 3.36 (m, 2H), 3.18 (m, 2H), 2.91 (m, 2H), 2.65 (m, 2H), 2.31 (m, 2H), 2.15 (m, 2H), 1.89 (m, 2H), 1.75 (m, 2H), 1.63 (m, 3H), 1.19 (m, 2H), 1.06 (m, 2H).

EXAMPLE 151

[1-(4-were)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)-amino]methyl]piperidine-1-s-1-yl]propyl]carbamate; hydrochloride

Followed the procedure outlined in Example 145, using as reagent N-[[1-[3-hydroxy-3-(4-were)propyl]piperidine-1-s-4-yl]-methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide from Example 141 instead of 3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide with obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.97 (m, 1H), 8.25 (m, 1H), 7.30-7.13 (m, 7H), 5.67 (m, 1H), 4.73 (m, 3H), 3.50 (m, 1H), 3.32 (m, 2H), 3.10 (m, 2H), 2.58 (m, 2H), 2.37 (m, 3H), 2.28 (m, 1H), 2.11 (m, 3H), 1.85 ( m, 3H), 1.72 (m, 1H), 1.58 (m, 6N).

EXAMPLE 152

[3-[4-[[(3-cyclopropyl-2-oxopentanoate-1-carbonyl)amino]methyl]-piperidine-1-s-1-yl]-1-(4-were)propyl]carbamate; hydrochloride

Followed the procedure in Approx the re 145, using as reagent 3-cyclopropyl-N-[[1-[3-hydroxy-3-(4-were)propyl]piperidine-1-s-4-yl]methyl]-2-oxopentanoate-1-carboxamide from Example 142 instead of 3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide, to obtain specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.90 (m, 1H), 8.20 (s, 1H), 7.32-7.13 (m, 7H), 5.66 (m, 1H), 4.73 (br, 2H), 3.35 (m, 2H), 3.12 (m, 2H), 2.91 (m, 1H), 2.60 (m, 2H), 2.40 (s, 3H), 2.27 (m, 2H), 1.61 (m, 2H), 1.87 (m, 2H), 1.72 (m, 1H), 1.59 (m, 2H), 1.20 (m, 2H), 1.06 (m, 2H).

EXAMPLE 153

[1-(4-methoxyphenyl)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-s-1-yl]propyl]carbamate; hydrochloride

Followed the procedure outlined in Example 145, using as reagent N-[[1-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperidine-1-s-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide from Example 143 instead of 3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 9.0 (m, 1H), 8.25 (m, 1H), 7.35 (m, 3H), 7.2 (m, 3H), 6.9 (m, 2H), 5.65 (m, 1H), 4.95 (m, 2H), 4.7 (m, 1H), 3.8 (s, 3H), 3.4 (m, 2H), 3.2 (m, 2H), 2.7 (m, 2H), 2.4-2.1 (m, 4H), 1.9 (m, 3H), 1.7 (m, 2H), 1.6 (m, 6N).

EXAMPLE 154

[3-[4-[[(3-cyclopropyl-2-oxopentanoate-1-carbonyl)amino]methyl]-piperidine-1-s-1-yl]-1-(4-methoxyphenyl)propyl]carbamate; hydrochloride

Followed the procedure of privedennoi Example 145, using as reagent 3-cyclopropyl-N-[[1-[3-hydroxy-3-(4-methoxyphenyl)propyl]-piperidine-1-s-4-yl]methyl]-2-oxopentanoate-1-carboxamide from Example 144 instead of the 3-cycle propyl-N-[[1-(3-hydroxy-3-phenyl propyl)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide, to obtain specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.95 (m, 1H), 8.2 (m, 1H), 7.4-7.2 (m, 5H), 6.95 (m, 2H), 5.65 (m, 1H), 4.8 (m, 2H), 3.8 (s, 3H), 3.4 (m, 2H), 3.2 (m, 2H), 2.9 (m, 1H), 2.7 (m, 2H), 2.5-2.1 (m, 4H), 1.9 (m, ZN), 1.75 (m, 2H), 1.4-1.0 (m, 4H).

EXAMPLE 155

N-[[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide; hydrochloride

A mixture of piperidine-4-ylmethyl)-amide 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (5.0 mmol), 2-bromo-4'-fortetienne (6.0 mmol) and potassium carbonate (7.6 mmol) was stirred in 15 ml of acetonitrile for 2 hours the solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture is then washed with brine and the organic layer was dried and purified column chromatography. It was dissolved in ethanol (10 ml) and at 0°C was added borohydride sodium (10.0 mmol) and stirred at 25°C for 2 h the solution was concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was washed with brine, dried and concentrated in vacuum. The residue was purified column of chromatogra the Oia. Obtained N-[[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-1-s-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide was dissolved in MC and the solution was treated with a solution of HCl in diethyl ether. The precipitate was filtered to obtain specified in the connection header.

1H-NMR (CDCb, 500 MHz) δ 9.01 (m, 1H), 8.26 (m, 1H), 7.37 (m, 2H), 7.20 (m, 3H), 7.05 (m, 2H), 4.90 (br, 2H), 3.38 (m, 2H), 3.30 (m, 1H), 3.08 (m, 1H), 2.63 (m, 2H), 2.50 (m, 1H), 2.25 (m, 1H), 1.91 (m, 2H), 1.80 (m, 1H), 1.59 (m, 8H).

EXAMPLE 156

N-[[1-[2-hydroxy-2-(3-methoxyphenyl)ethyl]piperidine-1-s-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide; hydrochloride

Followed the procedure described in Example 155, using as reagent of 2-bromo-3'-methoxyacetophenone instead of 2-bromo-4'-fortetienne, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 9.05 (m, 1H), 8.3 (m, 1H), 7.35-7.1 (m, 5H), 7.0 (m, 2H), 6.85 (m, 1H), 4.9 (m, 1H), 4.85 (m, 1H), 3.95 (s, 3H), 3.4 (m, 3H), 3.1 (m, 1H), 2.85 (m, 2H), 2.5 (m, 1H), 2.3 (m, 1H), 1.95-1.8 (m , 3H), 1.6-1.5 (m, 8H).

EXAMPLE 157

3-cyclopropyl-N-[[1-[2-hydroxy-2-(3-methoxyphenyl)ethyl]piperidine-1-s-4-yl]methyl]-2-oxopentanoate-1-carboxamide; hydrochloride

Followed the procedure described in Example 155 using as reagents (piperidine-4-ylmethyl)-amide 3-cyclopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid and 2-bromo-3'-methoxyacetophenone instead (piperidine-4-ylmethyl)-amide 3-isopropyl-2-oxo-2,3-dihydro-benzo is midazol-1-carboxylic acid and 2-bromo-4'-fortetienne, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 8.95 (m, 1H), 8.25 (m, 1H), 7.35-7.2 (m, 4H), 7.0 (m, 2H), 6.85 (m, 1H), 4.85 (m, 1H), 3.95 (s, 3H), 3.35 (m, 3H), 2.95 (m, 2H), 2.6 (m, 2H), 2.45 (m, 1H), 2.2 (m, 1H), 1.9 (m, 2H), 1.85 (m, 1H), 1.5 (m, 2H), 1.3-1.0 (m, 4H).

EXAMPLE 158

[1-(4-forfinal)-2-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)-amino]methyl]piperidine-1-s-1-yl]ethyl]carbamate; hydrochloride

Followed the procedure outlined in Example 145, using as reagent N-[[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide from Example 155 instead of 3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide, to obtain specified in the header connection.

1H-NMR (CDCl3, 500 MHz) δ 8.97 (m, 1H), 8.26 (m, 1H), 7.37 (m, 2H), 7.18 (m, 3H), 7.05 (m, 2H), 5.82 (m, 1H), 5.00 (m, 1H), 4.72 (m, 1H), 3.35 (m, 2H), 3.15-2.95 (m, 2H), 2.71 (m, 1H), 2.62 (m, 1H), 2.26 (m, 2H), 1.95 (m, 1H), 1.85 (m, 2H), 1.70 (m, 2H), 1.58 (m, 6N).

EXAMPLE 159

[1-(3-methoxyphenyl)-2-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)-amino]methyl]piperidine-1-s-1-yl]ethyl]carbamate; hydrochloride

Followed the procedure outlined in Example 145, using as reagent N-[[1-[2-hydroxy-2-(3-methoxyphenyl)ethyl]piperidine-1-s-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide from Example 156 instead of 3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamid the, obtaining specified in the connection header.

1H-NMR (CDCl3, 200 MHz) δ 9.05 (m, 1H), 8.25 (m, 1H), 7.35-7.1 (m, 4H), 7.0-6.85 (m, 3H), 5.9 (m, 1H), 4.7 (m, 1H), 3.8 (s, 3H), 3.5-3.1 (m, 4H), 2.8 (m, 1H), 2.5 (m, 2H), 2.1-1.85 (m, 6N), 1.6 (m, 6N).

EXAMPLE 160

[[2-[4-[[(3-cyclopropyl-2-oxopentanoate-1-carbonyl)amino]methyl]-piperidine-1-s-1-yl]-1-(3-methoxyphenyl)ethyl]carbamate; hydrochloride

Followed the procedure outlined in Example 145, using as reagent 3-cyclopropyl-N-[[1-[2-hydroxy-2-(3-methoxyphenyl)ethyl]piperidine-1-s-4-yl]methyl]-2-oxopentanoate-1-carboxamide from Example 157 instead of 3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide, to obtain specified in the title compound.

1H-NMR (CDCl3, 200 MHz) δ 9.0 (m, 1H), 8.2 (m, 1H), 7.4-7.2 (m, 4H), 7.05-6.9 (m, 3H), 5.95 (m, 1H), 3.85 (s, 3H), 3.6-3.4 (m, 3H), 2.95 (m, 2H), 2.7 (m, 2H), 2.2-1.8 (m, 5H), 1.7 (m, 2H), 1.4-1.0 (m, 4H).

EXAMPLE 161: Activity on enhancing gastric emptying

Male mice of ICR CD (body weight approximately 25-30 g; 8 mice per group) were left hungry for 24 hours, but left them free access to water within up to 3 hours before the test.

The test compound to stimulate peristalsis of the gastrointestinal tract were injected with intraperitoneally or given orally for 30 minutes or 60 minutes prior to the introduction of feed phenol red. Fifteen (15) minutes after the conduct of the test food (of 0.5% phenol red in a 1.5%solution of methyl cellulose) mice were killed and the stomach (pyloric~cardia) was removed and placed into the vial. The stomach along with its contents homogenized in 0.1 G. of NaOH and the mixture was centrifuged (700*(g) for 20 minutes. 2.5 ml of the supernatant was added to 0.25 ml of trichloroacetic acid (20% wt./about.) to precipitate proteins. After centrifugation (2600*g) for 20 minutes, 0.5 ml of supernatant was added to 0.25 ml of 1 N. NaOH. The mixture is homogenized and recorded the absorbance (Abs) at 560 nm.

In each experiment, one group was slaughtered immediately after administration of the test feed and considered it standard (0% empty). Gastric emptying (GE) within a period of 15 minutes was calculated according to the following formula:

GE(%)=(1-AbStest/AbSstandard)×100

Gain(%)=(CE%test-CE%media)/CE%media*100

As shown in Table 1, most of the compounds in this invention are expressed enhance gastric emptying effect at a dose of 3 mg/kg

As is evident from the above experimental results, the compounds of structural formulas (I) and their pharmaceutically acceptable salts have excellent activity increased peristalsis of the gastrointestinal tract and is therefore useful for the treatment of diseases of the gastrointestinal tract, such as irritable bowel syndrome (IBS), especially IBS with constipation, and disorders of motor functions of the stomach.

5-Hydroxytryptamine (5-HT), you shall woodeny of enterochromaffin cells, regulate gastrointestinal function either excitatory or inhibitory. Activity increased gastrointestinal peristalsis is characteristic of agonism against 5-NT receptors. Agonists of 5-NT receptors can stimulate peristalsis of the upper or lower intestine, whereas 5-NT antagonists inhibit the enhanced 5-NT agonists peristalsis.

Compounds of structural formula (I) possess binding activity against 5-NT receptors and stimulate peristalsis (see Table 1). So, I think that the increased intestinal motility compounds of structural formulas (I) - mediated agonism against 5-NT receptors.

Table 1:
Activity increased gastric emptying (3.0 mg/kg I.P. Pavlova. (intraperitoneally))
Example% gainExample% gain
242,6%56134,7%
371,1%5729,0%
474,1%5848,3%
576,1%5948,0%
851,6%6014,2%
955,8%6144,3%
1314,0%6217,9%
1578,7%6324,4%
1653,6%647,3%
1722,1%6593.1%of
2355,8%6684,1%
2471,1%6852,9
2748,5%70 67,5%
2961,3%7163,7%
3179,3%7248,1%
3240,0%7446,7%
33115,2%8342,5%
35105,5%8844,1%
3655,2%8945,3%
3770,7%96105,0%

3849,1%9771,4%
3940,0%9863,6%
4051,6%9947,5%
4124,3%10046,1%
4242,7%10388,8%
4346,1%10481,0%
4551,4%11137,2%
4645,9%12146,8%
4725,9%1226,8%
483,5%12356,8%
4917,8%12445,6%
503,9%12693,3%
51122,1%12711,3%
52131,0% 1295,4%
5328,4%13590,3%
5489,2%13664,1%
5566,7%14683,0%

Hypersensitivity to colorectal distension characteristic of patients with IBS and may be responsible for the primary symptom of visceral pain. To study the effect of the compound on visceral pain in IBS have been developed inflammatory and non-inflammatory animal model of visceral hyperalgesia in relation to stretching, as will be described in Examples 162 and 163, respectively.

EXAMPLE 162: Test on TNBS-induced colorectal hypersensitivity

Of Wistar rats (weighing 200-225 g; 8-10 rats per group) surgically prepared for EMG control according to previously described methodology (Morteau et al., Dig Dis Sci, 1994, 39 (6): 1239-1248). After laparotomy three groups of three electrodes implanted in layered muscles of the abdomen. The electrodes are led out on the rear surface of the neck and protected by a glass tube attached to the skin.

Colorectal distension (CRD) done by ulali with balloon, zapomnivshegosya 5 minute stages at 15 mm Hg (2 kPa) 0 to 60 mm Hg (8 kPa) by connecting the cylinder with computerized barostat. Rats were subjected to CRD for 1 day before (basic conditions) and after 3 days after vnutribruchinnogo introduction trinitrobenzenesulfonic acid (TNBS 80 mg/kg vnutriuretrale). The pressure in the colon and the volume of the cylinder continuously monitorrole on a potentiometric recorder (L6514, Linseis, Selb, Germany) with a speed of paper 1 cm·min-1.

Five days after administration of TNBS rats were treated with test drugs or vehicle (carboxymethylcellulose 0.5 %and 1 ml p./O.) one hour before stretching. The number of acute explosions", which correspond to the abdominal contractions was determined for 5-minute periods. Values were expressed as mean ±SEM (standard deviation). Statistical analysis was performed using t-student test, and the criterion for statistical significance was p<0,05.

Table 2 summarizes the results of the activity of the compound obtained in Example 68, as the test compound in the model of TNBS-induced colorectal hypersensitivity. A significant reduction of abdominal contractions was observed at 10 mg/kg and 30 mg/kg of the test compounds. This result shows that the connection according to one embodiment of the present image is to be placed has activity in reducing visceral pain in preclinical rat model.

Table 2:
The effect of compounds on TNBS-induced colorectal hypersensitivity in rats
The number of abdominal contractions/5 min
0 mm Hga)15 mm Hga)(2 kPa)30 mm Hga)(4 kPa)45 mm Hga)(6 kPa)60 mm Hga)(8 kPa)
Media1,1±0,65,3±1,614,0±2,925,7±2,930,7±2,7
TNBS+media3,2±1,113,3±1,627,5±4,039,0±5,245,5±4,7
TNBS+test compound (10 mg/kg p/o)4,7±1,214,7±2,519,9*±2,531,0±3,937,1±6,0
TNBS+test compound (30 mg/kg, p/o) 2,1±0,77,3*±1,815,3*±3,021,4*±2,128,3*±3,1
a)Pressure stretching
* p<0.05 is significantly different from TNBS+media

EXAMPLE 163: Test PRS (stress associated with partial limitation of mobility) - induced colorectal hypersensitivity

Adult female Wistar rats (weighing 225-250 g; 6-7 rats per group) were prepared for electromyography. After anesthesia with three pairs of electrodes of the nichrome wire was implanted bilaterally in layered muscle in 3 cm lateral from the midline. The free ends of the electrodes are taken out on the rear surface of the neck and protected by a glass tube attached to the skin.

PRS, relatively mild stress was carried out as previously described in Bradesi S, Eutamene h, Garcia-Villar R, Fioramonti J, Bueno L; 'Acute and chronic stress differently affect visceral sensitivity to rectal distension in female rats.' Neurogastroenterol. Mot. (2002) 14, 75-82.

Rats were placed in a plastic tunnel, where they were not given the opportunity to move or to escape for a few days before colorectal stretching (CRD). The balloon is attached to barostat, filled the progressive stages of 15 mm Hg, 0, 15, 30, 45 and 60 mm Hg (0, 2, 4, 6 and 8 kPa), each stage of filling lasted 5 minutes To determine antiniotic pivnogo action of the tested compounds on the PRS-induced visceral hypersensitivity test the connection, or the media (CMC 0,5%) was administered orally (PO), after 1 h 15 min after the beginning of the PRS. Three hours before and 15 min after the stress session was carried out by CRD.

The number of acute explosions", which correspond to the abdominal contractions was determined for 5-minute periods for each volume strain. The pressure in the colon and the volume of the cylinder continuously monitorrole on a potentiometric recorder (L6514, Linseis, Selb, Germany). Values were expressed as mean ±SEM.

Statistical analysis was performed by univariate analysis of variance (ANOVA) with subsequent test Dunnett. p<0.05 is considered significant.

Table 3 summarizes the results of the activity of the compound obtained in Example 68, as the test compound in the model PRS-induced colorectal hypersensitivity. A significant reduction of abdominal contractions was observed at 30 mg/kg This result shows that the connection according to one embodiment of the present invention has activity to reduce visceral pain.

Table 3:
The impact of connections on the PRS-induced colorectal hypersensitivity in rats
The number of abdominal contractions/5 min
0 mm Hga)15 mm Hga)(2 kPa)30 mm Hga)(4 kPa)45 mm Hga)(6 kPa)60 mm Hga)(8 kPa)
Media0,7±0,33,7±1,413,3±2,218,8±4,123,3±3,9
PRS+media2,0±0,87,0±3,133,2±7,954,2±6,557,8±6,3
PRS+test compound (30 mg/kg, p/o)4,9±1,12,7±0,911,9*±2,335,3*±5,346,0±3,3
a)Pressure stretching
* p<0.05 compared "PRS+media

1. Piperidino a compound selected from compounds of structural formula (I):

and its pharmaceutically acceptable salts, where
m represents the integer 1 or 2;
n is an integer from 0 to 2;
A is selected from phenyl groups and benzimidazole group, where the phenyl group substituted by one or more groups independently selected from C1-C6 linear or branched alkyl groups, C1-C6 linear or branched alkoxygroup, amino and halogen, and benzimidazole group substituted by one or more groups independently selected from C1-C6 linear or branched alkyl groups, C1-C6 linear or branched alkoxygroup, C3-C7 cyclic alkyl group, amino group, halogen and carbonyl group;
X represents a hydroxy or OCONR1R2where R1and R2independently selected from hydrogen and C1-C6 linear or branched alkyl group, or R1and R2form a 5-7-membered heterocyclic ring or a 3.5-dimethylpiperidine ring together with the nitrogen atom to which they are attached, and
Selected from phenyl groups, fenoxaprop, thienyl groups and naftilos group, where the phenyl group, fenoxaprop, thienyl group or naftalina group substituted by one or more groups independently selected from hydrogen, halogen, nitro, cyano, trifloromethyl, triptoreline, deformedarse, phenyl, C1-C6 linear or branched alkyl groups and C1-C6 linear or branched alkoxygroup.

2. Piperidine compound according to claim 1, where A Deputy is a phenyl group substituted by one or more group and, independently selected from C1-C6 linear or branched alkyl groups, C1-C6 linear or branched alkoxygroup, amino and halogen.

3. Piperidine compound according to claim 2, where A Deputy is represented by structural formula (II):

where R3represents a C1-C6 linear or branched alkyl.

4. Piperidine compound according to claim 1, where the Deputy represents A benzimidazole group, substituted by one or more identical or different groups independently selected from the group consisting of C1-C6 linear or branched alkyl groups, C1-C6 linear or branched alkoxygroup, C3-C7 cyclic alkyl group, amino group, halogen and carbonyl group.

5. Piperidino connection according to claim 4, where A Deputy is represented by structural formula (III):

where R4represents a C1-C6 linear or branched alkyl group or a C3-C7 cyclic alkyl.

6. Piperidino connection according to claim 3, where the specified connection is selected from the group consisting of the following compounds:
4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide : hydrochloride;
4-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-were)ethyl]piperidine-yl]methyl]-2-methoxybenzamide : hydrochloride;
4-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-methoxyphenyl)ethyl]piperidine-4-yl]methyl]-2-methoxybenzamide : hydrochloride;
4-amino-5-chloro-N-[[1-[2-(4-chlorophenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide : hydrochloride;
4-amino-5-chloro-N-[[1-[2-(3,4-dichlorophenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide : hydrochloride;
4-amino-5-chloro-N-[[1-[2-hydroxy-2-[4-(trifluoromethyl)phenyl]-ethyl]piperidine-4-yl]methyl]-2-methoxybenzamide : hydrochloride;
4-amino-5-chloro-N-[[1-[2-(3,4-differenl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide : hydrochloride;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-phenylethyl]carbamate : hydrochloride;
[2-[4-[1(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)ethyl]carbamate : hydrochloride;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(3,4-dichlorophenyl)ethyl]carbamate : hydrochloride;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(3,4-differenl)ethyl]carbamate : hydrochloride;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-[4-(trifluoromethyl)phenyl]ethyl]carbamate : hydrochloride;
4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide : hydrochloride;
4-amino-5-chloro-N-[[1-[3-(4-forfinal)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide : hydrochloride;
4-amino-5-chloro-N-[[1-[3-(3,4-dichlorophenyl)-3-hydrox is propyl]piperidine-4-yl]methyl]-2-methoxybenzamide : hydrochloride;
4-amino-5-chloro-N-[[1-(3-hydroxy-3-thiophene-2-ylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide : hydrochloride;
4-amino-5-chloro-N-[[1-[4-(4-forfinal)-3-hydroxybutyl]piperidine-4-yl]methyl]-2-methoxybenzamide : hydrochloride;
4-amino-5-chloro-N-[[1-[5-(4-forfinal)-3-hydroxyphenyl]piperidine-4-yl]methyl]-2-methoxybenzamide : hydrochloride;
[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-chlorophenyl)propyl]carbamate : hydrochloride;
[4-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)butane-2-yl]carbamate : hydrochloride;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-5-(4-forfinal)pentane-3-yl]carbamate : hydrochloride;
4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-methoxybenzamide : hydrochloride;
4-amino-5-chloro-N-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide : hydrochloride;
4-amino-5-chloro-N-[[1-[2-hydroxy-3-[4-(trifluoromethyl)phenoxy]propyl]-piperidine-4-yl]methyl]-2-methoxybenzamide : hydrochloride;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]carbamate : hydrochloride;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(4-pertenece)propan-2-yl] - for 3,5-dimethylpiperidin-1-carboxylate : hydrochloride;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(4-methoxyphenoxy)propan-2-yl]carbamate : g is drochloric;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(2,3-dichlorophenoxy)propan-2-yl]azepin-1-carboxylate : hydrochloride;
4-amino-5-chloro-N-[[1-[(2S)-2-hydroxy-2-phenylethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[(2R)-2-hydroxy-2-phenylethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(4-chlorophenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)propyl]carbamate;
(R)-[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)propyl]carbamate;
(S)-[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)propyl]carbamate;
4-amino-5-chloro-N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]piperidine-1-carboxylate; and
4-amino-5-chloro-N-[[1-[3-(2,5-dichlorophenoxy)-2-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide.

7. Piperidino connection according to claim 5, where the compound is selected from the group consisting of the following compounds:
[1-(2-methylphenoxy)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-yl]propan-2-yl]carbamate;
N-[[1-[2-hydroxy-3-(4-nitrophenoxy)propyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide;
N-[[1-[2-g is droxy-3-(4-methoxyphenoxy)propyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide;
N-[[1-[3-(4-pertenece)-2-hydroxypropyl]piperidine-4-yl]methyl]-3-methyl-2-oxopentanoate-1-carboxamide;
3-ethyl-N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide;
[1-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]carbamate;
[1-(4-pertenece)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-yl]propan-2-yl]carbamate;
[1-(4-methoxyphenoxy)-3-[4-[[(3-methyl-2-oxopentanoate-1-carbonyl)amino]methyl]piperidine-1-s-1-yl]propan-2-yl]carbamate;
[1-[4-[[(3-ethyl-2-oxopentanoate-1-carbonyl)amino]methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]carbamate;
[1-(4-chlorophenoxy)-3-[4-[[(3-ethyl-2-oxopentanoate-1-carbonyl)amino]methyl]piperidine-1-yl]propan-2-yl]carbamate;
3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide;
3-cyclopropyl-N-[[1-[3-(4-forfinal)-3-hydroxypropyl]piperidine-1-s-4-yl]methyl]-2-oxopentanoate-1-carboxamide;
[3-[4-[[(3-cyclopropyl-2-oxopentanoate-1-carbonyl) - amino]-methyl]piperidine-1-s-1-yl]-1-phenylpropyl]carbamate;
[1-(4-forfinal)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-s-1-yl]propyl]carbamate;
[1-(4-methoxyphenyl)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-s-1-yl]propyl]carbamate;
N-[[1-[2-(4-forfinal)-2-hydroxyethyl]piperidin-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide;
[1-(4-forfinal)-2-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-s-1-yl]ethyl]carbamate;
[[2-[4-[[(3-cyclopropyl-2-oxopentanoate-1-carbonyl) - amino]-methyl]piperidine-1-s-1-yl]-1-(3-methoxyphenyl)ethyl]carbamate;
[1-[4-[[(3-methyl-2-oxopentanoate-1-carbonyl)amino]methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]carbamate;
N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide and
[3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]-piperidine-1-yl]-1-phenylpropyl]carbamate.

8. Pharmaceutical composition for treatment of gastrointestinal diseases, which contains a therapeutically effective amount piperidinol compound according to any one of claims 1 to 7 or its pharmaceutically acceptable salt.

9. The pharmaceutical composition of claim 8, where gastro-intestinal disease includes at least one disorder selected from irritable bowel syndrome (IBS), disorders of motor function of the stomach, constipation and visceral pain.

10. The pharmaceutical composition of claim 8, where A Deputy is a phenyl group substituted by one or more identical or different groups independently selected from the group consisting of C1-C6 linear or branched alkyl groups, C1-C6 linear or branched alkoxygroup, amino and haloge the A.

11. The pharmaceutical composition of claim 10, where A Deputy is represented by structural formula (II):

where R3 represents a C1-C6 linear or branched alkyl.

12. The pharmaceutical composition of claim 8, where the Deputy represents A benzimidazole group, substituted by one or more identical or different groups independently selected from the group consisting of C1-C6 linear or branched alkyl groups, C1-C6 linear or branched alkoxygroup, C3-C7 cyclic alkyl group, amino group, halogen and carbonyl group.

13. The pharmaceutical composition according to item 12, where A Deputy is represented by structural formula (III):

where R4 represents a C1-C6 linear or branched alkyl group or a C3-C7 cyclic alkyl.

14. The pharmaceutical composition according to claim 11 where the compound is selected from the group consisting of the following compounds:
4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-were)ethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-methoxyphenyl)ethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-(4-chlorophenyl)-2-hydroxyethyl]p is peridin-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-(2-(3,4-dichlorophenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-hydroxy-2-[4-(trifluoromethyl)phenyl]ethyl]-piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[(1-[2-(3,4-differenl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-phenylethyl]carbamate;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)ethyl]carbamate;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(3,4-dichlorophenyl)ethyl]carbamate;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(3,4-differenl)ethyl]carbamate;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-[4-(trifluoromethyl)phenyl]ethyl]carbamate;
4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(4-forfinal)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(3,4-dichlorophenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-(3-hydroxy-3-thiophene-2-ylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[4-(4-forfinal)-3-hydroxybutyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[5-(4-forfinal)-3-hydroxyphenyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
[3-[4-[[(4-amino-5-chloro-2-methox the benzoyl)amino]methyl]piperidine-1-yl]-1-(4-chlorophenyl)propyl]carbamate;
[4-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)butane-2-yl]carbamate;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-5-(4-forfinal)pentane-3-yl]carbamate;
4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-hydroxy-3-[4-(trifluoromethyl)phenoxy]-propyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]carbamate;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(4-pertenece)propan-2-yl]3,5-dimethylpiperidin-1-carboxylate;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(4-methoxyphenoxy)propan-2-yl]carbamate;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(2,3-dichlorophenoxy)propan-2-yl]azepin-1-carboxylate;
4-amino-5-chloro-N-[[1-[(28)-2-hydroxy-2-phenylethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[(2R)-2-hydroxy-2-phenylethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(4-chlorophenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)propyl]carbamate;
(R)-[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]ethyl]piperidine-1-yl]-1-(4-forfinal)propyl]carbamate;
(S)-[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)propyl]carbamate;
4-amino-5-chloro-N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]piperidine-1-carboxylate;
4-amino-5-chloro-N-[[1-[3-(2,5-dichlorophenoxy)-2-hydroxypropyl]-piperidine-4-yl]methyl]-2-methoxybenzamide.

15. The pharmaceutical composition according to item 13, where the specified connection is selected from the group consisting of the following compounds:
[1-(2-methylphenoxy)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-yl]propan-2-yl]carbamate;
N-[[1-[2-hydroxy-3-(4-nitrophenoxy)propyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide;
N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide;
N-[[1-[3-(4-pertenece)-2-hydroxypropyl]piperidine-4-yl]methyl]-3-methyl-2-oxopentanoate-1-carboxamide;
3-ethyl-N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide;
[1-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl) - amino]-methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]carbamate;
[1-(4-pertenece)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-yl]propan-2-yl]carbamate;
[1-(4-methoxyphenoxy)-3-[4-[[(3-methyl-2-oxobis is imidazol-1-carbonyl)amino]methyl]piperidine-1-s-1-yl]propan-2-yl]carbamate;
[1-[4-[[(3-ethyl-2-oxopentanoate-1-carbonyl)amino]methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]carbamate;
[1-(4-chlorophenoxy)-3-[4-[[(3-ethyl-2-oxopentanoate-1-carbonyl)amino]methyl]piperidine-1-yl]propan-2-yl]carbamate;
3-cyclopropyl-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-oxopentanoate-1-carboxamide;
3-cyclopropyl-N-[[1-[3-(4-forfinal)-3-hydroxypropyl]piperidine-1-s-4-yl]methyl]-2-oxopentanoate-1-carboxamide;
[3-[4-[[(3-cyclopropyl-2-oxopentanoate-1-carbonyl) - amino]-methyl]piperidine-1-s-1-yl]-1-phenylpropyl]carbamate;
[1-(4-forfinal)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-s-1-yl]propyl]carbamate;
[1-(4-methoxyphenyl)-3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-s-1-yl]propyl]carbamate;
N-[[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide;
[1-(4-forfinal)-2-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbonyl)amino]methyl]piperidine-1-s-1-yl]ethyl]carbamate;
[[2-[4-[[(3-cyclopropyl-2-oxopentanoate-1-carbonyl)amino]methyl]-piperidine-1-s-1-yl]-1-(3-methoxyphenyl)ethyl]carbamate;
[1-[4-[[(3-methyl-2-oxopentanoate-1-carbonyl)amino]methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]carbamate;
N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-oxo-3-propan-2-Evenimentul-1-carboxamide and
[3-[4-[[(2-oxo-3-propan-2-Evenimentul-1-carbon is l)amino]methyl]-piperidine-1-yl]-1-phenylpropyl]carbamate.

16. The method of treatment of gastrointestinal diseases in a mammal, comprising introducing an effective amount of piperidinol compound according to any one of claims 1 to 7 or its pharmaceutically acceptable salt to a mammal in need of treatment of gastrointestinal diseases.

17. The method according to clause 16, where gastro-intestinal disease includes at least one disease selected from irritable bowel syndrome (IBS), disorders of motor function of the stomach, constipation and visceral pain.

18. Application piperidinol compound according to any one of claims 1 to 7 or its pharmaceutically acceptable salts in the manufacture of pharmaceutical compositions for the prevention or treatment of gastrointestinal diseases.

19. Use p, where gastro-intestinal disease includes at least one disorder selected from irritable bowel syndrome (IBS), disorders of motor function of the stomach, constipation and visceral pain.

20. The compound according to claim 1, where X represents-OH.

21. Connection claim 20, where the compound is selected from the group consisting of:
4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-(4-forfinal)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-were)ethyl]piperidine-4-yl]methyl]-2-methoxime Sumida;
4-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-methoxyphenyl)ethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-(4-cyanophenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-(4-chlorophenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-hydroxy-2-(4-phenylphenyl)ethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-hydroxy-2-(2-methoxyphenyl)ethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-hydroxy-2-(3-methoxyphenyl)ethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-(3,4-dichlorophenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-(2,4-differenl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-N-[[1-[2-(4-tert-butylphenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-5-chloro-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-(2-chlorophenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-(2,4-dimetilfenil)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-(2,5-acid)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-[4-(deformedarse)phenyl]-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-(3,4-differenl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-g is droxy-2-[4-(trifluoromethyl)phenyl]-ethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-(2,4-dichlorophenyl)-2-hydroxyethyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[(2S)-2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[(2R)-2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(4-forfinal)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(4-chlorophenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-hydroxy-3-(4-were)propyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(2-chlorophenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(3-chlorophenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(2-forfinal)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(3-forfinal)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(2,3-dichlorophenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(2,4-dichlorophenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(3,4-dichlorophenyl)-3-hydroxyp the filing]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(4-isopropylphenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(3-methoxyphenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-(3-hydroxy-3-thiophene-2-ylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[4-(4-forfinal)-3-hydroxybutyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[5-(4-forfinal)-3-hydroxyphenyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
(S)-4-amino-5-chloro-N-[[1-[3-(4-forfinal)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
(R)-4-amino-5-chloro-N-[[1-[3-(4-forfinal)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenoxypropan)piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(4-pertenece)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(4-chlorophenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(2,3-dichlorophenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(2,4-dichlorophenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(2,5-dichlorophenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-Amin is-5-chloro-N-[[1-[3-(2,6-dichlorophenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(3,4-dichlorophenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(2-chlorophenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(4-methylphenoxy)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[3-(3,4-divergence)-2-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-hydroxy-3-[4-(trifluoromethyl)phenoxy]propyl]-piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-[2-hydroxy-3-(4-phenyleneoxy)propyl]piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-(2-hydroxy-3-naphthalene-2-roxiprin)piperidine-4-yl]methyl]-2-methoxybenzamide, and
4-amino-5-chloro-N-[[1-(2-hydroxy-3-phenylpropyl)piperidine-1-s-4-yl]methyl]-2-methoxybenzamide.

22. Connection claim 20, where the compound is selected from the group consisting of:
4-amino-5-chloro-N-[[1-(2-hydroxy-2-phenylethyl)piperidine-4-yl]methyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[[1-(3-hydroxy-3-phenylpropyl)piperidine-4-yl]methyl]-2-methoxybenzamide, and
4-amino-5-chloro-N-[[1-[3-(4-chlorophenyl)-3-hydroxypropyl]piperidine-4-yl]methyl]-2-methoxybenzamide.

23. The compound according to claim 1, where X represents-O(CO)NH2.

24. Connection item 23, where the compound is selected from the group consisting of:
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-phenylethyl]carbama is a;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)ethyl]carbamate;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-were)ethyl]carbamate;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-cyanophenyl)ethyl]carbamate;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-phenylphenyl)ethyl]carbamate;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(3-methoxyphenyl)ethyl]carbamate;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(3,4-dichlorophenyl)ethyl]carbamate;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(2-chlorophenyl)ethyl]carbamate;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(2,4-dimetilfenil)ethyl]carbamate;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(2,5-acid)ethyl]carbamate;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-[4-(deformedarse)phenyl]ethyl]carbamate;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(3,4-differenl)ethyl]carbamate;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-[4-(trifluoromethyl)phenyl]ethyl]carbamate;
[2-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(2,4-dichlorophenyl)ethyl]carbamate;
[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]METI is]piperidine-1-yl]-1-phenylpropyl]carbamate;
[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)propyl]carbamate;
[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-chlorophenyl)propyl]carbamate;
[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(2-chlorophenyl)propyl]carbamate;
[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(2-forfinal)propyl]carbamate;
[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(3-forfinal)propyl]carbamate;
[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(2,3-dichlorophenyl)propyl]carbamate;
[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(2,4-dichlorophenyl)propyl]carbamate;
[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(3,4-dichlorophenyl)propyl]carbamate;
[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-isopropylphenyl)propyl]carbamate;
[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(3-methoxyphenyl)propyl]carbamate;
[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-thiophene-2-ylpropyl]carbamate;
[4-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)butane-2-yl]carbamate;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-5-(4-forfinal)pentane-3-yl]carbamate;
(S)-3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amine is]methyl]piperidine-1-yl]-1-(4-forfinal)propyl carbamate;
(R)-[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)propyl]carbamate;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-phenoxypropan-2-yl]carbamate;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(4-methoxyphenoxy)propan-2-yl]carbamate;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(2,3-dichlorophenoxy)propan-2-yl]carbamate;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(2,4-dichlorphenoxy)propan-2-yl]carbamate;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(2,5-dichlorophenoxy)propan-2-yl]carbamate;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(2,6-dichlorophenoxy)propan-2-yl]carbamate;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(3,4-dichlorophenoxy)propan-2-yl]carbamate;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-[4-(trifluoromethyl)phenoxy]propan-2-yl]carbamate;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-(4-phenyleneoxy)propan-2-yl]carbamate;
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-naphthalene-2-aloxiprin-2-yl]carbamate and
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-phenylpropane-2-yl]carbamate.

25. Connection item 23, where the compound is selected from the group consisting of:
[2[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(3-methoxyphenyl)ethyl]carbamate;
3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)propylgallate;
(S)-3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)propylgallate;
(R)-[3-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-1-(4-forfinal)propyl]carbamate and
[1-[4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]piperidine-1-yl]-3-phenylpropane-2-yl]carbamate.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where A is a 6-member heteroaryl, having 1 nitrogen atom as a heteroatom, substituted with 2-3 substitutes such as indicated in the claim, R5 is a halogen atom, cyano or C1-C6alkyl, optionally substituted with a halogen atom; R6 is C1-C6 alkyl, optionally substituted with OH; C1-C3 alkenyl; a 5-member heteroaryl, having 2-4 heteroatoms, each independently selected from N, O or S, substituted with 0-2 substitutes such as indicated in the claim, R10 is a 5-member heteroaryl, having 2-3 heteroatoms, each selected from N, O or S, substituted with 0-2 substitutes, which are C1-C3 alkyl; R7, R8, R17 denote a hydrogen or halogen atom. The invention also relates to a pharmaceutical composition, having BK B2 receptor inhibiting activity, which contains compounds of formula (I), a method of inhibiting, a method of localising or detecting the BK B2 receptor in tissue, use of the compounds of compositions to produce a medicinal agent and methods for treatment.

EFFECT: compounds of formula (I) as BK B2 receptor inhibitors.

22 cl, 1 tbl, 54 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a 2,4-diamino-1,3,5-triazine derivative of general formula I, having protein kinase inhibitor properties, use thereof and a pharmaceutical composition based thereon. In general formula I Y is CH2, CHR', O, S, S(O) or S(O)2; X1, X2, X3 are independently selected from a CH groups or N; R1 is a C1-8 aliphatic group, C3-8 cycloalkyl, C6-10 aryl, ethylene-dioxyphenyl, methylene dioxyphenyl, pyridyl, each of which is optimally substituted with one or more identical or different groups R"; R' is hydrogen, OH, halogen, such as F, Cl, Br, I, or carboxyl or carboxamide, optimally N-substituted with (C1-6)alkyl, or cyano or halo(C1-8)alkyl, (C1-8)alkoxy, piperidinyl, optimally substituted with methyl; R" is R' or RD; R21, R22, R23, R24 are independently selected from groups F, Cl, Br, I, CN, (C1-16)alkyl; furthermore, R21 and R22 and/or R23 and R24 can be combined and represent one oxo (=O) group or together with a carbon atom can form a spirocycle containing 3 to 7 carbon atoms; furthermore, R21 and R24 together with two carbon atoms can form an aliphatic or aromatic ring containing 4 to 8 atoms, optionally substituted with one or more groups R'; RD is an oxo group =O or =S.

EFFECT: invention can be used to treat autoimmune or cancerous diseases, rheumatoid arthritis and non-Hodgkin lymphoma.

13 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel sulphate of 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)benzamide, which can be used in treating diseases which respond to protein kinase inhibition. The sulphate is obtained by reacting 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)benzamide in form of a free base with sulphuric acid in a solvent medium.

EFFECT: salt has low hygroscopicity and high solubility.

2 cl, 8 dwg, 17 tbl, 11 ex

FIELD: biotechnologies.

SUBSTANCE: in a compound of formula ,

X means N or CH, R1 means hydrogen or cyano, R2 means saturated 4-7-membered residue of heterocyclyl, which is bound through a nitrogen atom that contains 1 to 2 heteroatoms chosen from N and O. Besides, heterocyclyl residue can be replaced with one substituent chosen from a group consisting of C3-C6-cycloalkyl, or with 1-4 fluorine atoms. The invention also refers to a method for obtaining compounds and to a medicine on their basis.

EFFECT: compounds can be used for production of a medicine suitable for being used in a method of treatment or prophylaxis of cardiovascular diseases, cardiac insufficiency, anemia, chronic diseases of kidneys and kidney failure.

16 cl, 1 tbl, 29 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyranyl aryl methylbenzoquinazolinone compounds of formula (I), which are positive allosteric modulators of the M1 receptor and which can be used to treat diseases associated with the M1 receptor, such as Alzheimer's disease, schizophrenia, pain disorders or sleep disturbance. In formula (I) X-Y are selected from a group comprising (1) -O-CRARB-, (2) -CRARB-O-, (3) -CRARB-SRC-, (4) -CRARB-NRC- and (5) -NRC-CRARB-, where each RA and RB is a hydrogen atom, and RC is selected from a group comprising (a) hydrogen, (b) -C(=O)-C1-6alkyl, (c) -C1-6alkyl, (d) -C(=O)-CH2-C6H5, (e) -S(=O)2-C1-6 alkyl, R1 is a hydroxy group, R2 is selected from a group comprising (1) -phenyl, (2) - heteroaryl, where the phenyl or heteroaryl group R2 is optionally substituted; the rest of the values of the radicals are given in the claim.

EFFECT: obtaining novel pyranyl aryl methylbenzoquinazolinone compounds.

28 cl, 12 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to 5-phenyl-1H-pyrazin-2-one derivatives of general formula II or pharmaceutically acceptable salts thereof, where R denotes -R1 or - R1-R2-R3; R1 denotes aryl or heteroaryl, and is optionally substituted with one or two R1'; where each R1' independently denotes C1-6alkyl, halogen or C1-6halogenalkyl; R2 denotes -C(=O), -CH2-; R3 denotes R4; where R4 denotes an amino group or heterocycloalkyl, and is optionally substituted with one or two substitutes selected from C1-6alkyl, hydroxy group, oxo group, C1-6hydroxyalkyl, C1-6alkoxy group; Q denotes CH2; Y1 denotes C1-6alkyl; Y2 denotes Y2b; where Y2b denotes C1-6alkyl, optionally substituted with one Y2b'; where Y2b' denotes a hydroxy group, n and m are equal to 0; Y4 denotes Y4c or Y4d; where Y4c denotes lower cycloalkyl, optionally substituted with halogen; and Y4d denotes an amino group, optionally substituted with one or more C1-6alkyl; where "aryl" denotes phenyl or naphthyl, "heteroaryl" denotes a monocyclic or bicyclic radical containing 5 to 9 atoms in the ring, which contains at least one aromatic ring containing 5 to 6 atoms in the ring, with one or two N or O heteroatoms, wherein the remaining atoms in the ring are carbon atoms, under the condition that the binding point of the heteroaryl radical is in the aromatic ring, "heterocycloalkyl" denotes a monovalent saturated cyclic radical consisting of one ring containing 5 to 6 atoms in the ring, with one or two ring heteroatoms selected from N, O or SO2. The invention also relates to use of the compound of formula II or a pharmaceutical composition based on the compound of formula II.

EFFECT: obtaining novel compounds that are useful for modulating Btk activity and treating diseases associated with excessive activity of Btk.

7 cl, 2 tbl, 53 ex

FIELD: chemistry.

SUBSTANCE: described are 1,2-disubstituted heterocyclic compounds of formula (I) where HET, X, Y and Z values are presented in description, which are phosphodiesterase 10 inhibitors. Also described are pharmaceutical composition and methods of treating central nervous system (CNS) disorders and other disorders, which can influence CNS function.

EFFECT: among disorders that can be subjected to treatment, there are neurological, neurodegenerative and psychiatric disorders, which include, but are not limited by them, disorders, associated with impairment of cognitive ability or schizophrenic symptoms.

14 cl, 824 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 5-phenyl-1 H-pyridin-2-one and 6-phenyl-2H-pyridazin-3-one of general formulas I-III: , where: R represents H, -R1, -R1-R2-R3, -R1-R3 or -R2-R3; R1 represents heteroaryl, which stands for monocyclic radical, which contains 5-6 atoms in cycle and one or several heteroatoms N, optionally substituted by one or some lower alkyls; R2 represents -C(=O), -C(=O)NR2'; where R2' represents H or lower alkyl; R3 represents H or R4; where R4 represents lower alkyl or heterocycloalkyl, which stands for monovalent saturated cyclic radical, consisting of one ring, which contains one or two ring-shaped heteroatoms, selected from N and O; X represents CH or N; Y1 represents H, lower alkyl or lower halogenalkyl; each Y2 independently represents lower alkyl, which is optionally substituted by one or several substituents, selected from group, which consists of hydroxygroup, lower alkoxygroup; n has value 0, 1, 2 or 4; Y3 represents Y4a, Y4b, Y4c or Y4d; where Y4a represents H; Y4b represents lower alkyl, optionally substituted by one or sseveral substituents, selected from group, consisting of lower halogenalkyl, halogen; Yc represents lower cycloalkyl, optionally substituted by one or some substituents, selected from group, consisting of lower alkyl, lower halogenalkyl, halogen; and Y4d represents aminogroup, optionally substituted by one or some lower alkyls; or to its pharmaceutically acceptable salt. Also described are: pharmaceutical composition, based on upper said compounds, as well as application of compounds of I-III formulas for treatment of inflammatory or autoimmune condition.

EFFECT: described are novel compounds, which can be useful for modulating Btk activity and treatment of diseases, associated with excess Btk activity.

14 cl, 102 ex, 1 tbl

Jnk inhibitors // 2504545

FIELD: biotechnologies.

SUBSTANCE: in formula

each of R1 and R2 independently represents H or C1-6alkyl; or R1 and R2 together form C3-6cycloalkyl circle, which is optionally replaced with one or more R2'; R2' represents C1-6alkyl, hydroxy group, halogen, amino group, C1-6alkoxy group, C1-6hydroxyalkyl or C1-6haloalkyl; R3 represents H or N(R4)(R5); R4 represents H, C1-6alkyl or C(=O)OR4'; R4' and R5 represents H or C1-6alkyl; represents H or C1-6alkyl; or R2 and R3 together form 5-membered heterocycle containing 1 atom of N in the amount of heteroatom, which is optionally replaced with one or more R2'; Q represents CH or N; Z1 represents (CH2)u; u and v mean 1; Z2 represents (CH2)v; m, n, p, r, q mean 0; Y1 represents CH(Y1'); Y1' represents H or C1-6alkyl; Y2 represents H or represents C1-6alkyl. Invention also refers to compounds of structural formulae (II), (IV) and to pharmaceutical composition containing the above compounds.

EFFECT: improving inhibiting activity in relation to JNK kinase.

10 cl, 4 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound, which contains pyridine ring, represented by formula (1) , where R0 represents C1-6alkoxygroup, C1-6alkoxy-C1-6alkoxygroup, C1-6alkoxy-C1-6alkyl group, 1,3-dioxan-2-yl-C1-6alkyl group or group CR01C(=NOR02) (where each of R01 and R02 independently represents C1-6alkyl group), R1 represents C1-2 alkoxycarbonyl group, acetyl group or benzoyl group, which can be substituted with nitrogroup, X represents halogen atom, and n represents quantity of X substituents and equals integer number from 0 to 3, and when n equals 2 or more, X substituents can be similar or different from each other, which can be synthesised in industrially profitable way and used as intermediate compound for obtaining tetrazolyloxime derivatives which demonstrate fungicidal activity.

EFFECT: industrially profitable methods of obtaining tetrazolyloxime derivatives are described.

10 cl, 3 tbl, 13 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: chemistry.

SUBSTANCE: described are 1,2-disubstituted heterocyclic compounds of formula (I) where HET, X, Y and Z values are presented in description, which are phosphodiesterase 10 inhibitors. Also described are pharmaceutical composition and methods of treating central nervous system (CNS) disorders and other disorders, which can influence CNS function.

EFFECT: among disorders that can be subjected to treatment, there are neurological, neurodegenerative and psychiatric disorders, which include, but are not limited by them, disorders, associated with impairment of cognitive ability or schizophrenic symptoms.

14 cl, 824 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining activated ester of formula (I): where R stands for C1-C6 alkyl, linear or branched, 6-membered heteroaryl with one nitrogen atom as heteroatom; Alk stands for C1-C6 alkyl, linear or branched, consisting in interaction of dicyclohexylamine salt P1 and disuccinimidylcarbonate (DSC) in solvent which represents ketone, in which salt of dicyclohexylamine and N-hydroxycuccinimide P2 precipitates.

EFFECT: method makes it possible to obtain target product with high output and good degree of purity.

10 cl, 1 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted pyrrolidine-2-carboxamides of formula I or their pharmaceutically acceptable salts, where values X, Y, R1, R2, R3, R3, R4, R5, R6 and R7 are given in item 1 of the formula. Compounds can be used in pharmaceutical composition, inhibiting interaction of MDM2-p53.

EFFECT: compounds can be used as anti-cancer medications.

46 cl, 4 dwg, 347 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel quinazoline derivatives of formula , where each of R1, R2 and R5, independently, represents H; one of R3 and R4 represents where n - 1 or 2; each Ra represents H, C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkoxy, C1-10alkansulfonyl carboxy-group, 5-6-membered monocyclic heterocycloalkyl, which has one or several heteroatoms, selected from O and N, where N atom can be substituted with C1-10alkyl, phenyl, optionally substituted with halogen, 5-6-membered monocyclic heteroaryl, which has one or several heteroatoms, selected from N and S, 7-membered bicyclic heterocycloalkyl, which has 2 N atoms; C2-10alkenyl; C2-10alkinyl; cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms; each of Rb and Rc, independently, represents H or C1-10alkyl, optionally substituted C1-10alkoxy, or Rb and Rc, together with atom of nitrogen, with which they are bound, form bicyclic ring of the following formula: , where each of m1, m2, m3, and m4 is 0, 1 or 2; A is CH; B is NR, where R is H or C1-10alkyl; and each of Ri, Rii, Riii, RiV, Rv, Rvi, Rvii and Rviii is H; or 6-7-membered monocyclic heterocycloalkyl, containing 1-2 N atoms, optionally substituted with substituent, selected from group, including hydroxy, C1-10alkyl, optionally substituted C1-10alkoxy, C1-10alkyl, optionally substituted with C3-6cycloalkyl; and each of Rd, Re, independently represents H, C2-10alkenyl; C2-10alkinyl; or C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkyloxy, hydroxy, CN, 5-6-membered monocyclic heterocycloalkyl, which has 1 or 2 N atoms, optionally substituted with C1-10alkyl, halogen or 5-6-membered heterocycloalkyl, which has 1 N atom, phenyl, optionally substituted with halogen, cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms, 5-6-membered monocyclic heteroaryl, which has one or 2 N atoms; or Rd and Re, together with nitrogen atom, with which they are bound, form 5-6-membered saturated heterocycloalkyl, which has 1-2 heteroatoms, selected from N and O, optionally substituted with substituent, selected from group, including C1-10alkyl (which is optionally substituted with C3-6cicloalkyl, C1-10alkoxy, halogen), 5-membered heterocycloalkyl, which has one N atom, halogen, C1-10alkansulfonyl, C1-10alkylcarbonyl, optionally substituted with halogen, or Rd and Re, together with nitrogen, with which they are bound, form 7-10-membered, saturated, bicyclic heterocycloalkyl, containing 1-2 heteroatoms, selected from N and O, optionally substituted with C1-10alkyl; and the other of R3 and R4 represents H, halogen or C1-10alkoxy; X represents NRf, where Rf represents phenyl, substituted with C2-4 alkinyl; and Z represents N. Invention also relates to particular quinazoline derivatives, based on it pharmaceutical composition, and to method of cancer treatment.

EFFECT: novel quinazoline derivatives, inhibiting EGFR activity are obtained.

11 cl, 171 ex

FIELD: agriculture.

SUBSTANCE: agent for control of plant diseases comprises: at least one compound chosen from tetrazolyl oxime derivatives represented by the formula , and their salts: in the formula (I) X is C1-6-alkyl group, C1-6-alkoxy group, halogen atom, nitro group, cyano group, C6-10-aryl group or C1-6-alkyl-sulfonyl group; n is an integer from 0 to 5; Y is C1-6 alkyl group; Z is a hydrogen atom, an amino group or a group represented by the formula NHC(-O)-Q; Q is a hydrogen atom, C1-8-alkyl group, C1-6-haloalkyl group, C3-6-cycloalkyl group, C1-8-alkoxy group, C3-6-cycloalkoxy group, C7-20-aralkoxy group, C1-4-alkylthio-C1-8 alkyl group, C1-4-alkoxy-C1-2-alkyl group, C1-4-acylamino-C1-6-alkyl group, C1-4-acylamino-C1-6-alkoxy group, C1-8-alkylamino group, C2-6-alkenyl group, C7-20-aralkyl group or C6-10-aryl group; R is an halogen atom; m is an integer from 0 to 3; and at least one compound selected from the group consisting of triflumizole, hydroxyisoxazole, acetamiprid and their salts.

EFFECT: invention enables to improve the efficiency of disease control.

2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or a salt thereof, where D1 is a single bond, -N(R11)- or -O-, where R11 is a hydrogen atom or C1-C3 alkyl; A1 is C2-C4 alkylene, or any of divalent groups selected from the following formulae , and ,

where n1 equals 0 or 1; n2 equals 2 or 3; n3 equals 1 or 2; R12 and R13 are each independently a hydrogen atom or C1 -C3 alkyl; v is a bond with D1; and w is a bond with D2; D2 is a single bond, C1-C3 alkylene, -C(O)-, S(O)2-, -C(O)-N(R15)-, or -E-C(O)-, where E is C1-C3 alkylene, and R15 is a hydrogen atom; R1 is a hydrogen atom, C1-C6 alkyl, a saturated heterocyclic group which can be substituted with C1-C6 alkyl groups, an aromatic hydrocarbon ring which can be substituted with C1-C3 alkyl groups, C1-C4 alkoxy groups, halogen atoms, cyano groups, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or the following formula ,

where n1 equals 0, 1 or 2; m2 equals 1 or 2; D12 is a single bond, -C(O)- or -S(O)2-; R18 and R19 denote a hydrogen atom; R17 is a hydrogen atom or C1-C3 alkyl; and x is a bond with D2; under the condition that when R17 denotes a hydrogen atom, D12 denotes a single bond; under the condition that when D1 denotes a single bond, A1 denotes a divalent group of said formula (1a-5) or (1a-6); when D1 denotes -N(R11)-, -O-, or -S(O)2-, A1 denotes a single bond, C2-C4 alkylene, or any of divalent groups selected from formulae (1a-1)-(1a-3), where, when A1 denotes a single bond, D2 denotes -E-C(O)-; and D3 is a single bond, -N(R21)-, -N(R21)-C(O) - or -S-, where R21 is a hydrogen atom; and R2 denotes a group of formula ,

where Q denotes an aromatic hydrocarbon ring, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, a condensed polycyclic aromatic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or a partially unsaturated monocyclic or a condensed bicyclic carbon ring and a heterocyclic ring; and y denotes a bond with D3; and R23, R24 and R25 each independently denotes a hydrogen atom, a halogen atom, a cyano group, C1-C3 alkyl, which can be substituted with hydroxyl groups, halogen atoms or cyano groups, C1-C4 alkoxy group, which can be substituted with halogen atoms, alkylamino group, dialkylamino group, acylamino group, or the formula ,

where D21 denotes a single bond or C1-C3 alkylene; D22 denotes a single bond or -C(O)-; R26 and R27 each independently denotes a hydrogen atom or C1-C3 alkyl; and z denotes a bond with Q; under the condition that when D22 denotes a single bond, R27 is a hydrogen atom. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula , a IKKβ inhibitor, a method of inhibiting IKKβ, a method of preventing and/or treating an NF-kB-associated or IKKβ-associated disease, and intermediate compounds of formulae and .

EFFECT: obtaining novel isoquinoline derivatives, having useful biological properties.

46 cl, 3 dwg, 38 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel acyl thiourea derivatives of formula or a pharmaceutically acceptable salt thereo, where R1 is a hydrogen atom or a C1-3 alkyl group; R2 is a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C6-14 aromatic hydrocarbon group or an optionally substituted saturated or unsaturated 5-7-member heterocyclic group containing 1 or 2 nitrogen or sulphur atoms, or R1 and R2, together with the nitrogen atom which they are bonded, can form an optionally substituted nitrogen-containing saturated heterocyclic group selected from a group comprising pyrrolinyl, piperidinyl, piperazinyl or morpholino group; where the substitute is selected from a group comprising a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1-6 alkanoyl group, a C1-6 alkyl group, a C3-10 cycloalkyl group, a C2-6 alkenyl group, C1-6 alkoxy group, an amino group, a C1-6 alkylamino group, a C1-6 alkanoylamino group, a C1-6 alkylaminocarbonyl group, a C1-6 alkylsulphonyl group, a C6-14 aromatic group, a saturated or unsaturated 5-7-member heterocyclic group containing 1-4 nitrogen and/or oxygen atoms, a saturated or unsaturated 5-7-member heterocycyl-carbonyl group containing 1 or 2 nitrogen and/or oxygen atoms, and an oxo group; R3 is a C1-6 alkyl group; and R4 is a halogen atom; R5 and R6, which can be identical or different from each other, denote a hydrogen atom, a halogen atom, a C1-3 alkyl group which can be substituted with a halogen atom, or a C1-6 alkoxy group. The invention also relates to a pharmaceutical or anti-tumour agent based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel acetyl thiourea derivatives having c-Met inhibiting activity are obtained.

11 cl, 2 dwg, 4 tbl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to compounds of formula or a pharmaceutically acceptable salt of such a compound, where - X is a carbon atom and R1a and R2a together form a bond; or - X is a carbon atom, R1a and R2a together form a bond, and R1 and R2 together form a moiety , where the asterisk shows the bonding site of R2; or - X is a carbon atom, R1a is hydrogen or (C1-4)alkoxy, and R2a is hydrogen; and R1 and R2, unless indicated otherwise, independently denote hydrogen; (C1-5)alkyl; aryl, where aryl denotes naphthyl or phenyl, where said aryl is unsubstituted or independently mono- or disubstituted, where the substitutes are independently selected from a group consisting of (C1-4)alkyl, (C1-4) alkoxy and halogen; or heteroaryl, selected from pyridyl, thienyl, oxazolyl or thiazolyl, where said heteroaryl is unsubstituted; under the condition that if R2 is aryl or heteroaryl, R1 cannot be aryl or heteroaryl, where the aryl and heteroaryl are independently unsubstituted or substituted as defined above; R3 is hydrogen or -CO-R31; R31 is (C1-5)alkyl, (C1-3)fluoroalkyl or (C3-6)cycloalkyl; n equals 1, 2, 3 or 4; B is a -(CH2)m- group, where m equals an integer from 1 to 3; A is-(CH2)P-, where p equals 2 or 3; R4 is (C1-5)alkyl; W is , where R5 is hydrogen or (C1-5)alkyl; R8, R9 and R10 is independently hydrogen, halogen, (C1-5)alkyl, hydroxy, -(C1-5)alkoxy, -O-CO-(C1-5)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, -CO-(C1-5)alkoxy, (C1-2)alkoxy-(C1-4)alkoxy or -NH-CO-(C1-5)alkyl. The invention also relates to a pharmaceutical composition based on a compound of formula (I).

EFFECT: novel compounds which are useful as calcium channel blockers are obtained.

11 cl, 2 tbl, 166 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to fluorinated catharantine derivatives of general formula I in which broken line represents possibility of double bond presence, when substitution X is absent, or simple bond, when X stands for substitution with another group: H, R1, R2 and R3 independent on each other represent a fluorine atom or methylated group, and n=2.

EFFECT: invention also relates to method of obtaining said derivative and to its application as intermediate compound for synthesis of fluorated dimeric Vinca alkaloids, in particular vinflunine, which in its turn is used as anti-cancer agent.

22 cl

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