Cyclic amine compounds

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of cyclic amine of the general formula (1): , their pharmaceutically acceptable salts or hydrates wherein each among R1, R2 and R3 represents independently hydrogen atom, halogen atom, hydroxy-group, (C1-C8)-alkoxy-group; each among W1 and W2 represents independently nitrogen atom (N) or -CH; X represents oxygen atom (O), -NR4, -COONR4 or -NR4CO; R4 represents hydrogen atom, (C1-C8)-alkyl, (C3-C6)-alkynyl, substituted or unsubstituted phenyl, unsubstituted benzyl, unsubstituted indanyl wherein substitute(s) of phenyl represent(s) 1-3 groups or atoms chosen from (C1-C8)-alkyl, (C1-C8)-alkoxy-group, (C1-C8)-alkoxy-group substituted with 1-3 halogen atoms, (C1-C8)-alkylthio-group, (C1-C8)-alkylsulfonyl, halogen atom, trifluoromethyl group and (C1-C3)-alkylenedioxy-group; each among l, m and n represents number 0 or 1. Proposed compounds possess inhibitory effect on cell adhesion and/or cell infiltration and can be used as a medicinal agent and pharmaceutical composition based on thereof.

EFFECT: valuable biological and medicinal properties of compounds and pharmaceutical composition.

6 cl, 1 tbl, 439 ex

 

The present invention relates to new compounds, cyclic amine, which have inhibitory effects on cell adhesion and cell infiltration, and are useful as anti-asthmatic medications, antiallergic agents, Antirheumatic means protivoateroskleroticheskim tools, anti-inflammatory drugs, anti-Sjogren syndrome, etc. and to medicines containing such compounds.

Description of the prior art

In various inflammatory diseases observed infiltration of leukocytes into inflamed areas. For example, described the infiltration of eosinophils in the bronchial tubes in asthma (Ohkawara y, et al., Am. J. Respir. Cell Mol. Biol.,12, 4-12 (1995)), infiltration of macrophages and T cells in the aorta when arteriosclerosis (A. Sakai et al., Arterioscler. Thromb. Vasc. Biol.,17, 310-316 (1997)), infiltration of T cells and eosinophils in the skin in atopic dermatitis (H. Wakita et al., J. Cutan. Pathol.,21, 33-39 (1994)) or contact dermatitis (T. Satoh et al., Eur. J. Immunol.,27, 85-91 (1997)), and the infiltration of various cells in rheumatoid synovial tissue (Tak PP. et al., Clin. Immunol. Immunopathol.,77, 236-242 (1995)).

Sjogren syndrome in humans is an organ-specific autoimmune disease characterized by the infiltration of leukocytes in the salivary and lacrimal glands, causing the destruction of g is angulares system and the emergence of such symptoms, as dry mouth and dry eyes due to lack of secretion of the glands (Fox RI. et al. "Sjogren''s syndrome: proposed criteria for classification", Arthritis Rheum., 1986, 29: 577-585).

Infiltration of such leukocytes induced by cytokines, chemokines, lipid and compliments produced in inflamed areas (Albeda SM. et al., FASEB J.,8, 504-512 (1994)). Activated leukocytes in the blood adhere to vascular endothelial cells as a result of interaction, called "rotation" or "binding" with endothelial cells activated in this way. Then leukocytes transmigrant through the endothelium, penetrating into the inflamed areas (Springer TA., Annu. Rev. Physiol.,57, 827-872 (1995)). When the adhesion of leukocytes to vascular endothelial cells during this process an important role is played by various cell adhesion molecules, such as immunoglobulin superfamily (ICAM-1, VCAM-1, and so on), the family of selectins (E-selectin and the like), a family of integrins (LFA-1, VLA-4, and so on) and CD44 induced on the cell surface as a result of stimulation by cytokines, etc. ("Rinsho Meneki (Clinical Immune)",30, Supple. 18 (1998)), it is noted the link between impaired status and aberrant expression of cell adhesion molecules.

Accordingly, the tool is able to inhibit cell adhesion or cell infiltration, may be useful as a means prevented the I and treatment of allergic diseases, such as bronchial asthma, dermatitis, rhinitis and conjunctivitis; autoimmune diseases such as rheumatoid arthritis, nephritis, Sjogren syndrome, inflammatory bowel disease, diabetes, and arteriosclerosis, and chronic inflammatory diseases. In fact, there are reports that antibodies against cell adhesion molecules on leukocytes, such as LFA-1, Mac-1 and VLA-4, or antibodies against ICAM-1, VCAM-1, P-selectin, E-selectin, etc. on vascular endothelial cells, which become their ligands, inhibit the infiltration of leukocytes into inflammatory sites in animal models. For example, neutralizing antibodies against VCAM-1 and VLA-4, representing their reading receptors, can slow the development of diabetes in the NOD mouse model that spontaneously causing diabetes (Michie SA. et al., Curr. Top. Environ. Immunol.,231, 65-83 (1998)). It was also found that the antibody against VLA-4 and ICAM-1 and its reading receptor LFA-1 inhibits the infiltration of eosinophils in the model of allergic conjunctivitis in Guinea pigs and mice (Ebihara et al., Current Eye Res.,19, 20-25 (1999); Whitcup SM. et al., Clin. Immuniol.,93, 107-113 (1999)), and a monoclonal antibody against VCAM-1 inhibits the infiltration of leukocytes on the model of DSS-induced colitis in mice, weakening it (A. Soriano et al., Lab. Invest.,80, 1541-1551 (2000)). In addition, anti-VLA-4 antibody and anti-CD44 antibody reduces the frequency is oznacevanje symptoms on the model of collagen-induced arthritis in mice (Zeidler A. et al., Autoimmunity,21, 245-252 (1995)). Even in mice with deficiency of cell adhesion molecules is observed inhibition of infiltration of leukocytes into inflamed tissue, such as in models of inflammation (Bendjelloul F. et al., Clin. Exp. Immunol.,119, 57-63 (2000); Wolyniec, WW. et al., Am. J. Respir. Cell Mol. Biol.,18, 777-785 (1998); Bullard DC. et al., J. Immunol.,157, 3153-3158 (1996)).

However, the development of drugs based on antibodies is difficult, because they are polypeptides and their oral administration is difficult. Moreover, the problem also is the possible side effects caused by antigenicity and allergic reactions.

On the other hand, has conducted various studies of low molecular weight compounds that have an inhibitory effect on cell adhesion, to ensure the possibility of oral administration. Such compounds include derivatives of benzothiophene (Boschelli DH. et al., J. Med. Chem.,38, 4597-4614 (1995)), derivatives of naphthalene (lined patent application of Japan No. 10-147568), hydroxybenzoic acid derivatives (patent application laid Japan No. 10-182550), lignans (lined patent application of Japan No. 10-67656), derivatives of 2-substituted benzothiazoles (lined patent application of Japan No. 2000-086641), condensed compounds pyrazine (lined patent application of Japan No. 2000-319277, filed as PCT), 2,6-dialkyl-4-Seeley is phenol (lined patent application of Japan No. 2000-509070), etc. However, in these cases, the goal is often not met. Cyclic diamine compounds described in patent applications laid Japan No. 9-143075, 11-92382 and WO 02/20477 not have a sufficient inhibitory effect on cell adhesion, so it is necessary to further strengthen their activity.

The aim of the present invention is the development of substances that have an inhibitory effect on cell adhesion and cell infiltration, plus a strong anti-asthmatic action, antiallergic action, anti-rheumatic effect, protivoateroskleroticheskim action, anti-inflammatory action and the action against Sjogren syndrome.

The invention

Taking into consideration the above circumstances, the authors of this invention have conducted extensive studies to develop a substance that inhibits cell adhesion and cell infiltration. In the result it was found that the compounds represented by the General formula (1)having phenylpyridine or biphenylene groups on both ends of the cyclic amine, have a strong effect on the inhibition of cell adhesion and cell infiltration and are useful as antiallergic agents, anti-asthmatic medications, Antirheumatic means protivoateroskleroticheskim funds against the inflammatory funds or anti-Sjogren syndrome.

The present invention provides for the connection of a cyclic amine represented by the following General formula (1):

where each of R1, R2and R3independently represents a hydrogen atom, halogen atom or hydroxy, alkyl, halogen-substituted alkyl, alkoxy, alkylthio, carboxyl, alkoxycarbonyl or alkanoyl;

each of W1and W2independently represents N or CH;

X represents O, NR4, CONR4or NR4CO;

each of R4independently represents a hydrogen atom or alkyl, alkenyl, quinil, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroalkyl and each of l, m and n represents the number 0 or 1,

or its acid additive salt or its hydrate.

In accordance with the present invention also provides a drug containing as an active ingredient the above-mentioned compound a cyclic amine, the acid additive salt or its hydrate.

In accordance with the present invention also provides a pharmaceutical composition comprising the above compound cyclic amine, the acid additive salt or its hydrate and farmaceuticas and an acceptable carrier.

In accordance with the present invention also provides the use of the above compounds, cyclic amine, the acid additive salt or hydrate for the manufacture of a medicinal product.

In accordance with the present invention also provides a method of treatment of a disease caused by cell adhesion and/or cell infiltration, including the introduction of an effective amount of the above compounds, cyclic amine, its salt or its hydrate the patient in need of such treatment.

Preferred embodiments of the invention

The compound of the present invention differs in that the cyclic amine has at both its ends two phenylpyridine or biphenylene group. So far, it was not known that compounds having such a structure, have a strong effect on the inhibition of cell adhesion and cellular infiltration.

In the General formula (1) halogen atoms for R1, R2and R3include fluorine atoms, chlorine, bromine and iodine.

The alkyl group for R1, R2, R3and R4usually includes straight, branched or cyclic With1-C8alkyl groups, such as straight, branched or cyclic With1-C8alkyl groups such as methyl, ethyl, propyl, BU is Il, pentyl, hexyl, heptyl and aktalnye group, and3-C8cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl and cyclohexylethyl. Among them, particularly preferred are1-C6alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, etc.

Halogen-substituted alkyl group for R1, R2and R3usually includes With1-C8alkyl group substituted by 1-3 halogen atoms. Among them, particularly preferred are1-C6alkyl group substituted by 1-3 halogen atoms, such as trifluoromethyl, 2,2,2-triptorelin etc.

Alkoxygroup usually includes straight, branched or cyclic With1-C8alkoxygroup, such as straight, branched or cyclic With1-C8alkoxygroup, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy and3-With8cycloalkylcarbonyl, for example, cyclopropane, CYCLOBUTANE, cyclopentyloxy, cyclohexyloxy, cyclohexylmethoxy and cyclohexylethylamine. Among them, particularly preferred are1-C6alkoxygroup, such as methoxy, ethoxy, n-propoxy, isopropoxy and n-butylacrylate.

Alkylthio which usually includes With 1-C8ancilliary and preferably represents a C1-C6allylthiourea, such as, for example, methylthio, ethylthio, n-propylthio, isopropylthio etc.

Alkoxycarbonyl group usually includes With1-With6alkoxycarbonyl group, and preferably represents a C1-C4alkoxycarbonyl group, such as methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl etc.

Alcoolica group usually includes With1-C6alcoholnye group, and preferably represents a C1-C4alkanoyloxy group, such as acetyl, propionyl, butyryl, isobutyryl etc.

Alchemilla group for R4usually includes With3-C8alkeneamine group, and preferably represents a C3-C6alkenylphenol group, such as 2-propenyl, 3-butenyl etc. Alchemilla group usually includes With3-C8alkyline group, and preferably represents a C3-C6alkylamino group, such as 2-PROPYNYL, 3-butynyl etc.

The aryl group for R4usually includes With6-C14aryl group, and preferably represents phenyl, naphthyl, antril, indenyl, indanyl, 5,6,7,8-tetrahydronaphthyl etc.

Heteroaryl group for R4usually includes heteroaryl groups are 5 - or 6-membered what olicom, containing 1-4 nitrogen atom in the ring, and preferably represents imidazolyl, pyridyl, pyrimidinyl etc.

Kalkilya group usually includes With6-C14arils1-C6alkyl groups, such as phenyl With1-C6alkyl groups and naftilos1-With6alkyl groups, for example benzyl, naphthylmethyl, phenylethyl, phenylpropyl etc. Heteroalkyl group for R4usually includes heteroaryl1-C6alkyl groups, 5 - or 6-membered ring containing 1-4 nitrogen atom of the ring such as imidazolyl-C1-C6alkyl, pyridyl1-C6alkyl, pyrimidinyl1-C6alkyl, etc.

Group that can substitute the above aryl, heteroaryl, aralkyl or heteroalkyl include 1 to 3 groups or atoms selected from alkyl, alkoxy, halogen-substituted alkoxy, alkylthio, alkylsulfonyl, alkylsulfonyl, halogen, nitro, amino, acetylamino, trifloromethyl, alkylenedioxy, where these alkyl, alkoxy and alkylthio include the values illustrated for R1˜R3. The alkyl group contained in alkylsulfonyl and alkylsulfonyl groups include1-C3alkyl groups such as methyl, ethyl, n-propyl and isopropyl group. Halogen-substituted alkoxy include1-C8alkoxygroup, someseni is 1 to 3 halogen atoms, and preferably represents a C1-C4alkoxygroup substituted by 1-3 halogen atoms, such as triptoreline or 2,2,2-triptoreline. Alkylenedioxy usually includes With1-C3alkylenedioxy, such as methylenedioxy, Ethylenedioxy and propyleneoxide.

X preferably represents NR4. More preferably X represents NR4where R4represents a substituted or unsubstituted With6-C14aryl group, or substituted or unsubstituted heteroaryl group with 5 - or 6-membered ring containing 1-4 nitrogen atom in the ring. As shown in the following example tests 1, the compounds of formula (1)in which X represents NR4have a particularly strong effect on the inhibition of cell adhesion.

R1, R2and R3preferably attached to the phenyl group in positions 3, 4 and 5. In this case, particularly preferably, R1and R3(in positions 3 and 5 of the phenyl ring) was alkoxygroup or halogen. Also preferably, R2(in position 4 of the phenyl ring) was a hydrogen atom, halogen atom or hydroxy, alkyl, halogen-substituted alkyl, alkoxy, alkylthio, carboxy, alkoxycarbonyl or alkanoyl.

l is 0 or 1, preferably 1.

W 1preferably represents n

W2preferably represents n

Preferred compounds include the compounds of formula (1)in which X represents NR4where R4is substituted or unsubstituted With6-C14aryl group or substituted or unsubstituted heteroaryl group with 5 - or 6-membered ring containing 1-4 nitrogen atom in the ring. Particularly preferably, R4represents phenyl or pyridyloxy group which may be substituted by one or two groups, or one or two atoms selected from halogen, alkyl, alkoxy, alkylthio, trifloromethyl, alkylenedioxy.

Acid additive salts of the compounds (1) in accordance with this invention have no particular restrictions, provided that they are pharmaceutically acceptable salts. Examples of such salts include acid additive salts of mineral acids, such as hydrochloride, hydrobromide, hydroiodide, sulfates and phosphates and acid additive salts of organic acids, such as benzoate, methanesulfonate, econsultancy, bansilalpet, p-toluensulfonate, oxalates, maleate, fumarate, tartratami, citrates and acetates.

The compounds of formula (1) may be present in the form of a solvate, examples of which are hydrates, such salt is ATA included in the scope of the present invention.

The compounds of formula (1) can be obtained in accordance with the following methods And˜L.

Method And: obtaining the compounds of formula (1)in which l=1, m=0, n=1 and X=CONR4

where W1, W2, R1, R2, R3and R4have the meanings specified above, W3has the same value as W1or W2and means removable group such as halogen atom, or methanesulfonate or p-toluensulfonate.

Connection (2) and its derivative N-(2-nitrobenzenesulfonamide (3) is subjected to interaction, receiving the connection (4). The obtained compound (4) is treated with thiophenols in the presence of a base such as potassium carbonate, to remove 2-nitrobenzenesulfonyl group, receiving the amine compound (5). Alternatively, if R4represents H, then the compound (2) may be subjected to interaction with phthalimide potassium and then derived phthalimide (6) can be treated with hydrazine to obtain the corresponding amine compounds (5).

On the other hand, the compound (2) is subjected to interaction with utilizedabated (7) in a solvent such as acetonitrile, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), dioxane, toluene, benzene, etc. in the presence of a base, that the CSOs as potassium carbonate and the like, at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at room temperature over night, receiving the connection (8). Compound (8) is subjected to conventional alkaline hydrolysis to obtain the corresponding compounds of carboxylic acid (9).

Connection carboxylic acid (9) is subjected to interaction with the amine compound (5)using a dehydrating condensing agent, such as hydrochloride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (water-soluble carbodiimide), hexaflurophosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (HBTU) and the like, in a solvent such as chloroform, dichloroethane, THF, dioxane, acetonitrile, etc. at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at room temperature for 12 hours, getting the final product (1A).

Method In: obtaining the compounds of formula (1)in which l=1, m=0, n=1, and X=O

where, W1, W2, R1, R2and R3have the meanings specified above, and J denotes a protective group, such as benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzoyl or benzyl.

Incidentally, in the reaction scheme shown above and below, the expression "(W 2→W1means that W2in the formula representing the compound (2)replaced by W1. The same applies to the reaction schemes below.

Connection 4-hydroxypiperidine (10) with a protected amino group is subjected to interaction with compound (2) in the presence of sodium hydride or potassium iodide in a solvent such as DMF, DMSO, etc. at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at room temperature for 2 days, getting a connection (11). The protective group in the compound (11) is removed in a known manner. The obtained compound (12) is subjected to interaction with compound (2) in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at room temperature for 4 hours, obtaining the final product (1B).

Way: obtaining the compounds of formula (1)in which l=1, m=0, n=0, X=NR4CO., where R4=H or Me

where, W1, W2, R1, R2and R3have the meanings indicated above and R4means a hydrogen atom or methyl.

p> Isonipecotamide (13) is subjected to interaction with compound (2) in the presence of a base such as potassium carbonate, sodium carbonate and the like, in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at room temperature for 4 hours, obtaining the compound (14). The compound (14) is subjected to rearrangement reaction Hoffman, receiving the connection amine (15).

On the other hand, subjecting the compound (14) rearrangement reaction Hoffman in ethanol, receive connection carbamate (16). Then, by subjecting the compound (16) response recovery using sociallyengaged get the connection of methylamine (17).

As a result of interaction of the compounds carboxylic acid (18) with the amine compound (15) or a compound of methylamine (17) similar to the condensation reaction in the Method And obtain the target compound (1C).

Method D: obtaining the compounds of formula (1)in which l=1, m=0, n=1 and X=NR4

where, W1, W2, R1, R2and R3have the meanings indicated above and R4means alkyl, alkenyl, quinil, aralkyl or heteroalkyl.

The above amine compound (15) is subjected to interaction with 2-Latrobe what solargorilla (19) in accordance with the known method, receiving a connection (20). The compound (20) is subjected to interaction with compound (2) in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at room temperature for 4 hours, obtaining the compound (21). Benzosulfimide group of the compound (21) is removed according to the method used for compound (4) in Method A, obtaining the target compound (1D) (R4=H). The compound (1D) is subjected to interaction with R4-B in the presence of a base such as sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate and the like, in a solvent such as acetonitrile, THF, dioxane, chloroform, dichloromethane, DMF, DMSO, etc. at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at 80°within 12 hours, obtaining the compound (1D').

On the other hand, the connection of methylamine (17) is subjected to interaction with compound (2) in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature of from 0°With up to a temperature of education phlegmy during the period in which the time from several hours to several days, preferably at room temperature for 4 hours, obtaining the compound (1D") (R4=Me).

Method E: obtaining the compounds of formula (1)in which l=1, m=0 or 1, n=1 and X=NR4

where In, J, W1, W2, R1, R2and R3have the meanings indicated above and R4means alkyl, alkenyl, quinil, aralkyl or heteroalkyl.

Derived aminopiperidine formula (22), in which the amino group in the ring is protected, is subjected to the interaction with the compound (2) in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at room temperature for 4 hours, obtaining the compound (23). The compound (23) is subjected to interaction with R4-B in the presence of a base such as sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate and the like, in a solvent such as acetonitrile, THF, dioxane, chloroform, dichloroethane, DMF, DMSO, etc. at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at 80°within 12 hours, receiving a connection (24). After removal of the protection of the Noah group in the compound (24) the compound obtained is subjected to interaction with compound (2) in the presence of a base, such as potassium carbonate, in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at room temperature for 4 hours, obtaining the compound (1E).

Method F: obtaining the compounds of formula (1)in which l=1, m=0, n=1 and X=NR4

where In, J, W1, W2, R1, R2and R3have the meanings indicated above and R4means alkyl, alkenyl, quinil, aralkyl, heteroalkyl, aryl or heteroaryl.

4-Piperidinemethanol (26) is subjected to interaction with compound (2) in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at room temperature for 4 hours, obtaining the compound (27), which, in turn, expose demetalization using acid, to obtain the compounds of the ketone (28).

On the other hand, 4-piperidone (29) is subjected to interaction with compound (2) in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc., at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at room temperature for 4 hours, obtaining the compound (28). As a result of application of the compound (28) in accordance with any of the following two methods of synthesis can be obtained amine compound (30).

The method of synthesis 1: Compound (28) is subjected to interaction with the amine compound of the formula R4-NH2in the presence of molecular sieves in toluene or benzene at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at a temperature of education phlegmy for 12 hours, followed by interaction with a reducing agent, such as borohydride sodium or lambrogini sodium, at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several minutes to several days, preferably at room temperature for 1 hour, to obtain the compound amine (30).

The method of synthesis 2: Compound (28) is subjected to interaction with the amine compound of the formula R4-NH2in the presence of a reducing agent, such as triacetoxyborohydride sodium in a solvent such as dichloromethane, 1,2-dichloroethane, methanol, ethanol, etc. at a temperature is t 0° With up to a temperature of education phlegmy during the period of time from several minutes to several days, preferably at room temperature for 4 hours, to obtain compound amine (30).

The obtained compound (30) is subjected to interaction with compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at room temperature for 4 hours to obtain the final product (IF).

Method G: obtaining the compounds of formula (1)in which l=1, m=0, n=1 and X=NR4

where In, J, W1, W2, R1, R2and R3have the meanings indicated above and R4means alkyl, alkenyl, quinil, aralkyl, heteroalkyl, aryl or heteroaryl.

Derived 4-piperidone formula (31), in which the amino group is protected, is subjected to the interaction with the amine compound R4-NH2similar to the method for obtaining compounds (30) Method F, to obtain the compound (32). Compound (32) is subjected to interaction with compound (2) in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature of from 0°With temperatures of education the project for phlegmy during the period of time from several hours to several days, preferably at room temperature for 4 hours, obtaining the compound (33). After removal of the protective group from the compound (33) the compound obtained in (34) is subjected to interaction with compound (2) in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at room temperature for 4 hours, obtaining the final product (1G).

Way N: obtaining the compounds of formula (1)in which l=0, m=0, n=1 and X=NH

where In, J, W1, W2, R1, R2and R3have the values specified above.

The derived 3-aminopyrrolidine (35) with a protected amino group in the ring is subjected to interaction with 2-nitrobenzenesulfonamide (19) in normal conditions, getting derived benzosulfimide (36). Derivative (36) is subjected to interaction with compound (2) in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at room temperature for 4 hours, the floor is tea connection (37). The protective group of the amino group is removed from compound (37), receiving the connection (38), which, in turn, is subjected to the interaction with the compound (2) in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at room temperature for 4 hours, to obtain the compound (39). Subjecting the compound (39) interaction, similar to obtaining the compound (5)described in the Method And get the final product (1H).

The way I: obtaining the compounds of formula (1)in which l=0, m=0, n=1 and X=NR4

where In, J, W1, W2, R1, R2and R3have the meanings indicated above and R4means alkyl, alkenyl, quinil or aralkyl.

Compound (36) is subjected to interaction with R4In the presence of a base such as sodium carbonate, potassium carbonate, etc. in a solvent such as acetonitrile, THF, dioxane, chloroform, dichloroethane, DMF, DMSO, etc. at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at 80°within 12 hours, receiving connection (40). Aminosidine GRU the PU is removed from compound (40) and the compound obtained in (41) is subjected to interaction with compound (2) in the presence of a base, such as potassium carbonate, in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at room temperature for 4 hours, obtaining the final product (42). Subjecting the compound (42) interaction, similar to obtaining the compound (5)described in the Method And get a connection (43). Compound (43) is subjected to interaction with compound (2) in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at room temperature for 4 hours to obtain the final product (1I).

Method J: obtaining the compounds of formula (1)in which R2=HE

where X, W1, W2, R1, R3, l, m and n have the meanings specified above.

As a result of interaction of methoxyamine (1J) with attributively in a solvent such as toluene, chloroform, dichloromethane, etc. at a temperature of from -25°With up to a temperature of education phlegmy during the period of time from several hours to several days, predpochtitel is but at 0° C for 2 hours, can be obtained in the final product (1J').

The way To: obtaining the compounds of formula (1)in which l=1, m=0, n=0 and X=NR4WITH

where In, J, W1, W2, R1, R2and R3have the meanings indicated above and R4means alkyl, alkenyl, quinil, aralkyl, heteroalkyl, aryl or heteroaryl.

Compound (32), described in Method G, is subjected to the interaction with the compound (18) in accordance with the method of obtaining the compounds (1A), described in Method A, to obtain the compound (44). After removal of the protective group from the compound (44) the compound obtained in (45) is subjected to interaction with compound (2) in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature of from 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at room temperature for 4 hours, obtaining the final product (1K).

Method L: obtaining the compounds of formula (1)in which l=1, m=0, n=1 and X=alkylsulfonamides

where, W1, W2, R1, R2and R3have the values specified above.

Compound (34), synthesized according to Method G, where X p is ecstasy alkyldiphenylamine, subjected to interaction with an oxidant such as 3-chloroperbenzoic acid, peracetic acid or hydrogen peroxide, in accordance with the known method, to obtain the derived alkylsulfonic (46). Compound (46) is subjected to interaction with compound (2) in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile, DMF, DMSO, THF or dioxane, at temperatures between 0°With up to a temperature of education phlegmy during the period of time from several hours to several days, preferably at 70°during the night, getting the final product (1L).

Compound (1) in accordance with the present invention can be obtained by any of the methods described above, and optionally subjected to additional cleaning using conventional purification methods such as recrystallization or column chromatography. If necessary, the obtained compound can also be converted into a desired salt or solvate method known in the art per se.

In the case where the compound (1) include an asymmetric carbon atom, the present invention includes any configuration isomers.

Compound (1) in accordance with the present invention, thus obtained, or its salt or solvate, as described below in test example 1, exert forces the Noah inhibitory effect on cell adhesion and are useful as medicines for the treatment and prevention of diseases of animals including humans, caused by cell adhesion or cell infiltration, such as asthma, allergies, rheumatism, arteriosclerosis, inflammation, Sjogren syndrome, etc.

Medicinal product in accordance with the present invention includes the compound (1), its salt or its MES as an active ingredient. The form of the introduction can be properly selected for the intended therapeutic purpose, without any specific limitation, including drugs for oral administration, injections, suppositories, ointments, pharmaceutical forms for inhalation, eye drops, nose drops and plasters. The composition is suitable for use in the above forms of introduction, can be obtained by mixing the pharmaceutically acceptable carrier in accordance with the traditional method of obtaining well-known to specialists in this field of technology.

When getting a solid preparation for oral administration to the compound (1) add excipient and optionally a binder, disintegrator, lubricant, colorant, flavoring substance, flavouring substance, and the like, the obtained composition may be prepared in the form of tablets, granules, powders, capsules, etc. in accordance with methods known in the art. As described above additives can be is used any additives, usually used in the pharmacological field. Examples include excipients such as lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropionic starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, and polyvinylpyrrolidone; disintegrators such as dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride and lactose; lubricants such as purified talc, salts of stearic acid, sodium tetraborate and polyethylene glycol, and flavoring agents such as sucrose, orange peel, citric acid and tartaric acid.

When receiving the liquid preparation for oral administration to the compound (1) add flavoring agent, buffer, stabilizer, flavoring agent and/or the like, the obtained composition may be prepared in the form of liquid preparations for internal use, syrups, elixirs, etc. in accordance with methods known in the art. In this case, vanillin can be used as a flavoring substance in the accordance with the above description. As the buffer may be given sodium citrate. As examples of the stabilizer may be provided tragakant, gum Arabic and gelatin.

Upon receipt of a solution for injection to the compound (1) in accordance with the present invention may be added as a pH regulator, buffer, stabilizer, isotonic agent, a local anesthetic and the like, the obtained composition may be prepared as solutions for subcutaneous, intramuscular and intravenous injection in accordance with methods known in the art. Examples of the pH regulator and buffer in this case include sodium citrate, sodium acetate and sodium phosphate. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid and timelocal acid. Examples of local anesthetic include procainamidesee and lidocaineydrocortisone. Examples of the isotonic agent include sodium chloride and glucose.

Upon receipt of the suppository to the compound (1) add the appropriate media known in the art, such as polyethylene glycol, lanolin, cocoa butter, triglyceride fatty acids and the like, and optional surfactant, such as "twin" (registered trademark) and the like, the obtained composition may be prepared in the form of suppositories in accordance with methods known what time in this field of technology.

Upon receipt of ointment is usually applied to the base material, stabilizer, moisturizer, preservative, etc. is mixed with compound (1) accordingly, and the resulting mixture was mixed and prepared in the form of ointments in accordance with the known method. Examples of the substrate material include liquid paraffin, white petrolatum, bleached beeswax, octyldodecyl alcohol and paraffin. Examples of the preservative include methyl p-hydroxybenzoate, ethyl-p-hydroxybenzoate and propyl-p-hydroxybenzoate.

In addition to the above drugs, pharmaceutical forms for inhalation, eye drops and nasal drops can also be prepared according to known methods.

The dose of the medicinal product in accordance with the present invention varies in accordance with age, weight and condition being treated patient, method of administration, the number of introductions, etc. in General, However, preferably oral or parenteral administration of this drug for one or more times in a dose of from 1 to 1000 mg per day of compound (1) for an adult.

Examples

What follows is a more detailed description of the present invention using examples. However, the present invention is not limited to these examples.

Example obtain 1

Synthesis of ethyl-2-(3,4,5-trimetoksi enyl)isonicotinate

3,4,5-Trimethoxyphenylacetic acid (20,10 g) and ethyl-2-chlorisondamine (18,56 g) is suspended in a mixed solvent of toluene (200 ml) and THF (100 ml) and to the suspension is added 2 M sodium carbonate (200 ml) and tetrakis(triphenylphosphine)palladium(0) (5,78 g). The mixture was stirred at 90°C overnight in an argon atmosphere. With the purpose of extraction to the reaction mixture are added ethyl acetate and the organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel with hexane/ethyl acetate (5:1), obtaining specified in the connection header.

Output 27,99 g (88%).

1H-NMR (400 MHz, CDCl3) δ: of 1.45 (t, 3H, J=7.0 Hz), to 3.92 (s, 3H), 3,99 (s, 6H), to 4.46 (q, 2H, J=7.0 Hz), 7,30 (s, 2H), 7,76 (DD, 1H, J=5,1 Hz to 1.6 Hz), 8,24 (DD, 1H, J=1.6 Hz, 0.8 Hz), 8,81 (DD, 1H, J=5,1 Hz, 0.8 Hz).

Example of getting 2

Synthesis of 4-hydroxymethyl-2-(3,4,5-trimethoxyphenyl)pyridine

Ethyl-2-(3,4,5-trimethoxyphenyl)isonicotinate (a 24.57 g) dissolved in dry THF (200 ml) and to the solution add sociallyengaged (2,94 g) at 0°C in argon atmosphere. In this state, the mixture is stirred at 0°within hours. To the reaction mixture a small amount of water and then sodium sulfate, after which the ner is stormie substance is filtered off through celite. The filtrate is concentrated under reduced pressure and the resulting raw crystals are recrystallized from a mixture of ethyl acetate/hexane, getting listed at the beginning of the connection.

Output 17,53 g (82%).

1H-NMR (400 MHz, CDCl3) δ: 3,90 (s, 3H), of 3.95 (s, 6H), 4,79 (s, 2H), 7,19 (d, 1H, J=5,1 Hz), 7,21 (s, 2H), 7,66 (s, 1H), at 8.60 (d, 1H, J=5,1 Hz).

Example of getting 3

Synthesis of 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine

4-Hydroxymethyl-2-(3,4,5-trimethoxyphenyl)pyridine (MT 19 : 18 g) is dissolved in chloroform (100 ml) and to the solution at 0°slowly add chloride. After 30 minutes the mixture is heated to room temperature and stirred for 4 hours. The reaction mixture was washed with aqueous saturated sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystalline residue is then recrystallized from a mixture of ethyl acetate/hexane, getting mentioned in the title compounds as a pale yellow crystalline powder.

Output 18,24 g (89%).

1H-NMR (400 MHz, CDCl3) δ: 3,91 (s, 3H), of 3.97 (s, 6H), br4.61 (s, 2H), 7,24 (s, 2H), 7,26 (d, 1H, J=5,1 Hz), 7,68 (s, 1H), 8,67 (d, 1H, J=5,1 Hz).

Example 4

Synthesis of N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]phthalimide

To a solution of 4-chloromethyl-2-(3,4,5-trimethoxy the Nile)pyridine (881 mg) in chloroform (10 ml) add phthalimide potassium (556 mg). The mixture is stirred at room temperature over night and add water. After separation of the organic layer the aqueous layer was extracted with chloroform. The organic layers are combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, obtaining mentioned in the title compound as a white powder.

The output of 1.16 g (96%).

Example of getting 5

Synthesis of 4-aminomethyl-2-(3,4,5-trimethoxyphenyl)pyridine

To a suspension of N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]phthalimide (1,16 g) in ethanol (30 ml) is added hydrazine monohydrate (1 ml). The mixture is refluxed for 3 hours. After cooling, the insoluble matter is filtered off. The filtrate is concentrated under reduced pressure and the residue is dissolved in chloroform. The solution was washed with saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, obtaining mentioned in the title compound as a pale yellow oil.

The output 418 mg (53%).

An example of obtaining 6

Synthesis of ethyl-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine-4-carboxylate

Ethylpiperidine-4-carboxylate (514 mg), 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (969 mg) and potassium carbonate (452 mg) WM is androuet in acetonitrile (20 ml). The suspension is stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and then added chloroform and water to separate an organic layer. The aqueous layer was extracted with chloroform. The organic layers are combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure the residue is purified column chromatography on silica gel, elwira a mixture of hexane/ethyl acetate (1:1) and then with a mixture of methanol/chloroform (40:1), obtaining specified in the title compound as white prisms.

Yield 1.20 g (88%).

1H-NMR (400 MHz, CDCl3) δ: of 1.25 (t, 3H, J=7.0 Hz), 1,72-of 1.93 (m, 4H), 2,10 (t, 2H, J=9.8 Hz), and 2.27 to 2.35 (m, 1H), 2,86 (d, 2H, J=11.3 Hz), 3,55 (s, 2H), 3,91 (s, 3H), 3,98 (s, 6H), 4,14 (q, 2H, J=7.0 Hz), 7,21 (d, 1H, J=4,9 Hz), 7,24 (s, 2H), 7,63 (s, 1H), 8,59 (d, 1H, J=5,1 Hz).

Example of getting 7

Synthesis of 1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine-4-carboxylic acid

To a solution of ethyl-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]piperidine-4-carboxylate (760 mg) in ethanol (10 ml) was added 1 M sodium hydroxide (10 ml). The mixture is stirred at room temperature for 4 hours and the ethanol is distilled off under reduced pressure. To the residue is added water (20 ml) and then gradually add 5% aqueous potassium bisulfate until then, until the pH reaches 7. Precipitated crystals with eraut by filtration and the product is used in the following stage without further purification.

Output 779 mg (theoretical amount).

Example 1

Synthesis maleate 1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]-4-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methylaminomethyl]piperidine

To a solution of 1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine-4-carboxylic acid (97 mg) and 4-aminomethyl-2-(3,4,5-trimethoxyphenyl)pyridine (68 mg) in acetonitrile (5 ml) add hexaphosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (95 mg). The mixture is stirred at room temperature for 12 hours and concentrated under reduced pressure. The residue is dissolved in chloroform, washed with a saturated solution of aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel, elwira a mixture of chloroform/methanol (40:1˜20:1). Specified in the title compound obtained as free base. Then by adding maleic acid free base is converted into the maleate.

Yield 93 mg (49%).

1H-NMR (400 MHz, defined as maleate, DMSO-d6) δ: 1,87 is 2.01 (m, 4H), 2,48-of 2.56 (m, 1H), 2,78-of 2.86 (m, 2H), 3,26-of 3.31 (m, 2H), of 3.78 (s, 3H), 3,79 (s, 3H), a 3.87 (s, 6H), 3,90 (s, 6H), is 4.15 (s, 2H), 4,39 (d, 2H, J=5,9 Hz), 6,16 (s, 2H), 7,16 (d, 1H, J=5,9 Hz), 7,35 (s, 2H), 7,39 (d, 1H, J=5,9 Hz), 7,39 (s, 2H), 7,73 (s, 1H), 7,95 (s, 1H), 8,15 (d, 1H, J=9 Hz), 8,54 (d, 1H, J=4.9 Hz), 8,68 (d, 1H, J=4,9 Hz).

Example obtain 8

Synthesis of 1-(benzyloxycarbonyl)-4[[2-(3,4,5-trimethoxyphenyl-4-yl]metiloksi]piperidine

To a solution of 1-(benzyloxycarbonyl)-4-hydroxypiperidine (1.0 g) in DMF (20 mg) is added sodium hydride (55% dispersion in mineral oil, 222 mg). The mixture is stirred at room temperature for one hour and then added 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (1,37 g) and potassium iodide (755 mg). The mixture was stirred at 70°during the night, add water and then extracted with chloroform. The organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel using a mixture of chloroform/methanol (99:1) as eluent, to obtain specified in the connection header.

The output 213 mg (10%).

1H-NMR (400 MHz, CDCl3) δ: 1,63 (W, 2H), 1,89 (W, 2H), 3,20-to 3.35 (m, 2H), 3,57-3,68 (m, 1H), 3,84-to 3.92 (m, 5H), of 3.94 (s, 6H), to 4.62 (s, 2H), 5,11 (s, 2H), 7,21-7,35 (m, 8H), to 7.61 (s, 1H), 8,61 (d, 1H, J=5.0 Hz).

Example of getting 9

Synthesis of 4-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]metiloksi]piperidine

To a solution of 1-(benzyloxycarbonyl)-4-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]metiloksi]piperidine (213 mg) in methanol (10 ml) was added 40% aqueous hydroxy is potassium (10 ml). The mixture was stirred at 100°C for 3 hours. After concentration under reduced pressure, to the residue water is added and extracted with chloroform. The organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel, elwira a mixture of chloroform/saturated methanol ammonia (20:1), obtaining specified in the connection header.

Yield 93 mg (60%).

1H-NMR (400 MHz, CDCl3) δ: 1,55 by 1.68 (m, 2H), 2,01 (W, 2H), 2,67-of 2.72 (m, 2H), 3,13-3,18 (m, 2H), 3,50-3,60 (m, 1H), 3,91 (s, 3H), of 3.97 (s, 6H), with 4.64 (s, 2H), 7,22 (d, 1H, J=4.3 Hz), 7,24 (s, 2H), to 7.64 (s, 1H), 8,63 (d, 1H, J=5,1 Hz).

Example 2

Synthesis of trihydrochloride 1-[2-[(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]-4-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]metiloksi]piperidine

4-[[2-[(3,4,5-Trimethoxyphenyl)pyridine-4-yl]metiloksi]piperidine (70 mg), 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (22 mg), potassium carbonate (56 mg) and potassium iodide (40 mg) is suspended in acetonitrile (5 ml). The mixture is stirred at room temperature for 5 hours and concentrated under reduced pressure. To the residue is added chloroform and water and the organic layer separated. The aqueous layer was then extracted with chloroform, the organic layers combined, dried over anhydrous magnesium sulfate, and concentrate the ri reduced pressure. The residue is purified column chromatography on silica gel using a mixture of chloroform/methanol (40:1) as eluent. The obtained free base is converted into trihydrochloride in accordance with the traditional method.

Yield 42 mg (39%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,53-to 2.42 (m, 6H), 2,80 (W, 2H), 3,57 (Shir, 3H), 3,88 (s, 6H), of 3.94 (s, 6H), of 3.95 (s, 6H), 4,60 (s, 2H), 7.18 in-7,24 (m, 6H), to 7.61 (s, 2H), 8,58-8,61 (m, 2H).

Example 10

Synthesis of (3S)-1-(tert-butoxycarbonyl)-3-[(2-nitrobenzene)sulfonylamino]pyrrolidine

It chilled with ice to a solution of (3S)-3-amino-1-(tert-butoxycarbonyl)pyrrolidine (404 mg) and triethylamine (220 mg) in THF (5 ml) is added 2-nitrobenzenesulfonamide (481 mg). The mixture is stirred at room temperature for 30 minutes and concentrated under reduced pressure. To the residue is added ethyl acetate. The solution is washed with water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel using a mixture of chloroform/methanol (20:1) as eluent, to obtain specified in the title compounds as a pale yellow amorphous substance.

Exit 597 mg (74%).

1H-NMR (400 MHz, CDCl3) δ: of 1.44 (s, 9H), 1,80-2,12 (m, 2H), 3,14-3,44 (m, 4H), was 4.02 (W, 1H),5,48 (d, 1H, J=7,2 Hz), to 7.77 (t, 2H, J=4.4 Hz), 7,87-of 7.90 (m, 1H), 8.17-a 8,19 (m, 1H).

Example of getting 11

Synthesis of (3S)-1-(tert-butoxycarbonyl)-3-[N-methyl-N-(2-nitrobenzenesulfonyl)amino]pyrrolidine

To a suspension of (3S)-1-(tert-butoxycarbonyl)-3-[2-nitrobenzene)sulfonylamino]pyrrolidine (371 mg) and potassium carbonate (138 mg) in acetonitrile (10 ml) add methyliodide (141 mg). The mixture was stirred at 60°C for 2 hours and concentrated under reduced pressure. To the mixture is added ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The rest is used for column chromatography on silica gel with hexane/ethyl acetate (2:1) as eluent to clean, with obtaining specified in the title compound as a yellow oil.

The output of 365 mg (95%).

1H-NMR (400 MHz, CDCl3) δ: of 1.44 (s, 9H), 1,95 (W, 1H), 2,09 (W, 1H), 2,87 (s, 3H), 3,20-of 3.31 (m, 2H), 3,53 (W, 2H), 4,58 (W, 1H), 7,65 (W, 1H), 7,71 (W, 2H), 8,04 (W, 1H).

Example 12

Synthesis of (3S)-3-[N-methyl-N-(2-nitrobenzenesulfonyl)amino]pyrrolidine

To a solution of (3S)-1-(tert-butoxycarbonyl)-3-[N-methyl-N-(2-nitrobenzenesulfonyl)amino]pyrrolidine (365 mg) in dichloromethane (25 ml) at 0°type Tr florexpo acid (1 ml). The mixture is stirred at room temperature for 3 hours, concentrated under reduced pressure and added to the chloroform. The solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure, obtaining mentioned in the title compound as a yellow oil.

Yield 135 mg (50%).

1H-NMR (400 MHz, CDCl3) δ: 1,69-of 1.74 (m, 1H), 1,87 (W, 1H), 1,95-2,02 (m, 1H), 2,80 (DD, 1H, J=11.7 Hz, 5.7 Hz), 2,84-only 2.91 (m, 4H), 2,96 was 3.05 (m, 1H), 3,10 (DD, 1H, J=11.7 Hz and 8.2 Hz), 4,48-4,56 (m, 1H), to 7.61-7,63 (m, 1H), 7,66-7,73 (m, 2H), 8,01-of 8.04 (m, 1H).

Example of getting 13

Synthesis of (3S)-3-[N-methyl-N-(2-nitrobenzenesulfonyl)amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]pyrrolidine

(3S)-3-[N-Methyl-N-(2-nitrobenzenesulfonyl)amino]pyrrolidine (135 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (139 mg) is treated according to the method similar to that described in example 2, obtaining mentioned in the title compound as a yellow amorphous substance.

Exit 247 mg (96%).

1H-NMR (400 MHz, CDCl3) δ: 1,80-to 1.87 (m, 1H), 2,15-of 2.30 (m, 2H), 2,52 (DD, 1H, J=10.5 Hz and 8.2 Hz), 2,71 (DD, 1H, J=10.5 Hz and 8.2 Hz), 2,90 (dt, 1H, J=8,8 Hz, 2.9 Hz), 2,96 (s, 3H), 3,53 (d, 1H, J=a 13.9 Hz), 3,68 (d, 1H, J=a 13.9 Hz), are 3.90 (s, 3H), of 3.96 (s, 6H), br4.61-and 4.68 (m, 1H), 7,16 (DD, 1H, J=4,9 Hz, 1.2 Hz), 7,21 (s, 2H), 7,58-of 7.60 (m, 2H), of 7.64-of 7.69 (m, 2H), 7,99-8,02 (m, 1H), 8,58 (d, 1H, J=4,9 Hz).

A sample receipt is 14

Synthesis of (3S)-3-methylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]pyrrolidine

To a solution of (3S)-3-[N-methyl-N-(2-nitrobenzenesulfonyl)amino]-1-[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]pyrrolidine (242 mg) in acetonitrile (5 ml) is added potassium carbonate (94 mg) and thiophenol (75 mg). The mixture was stirred at 80°within hours. After cooling, to the mixture are added ethyl acetate and the solution washed with saturated aqueous sodium bicarbonate, water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified preparative TLC, using a solution of chloroform/methanol (20:1) as eluent, to obtain specified in the title compound as a yellow oil.

Yield 104 mg (64%).

1H-NMR (400 MHz, CDCl3) δ: 1,32 (W, 1H), 1.56 to of 1.64 (m, 1H), 2,11-2,17 (m, 1H), of 2.38 (s, 3H), 2,44 (DD, 1H, J=7,4 Hz, 4.5 Hz), 2,50 is 2.55 (m, 1H), 2,66 is 2.75 (m, 2H), 3,20-3,26 (m, 1H), 3,66 (s, 2H), 3,90 (s, 3H), of 3.97 (s, 6H), 7,21 (d, 1H, J=4,1 Hz), 7,25 (s, 2H), to 7.64 (s, 1H), 8,59 (d, 1H, J=4,9 Hz).

Example 3

Synthesis of tetrahydrochloride (3S)-3-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]pyrrolidine

(3S)-3-Methylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]pyrrolidin (104 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (85 mg) is subjected cooperation is to work on technique, similar to that described in example 2. The resulting product is converted into tetrahydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 151 mg (68%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,89-of 1.92 (m, 1H), 2,04-of 2.08 (m, 1H), 2,18 (s, 3H), 2,60 was 2.76 (m, 4H), 3.25 to be 3.29 (m, 1H), 3,53 (d, 1H, J=14,3 Hz), 3,62 (d, 1H, J=14,3 Hz)to 3.64 (d, 1H, J=a 13.9 Hz), to 3.73 (d, 1H, J=a 13.9 Hz), 3,89 (, 6H), of 3.95 (s, 6H), of 3.96 (s, 6H), 7,20-7,21 (m, 2H), 7.23 percent (s, 2H), 7,24 (s, 2H), to 7.61 (s, 1H), 7,65 (s, 1H), 8,59 (d, 1H, J=5.7 Hz), at 8.60 (d, 1H, J=5.3 Hz).

Example get 15

Synthesis of 1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine-4-carboxamide

Piperidine-4-carboxamide (385 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (881 mg) is subjected to interaction by the method similar to that described in example 2, obtaining mentioned in the title compound as white needles.

Yield 1.01 g (87%).

1H-NMR (400 MHz, CDCl3) δ: 1,70-of 1.88 (m, 4H), 2,01-of 2.23 (m, 3H), 2.95 and (d, 2H, J=11,0 Hz), of 3.56 (s, 2H), 3,90 (s, 3H), 3,98 (s, 6H), 5,46 (d, 2H, J=16,3 Hz), 7,21 (d, 1H, J=5.0 Hz), 7,24 (s, 2H), to 7.64 (s, 1H), 8,59 (d, 1H, J=5.0 Hz).

Example 16

Synthesis of trihydrochloride 4-amino-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

To a solution of 1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine-4-carboxamide (192 mg) in a mixed solvent of water (50 ml) and acetonitrile (50ml) added [bis(triptoreline)iodine]benzene (323 mg). The mixture is stirred at room temperature overnight and concentrated under reduced pressure. To the residue is added saturated aqueous sodium bicarbonate for alkalizing and the residue extracted with chloroform. The chloroform layer is washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Thus obtained yellow oil is then converted into the hydrochloride, which gives a yellow powder. Specified in the header of the connection used in the next stage without further purification.

The output of 201 mg (theoretical amount).

Example of getting 17

Synthesis of 2-(3,4,5-trimethoxyphenyl)isonicotinic acid

To a solution of ethyl-2-(3,4,5-trimethoxyphenyl)isonicotinate (3,17 g) in ethanol (40 ml) was added 10% potassium hydroxide (2,42 g). The mixture is stirred at room temperature for 5 hours and concentrated under reduced pressure. To the residue add water and bring the pH to 7. The obtained white precipitate was filtered. Received specified in the header of the connection used in the following stage without further purification.

Output 2,60 g (90%).

Example 4

Synthesis maleate 1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]-4-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]carbylamine]piperidine

2-(3,4,5-T is methoxyphenyl)pyridine-4-carboxylic acid (72 mg) and 4-amino-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (117 mg) is subjected to interaction by the method, similar to that described in example 1. The resulting product is converted into the maleate, getting listed at the beginning of the connection.

Yield 173 mg (93%).

1H-NMR (400 MHz, defined as maleate, DMSO-d6) δ: 1,82-of 1.94 (m, 2H), 2,03-of 2.08 (m, 2H), 2.77-to and 2.83 (m, 2H), 3,20-of 3.27 (m, 2H), 3,79 (s, 6H), 3,90 (s, 12H), 4,00 (W, 1H), 4,06 (s, 2H), x 6.15 (s, 2H), was 7.36-7,38 (m, 1H), 7,39 (s, 2H), 7,41 (s, 2H), to 7.61-7,63 (m, 1H), of 7.90 (s, 1H), 8,12 (s, 1H), 8,27-8,32 (m, 1H), 8,67 (d, 1H, J=4.9 Hz), a total of 8.74 (d, 1H, J=5,1 Hz).

Example of getting 18

Synthesis of 4-[(2-nitrobenzenesulfonyl)amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-Amino-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (467 mg) and 2-nitrobenzenesulfonamide (244 mg) is subjected to interaction by the method similar to that described in example 10, receiving specified in the header of the connection.

The output of 494 mg (91%).

Example of getting 19

Synthesis of 4-[N-(2-nitrobenzenesulfonyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-[(2-Nitrobenzene)sulfonylamino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (494 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (267 mg) is subjected to interaction by the method similar to that described in example getting 2, receiving specified in the header of the connection.

Exit 443 mg (61%).

Example 5

Synthesis of difumarate 1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]-4-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methylamino]piperidine

4-[N-(2-Nitrobenzenesulfonyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (443 mg) is treated according to the method similar to that described in example receiving 14. Specified in the header connection receive in the form of difumarate.

Yield 103 mg (24%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,44-of 1.53 (m, 2H), 1,87 is 1.91 (m, 2H), 2,15 (t, 2H, J=1.1 Hz), 2.57 m-of 2.64 (m, 1H), 2,82-to 2.85 (m, 2H)and 3.59 (s, 2H), of 3.78 (s, 6H), to 3.89 (s, 12H), 3,90 (s, 2H), 6,63 (s, 4H), from 7.24 (d, 1H, J=4,9 Hz), 7,29 (d, 1H, J=4.9 Hz), 7,35 (s, 2H), 7,37 (s, 2H), 7,76 (s, 1H), a 7.85 (s, 1H), 8,53-8,56 (m, 2H).

Example of getting 20

Synthesis of 4-(ethoxycarbonyl)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

To a solution of 1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine-4-carboxamide (528 mg) in a mixed solvent of ethanol (10 ml) and acetonitrile (10 ml) was added [bis(triptoreline)iodine]benzene (884 mg). The mixture is stirred at room temperature overnight. After concentration under reduced pressure, the mixture is injected saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was washed with saturated dissolve the Ohm salt, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel using a mixture of chloroform/methanol (20:1) as eluent, to obtain specified in the connection header.

Exit 566 mg (96%).

1H-NMR (400 MHz, CDCl3) δ: to 1.21 (t, 3H, J=7.0 Hz), 1,40-is 1.51 (m, 2H), 1,92 (d, 2H, J=10,9 Hz), of 2.15 (t, 2H, J=10,9 Hz), 2,78 (d, 2H, J=11,6 Hz), 3,52 (Shir, 3H), a 3.87 (s, 3H), of 3.94 (s, 6H), 4,07 (q, 2H, J=7.0 Hz), 4,56 (width, 1H), 7,17 (d, 1H, J=4.9 Hz), 7,21 (s, 2H), to 7.59 (s, 1H), 8,56 (d, 1H, J=5,1 Hz).

Example of getting 21

Synthesis of 4-(methylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

To a suspension of sociallyengaged (100 mg) in dry THF (50 ml) is gradually added a solution of 4-(ethoxycarbonyl)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (566 mg) in dry THF (50 ml) in an argon atmosphere. The mixture is then refluxed overnight and then cooled. To the mixture is added saturated aqueous solution of ammonium chloride and the resulting mixture, after the allocation of vials, extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel using a mixture of chloroform/saturated ammonia methanol (:1), obtaining specified in the title compound as a yellow oil.

The output of 379 mg (78%).

1H-NMR (400 MHz, CDCl3) δ: 1,36 of 1.46 (m, 2H), 1,89 (d, 2H, J=12,5 Hz), 2,10 (dt, 2H, J=11.5 Hz, 1.1 Hz), 2,35 is 2.43 (m, 1H), 2,43 (s, 3H), 2,86 (d, 2H, J=11,6 Hz), of 3.56 (s, 2H), 3,90 (s, 3H), of 3.97 (s, 6H), 7,21 (d, 1H, J=5,1 Hz), 7,24 (s, 2H), to 7.64 (s, 1H), 8,59 (d, 1H, J=4,9 Hz).

Example of getting 22

Synthesis of atelectasia 1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]-4-piperidone

4-Piperidinemethanol (12.0 g) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (12.3 g) is subjected to interaction by the method similar to that described in example 2, obtaining specified in the header of the connection.

Output 19,0 g (theoretical amount).

1H-NMR (400 MHz, CDCl3) δ: 1,68 (t, 4H, J=5.6 Hz), 2,48 (Shir, 4H), 3,50 (s, 2H), 3,82 (s, 3H), 3,86 (s, 4H), 3,88 (s, 6H), 7,13 (d, 1H, J=4.9 Hz), 7,17 (s, 2H), EUR 7.57 (s, 1H), 8,51 (d, 1H, J=4,9 Hz).

An example of retrieving 23

Synthesis of 1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]-4-piperidone

To a solution of atelectasia 1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]-4-piperidone (19,0 g) in THF (200 ml) was added 1 M hydrochloric acid (200 ml). The mixture was stirred at 90°C overnight, then neutralized with 2 M sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and end tryout under reduced pressure. The residue is purified column chromatography on silica gel using a mixture of chloroform/methanol (40:1) as eluent, to obtain specified in the connection header.

Yield 15.0 g (75%).

1H-NMR (400 MHz, CDCl3) δ: 2,48 (t, 4H, J=6,1 Hz), and 2.79 (t, 4H, J=6.0 Hz), of 3.69 (s, 2H), with 3.89 (s, 3H), of 3.96 (s, 6H), 7,24 (s, 2H), 7,26 (d, 1H, J=4.9 Hz), 7,66 (s, 1H), to 8.62 (d, 1H, J=4,9 Hz).

Example of getting 24

Synthesis of 1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]-4-piperidone

The monohydrate of 4-piperidineacetate (of 3.07 g) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (2,94 g) is subjected to interaction by the method similar to that described in example 2, obtaining specified in the connection header.

Yield 3.55 g (99%).

Example get 25

Synthesis of 4-(methylamino)1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

To a solution of 1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]-4-piperidone (1,00 g) in 1,2-dichloroethane (60 ml) is added a 30% solution of methylamine in ethanol (750 g) and triacetoxyborohydride sodium (1.66 g). The mixture is stirred at room temperature for 3 hours, enter the water and concentrate under reduced pressure. After adding water, the residue is extracted with chloroform. The organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and concentrate under ponie nom pressure. The residue is purified column chromatography on silica gel using a mixture of chloroform/methanol (40:1) as eluent, to obtain specified in the connection header.

Yield 640 mg (62%).

Example of getting 26

Synthesis of ethyl-3-(3,4,5-trimethoxyphenyl)benzoate

3,4,5-Trimethoxyphenylacetic acid (3.7 g) and ethyl-3-bromobenzoate (as 4.02 g) is subjected to interaction by the method similar to that described in example obtain 1, getting listed at the beginning of the connection.

Output 5,09 g (92%).

1H-NMR (400 MHz, CDCl3) δ: of 1.42 (t, 3H, J=7,1 Hz), 3,90 (s, 3H), of 3.94 (s, 6H), to 4.41 (q, 2H, J=7,1 Hz), 6,79 (s, 2H), 7,50 (t, 1H, J=7.8 Hz), 7,73 (dt, 1H, J=7,1 Hz, 1.5 Hz), 8,01 (dt, 1H, J=7,8 Hz and 1.4 Hz), 8,23 (t, 1H, J=1,8 Hz).

Example of getting 27

Synthesis of 3-(3,4,5-trimethoxyphenyl)benzoic acid

Ethyl-3-(3,4,5-trimethoxyphenyl)benzoate (1.19 g) is treated according to the method similar to that described in example receiving 17, receiving specified in the header of the connection.

Output 986 mg (91%).

Example 6

The synthesis of the dihydrochloride of 4-[N-methyl-N-[3-(3,4,5-trimethoxyphenyl)benzoyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

3-(3,4,5-Trimethoxyphenyl)benzoic acid (1,03 g) and 4-(methylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (1,32 g) is subjected to interaction is eodice, similar to that described in example 1, obtaining mentioned in the title compound in the form of the dihydrochloride.

Yield 1.44 g (57%).

1H-NMR (400 MHz, defined as the dihydrochloride, DMSO-d6) δ: 1,89 (d, 2H, J=11.7 Hz), 2,54-2,62 (m, 2H), 2,89 (s, 3H), to 3.09 (t, 2H, J=a 12.7 Hz), 3.43 points (d, 2H, J=14.4 Hz), 3,76 (s, 3H), of 3.78 (s, 3H), 3,88 (s, 6H), 3,91 (s, 6H), 4,34 (Shir, 3H), 6,91 (s, 2H), 7,33 (d, 1H, J=7,6 Hz), 7,47-7,51 (m, 2H), 7,54 (s, 2H), 7,60 (s, 1H), 7,71 (d, 1H, J=7.8 Hz), 8,55 (s, 1H), 8,68 (d, 1H, J=5,1 Hz).

Example 7

Synthesis of difumarat 4-[N-methyl-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-Methylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (135 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (107 mg) is subjected to interaction by the method similar to that described in example 2, obtaining mentioned in the title compound in the form of difumarat.

Yield 180 mg (58%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,69-of 1.73 (m, 2H), 1,82-of 1.85 (m, 2H), 2,03-of 2.08 (m, 2H, in), 2.25 (s, 3H), 2,48 is 2.51 (m, 1H), 2,97-to 2.99 (m, 2H), of 3.56 (s, 2H), to 3.67 (s, 2H), 3,90 (s, 3H), 3,91 (s, 3H), of 3.94 (s, 6H), 3,98 (s, 6H), 6,76 (s, 2H), 7,22 (d, 1H, J=5,1 Hz), 7,24 (s, 2H), 7.62mm (s, 1H), 7,80 (s, 1H), and 8.50 (d, 1H, J=2.0 Hz), at 8.60 (d, 1H, J=4.3 Hz), 8,69 (d, 1H, J=5,1 Hz).

Example of getting 28

Synthesis of 1-bromo-4-chloro-3,5-dimethoxybenzene

A solution of sodium nitrite (97 mg) in water are added dropwise to ohla the established ice suspension of 4-bromo-2,6-dimethoxyaniline (232 mg) in 6.0 M chlorotoluron acid (2.5 ml) after adding the last of the crushed ice. After stirring the mixture in an ice bath for 30 minutes to the mixture add a solution of copper chloride (II) (495 mg) in concentrated chlorotoluron acid (2.0 ml). The reaction mixture was stirred at room temperature for 30 minutes, then at 100°C for 2 hours and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel with hexane/ethyl acetate (10:1) as eluent, to obtain specified in the title compound as a white powder.

Yield 230 mg (92%).

An example of obtaining 29

Synthesis of 4-chloro-3,5-dimethoxyphenylacetic acid

In an argon atmosphere to a dry THF (2 ml), cooled in a bath of dry ice/methanol, gradually add 1.57 M solution of n-utility in hexane (0.8 ml) followed by the addition dropwise of a solution of 1-bromo-4-chloro-3,5-dimethoxybenzene (160 mg) in dry THF (2 ml). After stirring the mixture for 20 minutes in a bath of dry ice/methanol add triisopropylsilyl (of 0.18 ml) and the mixture is additionally stirred for 20 minutes. The reaction mixture was then stirred at room temperature for one hour and the pH of the mixture was adjusted to 3 using 4 chlorotoluron acid. The mixture was stirred at 0°C for one hour and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is recrystallized from a mixture of ethyl acetate/hexane, getting mentioned in the title compound as a white powder.

Yield 90 mg (66%).

Example 30

Synthesis of ethyl-2-(4-chloro-3,5-acid)of isonicotinate

4-Chloro-3,5-dimethoxyaniline acid (7,45 g) and ethyl-2-chlorisondamine (6,39 g) is treated according to the method similar to that described in example obtain 1, getting listed at the beginning of the connection.

Output 8,55 g (77%).

1H-NMR (400 MHz, CDCl3) δ: of 1.45 (t, 3H, J=7,3 Hz), a 4.03 (s, 6H), of 4.45 (q, 2H, J=7,3 Hz), 7,32 (s, 2H), 7,80 (d, 1H, J=5,1 Hz), of 8.27 (s, 1H), 8,83 (d, 1H, J=5.0 Hz).

An example of retrieving 31

Synthesis of 2-(4-chloro-3,5-acid)isonicotinic acid

To a solution of ethyl-2-(4-chloro-3,5-acid)of isonicotinate (8,55 g) in ethanol (80 ml) is added 2 M sodium hydroxide (100 ml). The mixture is stirred at the boil under reflux for 30 minutes and the ethanol is distilled off under reduced pressure. The mixture is neutralized by adding 1 M chlorotoluron acid. The precipitate was dissolved in a mixed solvent of ethyl acetate/THF 3:1), dried over anhydrous sodium sulfate and concentrated under reduced pressure, obtaining specified in the header of the connection.

The output of 7.20 g (92%).

1H-NMR (400 MHz, CDCl3) δ: was 4.02 (s, 6H), 7,34 (s, 2H), 7,83 (d, 1H, J=4.9 Hz), to 7.84 (s, 1H), 8,82 (d, 1H, J=4,9 Hz).

Example of getting 32

Synthesis of 2-(4-chloro-3,5-acid)-4-hydroxymethylbenzene

To a solution of 2-(4-chloro-3,5-acid)isonicotinic acid (7.20 g) and triethylamine (5.6 ml) in THF (70 ml) at 0°With add ethylchloride (2.8 ml). The mixture is stirred at room temperature for one hour and the insoluble matter is filtered off. To the filtrate then add a solution of sodium borohydride (1.25 g) in water (4 ml). The mixture is stirred at room temperature for one hour and concentrated under reduced pressure. After adding water, the residue is extracted with chloroform. The organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel using a mixture of chloroform/methanol (20:1˜15:1), obtaining specified in the connection header.

The output of 4.10 g (60%).

1H-NMR (400 MHz, CDCl3+DMSO-d6) δ: 4,01 (s, 6H), was 4.76 (s, 2H), 7,20-7,35 (m, 3H), 7,78 (s, 1H), to 8.62 (s, 1H).

An example of obtaining 33

Synthesis of 2-(4-chlor,5-acid)-4-chloromethylpyridine

2-(4-Chloro-3,5-acid)-4-hydrometallurgy (4,10 g) dissolved in chloroform (20 ml), injected thionyl chloride (5.2 ml) and stirred at 70°within hours. After concentrating the mixture under reduced pressure, the obtained residue is neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, obtaining specified in the header of the connection.

Output 4,20 g (96%).

1H-NMR (400 MHz, CDCl3) δ: was 4.02 (s, 6H), 4,63 (s, 2H), 7,26 (s, 2H), 7,29 (d, 1H, J=4.9 Hz), 7,72 (s, 1H), 8,69 (d, 1H, J=4,9 Hz).

An example of retrieving 34

Synthesis of 1-[[2-(4-chloro-3,5-acid)pyridine-4-yl]methyl]piperidine-4-carboxamide

Piperidine-4-carboxamide (301 mg) and 2-(4-chloro-3,5-acid)-4-chloromethylpyridine (600 mg) is subjected to interaction by the method similar to that described in example 2, obtaining specified in the header of the connection.

Exit 743 mg (95%).

1H-NMR (400 MHz, CDCl3) δ: 1,75-1,90 (m, 4H), 2,07 was 2.25 (m, 3H), 2,94 (d, 2H, J=11,6 Hz), of 3.57 (s, 2H), was 4.02 (s, 6H), 7.24 to 7,31 (m, 3H), to 7.67 (s, 1H), 8,61 (d, 1H, J=5,1 Hz).

Example of getting 35

Synthesis of 1-[[2-(4-chloro-3,5-acid)pyridine-4-yl]methyl]-4-(ethoxycarbonyl)piperidine

1-[[2-(4-Chloro-3,5-acid)pyridine-4-yl]methyl]piperidine-4-carboxamide (743 mg) is treated according to the method similar to that described in example receiving 20, receiving specified in the header of the connection.

The output of 887 mg (theoretical amount).

1H-NMR (400 MHz, CDCl3) δ: 1,24 (t, 3H, J=7,1 Hz), 1,43-to 1.59 (m, 2H), 1,96 (d, 2H, J=11,4 Hz), 2,19 (t, 2H, J=11,0 Hz), 2,82 (d, 2H, J=11.5 Hz), of 3.56 (s, 2H), was 4.02 (s, 6H), 4,10 (q, 2H, J=7,1 Hz), 7,26 (s, 2H), 7,66 (s, 1H), 7,71 (DD, 1H, J=5.6 Hz, 1.0 Hz), or 8.6 (DD, 1H, J=4,9 Hz, 0.5 Hz).

Example of getting 36

Synthesis of 1-[[2-(4-chloro-3,5-acid)pyridine-4-yl]methyl]-4-methylaminopropane

1-[[2-(4-Chloro-3,5-acid)pyridine-4-yl]methyl]-4-ethoxycarbonyl)piperidine (887 mg) is treated according to the method similar to that described in example receiving 21, receiving specified in the header of the connection.

Yield 195 mg (27%).

1H-NMR (400 MHz, CDCl3) δ: 1,35-1,49 (m, 2H), 1,89 (d, 2H, J=12.3 Hz), 2,11 (t, 2H, J=9.4 Hz), 2,38 at 2.45 (m, 1H), 2,44 (s, 3H), 2,87 (d, 2H, J=10,7 Hz), of 3.57 (s, 2H), was 4.02 (s, 6H), 7.23 percent-7,29 (m, 3H), 7,68 (s, 1H), 8,61 (d, 1H, J=4,9 Hz).

Example 8

Synthesis of tetrahydrochloride 1-[[2-(4-chloro-3,5-acid)pyridine-4-yl]methyl]-4-[N-[[2-(4-chloro-3,5-acid)pyridine-4-yl]methyl]-N-methylamino]piperidine

1-[[2-(4-Chloro-3,5-acid)pyridine-4-yl]methyl]-4-methylaminopropane (195 mg) and 2-(4-chloro-3,5-acid)-4-chloromethylpyridine (152 mg is subjected to interaction by the method, similar to that described in example 2. Thus obtained free base is converted into tetrahydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 300 mg (75%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,60-1,90 (m, 4H), to 2.06 (t, 2H, J=11.7 Hz), and 2.26 (s, 3H), 2,45 is 2.55 (m, 1H), 2,97 (d, 2H, J=11.3 Hz), of 3.57 (s, 2H), to 3.67 (s, 2H), 4,01 (s, 6H), was 4.02 (s, 6H), 7.24 to 7,28 (m, 6H), the 7.65 (s, 1H), to 7.67 (s, 1H), 8,61 (d, 1H, J=5.4 Hz), to 8.62 (d, 1H, J=5.4 Hz).

An example of retrieving 37

Synthesis of 4-(p-anisidino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

To a solution of 1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]-4-piperidone (2.17 g) in toluene (40 ml) is added p-anisidine (900 mg) and molecular sieves 4Å (6.0 g). The mixture is refluxed overnight, then the molecular sieve is filtered off and the filtrate evaporated. The residue is dissolved in ethanol (40 ml) and add borohydride (276 mg) of sodium. The mixture is stirred at room temperature for 2 hours before concentrating in vacuo. In the remainder of the injected water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel using a mixture of chloroform/methanol (50:1), obtaining the decree is spent in the connection header.

Yield 1.56 g (55%).

1H-NMR (400 MHz, CDCl3) δ: 1,48 (W, 2H), 2.05 is (W, 2H), 2,20 (W, 2H), 2,86 (W, 2H), 3,23 (s, 1H), to 3.58 (s, 2H), 3,74 (s, 3H), 3,91 (s, 3H), of 3.97 (s, 6H), to 6.58 (d, 2H, J=8,8 Hz), 6,77 (d, 2H, J=9.0 Hz), 7,22 (d, 1H, J=5,1 Hz), 7,26 (s, 2H), to 7.64 (s, 1H), 8,59 (d, 1H, J=4,9 Hz).

An example of retrieving 38

Synthesis of ethyl-2-(3,4,5-trimethoxyphenyl)nicotinate

3,4,5-Trimethoxyphenylacetic acid (694 mg) and ethyl-2-chloronicotinate (608 mg) is subjected to interaction by the method similar to that described in example obtain 1, getting listed at the beginning of the connection.

Output 799 mg (77%).

1H-NMR (400 MHz, CDCl3) δ: of 1.10 (t, 3H, J=7.2 Hz), with 3.89 (s, 9H), 4,19 (q, 2H, J=7,2 Hz), 6,79 (s, 2H), 7,34 (DD, 1H, J=7.8 Hz, 4.8 Hz), of 8.06 (DD, 1H, J=7.8 Hz, 1.7 Hz), the rate of 8.75 (DD, 1H, J=4,8 Hz, 1.7 Hz).

An example of retrieving 39

Synthesis of 3-hydroxymethyl-2-(3,4,5-trimethoxyphenyl)pyridine

Ethyl-2-(3,4,5-trimethoxyphenyl)nicotinate (468 mg) is treated according to the method similar to that described in example getting 2, receiving specified in the header of the connection.

Yield 293 mg (72%).

1H-NMR (400 MHz, CDCl3) δ: 3,90 (s, 9H), 4.72 in (s, 2H), 6,83 (s, 2H), 7,32 (DD, 1H, J=7.9 Hz, 4.8 Hz), 7,92 (DD, 1H, J=7.9 Hz, 1.7 Hz), to 8.62 (DD, 1H, J=4,8 Hz, 1.7 Hz).

Example of getting 40

Synthesis of 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine

3-Hydroxymethyl-2-(3,4,5-trimethoxyphenyl)pyridine (293 mg) on srabatyvayut according to the method similar to that described in example receiving 3 receiving specified in the header of the connection.

Example 9

Synthesis of trihydrochloride 4-[N-(4-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-3-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

To a solution of 4-(p-anisidino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (139 mg) and 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) in acetonitrile (5 ml) is added potassium carbonate (83 mg) and potassium iodide (63 mg). The mixture was stirred at 70°during the night, and concentrate under reduced pressure. The residue is dissolved in chloroform, washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel using a mixture of ether/methanol (20:1) as eluent. Thus obtained free base is converted into trihydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 16 mg (8%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,60 (W, 2H), 1.77 in (W, 2H), 2,09 (W, 2H), 2,93 (W, 2H), 3.45 points (lat, 1H), 3,54 (s, 2H), of 3.73 (s, 3H), 3,90 (s, 6H), 3,91 (s, 6H), of 3.96 (s, 6H), 4,34 (s, 2H), 6,65 (d, 2H, J=9.0 Hz), of 6.71 (s, 2H,), 6,74 (d, 2H, J=9.0 Hz), 7,16-7,19 (m, 2H), 7,22 (s, 2H), 7,55 (s, 1H), 7,79 (d, 1H, J=7,0 Hz)and 8.50 (W, 1H), 8,58 (d, 1H, J=4,9 Hz).

When is EP 10

Synthesis of trihydrochloride 4-[N-(4-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(p-Anisidino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (1.56 g) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (1.08 g) is subjected to interaction by the method similar to that described in example 9. The obtained free base is converted into trihydrochloride, getting mentioned in the title compound as a yellow powder.

The output of 1.17 g (40%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,68-of 1.97 (m, 4H), 2,09-of 2.23 (m, 2H), 2,98 (W, 2H), 3 54-3,66 (m, 3H), of 3.73 (s, 3H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,93 (s, 6H), of 3.96 (s, 6H), of 4.45 (s, 2H), 6,74 (d, 2H, J=9,2 Hz), 6,79 (d, 2H, J=9,2 Hz), to 7.15 (s, 2H), 7,16-7,21 (m, 2H), 7.23 percent (s, 2H), EUR 7.57 (s, 1H), 7,60 (s, 1H), 8,54 (d, 1H, J=5,1 Hz), 8,59 (d, 1H, J=4,9 Hz).

An example of retrieving 41

Synthesis of 3-(3,4,5-trimethoxyphenyl)benzyl alcohol

Ethyl-3-(3,4,5-trimethoxyphenyl)benzoate (5,09 g) is treated according to the method similar to that described in example getting 2, receiving specified in the header of the connection.

The output of 4.25 g (97%).

1H-NMR (400 MHz, CDCl3) δ: 1,87 (t, 1H, J=6 0 Hz)to 3.89 (s, 3H), 3,92 (s, 6H), was 4.76 (d, 1H, J=5.6 Hz), 6,77 (s, 2H), 7,34 (d, 1H, J=7.4 Hz), 7,42 (t, 1H, J=7.5 Hz), of 7.48 (d, 1H, J=7,6 Hz), 7,55 (s, 1H).

An example of retrieving 42

Synthesis of 3-(3,4,5-trimethoxyphenyl)benzo is chloride

3-(3,4,5-Trimethoxyphenyl)benzyl alcohol (1,21 g) is treated according to the method similar to that described in example receiving 3 receiving specified in the header of the connection.

Output 893 mg (69%).

1H-NMR (400 MHz, CDCl3) δ: a 3.87 (s, 3H), 3,90 (s, 6H), to 4.62 (s, 2H), 6.75 in (s, 2H), 7,33 (d, 1H, J=7,6 Hz), 7,39 (t, 1H, J=7,7 Hz), of 7.48 (d, 1H, J=7,6 Hz), 7,54 (s, 1H).

Example 11

The synthesis of the dihydrochloride of 4-[N-(4-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(p-Anisidino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (139 mg) and 3-(3,4,5-trimethoxyphenyl)benzylchloride (114 mg) is subjected to interaction by the method similar to that described in example 9. The obtained free base is converted into the dihydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 52 mg (22%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,77-of 1.92 (m, 5H), 2,14-of 2.20 (m, 2H), 2.95 and 3.00 for (m, 5H), 2,14-of 2.20 (m, 2H), 2.95 and 3.00 for (m, 2H), to 3.58 (s, 2H), and 3.72 (s, 3H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), of 3.96 (s, 6H), 4,47 (s, 2H), 6,70 (s, 2H), 6,74-6,83 (m, 4H), 7,20 (d, 1H, J=7.4 Hz), 7.23 percent (s, 2H), 7,25-7,27 (m, 1H), 7,33 (t, 1H, J=7.4 Hz), 7,38 (d, 1H, J=8.7 Hz), the 7.43 (s, 1H), 7.62mm (s, 1H), 8,59 (d, 1H, J=5,1 Hz).

An example of retrieving 43

Synthesis of ethyl-6-(3,4,5-trimethoxyphenyl)nicotinate

3,4,5-Trimethoxyphenyl Bronevoy acid (1,16 g) and ethyl-6-chloronicotinate (1,02 g) is subjected to interaction by the method, as described in the example of obtaining 1, getting listed at the beginning of the connection.

Yield 1.42 g (82%).

1H-NMR (400 MHz, CDCl3) δ: of 1.43 (t, 3H, J=7.2 Hz), to 3.92 (s, 3H), 3,98 (s, 6H), of 4.44 (q, 2H, J=7,2 Hz), 7,32 (s, 2H), 7,76 (d, 1H, J=8,3 Hz), with 8.33 (DD, 1H, J=8,2 Hz, 2.2 Hz), 9,26 (d, 1H, J=2.2 Hz).

An example of retrieving 44

Synthesis of 5-hydroxymethyl-2-(3,4,5-trimethoxyphenyl)pyridine

Ethyl-6-(3,4,5-trimethoxyphenyl)nicotinate (658 mg) is treated according to the method similar to that described in example getting 2, receiving specified in the header of the connection.

The output 482 mg (85%).

1H-NMR (400 MHz, CDCl3) δ: 3,91 (s, 3H), of 3.97 (s, 6H), was 4.76 (s, 2H), 7.23 percent (s, 2H), 7,68 (d, 1H, J=7.4 Hz), 7,78 (DD, 1H, J=7,4 Hz, 2.3 Hz), 8,63 (d, 1H, J=2.3 Hz).

An example of retrieving 45

Synthesis of 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine

5-Hydroxymethyl-2-(3,4,5-trimethoxyphenyl)pyridine (685 mg) is treated according to the method similar to that described in example receiving 3 receiving specified in the header of the connection.

Output 717 mg (theoretical amount).

Example 12

Synthesis of trihydrochloride 4-[N-(4-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(p-Anisidino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (139 mg) and 5-chloromethyl-2-(3,4,5-trim is oxiranyl)pyridine (114 mg) is subjected to interaction by the method, similar to that described in example 9. The obtained free base is converted into trihydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 13 mg (5%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,76 (W, 2H), 1,88 (W, 2H), 2,14 (W, 2H), 2,97 (W, 2H), 3,51 (W, 1H), only 3.57 (s, 2H), of 3.73 (s, 3H), with 3.89 (s, 3H), 3,90 (s, 3H), of 3.94 (s, 6H), of 3.96 (s, 6H), was 4.42 (s, 2H), 6,78 (Shir, 4H), 7,20 (Shir, 3H), of 7.23 (s, 2H), EUR 7.57-of 7.70 (m, 3H), 8,58 at 8.60 (m, 2H).

An example of retrieving 46

Synthesis of ethyl-5-(3,4,5-trimethoxyphenyl)nicotinate

3,4,5-Trimethoxyphenylacetic acid (6,36 g) and ethyl-5-bromonicotinate (6,90 g) is subjected to interaction by the method similar to that described in example obtain 1, getting listed at the beginning of the connection.

Output 7,19 g (76%).

1H-NMR (400 MHz, CDCl3) δ: of 1.44 (t, 3H, J=7,1 Hz), 3,91 (s, 3H), of 3.95 (s, 6H), to 4.46 (q, 2H, J=7,1 Hz), 6,79 (s, 2H), 8,44 (t, 1H, J=2.1 Hz), 8,96 (d, 1H, J=2.1 Hz), 9,18 (d, 1H, J=1.8 Hz).

An example of retrieving 47

Synthesis of 3-hydroxymethyl-5-(3,4,5-trimethoxyphenyl)pyridine

Ethyl-5-(3,4,5-trimethoxyphenyl)nicotinate (7,19 g) is treated according to the method similar to that described in example getting 2, receiving specified in the header of the connection.

Output a 3.83 g (61%).

1H-NMR (400 MHz, CDCl3) δ: 3,88 (s, 3H), with 3.89 (s, 6H), 4,39 (W, 1H), 4,80 (s, 2H), 6,72 (s, 2H), 7,89 (t, 1H, J=1.2 Hz), of 8.47 (d, 1H, J=2.1 Hz), 8,63 (who, 1H, J=2.2 Hz).

Example obtain 48

Synthesis of 3-chloromethyl-5-(3,4,5-trimethoxyphenyl)pyridine

3-Hydroxymethyl-5-(3,4,5-trimethoxyphenyl)pyridine (2.85 g) is treated according to the method similar to that described in example receiving 3 receiving specified in the header of the connection.

The output of 1.97 g (65%).

1H-NMR (400 MHz, CDCl3) δ: 3,90 (s, 3H), of 3.94 (s, 6H), of 4.67 (s, 2H), 6.75 in (s, 2H), 7,87 (t, 1H, J=2.1 Hz), 8,59 (d, 1H, J=2.0 Hz), 8,76 (d, 1H, J=2.1 Hz).

Example 13

Synthesis of trihydrochloride 4-[N-(4-methoxyphenyl)-N-[[5-(3,4,5-trimethoxyphenyl)pyridine-3-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(p-Anisidino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (139 mg) and 3-chloromethyl-5-(3,4,5-trimethoxyphenyl)pyridine (114 mg) is subjected to interaction by the method similar to that described in example 9. The obtained free base is converted into trihydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 14 mg (5%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,73-of 1.75 (m, 2H), 1,88 (d, 2H, J=11.3 Hz), 2,13 (t, 2H, J=11.3 Hz), 2,96 (d, 2H, J=11.5 Hz), 3,50 (W, 1H), 3,55 (s, 2H), and 3.72 (s, 3H), 3,88 (s, 3H), with 3.89 (s, 9H), of 3.96 (s, 6H), of 4.45 (s, 2H), of 6.65 (s, 2H), 6,76 (d, 2H, J=9.6 Hz), to 6.80 (d, 2H, J=9.4 Hz), 7,20 (d, 1H, J=5.3 Hz), 7,22 (s, 2H), to 7.59 (s, 1H), to 7.67 (s, 1H), and 8.50 (s, 1H), 8,59 (d, 1H, J=4,7 Hz), to 8.62 (s, 1H).

An example of retrieving 49

Synthesis of 4-iodine-2,6-dimethoxyphenol

To a solution of 5-iodine-1,2,3-trimethoxybenzene (3.2 g) in 1,2-dichloroethane (40 ml) is added aluminum chloride (1.6 g). The mixture was stirred at 60°C for 4 hours and concentrated under reduced pressure. The residue is dissolved in 1 M aqueous sodium hydroxide solution and washed with ether. The aqueous layer was then acidified and extracted with chloroform. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, obtaining mentioned in the title compound in the form of white crystalline powder.

Yield 1.0 g (31%).

Example of getting 50

Synthesis of 1,3-dimethoxy-5-iodine-2-isopropoxybenzoic

To a suspension of 2,6-dimethoxy-4-itfinal (1.0 g) and potassium carbonate (938 mg) in DMF (10 ml) is added 2-jumprope (507 ml). The mixture was stirred at 60°C for 3 hours and concentrated under reduced pressure. To the residue is added ethyl acetate and water, the organic layer is removed, washed with saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel with hexane/ethyl acetate (5:1) as eluent, obtaining specified in the header of the connection.

The output of 788 mg (72%).

An example of retrieving 51

Synthesis of 3,5-dimethoxy-4-isopropoxyaniline acid

1,3-Dimethoxy-5-iodine-2-isopropoxyphenol (2.25 g) is treated according to the method similar to that described in example receiving 29, receiving specified in the header of the connection.

The output of 1.23 g (74%).

An example of retrieving 52

Synthesis of ethyl-2-(3,4,5-dimethoxy-4-isopropoxyphenyl)isonicotinate

3,5-Dimethoxy-4-isopropoxyaniline acid (1.23 g) and ethyl-2-chlorisondamine (0.95 g) is subjected to interaction by the method similar to that described in example obtain 1, getting listed at the beginning of the connection.

The output of 1.57 g (89%).

1H-NMR (400 MHz, CDCl3) δ: of 1.33 (d, 6H, J=4,9 Hz)of 1.44 (t, 3H, J=7,1 Hz), of 3.95 (s, 6H), 4,42 figure-4.49 (m, 3H), 7,29 (s, 2H), of 7.75 (DD, 1H, J=4,9 Hz and 1.4 Hz), 8,24 (s, 1H), 8,80 (d, 1H, J=4,9 Hz).

Example of getting 53

Synthesis of 2-(3,5-dimethoxy-4-isopropoxyphenyl)-4-hydroxymethylbenzene

To a suspension of sociallyengaged (190 mg) in THF (20 ml) added dropwise a solution of 2-(4-isopropoxy-3,5-acid)of isonicotinate (1,57 g) in THF (30 ml) under ice cooling in an argon atmosphere. The mixture was stirred at 0°C for 30 minutes and add saturated aqueous ammonium chloride. After extracting the mixture with ethyl acetate the organic layer was washed with saturated of rest the rum salt, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel, elwira a mixture of hexane/ethyl acetate (3:1) and then a mixture of chloroform/methanol (15:1), obtaining specified in the connection header.

The output of 1.31 g (95%).

1H-NMR (400 MHz, CDCl3) δ: of 1.32 (d, 6H, J=6,1 Hz), 3,93 (s, 6H), 4,45 (quintet, 1H, J=6,1 Hz), to 4.81 (s, 2H), 7,20 (d, 1H, J=5,1 Hz), 7.23 percent (s, 2H), 7,68 (s, 1H), to 8.62 (d, 1H, J=5,1 Hz).

An example of retrieving 54

Synthesis of 4-chloromethyl-2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridine

2-(3,5-Dimethoxy-4-isopropoxyphenyl)-4-hydroxymethyluracil (1,49 g) is treated according to the method similar to that described in example receiving 3 receiving specified in the header of the connection.

The output of 1.33 g (84%).

1H-NMR (400 MHz, CDCl3) δ: of 1.32 (d, 6H, J=6.2 Hz), of 3.94 (s, 6H), 4,45 (quintet, 1H, J=6,1 Hz), br4.61 (s, 2H), 7.23 percent-7,26 (m, 3H), of 7.69 (s, 1H), 8,66 (d, 1H, J=5,1 Hz).

Example of getting 55

Synthesis of atelectasia 1-[[2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridine-4-yl]methyl]-4-piperidone

4-Chloromethyl-2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridine (643 mg) and atlantal 4-piperidone (287 mg) is subjected to interaction by the method similar to that described in example 2, obtaining specified in the header of the connection.

The output 818 mg (95%).

1H-NMR (400 MHz, CDCl3) δ: of 1.32 (d, 6H, J6,1 Hz), 1,78 (t, 4H, J=5.7 Hz), 2.57 m (width, 4H), 3,49 (s, 4H)and 3.59 (s, 2H), 3,94 (s, 6H), of 4.44 (quintet, 1H, J=6,1 Hz), 7,21 (d, 1H, J=5,1 Hz), 7.23 percent (s, 2H), 7,65 (s, 1H), 8,59 (d, 1H, J=5,1 Hz).

An example of receiving 56

Synthesis of 1-[[2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridine-4-yl]methyl]-4-piperidone

Atlantal 1-[[2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridine-4-yl]methyl]-4-piperidone (818 mg) is treated according to the method similar to that described in example receiving 23, receiving specified in the header of the connection.

Output 717 mg (98%).

1H-NMR (400 MHz, CDCl3) δ: of 1.32 (d, 6H, J=6.2 Hz), of 2.50 (t, 4H, J=6,1 Hz), of 2.81 (t, 4H, J=6,1 Hz), of 3.69 (s, 2H), 3,95 (s, 6H), 4,45 (quintet, 1H, J=6.2 Hz), 7,24 (s, 2H), 7,25-7,27 (m, 1H), 7,68 (s, 1H), 8,63 (d, 1H, J=5,1 Hz).

An example of retrieving 57

Synthesis of 4-(p-anisidino)-1-[[2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridine-4-yl]methyl]piperidine

1-[[2-(3,5-Dimethoxy-4-isopropoxyphenyl)pyridine-4-yl]methyl]-4-piperidone (350 mg) and p-anisidine (123 mg) is treated according to the method similar to that described in example receiving 37, receiving specified in the header of the connection.

The output 307 mg (69%).

1H-NMR (400 MHz, CDCl3) δ: of 1.32 (d, 6H, J=6.3 Hz), 1,46-of 1.52 (m, 2H), 2,00-2,24 (m, 2H), 2,22 (t, 2H, J=11,1 Hz), 2,86 (d, 2H, J=12.1 Hz), 3,18 of 3.28 (m, 1H), to 3.58 (s, 2H), 3,74 (s, 3H), of 3.94 (s, 6H), 4,40 (quintet, 1H, J=6.3 Hz), to 6.58 (d, 2H, J=6.6 Hz), 6,78 (d, 2H, J=6.6 Hz), 7,20 (d, 1H, J=5,1 Hz), 7,24 (s, 2H), to 7.64 (s, 1H), 8,59 (d, 1H, J=5,1 Hz).

Example 14

Synthesis trihydrogen is Yes 1-[[2-(4-isopropoxy-3,5-acid)pyridine-4-yl]methyl]-4-[N-[[2-(4-isopropoxy-3,5-acid)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)aminopiperidine

4-(p-Anisidino)-1-[[2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridine-4-yl]methyl]piperidine (307 mg) and 4-chloromethyl-2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridine (201 mg) is subjected to interaction by the method similar to that described in example 9. The obtained free base is converted into trihydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 230 mg (46%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: of 1.31 (d, 6H, J=3.3 Hz), 1,32 (d, 6H, J=6.8 Hz), 1.70 to of 1.92 (m, 4H), 2,10-of 2.20 (m, 2H), 2,92-a 3.01 (m, 2H), of 3.56 (s, 2H), of 3.73 (s, 3H), 3,85-3,95 (m, 1H), 3,90 (s, 6H), 3,93 (s, 6H), 4,39-of 4.49 (m, 4H), 6.73 x (d, 2H, J=4,8 Hz), 6,78 (d, 2H, J=4,8 Hz), 7,14 (s, 2H), 7,15-7,20 (m, 2H), 7.23 percent (s, 2H), 7,58 (s, 1H), 7,60 (s, 1H), 8,53 (d, 1H, J=5,1 Hz), 8,58 (d, 1H, J=5,1 Hz).

An example of retrieving 58

Synthesis of 4-benzylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

1-[[2-(3,4,5-Trimethoxyphenyl)pyridine-4-yl]methyl-4-piperidone (1.40 g) and benzylamine (0.51 g) is subjected to interaction by the method similar to that described in example receiving 37, getting mentioned in the title compound as a yellow amorphous substance.

Yield 1.20 g (68%).

1H-NMR (400 MHz, CDCl3) δ: 1,40-1,60 (m, 2H), 1,88-of 2.09 (m, 5H), 2,54 (W, 1H), 2,82-to 2.85 (m, 2H), 3,52 (s, 2H), 3,80 (s, 2H), with 3.89 (s, 2H), 3,95 (s, 6H), 7.18 in-7,31 (m, 8H), to 7.64 (s, 1H), to 8.57 (d, 1H, J=5,1 Hz).

Example 15

Synthesis of tetrahydrochloride 4-[N-be the ZIL-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-3-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4 Benzylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (134 mg) and 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) is subjected to interaction by the method similar to that described in example 9. The obtained free base is converted into tetrahydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 43 mg (17%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,63 (Shir, 4H), 1,87 (W, 2H), 2,39 (W, 1H), 2,88 (W, 2H), 3,49 (s, 2H), only 3.57 (s, 2H), 3,68 (s, 2H), 3,86 (s, 6H), 3,88 (s, 3H), 3,90 (s, 3H), of 3.96 (s, 6H), 6,60 (s, 2H), 7,17 (d, 1H, J=5,1 Hz), 7,22-7,29 (m, 8H), 7,56 (s, 1H), 8,02 (d, 1H, J=8.0 Hz), and 8.50 (d, 1H, J=6.4 Hz), 8,58 (d, 1H, J=5,1 Hz).

Example 16

Synthesis of tetrahydrochloride 4-[N-benzyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4 Benzylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (230 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (158 mg) is subjected to interaction by the method similar to that described in example 9. The obtained free base is converted into tetrahydrochloride, to deliver specified in the title compound as a yellow powder.

Yield 172 mg (47%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,69-of 1.85 (m, 4H), 1.93 and of 1.99 (m, 2H), 2,56 (W, 1H), 2,9-3,00 (m, 2H), 3,51 (s, 2H), 3,71 (s, 2H), 3,74 (s, 2H), 3,90 (s, 6H), of 3.96 (s, 6H), of 3.96 (s, 6H), 7.18 in-7,32 (m, 9H), 7,38 (d, 2H, J=7,1 Hz), to 7.59 (s, 1H), 7,68 (s, 1H), 8,56 (d, 1H, J=5,1 Hz), at 8.60 (d, 1H, J=5,1 Hz).

Example 17

Synthesis of trihydrochloride 4-[N-benzyl-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4 Benzylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (134 mg) and 3-(3,4,5-trimethoxyphenyl)benzylchloride (114 mg) is subjected to interaction by the method similar to that described in example 9. The obtained free base is converted into trihydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 47 mg (18%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,70-to 1.86 (m, 4H), 1,96 (W, 2H), 2,59 (W, 1H), 2,94 (W, 2H), 3,51 (s, 2H), 3,70 (s, 2H), 3,74 (s, 2H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,92 (s, 6H), of 3.96 (s, 6H), 6.75 in (s, 2H), 7.18 in-7,30 (m, 6H), 7,35-7,40 (m, 5H), 7,56 (s, 1H), 7,60 (s, 1H), 8,58 (d, 1H, J=5,1 Hz).

Example 18

Synthesis of tetrahydrochloride 4-[N-benzyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4 Benzylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (134 mg) and 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) is subjected to interaction by the method similar to that described in example 9. The obtained free base is converted into tetrahydrochloride, receiving the result mentioned in the title compound as a yellow powder.

Yield 44 mg (17%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,81 (Shir, 4H), 1,96 (W, 2H), 2,55 (W, 1H), 2,96 (W, 2H), 3,52 (s, 2H), 3,69 (s, 4H), to 3.89 (s, 6H), of 3.95 (s, 6H), of 3.96 (s, 6H), 7,19-to 7.32 (m, 8H), was 7.36-7,38 (m, 2H), to 7.61 (d, 2H, J=7,6 Hz), 7,69-7,73 (m, 1H), 8,59 (d, 1H, J=4.9 Hz), 8,63 (s, 1H).

Example 19

Synthesis of tetrahydrochloride 4-[N-benzyl-N-[[5-(3,4,5-trimethoxyphenyl)pyridine-3-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4 Benzylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (134 mg) and 3-chloromethyl-5-(3,4,5-trimethoxyphenyl)pyridine (114 mg) is subjected to interaction by the method similar to that described in example 9. The obtained free base is converted into tetrahydrochloride, to deliver specified in the title compound as a yellow powder.

Yield 26 mg (10%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,83 (Shir, 4H), 1,97 (W, 2H), 2,58 (W, 1H), 2.95 and (W, 2H), 3,53 (s, 2H), 3,71 (s, 2H, in), 3.75 (s, 2H), 3,90 (s, 6H), 3,93 (s, 6H), of 3.96 (s, 6H), 6,74 (s, 2H), 7,19-7,30 (m, 6H), was 7.36 (d, 2H, J=the 6.8 Hz), 7,60 (s, 1H), 7,79 (s, 1H), 8,54 (s, 1H), 8,59 (d, 1H, J=5,1 Hz)8,64 (s, 1H).

Example retrieve 59

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]aminoethyl]piperidine

tert-Butoxycarbonyl)-4-aminomethylpyridine (200 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (183 mg) is subjected to interaction by the method similar to that described in example 2, obtaining mentioned in the title compound as a yellow oil.

Exit 264 mg (90%).

1H-NMR (400 MHz, CDCl3) δ: 1,12-of 1.27 (m, 3H), 1,45 (s, 9H), 1,60 (W, 1H), 1,74 (d, 2H, J=12.9 Hz), 2,54 (d, 2H, J=6.6 Hz), 2,69 (W, 2H), a 3.87 (s, 2H), 3,90 (s, 3H), of 3.97 (s, 6H), a 4.03-to 4.14 (m, 2H), 7,20 (d, 1H, J=3,9 Hz), from 7.24 (s, 2H), 7,65 (s, 1H), at 8.60 (d, 1H, J=4,9 Hz).

Example of getting 60

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]aminomethyl]piperidine

1-(tert-Butoxycarbonyl)-4-[N-[[3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]aminoethyl]piperidine (264 mg) is treated according to the method similar to that described in example receiving 11, getting mentioned in the title compound as a yellow oil.

Yield 157 mg (58%).

1H-NMR (400 MHz, CDCl3) δ: 1,00-of 1.09 (m, 2H), USD 1.43 (s, 9H), 1,65-1,70 (m, 1H), 1,79 (d, 2H, J=a 12.7 Hz), of 2.21 (d, 2H, J=7.4 Hz), of 2.23 (s, 3H), 2,69 (W, 2H), 3,52 (s, 2H), with 3.89 (s, 3H), of 3.96 (s, 6H), 4,07 is 4.13 (m, 2H), 7,20 (d, 1H, J=4.9 Hz), 7,24 (s, 2H), to 7.64 (s, 1H), 8,58 (d, 1H, J=5,1 Hz).

An example of retrieving 61

Synthesis of 4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]aminomethyl]piperidine

1-(tert-Butoxycarbonyl)-4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-and the]methyl]aminomethyl]piperidine (152 mg) is treated according to the method similar to that described in example 12, getting mentioned in the title compound as yellow crystals.

Yield 105 mg (88%).

1H-NMR (400 MHz, CDCl3) δ: 1,00-1,10 (m, 2H), 1,60 by 1.68 (m, 1H), 1,80 (d, 2H, J=12,5 Hz), 2,03 (W, 1H), 2,20 (d, 2H, J=8,4 Hz), of 2.21 (s, 3H), 2,58 (dt, 2H, J=12.1 Hz, 2.1 Hz), 3,05 (d, 2H, J=12.1 Hz), 3,51 (s, 2H), with 3.89 (s, 3H), of 3.95 (s, 6H), 7,20 (d, 1H, J=5,1 Hz), 7,24 (s, 2H), 7,65 (s, 1H), to 8.57 (d, 1H, J=5,9 Hz).

Example 20

Synthesis of dioxalate 4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]aminomethyl]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-[N-Methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]aminomethyl]piperidine (96 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (73 mg) is subjected to interaction by the method similar to that described in example 2. After transformation of the obtained product in dioxalate get mentioned in the title compound as a white powder.

Yield 109 mg (40%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,19-of 1.27 (m, 2H), 1.56 to (W, 1H), 1,81 (d, 2H, J=11,1 Hz), 1,99-2,04 (m, 2H), 2,23 (s, 5H), is 2.88 (d, 2H, J=11,1 Hz), 3,53 (s, 4H), to 3.89 (s, 3H), 3,90 (s, 3H), of 3.94 (s, 6H), of 3.96 (s, 6H), 7,20 (Shir, 2H), 7.23 percent (s, 4H), to 7.61 (s, 1H), to 7.64 (s, 1H), 8,58 (d, 2H, J=4,9 Hz).

An example of retrieving 62

Synthesis of 4-(3,5-dimethoxyaniline)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

1-[[2-(3,4,5-Trimethoxyphenyl)PI is one-4-yl]methyl]-4-piperidone (1.40 g) and 3,5-dimethoxyaniline (722 mg) is subjected to interaction by the method, similar to that described in example receiving 37, receiving specified in the header of the connection.

Yield 800 mg (41%).

1H-NMR (400 MHz, CDCl3) δ: 1,40-1,90 (m, 2H), 1,95-of 2.50 (m, 4H), 2,93 (W, 2H), 3,31 (W, 1H), 3,65 (W, 2H), and 3.72 (s, 6H), 3,88 (s, 3H), of 3.96 (s, 6H), USD 5.76 (s, 2H), to 5.85 (s, 1H), 7,20-7,35 (m, 3H), 7,73 (W, 1H), at 8.60 (d, 1H, J=4,9 Hz).

Example 21

Synthesis of trihydrochloride 4-[N-(3,5-acid)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-3-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(3,5-Dimethoxyaniline)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (148 mg) and 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) is subjected to interaction by the method similar to that described in example 9. The obtained free base is converted into trihydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 29 mg (11%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,60-to 1.63 (m, 2H), 1,79 (d, 2H, J=11.7 Hz), 2,13 (t, 2H, J=11,4 Hz)to 2.94 (d, 2H, J=11.3 Hz), of 3.54 (s, 2H), 3,71 (s, 6H), 3,78-a-3.84 (m, 1H), 3,90 (s, 3H), 3,91 (s, 6H), to 3.92 (s, 3H), of 3.96 (s, 6H), to 4.41 (s, 2H), of 5.84 (s, 2H), 6,72 (s, 2H), 7,09-of 7.24 (m, 5H), 7,53 (s, 1H), 7,71 (d, 1H, J=6.6 Hz), 8,51 (DD, 1H, J=4,7 Hz to 1.6 Hz), 8,59 (d, 1H, J=4,9 Hz).

An example of retrieving 63

Synthesis of ethyl-2-(3,4,5-trimethoxyphenyl)benzoate

3,4,5-Trimethoxyphenylacetic acid (649 mg) and ethyl-2-bromobenzoate 479 mg) is subjected to interaction by the method, as described in the example of obtaining 1, getting listed at the beginning of the connection.

The output 655 mg (69%).

1H-NMR (400 MHz, CDCl3) δ: was 1.04 (t, 3H, J=7.2 Hz), 3,86 (s, 6H), to 3.89 (s, 3H), of 4.12 (q, 2H, J=7,2 Hz), is 6.54 (s, 2H), 7,40-7,42 (m, 2H), 7,51 (t, 1H, J=7.8 Hz), to 7.77 (d, 1H, J=6,8 Hz).

Example of getting 64

Synthesis of 2-(3,4,5-trimethoxyphenyl)benzyl alcohol

Ethyl-2-(3,4,5-trimethoxyphenyl)benzoate (655 mg) is treated according to the method similar to that described in example getting 2, receiving specified in the header of the connection.

Yield 630 mg (theoretical amount).

1H-NMR (400 MHz, CDCl3) δ: 3,85 (s, 6H), 3,90 (s, 3H), br4.61 (s, 2H), is 6.61 (s, 2H), 7,26-7,39 (m, 3H), 7,53 (d, 1H, J=6,8 Hz).

Example getting 65

Synthesis of 2-(3,4,5-trimethoxyphenyl)benzylchloride

2-(3,4,5-Trimethoxyphenyl)benzyl alcohol (630 mg) is treated according to the method similar to that described in example receiving 3 receiving specified in the header of the connection.

Yield 615 mg (theoretical amount).

1H-NMR (400 MHz, CDCl3) δ: a 3.87 (s, 6H), 3,90 (s, 3H), 4.53-in (s, 2H), 6,66 (s, 2H), 7,29-7,32 (m, 1H), 7,34-7,39 (m, 2H), 7,50-7,52 (m, 1H).

Example 22

The synthesis of the dihydrochloride of 4-[N-(3,5-acid)-N-[2-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(3,5-Dimethoxyaniline)-1-[[2-(34,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (148 mg) and 2-(3,4,5-trimethoxyphenyl)benzylchloride (114 mg) is subjected to interaction by the method, similar to that described in example 9. The obtained free base is converted into the dihydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 20 mg (8%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,50-1,90 (m, 4H), 2.05 is-of 2.20 (m, 2H), 2,92 (W, 2H), 3,52 (Shir, 3H), 3,68 (s, 6H), 3,85 (s, 6H), 3,88 (s, 3H), with 3.89 (s, 3H), of 3.94 (s, 6H), or 4.31 (s, 2H), 5,85 (Shir, 3H), of 6.52 (s, 2H), 7,05-7,27 (m, 6H), 7,34 (s, 1H), 7,51 (s, 1H), 8,56 (s, 1H).

Example 23

Synthesis of trihydrochloride 4-[N-(3,5-acid)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(3,5-Dimethoxyaniline)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (148 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) is subjected to interaction by the method similar to that described in example 9. The obtained free base is converted into trihydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 40 mg (18%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,68-1,90 (m, 4H), 2,12-2,22 (m, 2H), 2,94-to 3.02 (m, 2H), only 3.57 (s, 2H), 3,71 (s, 6H), 3,81-a 3.83 (m, 1H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,93 (s, 6H), of 3.96 (s, 6H), to 4.52 (s, 2H), of 5.89-5,94 (m, 3H), 7,14 (d, 1H, J=5.3 Hz), 7,16 (s, 2H), 7,20 (d, 1H, J=3,7 Hz), 7,22 (s, 2H), 7,54-of 7.60 (m, 2H), 8,55 (d, 1H, J=5,1 Hz), 8,59 (d, 1H, J=5,1 Hz).

Example 24

The synthesis of the dihydrochloride of 4-[N-(3,5-acid)--[3-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(3,5-Dimethoxyaniline)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (148 mg) and 3-(3,4,5-trimethoxyphenyl)benzylchloride (114 mg) is subjected to interaction by the method similar to that described in example 9. The obtained free base is converted into the dihydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 41 mg (16%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,78-of 1.88 (m, 4H), of 2.16 (t, 2H, J=10,7 Hz), 2,96 (d, 2H, J=11.3 Hz), of 3.56 (s, 2H), 3,70 (s, 6H), to 3.73-a-3.84 (m, 1H), a 3.87 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), of 3.95 (s, 6H), of 4.54 (s, 2H), 5,95 (, 2H), of 6.71 (s, 2H), 7,19-7,26 (m, 4H), 7,31-7,39 (m, 3H), 7,42 (s, 1H), to 7.59 (s, 1H), 8,58 (d, 1H, J=4,9 Hz).

Example 25

Synthesis of trihydrochloride 4-[N-(3,5-acid)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(3,5-Dimethoxyaniline)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (148 mg) and 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) is subjected to interaction by the method similar to that described in example 9. The obtained free base is converted into trihydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 23 mg (10%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,64 (W, 2H), 1,82 (W, 2H), 2,10 (Shi is, 2H), 2,94 (W, 2H), 3,48-of 3.60 (m, 3H), of 3.64 (s, 6H), 3,82 (s, 3H), 3,83 (s, 3H), a 3.87 (s, 6H), 3,90 (s, 6H), to 4.46 (s, 2H), 5,85 (Shir, 3H), 7,05-7,24 (m, 6H), 7,53-rate of 7.54 (m, 2H), 8,51 (s, 1H), 8,54 (W, 1H).

An example of retrieving 66

Synthesis of ethyl-4-(3,4,5-trimethoxyphenyl)benzoate

3,4,5-Trimethoxyphenylacetic acid (2,01 g) and ethyl-4-bromobenzoate (to 2.29 g) is subjected to interaction by the method similar to that described in example obtain 1, getting listed at the beginning of the connection.

Output 2,99 g (95%).

1H-NMR (400 MHz, CDCl3) δ: of 1.42 (t, 3H, J=7.2 Hz), 3,90 (s, 3H), of 3.94 (s, 6H), to 4.38 (q, 2H, J=7,2 Hz), for 6.81 (s, 2H), a 7.62 (d, 2H, J=8,2 Hz), 8,10 (d, 2H, J=8,2 Hz).

An example of retrieving 67

Synthesis of 4-(3,4,5-trimethoxyphenyl)benzyl alcohol

Ethyl-4-(3,4,5-trimethoxyphenyl)benzoate (2,99 g) is treated according to the method similar to that described in example getting 2, receiving specified in the header of the connection.

The output of 1.83 g (71%).

Example of getting 68

Synthesis of 2-(3,4,5-trimethoxyphenyl)benzylchloride

4-(3,4,5-Trimethoxyphenyl)benzyl alcohol (1,83 g) is treated according to the method similar to that described in example receiving 3 receiving specified in the header of the connection.

The output of 1.65 g (84%).

1H-NMR (400 MHz, CDCl3) δ: 3,90 (s, 3H), 3,93 (s, 6H)and 4.65 (s, 2H), 6,77 (s, 2H), 7,46 (d, 2H, J=8.0 Hz), 7,55 (d, 2H, J=8.0 Hz).

Example 26

Synthesis of dihydrochloride is a 4-[N-(3,5-acid)-N-[[4-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(3,5-Dimethoxyaniline)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (148 mg) and 4-(3,4,5-trimethoxyphenyl)benzylchloride (114 mg) is subjected to interaction by the method similar to that described in example 9. The obtained free base is converted into the dihydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 35 mg (14%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,80-1,89 (m, 4H), 2,17 (W, 2H), 2,97 (d, 2H, J=10.5 Hz), of 3.57 (s, 2H), 3,70 (s, 6H), of 3.77-a-3.84 (m, 1H), a 3.87 (s, 3H), 3,90 (s, 3H), 3,91 (s, 6H), of 3.96 (s, 6H), to 4.52 (s, 2H), to 5.93 (s, 2H), 6,74 (s, 2H), 7,19-7,22 (m, 4H), 7,31 (d, 2H, J=8,2 Hz), 7,46 (d, 2H, J=8,2 Hz), 7,60 (s, 1H), 8,59 (d, 1H, J=5,1 Hz).

Example of getting 69

Synthesis of 4-(3,4-methylenedioxyphenyl)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

1-[[2-(3,4,5-Trimethoxyphenyl)pyridine-4-yl]methyl]-4-piperidone (1.40 g) and 3,4-methylenedioxyaniline (646 mg) is subjected to interaction by the method similar to that described in example receiving 37, receiving specified in the header of the connection.

The output of 810 mg (43%).

1H-NMR (400 MHz, CDCl3) δ: 1,63 (W, 2H), 2,02-2,60 (m, 4H), 2,80 is 3.15 (m, 2H), 3,25 (W, 1H), 3,70 (W, 2H), 3,88 (s, 3H), of 3.96 (s, 6H), of 5.83 (s, 2H), 6,02 (d, 1H, J=8,3 Hz), to 6.22 (s, 1H), is 6.61 (d, 1H, J=8,3 Hz), 7.18 in-7,28 (m, 3H), of 7.64 (W, 1H), at 8.60 (d, 1H, J=4,9 Hz).

Example 27

Synthesis of trihydrochloride 4-[N-(3,4-methylendioxyphenyl the)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-3-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(3,4-Methylenedioxyphenyl)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (119 mg) and 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) is subjected to interaction by the method similar to that described in example 9. The obtained free base is converted into trihydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 30 mg (14%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,45 was 2.25 (m, 6H), 2,90 (W, 2H), 3,40 (W, 1H), 3,55 (W, 2H), a 3.87 (s, 3H), 3,88 (s, 9H), 3,93 (s, 6H), 4,28 (s, 2H), of 5.82 (s, 2H), 6,10 (W, 1H), 6,28 (s, 1H), return of 6.58 (d, 1H, J=8,4 Hz), 6,67 (, 2H), 7,12-7,30 (m, 4H), 7,52 (W, 1H), 7,75 (W, 1H), 8,51 (W, 1H), 8,57 (W, 1H).

Example 28

The synthesis of the dihydrochloride of 4-[N-(3,4-methylenedioxyphenyl)-N-[2-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(3,4-Methylenedioxyphenyl)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (119 mg) and 2-(3,4,5-trimethoxyphenyl)benzylchloride (114 mg) is subjected to interaction by the method similar to that described in example 9. The obtained free base is converted into the dihydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 13 mg (6%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,61 (W, 2H), 1,78 (W, 2H), 2,10 (W, H), 2.91 in (W, 2H), 3,50-of 3.54 (m, 3H), a 3.87 (s, 6H), 3,90 (s, 3H), 3,92 (s, 3H), 3,99 (s, 6H), 4.26 deaths (s, 2H), of 5.82 (s, 2H), 6,12 (d, 1H, J=8.6 Hz), 6,32 (s, 1H), 6,53 (s, 2H), 6,62 (d, 1H, J=8.6 Hz), 7,17-7,26 (m, 6H), 7,42 (W, 1H), 7,55 (s, 1H), 8,58 (d, 1H, J=4,9 Hz).

Example 29

Synthesis of trihydrochloride 4-[N-(3,4-methylenedioxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(3,4-Methylenedioxyphenyl)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (119 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) is subjected to interaction by the method similar to that described in example 9. The obtained free base is converted into trihydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 52 mg (25%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,60-of 1.95 (m, 4H), 2,20 (W, 2H), 3.00 and (W, 2H), to 3.58 (Shir, 3H), 3,86 (s, 3H), a 3.87 (s, 3H), 3,91 (s, 6H), of 3.94 (s, 6H), to 4.41 (s, 2H), of 5.82 (s, 2H), 6,17 (d, 1H, J=8,4 Hz), to 6.39 (s, 1H), 6,62 (d, 1H, J=8,4 Hz), 7,12-7,13 (m, 3H), 7,18 (d, 1H, J=4,1 Hz), 7.23 percent (W, 2H), 7,54 (Shir, 2H), 8,51 (d, 1H, J=5,1 Hz), to 8.57 (d, 1H, J=4,9 Hz).

Example 30

The synthesis of the dihydrochloride of 4-[N-(3,4-methylenedioxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(3,4-Methylenedioxyphenyl)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (119 mg) and 3-(34,5-trimethoxyphenyl)benzylchloride (114 mg) is subjected to interaction by the method, similar to that described in example 9. The obtained free base is converted into the dihydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 58 mg (29%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,60-of 1.97 (m, 4H), 2,15 (W, 2H), 3.00 and (W, 2H), to 3.58 (Shir, 3H), 3,86 (s, 3H), 3,88 (s, 9H), of 3.94 (s, 6H), 4,43 (s, 2H), of 5.81 (s, 2H), 6,21 (W, 1H), 6.42 per (s, 1H), 6,62 (d, 1H, J=8,4 Hz), 6,69 (, 2H), 7,18 (d, 1H, J=4.9 Hz), 7,22-7,39 (m, 6H), 7,60 (W, 1H), to 8.57 (d, 1H, J=4,9 Hz).

Example 31

Synthesis of trihydrochloride 4-[N-(3,4-methylenedioxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(3,4-Methylenedioxyphenyl)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (119 mg) and 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) is subjected to interaction by the method similar to that described in example 9. The obtained free base is converted into trihydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 69 mg (27%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,71-of 1.88 (m, 4H), and 2.14 (d, 2H, J=11.2 Hz), 2,97 (d, 2H, J=11.5 Hz), 3,45-to 3.52 (m, 1H), of 3.56 (s, 2H), with 3.89 (s, 3H), 3,90 (s, 3H), of 3.94 (s, 6H), of 3.96 (s, 6H), of 4.12 (s, 2H), to 5.85 (s, 2H), 6,24 (DD, 1H, J=8,5 Hz, 2.5 Hz), 6,45 (d, 1H, J=2.4 Hz), only 6.64 (d, 1H, J=8.5 Hz), 7,20-7,21 (m, 1H), 7,21 (s, 2H), 7.23 percent (s, 2H), 7,58-the 7.65 (m, 3H), to 8.57 (d, 1H, J=1.5 Hz), 8,59 (d, 1H, J=4,9 Hz.

Example 32

The synthesis of the dihydrochloride of 4-[N-(3,4-methylenedioxyphenyl)-N-[4-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(3,4-Methylenedioxyphenyl)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (119 mg) and 4-(3,4,5-trimethoxyphenyl)benzylchloride (114 mg) is subjected to interaction by the method similar to that described in example 9. The obtained free base is converted into the dihydrochloride, getting mentioned in the title compound as a yellow powder.

Yield 29 mg (14%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,62-2,00 (m, 4H), 2,20 (W, 2H), 2,99 (W, 2H), to 3.58 (Shir, 3H), 3,86 (s, 3H), a 3.87 (s, 3H), 3,88 (s, 6H), to 3.89 (s, 6H), to 4.41 (s, 2H), of 5.82 (s, 2H), to 6.19 (d, 1H, J=8.6 Hz), to 6.39 (s, 1H), 6,63 (d, 1H, J=8,4 Hz), 6,72 (s, 2H), 7,18 (d, 1H, J=5,1 Hz), 7.23 percent (s, 2H), 7,29 (d, 2H, J=8.0 Hz), the 7.43 (d, 2H, J=8,2 Hz), 7,60 (W, 1H), to 8.57 (d, 1H, J=4,9 Hz).

Example of getting 70

Synthesis of 4-[N-methyl-N-[(2-nitrobenzene)sulfonyl]aminomethyl]-2-(3,4,5-trimethoxyphenyl)pyridine

4-Chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (232 mg), N-methyl-2-nitrobenzenesulfonamide (171 mg) and potassium carbonate (138 mg) is suspended in acetonitrile (10 ml). The mixture is stirred at room temperature overnight and concentrated under reduced pressure. The residue is dissolved in chloroform, washed with saturated water is a sodium bicarbonate and a saturated solution of salt, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, obtaining specified in the header of the connection.

The output of 362 mg (97,0%).

Example of getting 71

Synthesis of 4-(methylaminomethyl)-2-(3,4,5-trimethoxyphenyl)pyridine

To a suspension of 4-[N-methyl-N-[(2-nitrobenzene) sulfonyl] aminomethyl]-2-(3,4,5-trimethoxyphenyl)pyridine (691 mg) and potassium carbonate (203 mg) in acetonitrile (20 ml) add thiophenol (228 μl). The mixture is stirred at a temperature of 50°during the night, and concentrate under reduced pressure. The residue is dissolved in chloroform, washed with saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel using a mixture of chloroform/methanol (40:1˜10:1) as eluents, getting listed at the beginning of the connection.

The output of 356 mg (84%).

Example 33

Synthesis maleate 4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]aminocarbonyl]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

1-[[2-(3,4,5-Trimethoxyphenyl)pyridine-4-yl]methyl]piperidine-4-carboxylic acid (98 mg) and 4-(methylaminomethyl)-2-(3,4,5-trimethoxyphenyl)pyridine (73 mg) is treated according to the method similar to that described in the example 1, getting maleate specified in the connection header.

Yield 145 mg (75%).

1H-NMR (400 MHz, defined as maleate, DMSO-d6) δ: 1,89-of 1.97 (m, 4H), 2,75-2,96 (m, 3H), 3,03 (s, 3H), 3.27 to (d, 2H, J=12.0 Hz), of 3.78 (s, 3H), 3,79 (s, 3H), a 3.87 (s, 6H), 3,90 (s, 6H), 4.09 to (s, 2H), with 4.64 (s, 2H), 6,14 (s, 2H), to 7.09 (d, 1H, J=5.0 Hz), 7,33 (s, 2H), 7,37 (d, 1H, J=5.0 Hz), 7,38 (s, 2H), 7,65 (s, 1H), of 7.90 (s, 1H), to 8.57 (d, 1H, J=5.0 Hz), 8,67 (d, 1H, J=5.0 Hz).

Example of getting 72

Synthesis of (3S)-1-(tert-butoxycarbonyl)-3-[N-[(2-nitrobenzene)sulfonyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]pyrrolidine

(3S)-1-(tert-Butoxycarbonyl)-3-[(2-nitrobenzene)sulfonylamino]pyrrolidin (72 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (57 mg) is subjected to interaction by the method similar to that described in example getting 2, getting mentioned in the title compound as a colorless amorphous substance.

Yield 103 mg (85%).

Example of getting 73

Synthesis of (3S)-3-[N-[(2-nitrobenzene)sulfonyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]pyrrolidine

(3S)-1-(tert-Butoxycarbonyl)-3-[N-[(2-nitrobenzene)sulfonyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]pyrrolidine (103 mg) is treated according to the method similar to that described in example 12, getting mentioned in the title compound as a yellow amorphous substance.

Yield 72 mg (84%).

1H-YAM who (400 MHz, CDCl3) δ: of 1.66 and 1.75 (m, 1H), 2,03-2,05 (m, 1H), 2,78-to 2.85 (m, 2H), 3.00 and-3,10 (m, 2H), 3,39 (W, 1H), 3,90 (s, 3H), of 3.96 (s, 6H), 4,59-of 4.67 (m, 1H), 4,70 (s, 2H), 7,13-to 7.18 (m, 1H), 7,20 (s, 2H), 7,52-to 7.64 (m, 4H), 7,95 (DD, 1H, J=7.9 Hz, 1.1 Hz), charged 8.52 (d, 1H, J=5,1 Hz).

Example of getting 74

Synthesis of (3S)-3-[N-[(2-nitrobenzene)sulfonyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]pyrrolidine

(3S)-3-[N-[(2-Nitrobenzene)sulfonyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]pyrrolidine (72 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (40 mg) is subjected to interaction by the method similar to that described in example 2, obtaining mentioned in the title compound as a yellow amorphous substance.

Yield 97 mg (91%).

1H-NMR (400 MHz, CDCl3) δ: 1,59 (W, 1H), 1,80-1,90 (m, 1H), 2,20-of 2.30 (m, 2H), by 2.55 (DD, 1H, J=10.5 Hz and 8.2 Hz), 2,78 (DD, 1H, J=10,6 Hz, 3.2 Hz), 2,87 (t, 1H, J=7,2 Hz), 3,50 (d, 1H, J=13,7 Hz)to 3.64 (d, 1H, J=13,7 Hz), 3,89 (, 3H), 3,90 (s, 3H), 3,92 (s, 6H), 3,93 (s, 6H), of 4.83 (d, 2H, J=4.5 Hz), 7,07 (d, 1H, J=5,1 Hz), 7,10 (d, 1H, J=4.9 Hz), to 7.15 (s, 2H), 7,17 (s, 2H), 7,41 was 7.45 (m, 1H), 7,50-of 7.55 (m, 3H), to 7.61 (s, 1H), 7,81 (d, 1H, J=7.4 Hz), to 8.45 (d, 1H, J=4.9 Hz), 8,51 (d, 1H, J=5,1 Hz).

Example 34

Synthesis of trihydrochloride (3S)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]-3-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methylamino]pyrrolidine

(3S)-3-[N-[(2-Nitrobenzenesulfonyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]-1-[[2-(3,4,5-Tr is methoxyphenyl)pyridine-4-yl]methyl]pyrrolidin (97 mg) is treated according to the method as described in the example of a 14. The product is converted into trihydrochloride in accordance with the known method, getting mentioned in the title compound as a yellow powder.

Yield 80 mg (89%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,71 (W, 2H), 2,19-of 2.21 (m, 1H), 2,52 is 2.55 (m, 2H), 2,73-2,77 (m, 2H), 3,39 (W, 1H), 3,66 (d, 1H, J=13,7 Hz), 3,71 (d, 1H, J=13,7 Hz), 3,82 (s, 2H), 3,90 (s, 6H), of 3.95 (s, 12H), 7,18-7,21 (m, 2H), of 7.23 (s,2H),from 7.24 (s, 2H), 7,63 (s, 2H), 8,59 (d, 1H, J=4.3 Hz), at 8.60 (d, 1H, J=4.3 Hz).

Example 35

Synthesis maleate 4-[3-(3,4,5-trimethoxyphenyl)benzoylamine]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

3-(3,4,5-Trimethoxyphenyl)benzoic acid (69 mg) and 4-amino-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (114 mg) is subjected to interaction by the method similar to that described in example 1. After transformation of the product into maleate receive specified in the header of the connection.

Yield 100 mg (56%).

1H-NMR (400 MHz, defined as maleate, DMSO-d6) δ: 1,85-2,10 (m, 4H), 2.77-to of 2.93 (m, 2H), 3,20-of 3.31 (m, 2H), of 3.77 (s, 3H, 3,79 (s, 3H), with 3.89 (s, 6H), 3,91 (s, 6H), 3,98-4,07 (m, 1H), 4,13 (s, 2H), x 6.15 (s, 2H), 6,94 (s, 2H), 7,40-7,52 (m, 4H), 7,73-7,80 (m, 2H), 8,02-8,10 (m, 3H), 8,67-8,68 (m, 1H).

Example 36

Synthesis of tetrahydrochloride 4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(Methylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (2.67 g) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (2,12 g) is subjected to interaction by the method similar to that described in example 2. After transformation of the product into tetrahydrochloride receive specified in the header of the connection.

The output of 2.55 g (46%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,66-of 1.74 (m, 2H), equal to 1.82 (d, 2H, J=10,7 Hz), 2,04 (t, 2H, J=11,0 Hz in), 2.25 (s, 3H), 2,45 is 2.51 (m, 1H), 2,98 (d, 2H, J=11.7 Hz), 3,55 (s, 2H), 3,66 (s, 2H), 3,90 (s, 3H), 3,91 (s, 3H), of 3.96 (s, 6H), of 3.97 (s, 6H), 7,21-of 7.23 (m, 2H), 7,24 (s, 2H), 7,25 (s, 2H), 7.62mm (s, 1H), 7,63 (s, 1H), 8,59 (d, 1H, J=5,1 Hz), at 8.60 (d, 1H, J=5.3 Hz).

Example of getting 75

Synthesis of 1-(etoxycarbonyl)-4-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methylamino]piperidine

1-(Etoxycarbonyl)piperidine (341 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (300 mg) is subjected to interaction by the method similar to that described in example getting 2, receiving specified in the header of the connection.

The output of 438 mg (theoretical output).

1H-NMR (400 MHz, CDCl3) δ: of 1.25 (t, 3H, J=7,1 Hz), of 1.27 to 1.34 (m, 2H), 1,60 (W, 1H), 1,90 (d, 2H, J=10,9 Hz), 2,67-of 2.72 (m, 1H), 2,87 (t, 2H, J=11.5 Hz), 3,90 (s, 3H), 3,91 (W, 2H), 3.96 points (s, 6H), 4.09 to (W, 2H), 4,12 (kV, 2H, J=7,0 Hz), 7,21 (d, 1H, J=3.5 Hz), 7,24 (s, 2H), 7,65 (s, 1H), 8,59 (d, 1H, J=4,9 Hz).

Example of getting 76

Synthesis of 1-(etoxycarbonyl)-4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-the l]methyl]amino]piperidine

1-(Etoxycarbonyl)-4-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methylamino]piperidine (438 mg) is treated according to the method similar to that described in example receiving 11, getting mentioned in the title compound as a yellow oil.

Yield 235 mg (52%).

1H-NMR (400 MHz, CDCl3) δ: of 1.26 (t, 3H, J=7,1 Hz), 1,42-of 1.57 (m, 2H), equal to 1.82 (d, 2H, J=11,9 Hz), 2,24 (s, 3H), 2,59-to 2.65 (m, 1H), 2,75 (t, 2H, J=12.0 Hz), the 3.65 (s, 2H), 3,90 (s, 3H), of 3.97 (s, 6H), of 4.13 (q, 2H, J=7.0 Hz), to 4.23 (W, 2H), 7,22 (DD, 1H, J=5.0 Hz, 1.3 Hz), 7,24 (s, 2H), 7,63 (s, 1H), 8,59 (d, 1H, J=4.5 Hz).

Example of getting 77

Synthesis of 4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

To a solution of 1-(etoxycarbonyl)-4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine (100 mg) in ethanol (2 ml) is added 4 M sodium hydroxide (8 ml). The mixture is stirred overnight and extracted with chloroform. The extract is washed with water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel using a mixture of chloroform/methanol (20:1), obtaining specified in the title compound as a yellow oil.

Yield 73 mg (88%).

1H-NMR (400 MHz, CDCl3) δ: 1,50-1,55 (m, 2H), 1,84 (d, 2H, J=12.0 Hz), 1,99 (Shir, 1H, in), 2.25 (s, 3H), by 2.55 2.63 in (m, 3H), and 3.16 (d, 2H, J=and 12.2 Hz), the 3.65 (s, 2H), 3,90 (s, 3H), of 3.97 (s, H), 7,22 (d, 1H, J=6,1 Hz), 7,24 (s, 2H), to 7.64 (s, 1H), 8,58 (d, 1H, J=5,1 Hz).

Example 37

Synthesis of tetrahydrochloride 4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-[N-Methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine (73 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (58 mg) is subjected to interaction by the method similar to that described in example 2. After transformation of the product into tetrahydrochloride receive specified in the header of the connection.

Yield 126 mg (84%).

Example 38

Synthesis of difumarat 4-[N-methyl-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(Methylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (111 mg) and 3-(3,4,5-trimethoxyphenyl)benzylchloride (88 mg) is subjected to interaction by the method similar to that described in example 2. After transformation product in difumarat get mentioned in the title compound as a white powder.

The yield 59 mg (23%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1.70 to 1.77 in (m, 2H), 1.85 to to 1.87 (m, 2H), 2,03-of 2.08 (m, 2H), and 2.27 (s, 3H), 2,55 at 2.59 (m, 1H), 2,98 (d, 2H, J=11.3 Hz), of 3.56 (s, 2H), 3,69 (s, 2H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,93 (s, 6H), 3,98 (s, 6H), 6,79 (s, 2H), 7,22 (d, 1H, J=4.9 Hz), 7,28 (s, 2H), 7,31 (d, 1H, J=7,6 Hz), 7,38 (t, 1H, J=7.4 Hz), was 7.45 (d, 1H, J=7.6 G is), 7,51 (s, 1H), 7,63 (s, 1H), at 8.60 (d, 1H, J=5,1 Hz).

Example 39

Synthesis of tetrahydrochloride 1-[[2-(4-hydroxy-3,5-acid)pyridine-4-yl]methyl]-4-[N-[[2-(4-hydroxy-3,5-acid)pyridine-4-yl]methyl]-N-methylamino]piperidine

To a solution of 4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (100 mg) in dichloromethane (5 ml) at 0°With add attributively (173 μl). The mixture was stirred at 0°C for 2 hours and then at room temperature overnight. To the mixture at 0°add a small amount of water, ethyl acetate and saturated aqueous sodium bicarbonate, then separate the organic layer. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified preparative TLC on silica gel using a mixture of chloroform/saturated methanol ammonia (15:1), and turn in tetrahydrochloride known manner, receiving specified in the header of the connection.

Yield 50 mg (52,3%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,68-1,89 (m, 4H), 2,03-2,12 (m, 2H), and 2.26 (s, 3H), 2,48-2,60 (m, 1H), 2,98 was 3.05 (m, 2H), only 3.57 (s, 2H), the 3.65 (s, 2H), 3,94 (s, 6H), of 3.95 (s, 6H), 7,16-7,19 (m, 2H), 7,26 (s, 2H), 7,27 (s, 2H), a 7.62 to 7.68 (m, 2H), 8,56 (d, 1H, J=5.3 Hz), 8,58 (d, 1H, J=5,2 Hz).

An example of retrieving 78

Synthesis(etoxycarbonyl)-4-[N-ethyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

To a solution of 1-(etoxycarbonyl)-4-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methylamino]piperidine (400 mg) in acetonitrile (5 ml) is added potassium carbonate (13 mg) and Iodate (145 mg). The mixture is placed in a sealed vessel and stirred at 80°C for 2 hours. After concentrating the reaction liquid under vacuum in the remainder enter ethyl acetate, washed with water and saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. The residue is subjected to column chromatography on silica gel, using as eluent a mixture of chloroform/methanol (30:1), obtaining specified in the title compound as a yellow oil.

Exit 242 mg (57%).

1H-NMR (400 MHz, CDCl3) δ: was 1.04 (t, 3H, J=7,1 Hz), 1,25 (t, 3H, J=7,1 Hz), 1,43-of 1.52 (m, 2H), 1,79 (d, 2H, J=11.5 Hz), 2,60 (q, 2H, J=7.0 Hz), 2,66 was 2.76 (m, 3H), 3,70 (s, 2H), 3,90 (s, 3H), of 3.97 (s, 6H), of 4.12 (q, 2H, J=7,0 Hz), 4,20 (W, 2H), 7.23 percent (s, 2H), 7,26 (d, 1H, J=5.7 Hz), to 7.67 (s, 1H), 8,58 (d, 1H, J=4,9 Hz).

Example of getting 79

Synthesis of 4-[N-ethyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(Etoxycarbonyl)-4-[N-ethyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine (242 mg) is treated according to the method similar to that described in example getting 77, receiving specified in the title compound as a yellow oil.

Yield 150 mg (74%).

1 H-NMR (400 MHz, CDCl3) δ: of 1.03 (t, 3H, J=7.0 Hz), 1,43-of 1.52 (m, 2H), 1.70 to (W, 1H), 1,79 (d, 2H, J=12.3 Hz), 2,53-to 2.67 (m, 5H), 3,13 (d, 2H, J=11,9 Hz), 3,71 (s, 2H), 3,90 (s, 3H), of 3.97 (s, 6H), 7,24 (s, 2H), 7,27 (d, 1H, J=5,1 Hz), 7,68 (s, 1H), to 8.57 (d, 1H, J=4.3 Hz).

Example 40

Synthesis of tetrahydrochloride 4-[N-ethyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-[N-Ethyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine (65 mg) is subjected to interaction with 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (50 mg) by the procedure similar to that described in example 2. After transformation of the product into tetrahydrochloride receive specified in the header of the connection.

Yield 121 mg (90%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: of 1.03 (t, 3H, J=7,1 Hz), 1,64 was 1.69 (m, 2H), 1.77 in (d, 2H, J=10,7 Hz), a 2.01 (t, 2H, J=10,8 Hz), 2,55-of 2.64 (m, 3H), 2.95 and (d, 2H, J=11,1 Hz), 3,53 (s, 2H), 3,71 (s, 2H), 3,90 (s, 6H), of 3.97 (s, 12H), 7,20-7,27 (m, 6H), 7,60 (s, 1H), 7,68 (s, 1H), to 8.57 (d, 1H, J=4.9 Hz), 8,59 (d, 1H, J=5,1 Hz).

Example of getting 80

Synthesis of 4-(cyclohexylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

1-[[2-(3,4,5-Trimethoxyphenyl)pyridine-4-yl]methyl]-4-piperidone (400 mg) and cyclohexylamine (134 mg) is subjected to interaction by the method similar to that described in example receiving 37, receiving specified in the header of the connection.

Output 342 is g (69%).

1H-NMR (400 MHz, CDCl3) δ: 1,05-1,30 (m, 6H), 1,38-of 1.52 (m, 2H), 1,53 and 1.80 (m, 3H), 1,87 (Shir, 4H), 2,07 (t, 2H, J=10,7 Hz), 2,59 (W, 2H), 2,86 (W, 2H), 3,54 (s, 2H), 3,90 (s, 3H), of 3.97 (s, 6H), 7,19 (d, 1H, J=4.9 Hz), 7.24 to (s, 2H), to 7.64 (s, 1H), 8,58 (d, 1H, J=4,9 Hz).

Example 41

Synthesis of tetrahydrochloride 4-[N-cyclohexyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(Cyclohexylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (342 mg) is subjected to interaction with 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (252 mg) by the procedure similar to that described in the example of a 9. After transformation of the product into tetrahydrochloride receive specified in the header of the connection.

Yield 55 mg (8%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,00-of 1.39 (m, 6H), 1,58-of 1.88 (m, 8H), 2,07 (W, 2H), 2,61 (W, 2H), 2,96 (W, 2H), 3,57 (W, 2H), 3,85 (s, 2H), 3,90 (s, 3H), 3,91 (s, 3H), of 3.97 (s, 12H), 7,19-7,28 (m, 6H), 7,70 (W, 2H), 8,56 (d, 1H, J=5,1 Hz), at 8.60 (d, 1H, J=5,1 Hz).

Example of getting 81

Synthesis of 4-aniline-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

1-[[2-(3,4,5-Trimethoxyphenyl)pyridine-4-yl]methyl]-4-piperidone (1.1 g) and aniline (344 mg) is subjected to interaction by the method similar to that described in example receiving 37, receiving specified in the header of the connection.

The output of 1.09 g (81%).

1H-NMR (400 MHz, CDCl3) δ: 1,53 (W, 2H), 2,02 and 2.13 (m, 2H), 2,16 of-2.32 (m, 2H), 2,86 (W, 2H), 3,32 (W, 1H)and 3.59 (s, 2H), 3,88 (s, 3H), of 3.95 (s, 6H), to 6.57 (d, 2H, J=8.6 Hz), of 6.66 (t, 1H, J=7,3 Hz), 7,14 (t, 2H, J=7.9 Hz), 7,20-of 7.24 (m, 5H), 7,65 (W, 1H), 8,59 (d, 1H, J=5,1 Hz).

Example 42

Synthesis of trihydrochloride 4-[N-phenyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-Aniline-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (1.64 g) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (1,33 g) is subjected to interaction by the method similar to that described in the example of a 9. After transformation of the product into trihydrochloride receive specified in the header of the connection.

Output 635 mg (20%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,60-2,00 (m, 4H), of 2.10 to 2.35 (m, 2H), 2,99 (W, 2H), to 3.58 (Shir, 3H), 3,86 (s, 3H), 3,88 (s, 3H), 3,90 (s, 6H), of 3.94 (s, 6H), to 4.52 (s, 2H), 6,66-of 6.78 (m, 3H), 7,13-7,28 (m, 8H), 7,54 (Shir, 2H), 8,53 (d, 1H, J=5,1 Hz), 8,58 (d, 1H, J=4,9 Hz).

Example of getting 82

Synthesis of atelectasia 1-[[2-(4-chloro-3,5-acid)pyridine-4-yl]methyl]-4-piperidone

Atlantal 4-piperidone (573 mg) is subjected to interaction with 2-(4-chloro-3,5-acid)-4-chloromethylpyridine (1.19 g) by the procedure similar to that described in example 2, obtaining specified in the header of the connection.

The output rate of 1.67 g (theoretical if esto).

1H-NMR (400 MHz, CDCl3) δ: 1,78 (t, 4H, J=5.6 Hz), 2,58 (Shir, 4H), 3,61 (s, 2H), to 3.67 (s, 4H), was 4.02 (s, 6H), 7,25-7,29 (m, 3H), 7,68 (s, 1H), 8,61 (d, 1H, J=4,9 Hz).

Example of getting 83

Synthesis of 1-[[2-(4-chloro-3,5-trimethoxyphenyl)pyridine-4-yl]methyl]-4-piperidone

Atlantal 1-[[2-(4-Chloro-3,5-acid)pyridine-4-yl]methyl]-4-piperidone (1,67 g) is treated according to the method similar to that described in example receiving 23, receiving specified in the header of the connection.

Yield 1.29 g (89%).

1H-NMR (400 MHz, CDCl3) δ: of 2.50 (t, 4H, J=5.8 Hz), of 2.81 (t, 4H, J=5.8 Hz), 3,71 (s, 2H), was 4.02 (s, 6H), 7,26 (s, 2H), 7,33 (d, 1H, J=4.3 Hz), of 7.70 (s, 1H), 8,66 (d, 1H, J=4,9 Hz).

Example of getting 84

Synthesis of 4-aniline-1-[[2-(4-chloro-3,5-acid)pyridine-4-yl]methyl]piperidine

1-[[2-(4-Chloro-3,5-acid)pyridine-4-yl]methyl]-4-piperidone (600 mg) and aniline (0,18 ml) is treated according to the method similar to that described in example receiving 37, receiving specified in the header of the connection.

The output of 465 mg (63%).

1H-NMR (400 MHz, CDCl3) δ: 1,49 was 1.69 (m, 2H), 2,08 (d, 2H, J=7.8 Hz), of 2.23 (t, 2H, J=9,3 Hz), 2,87 (d, 2H, J=7.8 Hz), 3,34 (W, 1H), 3,60 (s, 2H), was 4.02 (s, 6H), 6,60 (d, 2H, J=7,6 Hz), 6,69 (t, 1H, J=7,3 Hz), 7,10-7,20 (m, 2H), 7,20-7,30 (m, 3H), to 7.67 (s, 1H), to 8.62 (d, 1H, J=5,2 Hz).

Example 43

Synthesis of trihydrochloride 1-[[2-(4-chloro-3,5-acid)pyridine-4-yl]methyl]-4-[N-[[2-(4-chloro-3,5-acid)pyridine-4-yl]methyl]-N-penilai what about]piperidine

4-Aniline-1-[[2-(4-chloro-3,5-acid)pyridine-4-yl]methyl]piperidine (230 mg) is subjected to interaction with 2-(4-chloro-3,5-acid)-4-chloromethylpyridine (157 mg) by the procedure similar to that described in example 9. After transformation of the product into trihydrochloride get mentioned in the title compound as a yellow powder.

Yield 104 mg (24%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,70-of 1.85 (m, 4H), of 2.20 (t, 2H, J=2.3 Hz), 3.00 and (d, 2H, J=1.3 Hz)and 3.59 (s, 2H), 3.96 points (s, 6H), 4.00 points (s, 6H), 4,56 (s, 2H), 6,65-of 6.78 (m, 3H), 7,16 (s, 2H), 7.18 in-7,28 (m, 6H), to 7.59 (s, 1H), 7,62 (s, 1H), to 8.57 (d, 1H, J=5,1 Hz), to 8.57 (d, 1H, J=4,8 Hz).

An example of retrieving 85

Synthesis of 4-(p-anisidino)-1-[[2-(4-chloro-3,5-acid)pyridine-4-yl]methyl]piperidine

1-[[2-(4-Chloro-3,5-acid)pyridine-4-yl]methyl]-4-piperidone (690 mg) and p-anisidine (283 mg) is treated according to the method similar to that described in example receiving 37, receiving specified in the header of the connection.

The output 646 mg (72%).

1H-NMR (400 MHz, CDCl3) δ: 1,45-1,55 (m, 2H), 2.05 is (d, 2H, J=11.7 Hz), measuring 2.20 (t, 2H, J=11.2 Hz), 2,87 (d, 2H, J=11.7 Hz), 3,20-to 3.35 (m, 1H)and 3.59 (s, 2H), 3,74 (s, 3H), was 4.02 (s, 6H), to 6.58 (d, 2H, J=8.7 Hz), 6,77 (d, 2H, J=8,7 Hz), 7,25-7,28 (m, 3H), to 7.67 (s, 1H), to 8.62 (d, 1H, J=4,9 Hz).

Example 44

Synthesis of trihydrochloride 1-[[2-(4-chloro-3,5-acid)pyridine-4-yl]methyl]-4-[N-[[2-(4-chloro-3,5-acid)pyridine-4-yl]methyl]-N-(4-methox is phenyl)amino]piperidine

4-(p-Anisidino-1-[[2-(4-chloro-3,5-acid)pyridine-4-yl]methyl]piperidine (271 mg) is subjected to interaction with 2-(4-chloro-3,5-acid)-4-chloromethylpyridine (173 mg) by the procedure similar to that described in example 9. After transformation of the product into trihydrochloride get mentioned in the title compound as a yellow powder.

The output 324 mg (67%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,65-1,90 (m, 4H), of 2.16 (t, 2H, J=10.4 Hz), 2,97 (d, 2H, J=7.5 Hz), 3,54-of 3.60 (m, 1H), to 3.58 (s, 2H), of 3.73 (s, 3H), of 3.97 (s, 6H), 4.00 points (s, 6H), to 4.46 (s, 2H), 6,74 (d, 2H, J=9.4 Hz), 6,79 (d, 2H, J=9.4 Hz), 7,16 (s, 2H), 7,20-7,29 (m, 4H), to 7.59 (s, 1H), 7.62mm (s, 1H), 8,56 (d, 1H, J=4,8 Hz), at 8.60 (d, 1H, J=4,8 Hz).

An example of retrieving 86

Synthesis of 4-(3-methylaniline)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

1-[[2-(3,4,5-Trimethoxyphenyl)pyridine-4-yl]methyl]-4-piperidone (1.40 g) and 3-methylthioinosine (655 mg) is treated according to the method similar to that described in example receiving 37, receiving specified in the header of the connection.

Yield 1.01 g (54%).

1H-NMR (400 MHz, CDCl3) δ: 1,44-to 1.60 (m, 2H), 1,98 is 2.10 (m, 2H), 2,23 (W, 2H), 2,42 (s, 3H), 2,88 (W, 2H), 3,30 (W, 1H)and 3.59 (s, 2H), 3,88 (s, 3H), of 3.95 (s, 6H), 6.35mm (d, 1H, J=7,6 Hz), 6,47 (s, 1H), 6,55 (d, 1H, J=8.6 Hz), 7,05 (t, 1H, J=7.9 Hz), 7,20 (d, 1H, J=4.9 Hz), 7,24 (s, 2H), 7,68 (W, 1H), 8,58 (d, 1H, J=4,9 Hz).

Example 45

Synthesis of trihydrochloride 4-[N-(3-methylthiophenyl)-N-[[2-(3,4,5-three is ethoxyphenyl)pyridine-3-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(3-Methylthioinosine-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (143 mg) is subjected to interaction with 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) by the procedure similar to that described in example 9. After transformation of the product into trihydrochloride get mentioned in the title compound as a yellow powder.

Yield 45 mg (18%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,58-1,71 (s, 2H), 1,79 (d, 2H, J=10,7 Hz)of 2.16 (t, 2H, J=11.2 Hz), of 2.38 (s, 3H), 2,96 (d, 2H, J=11.2 Hz), of 3.56 (s, 3H), 3,68-of 3.97 (m, 1H), 3,90 (s, 3H), 3,92 (s, 9H), of 3.96 (s, 9H), was 4.42 (s, 2H,), of 6.45 (d, 1H, J=8,3 Hz), of 6.52 (s, 1H), is 6.61 (d, 1H, J=7,3 Hz), 6,74 (s, 2H), 7,11 (t, 1H, J=8.1 Hz), 7,15-7,26 (m, 4H), 7,54 (s, 1H), 7,68 (d, 1H, J=7.8 Hz), 8,53 (d, 1H, J=3.2 Hz), 8,59 (d, 1H, J=4,8 Hz).

Example 46

The synthesis of the dihydrochloride of 4-[N-(3-methylthiophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(3-Methylthioinosine-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (143 mg) is subjected to interaction with 2-(3,4,5-trimethoxyphenyl)benzylchloride (114 mg) by the procedure similar to that described in example 9. After transformation of the product into the dihydrochloride receive specified in the title compound as a yellow powder.

Yield 51 mg (23%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,56-of 1.73 (m, 2H), 1,78-1,87 (who, 2H), 2,10-of 2.20 (m, 2H), of 2.38 (s, 3H), 2.91 in are 2.98 (m, 2H), 3,55 (s, 2H), 3,70-of 3.80 (m, 1H), 3,88 (s, 6H), 3,90 (s, 3H), 3,92 (s, 3H), of 3.96 (s, 6H), 4,35 (s, 2H), 6,47 (d, 1H, J=8,2 Hz), 6,53-6,62 (m, 5H), to 7.09 (t, 1H, J=8.0 Hz), 7.18 in-7,40 (m, 6H), 7,54 (s, 1H), 8,58 (d, 1H, J=4,7 Hz).

Example 47

Synthesis fumarata 4-[N-(3-methylthiophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(3-Methylthioinosine-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (143 mg) is subjected to interaction with 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) by the procedure similar to that described in example 9. After transformation of the product into fumarate get mentioned in the title compound as a white powder.

Yield 14 mg (5%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,76-to 1.86 (m, 5H), 2,17-of 2.23 (m, 2H), 2,39 (s, 3H), 2,97-3,00 (m, 2H), to 3.58 (s, 2H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,93 (s, 6H), of 3.96 (s, 6H), of 4.54 (s, 2H), 6,47-6,50 (m, 1H), 6,63 (s, 1H), 6,64 (s, 1H), 7,10-to 7.15 (m, 2H), 7,15 (s, 2H), 7,20-7,21 (m, 1H), 7,22 (s, 2H), 7,55 (s, 1H), to 7.59 (s, 1H), 8,56 (d, 1H, J=5,1 Hz), 8,59 (d, 1H, J=5,1 Hz).

Example 48

The synthesis of the dihydrochloride of 4-[N-(3-methylthiophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(3-Methylthioinosine-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (143 mg) is subjected to interaction with 3-(3,4,5-trimethoxyphenyl)benzylchloride the m (114 mg) by the procedure similar to that described in example 9. After transformation of the product into the dihydrochloride receive specified in the title compound as a yellow powder.

Yield 60 mg (24%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,65 is 1.91 (m, 4H), to 2.18 (t, 2H, J=10.5 Hz), of 2.33 (s, 3H), of 2.97 (d, 2H, J=10,9 Hz)to 3.58 (s, 2H), 3,70-of 3.85 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), of 3.96 (s, 6H), 4,56 (s, 2H), 6,52 (d, 1H, J=8,4 Hz), 6,59 (d, 1H, J=7,6 Hz), of 6.65 (s, 1H), 6,72 (s, 2H), 7,10 (t, 2H, J=8.0 Hz), 7,19-7,25 (m, 4H), 7,31-7,42 (m, 3H), 7,60 (s, 1H), 8,59 (d, 1H, J=7,8 Hz).

Example 49

Synthesis of trihydrochloride 4-[N-(3-methylthiophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(3-Methylthioinosine-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (143 mg) is subjected to interaction with 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) by the procedure similar to that described in example 9. After transformation of the product into trihydrochloride get mentioned in the title compound as a yellow powder.

Yield 22 mg (9%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,50-2,05 (m, 4H), 2,20 (W, 2H), is 2.37 (s, 3H), 3,05 (W, 2H), 3,50-3,70 (Shir, 3H), 3,86 (s, 3H), a 3.87 (s, 3H), 3,92 (s, 6H), of 3.95 (s, 6H), to 4.52 (s, 2H), of 6.49 (d, 1H, J=8,3 Hz), 6,62 (W, 2H), 7,09 (t, 1H, J=8,2 Hz), 7.18 in-7,30 (m, 6H), 7,58 (s, 2H), 8,54 (W, 1H), 8,60 (W, 1H).

Example 50

The synthesis of the dihydrochloride of 4-[N-(3-methylthio enyl)-N-[[4-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(3-Methylthioinosine-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (143 mg) is subjected to interaction with 4-(3,4,5-trimethoxyphenyl)benzylchloride (114 mg) by the procedure similar to that described in example 9. After transformation of the product into the dihydrochloride receive specified in the title compound as a yellow powder.

Yield 57 mg (22%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,58 of-1.83 (m, 4H), of 2.20 (t, 2H, J=11.3 Hz), 2,39 (s, 3H), 2,98 (d, 2H, J=11,1 Hz)to 3.58 (s, 2H), 3,88 (s, 3H), 3,90 (s, 3H), 3,91 (s, 6H), of 3.96 (s, 6H), a 4.53 (s, 2H), 6,51 (DD, 1H, J=8,4 Hz, 2,4 Hz), 6,60 (d, 1H, J=8.0 Hz), only 6.64 (s, 1H), 6.75 in (s, 2H), 7,10 (t, 1H, J=8.1 Hz), 7.24 to 7,33 (m, 4H), 7,47 (d, 2H, J=8.0 Hz), to 7.61 (s, 1H), 8,59 (d, 1H, J=5.0 Hz).

Example of getting 87

Synthesis of 4-propargylamine-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

1-[[2-(3,4,5-Trimethoxyphenyl)pyridine-4-yl]methyl]-4-piperidone (400 mg) and propargylamine (80 mg) is treated according to the method similar to that described in example receiving 25, receiving specified in the header of the connection.

Exit 227 mg (63%).

1H-NMR (400 MHz, CDCl3) δ: 1,38-is 1.51 (m, 2H), 1,83 is 1.86 (m, 3H), 2,10-of 2.15 (m, 2H), 2,21 (s, 1H), 2,74 (W, 1H), 2,83-2,87 (m, 2H), 3.45 points (s, 2H), of 3.56 (s, 2H), with 3.89 (s, 3H), of 3.96 (s, 6H), 7,19 (d, 1H, J=4.9 Hz), 7,24 (s, 2H), the 7.65 (s, 1H), 8,58 (d, 1H, J=4,9 Hz).

Example 51

Synthesis of tetrahydrochloride 4-[N-propargyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]AMI is about]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-Propargylamine-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (227 mg) is subjected to interaction with 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (226 mg) by the procedure similar to that described in example 9. After transformation of the product into tetrahydrochloride get mentioned in the title compound as a yellow powder.

Yield 128 mg (23%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,48-to 2.40 (m, 7H), 2,72 (W, 1H), 3,02 (W, 2H), 3,39 (s, 2H), 3,64 (W, 2H), 3,84 (s, 2H), 3,91 (s, 6H), 3,98 (s, 6H), to 3.99 (s, 6H), 7,22-7,29 (m, 6H), 7,66 (W, 2H), at 8.60 (d, 1H, J=4.9 Hz), 8,62 (d, 1H, J=4,9 Hz).

Example of getting 88

Synthesis of 4-(5-indanamine)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

1-[[2-(3,4,5-Trimethoxyphenyl)pyridine-4-yl]methyl]-4-piperidone (1.40 g) and 5-aminoindan (680 mg) is treated according to the method similar to that described in example receiving 37, receiving specified in the header of the connection.

Yield 1.22 g (59%).

1H-NMR (400 MHz, CDCl3) δ: 1,40-of 1.57 (m, 2H), 2.00 in to 2.15 (m, 5H), 2,19 was 2.25 (m, 2H), 2.77-to of 2.93 (m, 6H), 3,30 (W, 1H), to 3.58 (s, 2H), 3,91 (s, 3H), of 3.97 (s, 6H), 6,41 (d, 1H, J=8.0 Hz), of 6.52 (s, 1H), 7,01 (d, 1H, J=8.0 Hz), 7,21-7,26 (m, 3H), of 7.64 (s, 1H), at 8.60 (d, 1H, J=4,9 Hz).

Example 52

Synthesis of trihydrochloride 4-[N-(indan-5-yl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-3-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(5-Indanamine)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (142 mg) is subjected to interaction with 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) by the procedure similar to that described in example 9. After transformation of the product into trihydrochloride get mentioned in the title compound as a yellow powder.

Yield 90 mg (41%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,54-to 1.67 (m, 2H), 1,74 of-1.83 (m, 2H), 1,98-2,07 (m, 2H), 2,09 are 2.98 (m, 2H), 3,55 (s, 2H), 3,64-3,74 (m, 1H), 3,90 (s, 3H), 3,91 (s, 6H), to 3.92 (s, 3H), of 3.96 (s, 6H), to 4.41 (s, 2H), of 6.49 (DD, 1H, J=8,2 Hz, 2.4 Hz), 6,59 (s, 1H), 6,74 (s, 2H),? 7.04 baby mortality (d, 1H, J=8,2 Hz), 7,15-7,20 (m, 2H), 7,22 (s, 2H), 7,54 (s, 1H), to 7.77 (DD, 1H, J=7,8 Hz and 1.4 Hz), charged 8.52 (DD, 1H, J=4,7 Hz, 1.8 Hz), 8,59 (d, 1H, J=5,1 Hz).

Example 53

The synthesis of the dihydrochloride of 4-[N-(indan-5-yl)-N-[[2-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(5-Indanamine)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (142 mg) is subjected to interaction with 2-(3,4,5-trimethoxyphenyl)benzylchloride (114 mg) by the procedure similar to that described in example 9. After transformation of the product into the dihydrochloride receive specified in the title compound as a yellow powder.

Yield 115 mg (47%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,56-of 1.66 (m, 2H), 1,80 of-1.83 (m, 2H), 2.00 in was 2.05 (m, 2H), 2,11-to 2.18 (m, 2H), 2.77-to and 2.83 (m, 4H), 2,92-,95 (m, 2H), 3,55 (s, 2H), 3.72 points Shir, 1H), a 3.87 (s, 6H), 3,90 (s, 3H), 3,92 (s, 3H), of 3.96 (s, 6H), 4,34 (s, 2H), of 6.49 (d, 1H, J=8,3 Hz), 6,56 (s, 2H), 6,60 (s, 1H), 7,02 (d, 1H, J=8,3 Hz), 7,17-7,27 (m, 5H), 7,42 was 7.45 (m, 1H), 7,54 (s, 1H), 8,58 (d, 1H, J=4,9 Hz).

Example 54

Synthesis of trihydrochloride 4-[N-(indan-5-yl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(5-Indanamine)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (142 mg) is subjected to interaction with 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) by the procedure similar to that described in example 9. After transformation of the product into trihydrochloride get mentioned in the title compound as a white powder.

Yield 23 mg (9%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,60-of 1.95 (m, 4H), 2.00 (quintet, 2H, J=7,3 Hz), 2,20 (W, 2H), 2,75-of 2.81 (m, 4H), 2,99 (W, 2H), to 3.58 (W, 2H), of 3.77 (s, 1H), 3,86 (s, 3H), a 3.87 (s, 3H), 3,91 (s, 6H), of 3.94 (s, 6H), of 4.49 (s, 2H), 6,51 (d, 1H, J=8,3 Hz), 6,62 (s, 1H), 7,02 (d, 1H, J=8.0 Hz), 7,16 (s, 2H), 7.18 in-7,22 (m, 4H), EUR 7.57 (W, 2H), charged 8.52 (d, 1H, J=4.9 Hz), to 8.57 (d, 1H, J=4,9 Hz).

Example 55

The synthesis of the dihydrochloride of 4-[N-(indan-5-yl)-N-[[3-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(5-Indanamine)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (60 mg) is subjected to interaction with 3-(3,4,5-trimethoxyphenyl)bansidhar the house (114 mg) by the procedure similar to that described in example 9. After transformation of the product into the dihydrochloride receive specified in the title compound as a yellow powder.

Yield 18 mg (19%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,60-of 1.95 (m, 4H), 2.00 (quintet, 2H, J=7,2 Hz), 2,20 (W, 2H), 2,75-of 2.81 (m, 4H), 2.95 and (W, 2H), 3,60 (W, 2H), 3,85 (W, 1H), 3,86 (s, 3H), a 3.87 (s, 6H), 3,88 (s, 3H), of 3.94 (s, 6H), 4,51 (s, 2H), 6,54 (d, 1H, J=8,2 Hz), of 6.66 (s, 1H), 6,70 (s, 2H), 7,01 (d, 1H, J=8,4 Hz), 7,19 (d, 1H, J=4.9 Hz), 7,19-7,42 (m, 6H), 7,60 (W, 1H), 8,59 (W, 1H).

Example 56

Synthesis of trihydrochloride 4-[N-(indan-5-yl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(5-Indanamine)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (143 mg) is subjected to interaction with 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) by the procedure similar to that described in example 9. After transformation of the product into trihydrochloride get mentioned in the title compound as a white powder.

The output 138 mg (63%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,71 is 1.91 (m, 4H), 1,98-to 2.06 (m, 2H), 2,13-2,22 (m, 2H), was 2.76-2,84 (m, 4H), 2,94 was 3.05 (m, 2H), only 3.57 (s, 2H), 3,69-of 3.78 (m, 1H), with 3.89 (s, 3H), 3,90 (s, 3H), of 3.94 (s, 6H), of 3.96 (s, 6H), 4,50 (s, 2H,), to 6.57 (DD, 1H, J=8,2 Hz, 2.3 Hz), to 6.67 (s, 1H),? 7.04 baby mortality (d, 1H, J=8,4 Hz), 7,20-7,22 (m, 1H), 7,22 (s, 2H), 7.23 percent (s, 2H), EUR 7.57 to 7.62 (m, 1H), 7,60 (s, 1H), 7,65 (DD, 1H, J=8,2 Hz, 2.2 Hz), 8,58-to 8.62 (m, 2H).

Example 57

The synthesis of the dihydrochloride of 4-[N-(indan-5-yl)-N-[[4-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(5-Indanamine)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (143 mg) is subjected to interaction with 4-(3,4,5-trimethoxyphenyl)benzylchloride (114 mg) by the procedure similar to that described in example 9. After transformation of the product into the dihydrochloride receive specified in the title compound as a yellow powder.

Yield 95 mg (39%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,74-1,90 (m, 4H), 2,01-to 2.06 (m, 2H), 2,16-2,22 (m, 2H), 2,78-2,84 (m, 4H), 2,96-to 2.99 (m, 2H), to 3.58 (s, 2H), 3.72 points Shir, 1H), 3,88 (s, 3H), 3,90 (s, 3H), 3,91 (s, 6H), of 3.96 (s, 6H), 4,51 (s, 2H), 6,55 (d, 1H, J=8,3 Hz), to 6.67 (s, 1H), 6,72 (s, 2H),? 7.04 baby mortality (d, 1H, J=8,3 Hz), 7,20 (d, 1H, J=5,1 Hz), 7.23 percent (s, 2H), 7,35 (d, 2H, J=8.1 Hz), 7,47 (d, 2H, J=8.1 Hz), to 7.61 (s, 1H), 8,59 (d, 1H, J=4,9 Hz).

Example of getting 89

Synthesis of 4-(4-butylaniline)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

1-[[2-(3,4,5-Trimethoxyphenyl)pyridine-4-yl]methyl]-4-piperidone (1.24 g) and 4-butylaniline (149 mg) is treated in accordance with the method described in example receiving 37, receiving specified in the header of the connection.

The output of 1.23 g (72%).

1H-NMR (400 MHz, CDCl3) δ: of 0.82 (t, 3H, J=7,3 Hz), 1,20-1,30 (m, 2H), 1,38 of 1.50 (m, 4H), 1,92 was 2.25 (m, 4H), 2.40 a (t, 2H, J=7,7 Hz), 2,77 (W, 2H), 3,21 (Shi is, 1H), 3,50 (s, 2H), 3,82 (s, 3H), with 3.89 (s, 6H), 6,45 (d, 2H, J=7.8 Hz), 6.89 in (d, 2H, J=8.0 Hz), 7,13 (d, 1H, J=4.9 Hz), 7,18 (s, 2H), 7,58 (s, 1H), charged 8.52 (d, 1H, J=4,9 Hz).

Example 58

Synthesis of trihydrochloride 4-[N-(4-butylphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-3-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(4-Butylaniline)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (147 mg) is subjected to interaction with 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) by the procedure similar to that described in example 9. After transformation of the product into trihydrochloride get mentioned in the title compound as a yellow powder.

Yield 58 mg (27%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: of 0.91 (t, 3H, J=7,3 Hz), 1.32 to about 1.35 (m, 2H), 1,50-1,70 (m, 4H), 1.75 of (W, 2H), 2,10-of 2.20 (m, 2H), 2.49 USD (t, 2H, J=7,6 Hz), 2.95 and (W, 2H), 3,55 (s, 2H), 3,70 (W, 1H), 3,90 (s, 3H), 3,91 (s, 6H), 3,92 (s, 3H), of 3.96 (s, 6H), to 4.41 (s, 2H), 6,59 (d, 2H, J=8,8 Hz), 6,74 (s, 2H), 7,00 (d, 2H, J=8.6 Hz), 7,16-7,17 (m, 1H), 7,19 (d, 1H, J=4.9 Hz), 7,22 (s, 2H), 7,54 (s, 1H), 8,59 (d, 1H, J=7.5 Hz), charged 8.52 (Shir, 1H), 8,59 (d, 1H, J=4,9 Hz).

Example 59

The synthesis of the dihydrochloride of 4-[N-(4-butylphenyl)-N-[2-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(4-Butylaniline)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (147 mg) is subjected to interaction with 2-(3,4,5-trimethoxyphenyl)benzylchloride is ω (114 mg) by the procedure similar to that described in example 9. After transformation of the product into the dihydrochloride receive specified in the title compound as a yellow powder.

The yield 59 mg (24%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: of 0.90 (t, 3H, J=7.4 Hz), 1,25-of 1.41 (m, 2H), 1,48 is 1.75 (m, 4H), of 1.81 (d, 2H, J=11.7 Hz), 2,13 (t, 2H, J=11.2 Hz), 2,48 (t, 2H, J=7.5 Hz), with 2.93 (d, 2H, J=11.2 Hz), 3,55 (s, 2H), 3,65-of 3.80 (m, 1H), a 3.87 (s, 6H), 3,90 (s, 3H), 3,92 (s, 1H), 3.96 points (s, 6H), to 4.33 (s, 2H), 6,56 (s, 2H), 6,60 (d, 2H, J=8.5 Hz), 6,98 (d, 2H, J=8.5 Hz), 7,18 (d, 1H, J=4.9 Hz), 7,21 (s, 2H), 7,20-7,37 (m, 3H), 7,41 (W, 1H), 7,54 (s, 1H), 8,58 (d, 1H, J=4,9 Hz).

Example 60

Synthesis of trihydrochloride 4-[N-(4-butylphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(4-Butylaniline)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (196 mg) is subjected to interaction with 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (129 mg) by the procedure similar to that described in example 9. After transformation of the product into trihydrochloride get mentioned in the title compound as a white powder.

Yield 20 mg (6%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: to 0.88 (t, 3H, J=7,3 Hz)of 1.20 and 1.35 (m, 2H), 1,49 is 1.60 (m, 2H), 1,62-2,02 (m, 4H), 2,20 (W, 2H), 2,46 (t, 2H, J=7,3 Hz), 3,05 (W, 2H), 3,60 (Shir, 3H), a 3.87 (s, 3H), 3,88 (s, 3H), 3,90 (s, 6H), 3,94 (s, 6H), of 4.49 (s, 2H), 6,62 (d, 2H, J=8,3 Hz), 6,98 (d, 2H, J=8,3 Hz), 7,13 (s, 2H), 7,15-7,40 (m, 4H), 7,55 (W, 2H),charged 8.52 (d, 1H, J=4.9 Hz), 8,60 (W, 1H).

Example 61

The synthesis of the dihydrochloride of 4-[N-(4-butylphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(4-Butylaniline)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (147 mg) is subjected to interaction with 3-(3,4,5-trimethoxyphenyl)benzylchloride (114 mg) by the procedure similar to that described in example 9. After transformation of the product into the dihydrochloride receive specified in the title compound as a yellow powder.

Yield 102 mg (42%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: of 0.90 (t, 3H, J=7.4 Hz), 1.30 and of 1.36 (m, 2H), 1,48-of 1.56 (m, 2H), 1,76-1,89 (m, 4H), 2,19 (W, 2H), 2,48 (t, 2H, J=7.8 Hz), 2,97 (W, 2H), to 3.58 (s, 2H), 3,86 (W, 1H), 3,88 (s, 3H), to 3.58 (s, 2H), 3,86 (Shir, 1H), 3,88 (s, 3H), 3,90 (s, 3H), of 3.95 (s, 6H), of 4.54 (s, 2H), of 6.68 (d, 2H, J=8.6 Hz), 6,72 (s, 2H), 7,00 (d, 2H, J=8.6 Hz), 7,20-7,27 (m, 2H), 7.23 percent (s, 2H), 7,32-7,40 (m, 2H), 7,44 (s, 1H), 7.62mm (, 1H), 8,59 (d, 1H, J=5,1 Hz).

Example 62

Synthesis of trihydrochloride 4-[N-(4-butylphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(4-Butylaniline)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (147 mg) is subjected to interaction with 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) by the procedure similar to that described in example 9. After transformation product in t is hydrochlorid get mentioned in the title compound as a white powder.

Yield 65 mg (21%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: of 0.90 (t, 3H, J=7,3 Hz), 1.32 to about 1.36 (m, 2H), 1,50-and 1.54 (m, 2H), 1.70 to 1,95 (m, 4H), 2,17 (W, 2H), 2.49 USD (t, 2H, J=7,7 Hz), 2,96 (W, 2H), to 3.58 (s, 2H), 3.75 to (W, 1H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,94 (s, 6H), of 3.96 (s, 6H), 4,50 (s, 2H), of 6.68 (d, 2H, J=8.6 Hz), 7,00 (d, 2H, J=8.6 Hz), 7,20-7,22 (m, 3H), of 7.23 (s, 2H), 7,58-7,66 (m, 3H), 8,59 (W, 1H), 8,60 (W, 1H).

Example 63

The synthesis of the dihydrochloride of 4-[N-(4-butylphenyl)-N-[4-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

4-(4-Butylaniline)-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (147 mg) is subjected to interaction with 4-(3,4,5-trimethoxyphenyl)benzylchloride (114 mg) by the procedure similar to that described in example 9. After transformation of the product into the dihydrochloride receive specified in the title compound as a yellow powder.

Yield 82 mg (33%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: of 0.90 (t, 3H, J=7,3 Hz), 1.30 and of 1.36 (m, 2H), 1,51-of 1.55 (m, 2H), 1,79-1,90 (m, 4H), 2,18 (W, 2H), 2,48 (t, 2H, J=7,7 Hz), 2,98 (d, 2H, J=10,7 Hz), of 3.57 (s, 2H), 3.72 points-of 3.85 (m, 1H), 3,88 (s, 3H), 3,90 (s, 3H), 3,91 (s, 6H), of 3.96 (s, 6H), 4,50 (s, 2H), 6,66 (d, 2H, J=8,8 Hz), 6.75 in (s, 2H), 7,00 (d, 2H, J=8,8 Hz), 7,20 (d, 1H, J=4.9 Hz), 7,22 (s, 2H), 7,33 (d, 2H, J=8,2 Hz), 7,47 (d, 2H, J=8,2 Hz), to 7.61 (s, 1H), 8,59 (d, 1H, J=5,1 Hz).

Example of getting 90

Synthesis of 1-(4-picolyl)-4-piperidone

Monohydrate hydrochloride 4-piperidin the (922 mg) and the hydrochloride of 4-picolylamine (820 mg) is subjected to interaction in accordance with the method, described in example 2, obtaining specified in the header of the connection.

The output of 870 mg (92%).

1H-NMR (400 MHz, CDCl3) δ: of 2.46 (t, 4H, J=5,9 Hz), is 2.74 (t, 4H, J=6.2 Hz), 3,61 (s, 2H), 7,29 (d, 2H, J=6.2 Hz), 8,55 (DD, 2H, J=6.2 Hz, 1.1 Hz).

Example of getting 91

Synthesis of tetrahydrochloride 1-(4-picolyl)-4-(4-picolylamine)piperidine

1-(4-Picolyl)-4-piperidone (870 mg) is subjected to interaction with 4-picolylamine (497 mg) by the procedure similar to that described in example getting 37. The target compound obtained as pale-brown tetrahydrochloride.

The output of 363 mg (19%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,37-is 1.51 (m, 2H), 1,82-1,90 (m, 2H), 2,04 (dt, 2H, J=11,6 Hz, 2.7 Hz), 2,44 is 2.55 (m, 1H), was 2.76-2.82 from (m, 2H), 3,47 (s, 2H), 3,82 (s, 2H), 7.23 percent-7,26 (m, 4H), 8,50 are 8.53 (m, 4H).

Example of getting 92

Synthesis of 4-(p-anisidino)-1-(tert-butoxycarbonyl)piperidine

1-(tert-Butoxycarbonyl)-4-piperidone (116 g) is subjected to interaction with p-anisidine (68,3 g) by the procedure similar to that described in example receiving 37, receiving specified in the header of the connection.

An output of 125 g (74%).

1H-NMR (400 MHz, CDCl3) δ: of 1.23 and 1.35 (m, 2H), of 1.46 (s, 9H), 1,96-to 2.06 (m, 2H), 2,83-2,96 (m, 2H), 3.27 to to 3.38 (m, 1H), 3,74 (s, 9H), 3,94-4,12 (m, 2H), return of 6.58 (d, 2H, J=9.0 Hz), 6,77 (d, 2H, J=9.0 Hz).

Example of getting 93

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[3(3,4,5-trimethoxyphenyl)benzoylamine]piperidine

4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) is subjected to interaction with 3-(3,4,5-trimethoxyphenyl)benzoic acid (577 mg) by the procedure similar to that described in example 1, obtaining specified in the header of the connection.

The output of 416 mg (36%).

Example of getting 94

Synthesis of the hydrochloride of 4-[N-(4-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzoyl]amino]piperidine

To a solution of 1-(tert-butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzoylamine]piperidine (416 mg) in ethyl acetate (5 ml) is added 4 M solution of hydrogen chloride in ethyl acetate (5 ml). The mixture is stirred at room temperature for 4 hours, the resulting precipitation was filtered, washed with ethyl acetate using a funnel and dried, obtaining specified in the header of the connection.

The output of 315 mg (85%).

Examples 64-66

These connections receive interaction hydrochloride 4-[N-(4-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzoyl]amino]piperidine derivative chloride obtained in the examples for the preparation of 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride. Outputs and NMR data of their free bases listed below.

ExampleStructureOutput These NMR (400 MHz, defined as the free base, CDCl3) δ
6468%1,53-of 1.55 (m, 2H), 1,89 (d, 2H, J=12.0 Hz), of 2.23 (t, 2H, J=12.0 Hz), 2.91 in (d, 2H, J=11,0 Hz), 3,51 (s, 2H), 3,70 (s, 3H), of 3.84 (s, 3H), a 3.87 (s, 9H), to 3.92 (s, 6H), 4,78 (W, 1H), 6,54 (s, 2H), 6,72 (d, 2H, J=8.5 Hz), 6,94 (d, 2H, J=8.5 Hz), 7,13-7,20 (m, 4H), 7,18 (s, 2H), 7,32 (d, 1H, J=5.3 Hz), 7,45 (s, 1H), 8,19 (d, 1H, J=4,9 Hz).
6552%1,66-1,89 (m, 4H), 2.05 is-2,17 (m, 2H), 2,97 (d, 2H, J=10.3 Hz), 3.43 points-of 3.60 (m, 1H), only 3.57 (s, 2H), 3,86 (s, 3H), a 3.87 (s, 6H), a 3.87 (s, 6H), 3,91 (s, 6H), was 4.42 (s, 2H), 6,63 (s, 2H), 6,72-6,79 (m, 6H), to 7.64 (, 1H), 7,78 (W, 1H), 8,46 (d, 2H, J=1.6 Hz), 8,59 (d, 1H, J=2.4 Hz), 8,68 (d, 1H, J=2.2 Hz).
6675%1,42 is 1.58 (m, 2H), 1.85 to of 1.92 (m, 2H), 2,14-of 2.23 (m, 2H), 2,93-3,03 (m, 2H), of 3.56 (s, 2H), 3,70 (s, 3H), 3,85 (s, 3H), a 3.87 (s, 3H), a 3.87 (s, 6H), 3,90 (s, 6H), 4,79 (W, 1H), 6,54 (s, 2H), 6,70 (d, 2H, J=the 8.9 Hz), 6,74 (s, 2H), 6,93 (d, 2H, J=8,9 Hz), 7,17-of 7.23 (m, 3H), 7,31-the 7.43 (m, 5H).

Example obtain 95

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (2,21 g) is subjected to interaction with 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (2,12 g) by the procedure similar to that described in example 9, receiving specified in the header is Obedinenie.

Output 3,76 g (93%).

1H-NMR (400 MHz, CDCl3) δ: 1,40-of 1.64 (m, 2H), of 1.44 (s, 9H), 1,82 is 1.91 (m, 2H), 2.71 to 2,84 (m, 2H), 3,62-to 3.73 (m, 1H), 3,74 (s, 3H), with 3.89 (s, 3H), of 3.94 (s, 6H), 4,10-4,30 (m, 2H), and 4.40 (s, 2H), 6,76 (d, 2H, J=9.4 Hz), 6,79 (d, 2H, J=9.8 Hz), 7,14-7,19 (m, 3H), 7,56 (s, 1H), 8,55 (d, 1H, J=5,1 Hz).

An example of retrieving 96

The synthesis of the dihydrochloride of 4-[N-(4-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine (3,76 g) is treated according to the method similar to that described in example getting 94, receiving specified in the header of the connection.

The output of 3.77 g (theoretical yield).

Example of getting 97

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) is subjected to interaction with 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) by the procedure similar to that described in example receiving 9, getting mentioned in the title compound as a yellow amorphous substance.

Exit 159 mg (14%).

1H-NMR (400 MHz, CDCl3) δ: of 1.44 (s, 9H), 1,50-of 1.65 (m, 2H), 1,83 is 1.91 (m, 2H), 2,70-2,84 (m, 2H), 3,53-3,62 (m, 1H), of 3.73 (s, 3H), with 3.89 (s, 3H), 3,91 (s, 6H), 4,10-the 4.29 (m, 2H), to 4.41 (s, 2H), 6,66 (s, 2H), 6,76-6,84 (m, 4H), of 7.70 (s, 1H), 8,49 (s, 1H), 8,63 (d, 1H, J=2.1 Hz).

At the er getting 98

The synthesis of the dihydrochloride of 4-[N-(4-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine (159 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a yellow powder.

The output 142 mg (94%).

Example of getting 99

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 3-(3,4,5-trimethoxyphenyl)benzylchloride (586 mg) is treated according to the method similar to that described in example 9, getting mentioned in the title compound as a yellow amorphous substance.

The output of 1.12 g (90%).

1H-NMR (400 MHz, CDCl3) δ: of 1.44 (s, 9H), 1,50-to 1.63 (m, 2H), 1,82 is 1.91 (m, 2H), 2.71 to and 2.83 (m, 2H), 3,69 (TT, 1H, J=11.5 Hz, 3.5 Hz), to 3.73 (s, 3H), 3,88 (s, 3H), 3,90 (s, 6H), 4,10-to 4.28 (m, 2H), 4,42 (s, 2H), of 6.71 (s, 2H), 6,78 (s, 4H), 7.24 to 7,28 (m, 1H), 7,31-7,40 (m, 2H), 7,42 (s, 1H).

Example 100

Synthesis of the hydrochloride of 4-[N-(4-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1.12 g) is treated according to the method, the anal is Gino described in example getting 94, getting listed in the title compound as a yellow powder.

The output of 980 mg (99%).

Examples 67-71

The above compound is produced by interaction of amines obtained in examples getting 96, 98 and 100, with derivative chloride obtained in the examples of the preparation 42 and 48. The obtained free base is then converted into the corresponding hydrochloride. Outputs and NMR data of their free bases listed below.

ExampleStructureOutputThese NMR (400 MHz, defined as the free base, CDCl3) δ
6762%1,60-of 1.92 (m, 4H), 2,08-2,22 (m, 2H), 2,92-of 3.06 (m, 2H), 3,54-to 3.64 (m, 3H), of 3.73 (s, 3H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,93 (s, 12H), 4,43 (s, 2H), 6,70-for 6.81 (m, 6H), 7,12-7,17 (m, 3H), 7,56 (s, 1H), 7,76 (s, 1H), 8,49 (d, 1H, J=1.8 Hz), 8,53 (d, 1H, J=5,1 Hz), to 8.70 (s, 1H).
6854%1,65-to 1.79 (m, 2H), 1,81-1,90 (m, 2H), 2,04-to 2.18 (m, 2H), 2,94-of 3.06 (m, 2H), 3,52-3,66 (m, 3H), and 3.72 (s, 3H), with 3.89 (s, 6H), to 3.92 (s, 6H), 3,93 (s, 6H),of 4.44 (s, 2H), 6,70-to 6.80 (m, 6H), 7,13-7,17 (m, 3H), 7.24 to to 7.50 (m, 4H), 7,55 (s, 1H), 8,53 (d, 1H, J=4,9 Hz).
6952%1,66-1,89 (m, 4H), 2.05 is-2,17 (m, 2H), 2,97 (d, 2H, J=10.3 Hz), 3.43 points-of 3.60 (m, 1H), only 3.57 (s, 2H), 3,86 (s, 3H), a 3.87 (s, 6H), a 3.87 (s, 6H), 3,91 (s, 6H), was 4.42 (s, 2H), 6,63 (s, 2H), 6,72-6,79(m, 6H), to 7.64 (s, 1H), 7,78 (W, 1H), 8,46 (d, 2H, J=1.6 Hz), 8,59 (d, 1H, J=2.4 Hz), 8,68 (d, 1H, J=2.2 Hz).
7069%1,55-of 1.97 (m, 4H), 2.06 to of 2.21 (m, 2H), 2,92-of 3.07 (m, 2H), 3,53-3,68 (m, 3H), and 3.72 (s, 3H), a 3.87 (s, 3H), with 3.89 (s, 6H), to 3.89 (s, 3H), of 3.94 (s, 3H), of 4.46 (s, 2H), 6,69 (s, 2H), 6.73 x-PC 6.82 (m, 6H), 7,22-7,29 (m, 1H), 7,32 (t, 1H, J=7.4 Hz), was 7.36 (d, 1H, J=7.8 Hz), 7,41 (s, 1H), 7,79 (W, 1H), 8,48 (s, 1H), 8,71 (W, 1H).
7175%1,69-1,89 (m, 4H), 2.06 to to 2.15 (m, 2H), 2,96 totaling 3.04 (m, 2H), 3,56-3,66 (m, 1H), only 3.57 (s, 2H), and 3.72 (s, 3H), a 3.87 (s, 3H), with 3.89 (s, 9H), to 3.92 (s, 6H), to 3.92 (s, 6H), to 4.46 (s, 2H), 6,70 (s, 2H), of 6.71-6,79 (m, 6H), of 7.23-7,47 (m, 8H).

An example of retrieving 101

Synthesis of 1-(tert-butoxycarbonyl)-4-(4-ethoxybenzylidene)piperidine

1-(tert-Butoxycarbonyl)-4-piperidinol (5,00 g) is subjected to interaction with p-phenetidine (3.28 g) by the procedure similar to that described in example receiving 37, getting mentioned in the title compound as a brown powder.

The output of 7.00 g (91%).

1H-NMR (400 MHz, CDCl3) δ: to 1.21 to 1.31 (m, 2H), of 1.37 (t, 3H, J=7,0 Hz)of 1.46 (s, 9H), 1,97-2,05 (m, 2H), 2,84-2,95 (m, 2H), 3,28-3,37 (m, 1H), 3.96 points (q, 2H, J=7.0 Hz), 3,99-4,10 (m, 2H), to 6.57 (d, 2H, J=8,8 Hz), 6,77 (d, 2H, J=9,0 Hz).

Example of getting 102

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-ethoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tre is-Butoxycarbonyl)-4-[(4-ethoxyphenyl)amino]piperidine (641 mg) is subjected to interaction with 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a yellow amorphous substance.

The output of 2.08 g (94%).

1H-NMR (400 MHz, CDCl3) δ: of 1.36 (t, 3H, J=7.9 Hz), the 1.44 (s, 9H), 1,49 is 1.58 (m, 2H), 1,82-of 1.92 (m, 2H), 2,70-to 2.85 (m, 2H), 3,62-and 3.72 (m, 1H), with 3.89 (s, 3H), of 3.94 (s, 6H), 4,12-the 4.29 (m, 2H), 4,39 (s, 2H), 6.75 in (d, 2H, J=9,2 Hz), 6,78 (d, 2H, J=9.6 Hz), 7,14-to 7.18 (m, 3H), 7,55 (s, 1H), 8,54 (d, 1H, J=5,1 Hz).

Example of getting 103

The synthesis of the dihydrochloride of 4-[N-(4-ethoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-ethoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine (1.08 g) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Yield 1.01 g (98%).

Example of getting 104

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-ethoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[(4-ethoxyphenyl)amino]piperidine (641 mg) is subjected to interaction with 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a yellow amorphous substance.

The output 452 mg (39%).

1H-NMR (400 MHz, CDCl3) δ: of 1.36 (t, 3H, J=6.8 Hz), the 1.44 (s, 9H), 1,50-1,60 (m, 2H) 1,82-1,90 (m, 1H), 2,68-2,82 (m, 2H), 3,52-3,61 (m, 1H), 3,88 (s, 3H), 3,90 (s, 6H), of 3.94 (q, 2H, J=7.0 Hz), 4,10-of 4.25 (m, 2H), and 4.40 (s, 2H), 6,66 (s, 2H), 6,77 (d, 2H, J=9,2 Hz), for 6.81 (d, 2H, J=9,2 Hz), to 7.67 (s, 1H), 8,49 (d, 1H, J=2.0 Hz), to 8.62 (d, 1H, J=2.1 Hz).

Example of getting 105

The synthesis of the dihydrochloride of 4-[N-(4-ethoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-ethoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine (452 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

The output of 380 mg (88%).

Example of getting 106

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-ethoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[(4-ethoxyphenyl)amino]piperidine (641 mg) is subjected to the interaction of 3-(3,4,5-trimethoxyphenyl)benzylchloride (586 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

Yield 1.06 g (92%).

1H-NMR (400 MHz, CDCl3) δ: of 1.36 (t, 3H, J=7.0 Hz), the 1.44 (s, 9H), 1,53-to 1.59 (m, 2H), 1,83 is 1.91 (m, 2H), 2,70-and 2.83 (m, 2H), 3,64-to 3.73 (m, 1H), 3,88 (s, 3H), 3,90 (s, 6H), of 3.94 (q, 2H, J=7.0 Hz), 4,10-the 4.29 (m, 2H), to 4.41 (s, 2H), of 6.71 (s, 2H), 6,76 (s, 4H), 7,26 (d, 1H, J=7.9 Hz), 7,33 (DD, 1H, J=7,4 Hz, 7.4 Hz), 7,38 (d, 1H, J=7,6 Hz), 7,42 (s, 1H).

Example of getting 107

<> Synthesis of the hydrochloride of 4-[N-(4-ethoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-ethoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1.06 g) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

The output 913 mg (97%).

Examples 72-79

The above compound is produced by interaction of amines obtained in examples getting 103, 105 and 107, with derivative chloride obtained in the examples for the preparation of 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride. Outputs and NMR data of their free bases listed below.

ExampleStructureOutputThese NMR (400 MHz, defined as the free base, CDCl3) δ
7249%of 1.36 (t, 3H, J=7,1 Hz), 1,68-of 1.94 (m, 4H), 2,10-of 2.24 (m, 2H), 2,93 totaling 3.04 (m, 2H), 3,54-the 3.65 (m, 3H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,93 (s, 6H), of 3.96 (s, 6H), of 4.45 (s, 2H), 6,72 (d, 2H, J=9,2 Hz), 6,78 (d, 2H, J=9,3 Hz),to 7.15 (s, 2H), 7,17 (d, 1H, J=6,1 Hz), 7,20 (DD, 1H, J=4,9 Hz, 1.0 Hz), 7.23 percent (s, 2H), EUR 7.57 (s, 1H), to 7.61 (W, 1H), 8,54 (d, 1H, J=5,2 Hz), 8,59 (d, 1H, J=4,9 Hz).
7363% of 1.36 (t, 3H, J=7.0 Hz), 1.56 to around 1.74 (m, 2H), 1,80-1,90 (m, 2H), 2,07-2,19 (m, 2H), 2,92-to 3.02 (m, 2H), to 3.58 (s, 2H), 3,88-3,95 (m, 2H), with 3.89 (s, 3H), 3,93 (s, 12H), 4,43 (s, 2H), 6,69-6,79 (m, 6H), 7,12-7,17 (m, 3H), 7,55 (s, 1H), 7,76 (s, 1H), 8,49 (d, 1H, J=1.8 Hz), 8,53 (d, 1H, J=5,1 Hz), 8,69 (s, 1H).
7465%of 1.36 (t, 3H, J=7.0 Hz), 1,58-of 1.78 (m, 2H), 1,80-1,89 (m, 2H), 2,04-of 2.16 (m, 2H), 2.95 and was 3.05 (m, 2H), 3,52-3,66 (m, 1H), 3,57 (s, 1H), 3,85-of 3.97 (m, 2H), with 3.89 (s, 6H), to 3.92 (s, 6H), 3,93 (s, 6H), of 4.44 (s, 2H), 6,67-to 6.80 (m, 6H), 7,13-to 7.18 (m, 3H), 7,25-7,31 (m, 1H), 7,37 (DD, 1H, J=7,6 Hz and 7.6 Hz), 7,41-of 7.48 (m, 2H), 7,55 (s, 1H), 8,53 (d, 1H, J=4,9 Hz).
7542%of 1.36 (t, 3H, J=7.0 Hz), 1,74-of 2.34 (m, 6H), 2,96-3,10 (m, 2H), 3,47-to 3.73 (m, 3H), a 3.87-3,98 (m, 2H), 3,88 (s, 3H), 3,90 (s, 9H), of 3.97 (s, 6H), of 4.44 (s, 2H), 6,65 (s, 2H), 6,74-PC 6.82 (m, 4H), 7.18 in-7,32 (m, 4H), to 7.67 (s, 1H), 8,49 (d, 1H, J=1.6 Hz), 8,57-8,65 (m, 2H).
7643%of 1.36 (t, 3H, J=6.8 Hz), 1,63 is 1.96 (m, 4H), 2.00 in of 2.26 (m, 2H), 2,92-3,03 (m, 2H), 3,44-3,66 (m, 3H), 3,86-of 3.96 (m, 2H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), 3,93 (s, 6H), of 4.44 (s, 2H), 6,65 (s, 2H), 6,72-to 6.80 (m, 6H), to 7.67 (s, 1H), to 7.77 (W, 1H), of 8.47 are 8.53 (m, 2H), to 8.62 (d, 1H, J=1.9 Hz), to 8.70 (s, 1H).
7782%of 1.35 (t, 3H, J=6.8 Hz), 1.70 to to 1.82 (m, 2H), 1,84-of 1.92 (m, 2H), 2,10-2,19 (m, 2H), 2,92-3,00 (m, 2H), 3,52-the 3.65 (m, 3H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), 3,93 (q, 2H, J=7,1 Hz), of 3.96 (s, 6H), 4,47 (, 2H), 6,70 (s, 2H), 6.73 x (d, 2H, J=9,3 Hz), 6,77 (d, 2H, J=9,3 Hz), 7.18 in-7,28 (m, 4H), 7,33 (DD, 1H, J=7,3 Hz and 7.3 Hz), 7,37(d, 1H, J=7,6 Hz), the 7.43 (s, 1H), to 7.59 (s, 1H), 8,58 (d, 1H, J=4,9 Hz).
7861%of 1.35 (t, 3H, J=6.9 Hz), 1,58 and 1.80 (m, 2H), 1,82 is 1.91 (m, 2H), 2,09-to 2.18 (m, 2H), 2,93-3,20 (m, 2H), 3,56-the 3.65 (m, 1H), to 3.58 (s, 2H), a 3.87 (s, 3H), with 3.89 (s, 6H), to 3.89 (s, 3H), 3,91-of 3.94 (m, 2H), 3,93 (s, 6H), of 4.45 (s, 2H), 6,69 (s, 2H), of 6.71-of 6.78 (m, 6H), 7.23 percent-7,28 (m, 1H), 7,32 (t, 1H, J=7.5 Hz), was 7.36 (d, 1H, J=7,6 Hz), 7,42 (s, 1H), to 7.77 (s, 1H), 8,49 (d, 1H, J=1.8 Hz), 8,69 (d, 1H, J=1.8 Hz).
7973%of 1.35 (t, 3H, J=6.8 Hz), 1,68 and 1.80 (m, 2H), 1,81-1,89 (m, 2H), 2.06 to and 2.14 (m, 2H), 2,96-3,03 (m, 2H), only 3.57 (s, 2H), 3,57-the 3.65 (m, 1H), a 3.87 (s, 3H), with 3.89 (s, 9H), 3,91-of 3.96 (m, 2H), 3,92 (s, 6H), to 4.46 (s, 2H), 6,69-6,79 (m, 9H), 7.23 percent-7,47 (m, 7H).

Example of getting 108

Synthesis of 1-(tert-butoxycarbonyl)-4-(4-butoxyaniline)piperidine

1-(tert-Butoxycarbonyl)-4-piperidinol (5,00 g) is subjected to interaction with 4-butoxyaniline (3,95 g) in accordance with the method described in example receiving 37, getting mentioned in the title compound as a brown powder.

Output 6,91 g (83%).

1H-NMR (400 MHz, CDCl3) δas 0.96 (t, 3H, J=7.2 Hz), of 1.23 and 1.35 (m, 2H), 1,42-of 1.53 (m, 2H), of 1.46 (s, 9H), by 1.68 to 1.76 (m, 2H), 1,97-2,05 (m, 2H), 2,84-2,95 (m, 2H), 3,28-3,37 (m, 1H), 3,88 (t, 2H, J=6.6 Hz), 3.96 points-of 4.12 (m, 2H), to 6.57 (d, 2H, J=9.0 Hz), 6,77 (d, 2H, J=8,8 Hz).

Example of getting 109

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-butoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]the Mino]piperidine

1-(tert-Butoxycarbonyl)-4-[(4-butoxyphenyl)amino]piperidine (696 mg) is subjected to interaction with 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

The output of 980 mg (81%).

1H-NMR (400 MHz, CDCl3) δ: of 0.95 (t, 3H, J=7.4 Hz), of 1.40-1.50 (m, 2H), of 1.44 (s, 9H), 1,67 to 1.76 (m, 2H), 1,82-1,90 (m, 2H), 1,82-1,90 (m, 2H), 2,70-2,82 (m, 2H), 3,61-3,71 (m, 1H), 3,84-3,90 (m, 5H), of 3.94 (s, 6H), 4,10-4,28 (m, 2H), 4,39 (s, 2H), 6,74 (d, 2H, J=9.4 Hz), 6,78 (d, 2H, J=9.4 Hz), 7,14-to 7.18 (m, 3H), 7,56 (s, 1H), 8,54 (d, 1H, J=5,1 Hz).

An example of retrieving 110

The synthesis of the dihydrochloride of 4-[N-(4-butoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-butoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine (980 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a yellow powder.

Output 926 mg (99%).

Example of getting 111

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-butoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[(4-butoxyphenyl)amino]piperidine (697 mg) is subjected to interaction with 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyrid the nom (588 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

The output of 485 mg (40%).

1H-NMR (400 MHz, CDCl3) δ: of 0.95 (t, 3H, J=7.4 Hz), 1,40-of 1.57 (m, 2H), of 1.44 (s, 9H), 1,67 is 1.75 (m, 2H), 1,82-1,90 (m, 2H), 2,69-of 2.81 (m, 2H), 3,51-of 3.60 (m, 1H), a 3.87 (q, 2H, J=6.6 Hz), 3,88 (s, 3H), 3,90 (s, 6H), 4,06-to 4.23 (m, 2H), 4,39 (s, 2H), 6,66 (s, 2H), 6,77 (d, 2H, J=9,2 Hz), for 6.81 (d, 2H, J=9,2 Hz), for 6.81 (d, 2H, J=9.4 Hz), to 7.67 (s, 1H), 8,49 (d, 1H, J=1.8 Hz), to 8.62 (d, 1H, J=2.2 Hz).

Example of getting 112

The synthesis of the dihydrochloride of 4-[N-(4-butoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-butoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine (485 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

The output of 456 mg (98%).

Example of getting 113

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-butoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[(4-butoxyphenyl)amino]piperidine (697 mg) is subjected to interaction with 3-(3,4,5-trimethoxyphenyl)benzylchloride (586 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

The output of 1.17 g (97%).

1H-YAM who (400 MHz, CDCl3) δ: of 0.95 (t, 3H, J=7,3 Hz), 1,40-to 1.61 (m, 4H), of 1.44 (s, 9H), 1,67 is 1.75 (m, 2H), 1,83-1,90 (m, 2H), 2,70-and 2.83 (m, 2H), 3,63-and 3.72 (m, 2H), a 3.87 (q, 2H, J=6.6 Hz), 3,88 (s, 3H), 3,90 (s, 6H), 4.09 to 4,28 (m, 2H), to 4.41 (s, 2H), 6,70 (s, 2H), 6,76 (s, 4H), 7,26 (d, 2H, J=8.0 Hz), 7,33 (t, 1H, J=7,6 Hz), 7,38 (d, 1H, J=7,3 Hz), 7,42 (s, 1H).

Example of getting 114

The synthesis of the dihydrochloride of 4-[N-(4-butoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-butoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1,17 g) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

The output of 1.02 g (98%).

Examples 80-87

The above compound is produced by interaction of amines obtained in examples obtain 110, 112 and 114, with derivative chloride obtained in the examples for the preparation of 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride. Outputs and NMR data of their free bases listed below.

ExampleStructureOutputThese NMR (400 MHz, defined as the free base, CDCl3) δ
8063%of 0.95 (t, 3H, J=7,3 Hz), 1,40-is 1.51 (m, 2H), 1,66-1, 79 (m, 2H), 1,83-of 1.92 (m, 2H), 2,10-of 2.21 (m, 2H), ,92-3,02 (m, 2H), 3,53-3,63 (m, 3H), 3,84-3,90 (m, 2H), with 3.89 (s, 3H), 3,93 (s, 6H), of 3.96 (s, 6H), 6,72 (d, 2H, J=9,3 Hz), 6,77 (d, 2H, J=9,3 Hz), to 7.15 (s, 2H), 7,17 (d, 1H, J=5,1 Hz), 7,20 (d, 1H, J=6,1 Hz), 7,22 (, 2H), EUR 7.57 (s, 1H), to 7.59 (s, 1H), 8,54 (d, 1H, J=4.9 Hz), 8,59 (d, 1H, J=5,1 Hz).
8144%of 0.95 (t, 3H, J=7.4 Hz), 1,42-is 1.51 (m, 2H), 1,67 to 1.76 (m, 4H), 1,80 is 1.91 (m, 2H), 2,08-of 2.20 (m, 2H), 2,92-3,03 (m, 2H), 3,84-of 3.96 (m, 3H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,93 (s, 12H), 4,43 (s, 2H), 6,69-6,79 (m, 6H), 7,14 (s, 2H), 7,16 (d, 1H, J=5,2 Hz), 7,55 (s, 1H), 7,76 (s, 1H), 8,49 (d, 1H, J=1.8 Hz), 8,53 (d, 1H, J=5.0 Hz), 8,69 (s, 1H).
8253%of 0.95 (t, 3H, J=7.2 Hz), 1,40-is 1.51 (m, 2H), 1,65-of 1.78 (m, 4H), 1,81-1,89 (m, 2H), 2.05 is-to 2.18 (m, 2H), 3,05-of 3.06 (m, 2H), 3,54-the 3.65 (m, 3H), 3,84-of 3.96 (m, 20H), of 4.44 (s, 2H), 6,70 (d, 2H, J=9,2 Hz), 6,74-to 6.80 (m, 4H), 7,11-7,19 (m, 3H), 7,22-7,32 (m, 1H), 7,34-to 7.50 (m, 3H), 7,55 (s, 1H), 8,53 (d, 1H, J=5,1 Hz).
8342%of 0.95 (t, 3H, 7,4 Hz), 1,40-is 1.51 (m, 2H), 1,67 is 1.86 (m, 6H), 2,03-of 2.30 (m, 2H), 2,92-of 3.06 (m, 2H), 3.46 in of 3.56 (m, 1H), 3,60 (s, 2H), 3,84-3,91 (m, 2H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), of 3.96 (s, 6H), of 4.44 (s, 2H), 6,65 (s, 2H), 6,74-for 6.81 (m, 4H), 7,20 (d, 1H, J=4.9 Hz), 7,25 (s, 2H), to 7.67 (W, 2H), and 8.50 (d, 1H, J=1.6 Hz), at 8.60 (d, 1H, J=5.6 Hz).
8436%of 0.95 (t, 3H, J=7.4 Hz), 1,40-is 1.51 (m, 2H), 1,66-to 1.79 (m, 4H), 1,82-of 1.92 (m, 2H), 2.00 in 2,22 (m, 2H), 2,83-of 3.06 (m, 2H), 3,44-to 3.67 (m, 3H), 3,82-of 3.97 (m, 2H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), 3,93 (s, 6H), of 4.44 (s, 2H), 6,65 (s, 2H), 6,72-to 6.80 (m, 6H), to 7.67 (s, 1H), 7,76 (W, 1H),of 8.47 are 8.53 (m, 2H), to 8.62 (d, 1H, J=2.2 Hz), to 8.70 (s, 1H).
8572%of 0.95 (t, 3H, J=7,3 Hz), 1,40-is 1.51 (m, 2H), 1,66-to 1.82 (m, 4H), 1,84-of 1.92 (m, 2H), 2,10-of 2.20 (m, 2H), 2,92-3,00 (m, 2H), 3,53-3,66 (m, 3H), 3,83-to 3.92 (m, 2H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), of 3.96 (s, 6H), 4,47 (s, 2H), to 6.67 (s, 2H), 6.73 x (d, 2H, J=9,2 Hz), 6,77 (d, 2H, J=9.5 Hz), 7.18 in-7,29 (m, 4H), 7,33 (DD, 1H, J=7,3 Hz and 7.3 Hz), 7,37 (d, 1H, J=7,6 Hz), the 7.43 (s, 1H), 7,60 (s, 1H), 8,58 (d, 1H, J=4,9 Hz).
8624%of 0.94 (t, 3H, J=7.4 Hz), 1.41 to a rate of 1.51 (m, 2H), 1,61 and 1.80 (m, 4H), 1,82-of 1.92 (m, 2H), 2,08-2,19 (m, 2H), 2,92-to 3.02 (m, 2H), 3,55-the 3.65 (m, 1H), only 3.57 (s, 2H), 3,84-3,91 (m, 2H), a 3.87 (s, 3H), 3,88 (s, 6H), to 3.89 (s, 3H), 3,93 (s, 6H), of 4.45 (s, 2H), 6,69 (s, 2H), of 6.71-of 6.78 (m, 4H), 6.75 in (s, 2H), 7.23 percent-7,28 (m, 1H), 7,32 (t, 1H, J=7.4 Hz), was 7.36 (d, 1H, J=7,6 Hz), 7,42 (s, 1H), to 7.77 (s, 1H), 8,49 (d, 1H, J=1.6 Hz), 8,69 (s, 1H).
8778%of 0.94 (t, 3H, J=7,3 Hz), of 1.40-1.50 (m, 2H), 1,66-of 1.88 (m, 4H), 1,82-1,89 (m, 2H), 2,04-of 2.16 (m, 2H), 2,96-3,03 (m, 2H), 3,55-the 3.65 (m, 3H), 3,83-3,90 (m, 2H), a 3.87 (s, 3H), with 3.89 (s, 9H), to 3.92 (s, 6H), to 4.46 (s, 2H), 6,69-6,79 (m, 9H), 7.23 percent-of 7.48 (m, 7H).

Example of getting 115

Synthesis of 4-(m-anisidino)-1-(tert-butoxycarbonyl)piperidine

1-(tert-Butoxycarbonyl)-4-piperidinol (4,78 g) is subjected to interaction with m-anisidine (2,96 g) in accordance with the method described in example receiving 37, receiving specified in the header of the connection.

Yield 4.83 g (66%).

1 H-NMR (400 MHz, CDCl3) δ: 1,20-of 1.39 (m, 2H), of 1.44 (s, 9H), 1,99-2,05 (m, 2H), 2,89 (dt, 2H, J=13.5 Hz and 2.2 Hz), 3.33 and-3,44 (m, 1H, in), 3.75 (s, 3H), 3.96 points-4,07 (m, 2H), 6,14 (t, 1H, J=2.2 Hz), 6,18-of 6.29 (m, 2H), 7,05 (t, 1H, J=8,1 Hz).

Example of getting 116

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(3-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

4-(m-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) is subjected to interaction with 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

Exit 789 mg (70%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,50-to 1.67 (m, 2H), 1,82 is 1.91 (m, 2H), 2,74-2,87 (m, 2H), 3,74 (s, 3H), 3,88-3,98 (m, 1H), with 3.89 (s, 3H), of 3.94 (s, 6H), 4,14-4,32 (m, 2H), 4,48 (s, 2H), 6,28 (DD, 1H, J=2,2 Hz, 2.2 Hz), of 6.31-6,37 (m, 2H), 7,10-to 7.15 (m, 2H), 7,16 (s, 2H), 7,55 (s, 1H), 8,56 (d, 1H, J=5,1 Hz).

Example of getting 117

The synthesis of the dihydrochloride of 4-[N-(3-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(3-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine (789 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Yield 710 mg (95%).

Example of getting 118

The synthesis of 1(tert-butoxycarbonyl)-4-[N-(3-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

4-(m-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) is subjected to interaction with 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

The output of 396 mg (35%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,54-of 1.66 (m, 2H), 1,81 is 1.91 (m, 2H), 2,73-2,87 (m, 2H), 3,74 (s, 3H), a 3.87-3,93 (m, 1H), 3,88 (s, 3H), 3,90 (s, 6H), 4,14-the 4.29 (m, 2H), 4,51 (s, 2H), 6,30 to 6.35 (m, 2H), 6,38 (d, 1H, J=7,2 Hz), of 6.68 (s, 2H), 7,12 (DD, 1H, J=8,8 Hz, 8,88 Hz), 7,66 (s, 1H), 8,49 (d, 1H, J=2.0 Hz), 8,66 (d, 1H, J=2.2 Hz).

Example of getting 119

The synthesis of the dihydrochloride of 4-[N-(3-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(3-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine (396 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

The output of 348 mg (92%).

Example obtain 120

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(3-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

4-(m-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) is subjected to interaction with 3-(3,4,5-trimethoxyphenyl)benzylchloride (586 mg) by the procedure similar is the rule described in example 9, getting listed in the title compound as a pale yellow amorphous substance.

Yield 1.01 g (90%).

1H-NMR (400 MHz, CDCl3) δ: of 1.44 (s, 9H), 1.56 to to 1.67 (m, 2H), 1,83 is 1.91 (m, 2H), 2,72-of 2.86 (m, 2H), of 3.73 (s, 3H), 3,85-3,98 (m, 1H), 3,88 (s, 3H), 3,90 (s, 6H), 4,12-4,30 (m, 2H), 4,50 (s, 2H), 6,27-6,34 (m, 2H), 6,38 (DD, 1H, J=8,2 Hz, 2.4 Hz), 6,72 (s, 2H), 7,10 (DD, 1H, J=8,2 Hz and 8.2 Hz), 7,21-7,27 (m, 1H), 7,32-the 7.43 (m, 3H).

Example of getting 121

Synthesis of the hydrochloride of 4-[N-(3-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(3-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1.01 g) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Yield 820 mg (92%).

Examples 88-95

The above compound is produced by interaction of amines obtained in examples getting 117, 119 and 121, with derivative chloride obtained in the examples for the preparation of 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride. Outputs and NMR data of their free bases listed below.

ExampleStructureOutputThese NMR (400 MHz, defined as the free base, CDCl3) δ
88 63%1,70-to 1.82 (m, 2H), 1,83-1,90 (m, 2H), 2,14-of 2.23 (m, 2H), 2,94-a 3.01 (m, 2H), only 3.57 (s, 2H), of 3.73 (s, 3H), 3,76-3,88 (m, 1H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,93 (s, 6H), of 3.96 (s, 6H), a 4.53 (s, 2H), 6,26-6,35 (m, 3H), 7,11 (DD, 1H, J=8,3 Hz and 8.3 Hz), 7,12-7,14 (m, 1H), 7,15 (s, 2H), 7,20 (d, 1H, J=5,1 Hz), 7,22 (s, 2H), 7,55 (s, 1H), 7,58 (s, 1H), 8,55 (d, 1H, J=4.9 Hz), 8,59 (d, 1H, J=4,9 Hz).
8972%1,67-1,90 (m, 4H), 2,13-2,22 (m, 2H), 2,94 totaling 3.04 (m, 2H)and 3.59 (s, 2H), 3,74 (s, 3H), of 3.77-a 3.87 (m, 1H), with 3.89 (s, 3H), with 3.89 (s, 3H), 3,92 (s, 6H), 3,93 (s, 6H), to 4.52 (s, 2H), 6,27 (DD, 1H, J=2.4 Hz, 2.4 Hz), 6,29-6,34 (m, 2H), 6.75 in (s, 2H), 7,08-7,17 (m, 4H), 7,54 (s, 1H), of 7.75 (s, 1H), and 8.50 (d, 1H, J=1.8 Hz), 8,54 (d, 1H, J=5,1 Hz), 8,69 (d, 1H, J=2.0 Hz).
9060%1,68-1,90 (m, 4H), 2,09-2,19 (m, 2H), 2,97-of 3.06 (m, 2H), to 3.58 (s, 2H), of 3.73 (s, 3H), 3,76-a 3.87 (m, 1H), with 3.89 (s, 6H), to 3.92 (s, 6H), to 3.92 (s, 6H), to 4.52 (s, 2H), from 6.25 to 6.35 (m, 3H), 6,76 (s, 2H), 6,78-7,17 (m, 4H), 7,25-7,32 (m, 1H), 7,37 (DD, 1H, J=7,4 Hz, 7.4 Hz), 7,41-7,47 (m, 2H), 7,54 (s, 1H), 8,54 (d, 1H, J=5,1 Hz).
9150%1,80-of 1.93 (m, 4H), 2.13 and of-2.32 (m, 2H), 2,87-3,10 (m, 2H), 3,60 (s, 1H), 3,69-of 3.85 (m, 1H), of 3.73 (s, 3H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), of 3.96 (s, 6H), of 4.57 (s, 2H), 6,29-6,34 (m, 2H), 6,37 (DD, 1H, J=8,2 Hz, 8.1 Hz), to 6.67 (s, 2H), 7,11 (DD, 1H, J=8.6 Hz, 8.6 Hz), 7,20-7,28 (m, 3H), 7,58-7,72 (m, 1H), 7,68 (s, 1H), and 8.50 (d, 1H, J=1.8 Hz), at 8.60 (d, 1H, J=4,7 Hz), 8,65 (d, 1H, J=2.0 Hz).
9235%1,70-1,90 (m, 4H), 2,12 was 2.25 (m, 2H), 2.95 and-3,03 (m, 2H), 3,59 (s, 2H), 3.72 points-of 3.97 (m, 1H), of 3.73 (s, 3H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), 3,93 (s, 6H), of 4.54 (s, 2H), 6,25-6,38 (m, 2H), 6,36 (d, 1H, J=8,4 Hz and 8.4 Hz), to 6.67 (s, 2H), 6.75 in (s, 2H), 7,11 (DD, 1H, J=8,4 Hz), 7,66 (s, 1H), 8,49 (s, 1H), and 8.50 (d, 1H, J=1.8 Hz), 8,64 (d, 1H, J=2.0 Hz), to 8.70 (d, 1H, J=1.9 Hz).
9386%1,73-of 1.93 (m, 4H), 2,13-of 2.23 (m, 2H), 2,94-to 3.02 (m, 2H), only 3.57 (s, 2H), of 3.73 (s, 3H), of 3.77-a 3.87 (m, 1H), 3,88 (s, 3H), 3,88 (s, 6H), 3,90 (s, 3H), of 3.96 (s, 6H), 4,56 (s, 2H), 6,27 (DD, 1H, J=8,0 Hz, 2.2 Hz), of 6.31 (DD, 1H, J=2,2 Hz, 2.2 Hz), 6,36 (DD, 1H, J=8,2 Hz, 2.2 Hz), of 6.71 (s, 2H), to 7.09 (DD, 1H, J=8,1 Hz, 8.1 Hz), 7.18 in-7,28 (m, 4H), 7,34 (DD, 1H, J=7,4 Hz, 7.4 Hz), 7,38 (d, 1H, J=7,6 Hz), 7,42 (s, 1H), to 7.59 (s, 1H), 8,59 (d, 1H, J=4,9 Hz).
9456%1,72-of 1.92 (m, 4H), 2,10-of 2.23 (m, 2H), 2,92-of 3.60 (m, 2H)and 3.59 (s, 2H), and 3.72 (s, 3H), of 3.77-to 3.89 (m, 1H), a 3.87 (s, 3H), 3,88 (s, 6H), 3,93 (s, 6H), 4,55 (s, 2H), 6,27 (DD, 1H, J=8,0 Hz, 2.2 Hz), of 6.31 (DD, 1H, J=2.1 Hz and 2.1 Hz), 6,36 (DD, 1H, J=8,4 Hz, 2.4 Hz), 6,70 (s, 2H), 6.75 in (s, 2H), to 7.09 (DD, 1H, J=8,2 Hz and 8.2 Hz), 7,22 (d, 1H, J=7.4 Hz), 7,33 (DD, 1H, J=7,4 Hz, 7.4 Hz), 7,38 (d, 1H, J=7.8 Hz), 7,40 (s, 1H), to 7.77 (s, 1H), and 8.50 (d, 1H, J=1.8 Hz), 8,69 (d, 1H, J=1.8 Hz).
9577%1,66-1,89 (m, 4H), 2,08-to 2.18 (m, 2H), 2.95 and was 3.05 (m, 2H), to 3.58 (s, 2H), and 3.72 (s, 3H), 3.75 to-a-3.84 (m, 1H), a 3.87 (s, 3H), 3,88 (s, 6H), to 3.89 (s, 3H), 3,92 (s, 6H), 4,55 (s, 2H), of 6.26 (DD, 1H, J=8,0 Hz, 2.2 Hz), 6,30 (DD, 1H, 1=2,2 Hz, 2.2 Hz), 6,36 (DD, 1H, J=8,3 Hz, 2.2 Hz), 6,70 (s, 2H), 6,76 (s, 2H), was 7.08 (DD, 1H, J=8,3 Hz and 8.3 Hz), 7,22 (d, 1H, J=7,3 Hz), 7,27-7,47 (m, 7H).

Example of getting 122

Sin is ez 4-(o-anisidino)-1-(tert-butoxycarbonyl)piperidine

1-(tert-Butoxycarbonyl)-4-piperidone (4,78 g) is subjected to interaction witho-anisidine (2,96 g) by the procedure similar to that described in example receiving 37, receiving specified in the header of the connection.

Output 2,61 g (36%).

1H-NMR (400 MHz, CDCl3) δ: 1,31-of 1.41 (m, 2H), 1,47 (s, 9H), 2.00 in of 2.08 (m, 2H), 2,90-a 3.01 (m, 2H), 3,38-3,47 (m, 1H), 3,83 (s, 3H), 4,00-is 4.21 (m, 2H), 6,60-6,69 (m, 2H),6,76-6,89 (m, 2H).

Example of getting 123

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(2-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

4-(o-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) is subjected to interaction with 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

Exit 763 mg (68%).

1H-NMR (400 MHz, CDCl3) δ: 1,41 is 1.58 (m, 2H), of 1.44 (s, 9H), 1,81 is 1.91 (m, 2H), 2,62-2,78 (m, 2H), 3,29 (TT, 1H, J=7,6 Hz and 3.7 Hz), 3,86 (s, 3H), with 3.89 (s, 3H), of 3.95 (s, 6H), 4,06-4,16 (m, 2H), 4,37 (s, 2H), 6,80 (DDD, 1H, J=7,6 Hz and 7.6 Hz, 1.2 Hz), 6.87 in (DD, 1H, J=8,5 Hz, 1.0 Hz), 7,00-7,06 (m, 2H), 7,14 (s, 2H), 7,20 (DD, 1H, J=4,9 Hz, 1.0 Hz), to 7.61 (s, 1H), 8,49 (d, 1H, J=4,9 Hz).

Example of getting 124

The synthesis of the dihydrochloride of 4-[N-(2-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl is)-4-[N-(2-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine (763 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Output 701 mg (97%).

An example of retrieving 125

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(2-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

4-(about-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) is subjected to interaction with 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

The output of 353 mg (31%).

1H-NMR (400 MHz, CDCl3) δ: of 1.44 (s, 9H), 1,46-of 1.53 (m, 2H), 1,82 is 1.91 (m, 2H), 2,62-2,78 (m, 2H), 3,24-to 3.33 (m, 1H), 3,83 (s, 3H), with 3.89 (s, 3H), 3,91 (s, 6H), a 4.03-4,16 (m, 2H), 4,37 (s, 2H), only 6.64 (s, 2H), 6,79 (DDD, 1H, J=7,6 Hz and 7.6 Hz, 1.2 Hz), at 6.84 (DD, 1H, J=7,0 Hz, 1.2 Hz), 6,97-7,06 (m, 2H), 7,68 (DD, 1H, J=1.3 Hz, 1.3 Hz), 8,49 (d, 1H, J=2.0 Hz), 8,56 (d, 1H, J=2.2 Hz).

Example of getting 126

The synthesis of the dihydrochloride of 4-[N-(2-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(2-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine (353 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

The output 312 mg (93%).

the example of obtaining 127

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(2-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

4-(o-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) is subjected to interaction with 3-(3,4,5-trimethoxyphenyl)benzylchloride (586 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

The output of 1.12 g (100%).

1H-NMR (400 MHz, CDCl3) δ: of 1.43 (s, 9H), 1,46-of 1.57 (m, 2H), 1,81-1,90 (m, 2H), 2,62 was 2.76 (m, 2H), 3,31 (TT, 1H, J=11,1 Hz, 3.3 Hz), of 3.84 (s, 3H), 3,88 (s, 3H), 3,91 (s, 6H), 4,00-4,16 (m, 2H), 4,36 (s, 2H), to 6.67 (s, 2H), 6,78 (t, 1H, J=7,3 Hz), 6,85 (d, 1H, J=7.9 Hz), of 6.96-7.03 is (m, 2H), 7.24 to 7,34 (m, 3H), 7,43 (s, 1H).

Example of getting 128

Synthesis of the hydrochloride of 4-[N-(2-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(2-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1.12 g) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Output 987 mg (99%).

Examples 96-101

The above compound is produced by interaction of amines obtained in examples obtain 124, 126 and 128, with derivative chloride obtained in the examples for the preparation of 3 and 48. The obtained free base is then converted into the corresponding hydrochloride. Outputs and NMR data of their free bases listed below.

ExampleStructureOutputThese NMR (400 MHz, defined as the free base, CDCl3) δ
9673%1,62-of 1.74 (m, 2H), 1,82-1,90 (m, 2H), 1,98-of 2.08 (m, 2H), 2,86-to 2.94 (m, 2H), 3,13-up 3.22 (m, 1H), 3,52 (s, 2H), 3,85 (s, 3H), with 3.89 (s, 3H), 3,90 (s, 3H), of 3.94 (s, 6N), of 3.96 (s, 6N), and 4.40 (s, 2H), 6,80 (DDD, 1H, J=7,6 Hz and 7.6 Hz, 1.2 Hz), 6,86 (DD, 1H, J=8.1 Hz, 1.2 Hz), 6,98-7,05 (m, 1H), 7,14 (s, 2H), 7,18 (DD, 1H, J=4,9 Hz, 1.2 Hz), 7,20-7,24 (m, 1H), 7,22 (s, 2H), 7,58 (s, 1H), 7.62mm (s, 1H), 8,49 (d, 1H, J=4.9 Hz), to 8.57 (d, 1H, J=5,2 Hz).
9755%1,60-of 1.73 (m, 4H), 1,82-of 1.93 (m, 2H), 1,98-2,07 (m, 2H), 2,87-of 2.97 (m, 2H), 3,12-up 3.22 (m, 1H), 3,54 (s, 2H), 3,85 (s, 3H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,93 (C, 6N), of 3.94 (s, 6N), 4,39 (s, 2H), 6.75 in (s, 2H), 6,79 (DD, 1H, J=7,4 Hz, 7.4 Hz), 6,86 (d, 1H, J=7.8 Hz), 6,97-7,05 (m, 2H), 7,13 (s, 2H), 7,20 (d, 1H, J=4,7 Hz), to 7.61 (s, 1H), of 7.75 (s, 1H), 8,46-of 8.50 (m, 2H), 8,68 (d, 1H, J=2.0 Hz).
9829%1,64-to 1.82 (m, 2H), 1,84-of 1.97 (m, 2H), 2.00 in to 2.15 (m, 2H), 2,84-a 3.01 (m, 2H), 3,13-of 3.27 (m, 1H), of 3.56 (s, 2H), 3,82 (s, 3H), 3,88 (s, 3H), 3,90 (s, 3H), 3,91 (C, 6N), of 3.96 (s, 6N), and 4.40 (s, 2H), 6,63 (s, 2H)that's 6.75 to 6.88 (m, 2H), 6,97? 7.04 baby mortality (m, 2H), 7,19 (d, 1H, J=4.3 Hz), 7,25 (s, 2H), 7,58-7,73 (m, 2H), and 8.50 (d, 1H, J=1.6 Hz), 8,56 (d, 1H, J=2.2 Hz), 8,58 (d, 1H, J=4,9 Hz).
99 30%of 1.62 and 1.75 (m, 2H), 1,83-of 1.94 (m, 2H), 1,95-2,11 (m, 2H), 2,84-a 3.01 (m, 2H), 3,12 is 3.23 (m, 1H), 3,55 (s, 2H), 3,82 (s, 3H), 3,88 (s, 3H), 3,90 (s, 3H), 3,90 (C, 6N), 3,93 (C, 6N), 4,39 (s, 2H), 6,63 (s, 2H), 6,70-6,86 (m, 4H), 6,94-7,06 (m, 2H), 7,68 (s, 1H), 7,76 (s, 1H), of 8.47 (d, 1H, J=1.7 Hz), 8,49 (d, 1H, J=1.7 Hz), 8,55 (d, 1H, J=2.2 Hz), 8,69 (s, 1H).
10067%1,64-to 1.79 (m, 2H), 1.85 to of 1.93 (m, 2H), 1,99-of 2.09 (m, 2H), 2,86-2,95 (m, 2H), 3,16-3,26 (m, 1H), 3,52 (s, 2H), of 3.84 (s, 3H), 3,88 (s, 3H), 3,90 (C, 6N), of 3.96 (s, 6N), and 4.40 (s, 2H), to 6.67 (s, 2H), 6,78 (DD, 1H, J=7,4 Hz, 7.4 Hz), 6,85 (d, 1H, J=8,2 Hz), 6,97 (DD, 1H, J=7.8 Hz, 7.8 Hz), 7,02 (DD, 1H, J=7,8, and 1.6 Hz), 7,17-7,33 (m, 6N), 7,44 (s, 1H), to 7.59 (s, 1H), to 8.57 (d, 1H, J=5,1 Hz).
10155%of 1.62-1.77 in (m, 2H), 1,82-of 1.94 (m, 2H), 1,98-of 2.08 (m, 2H), 2,86-2,96 (m, 2H), 3,16-3,26 (m, 1H), 3,54 (s, 2H), 3,83 (s, 3H), a 3.87 (s, 3H), 3,90 (s, N), 3,93 (C, 6N), 4,39 (s, 2H), 6,66 (s, 2H), 6.73 x-to 6.80 (m, 3H), at 6.84 (d, 1H, J=7.8 Hz), 6,97 (DD, 1H, J=7.8 Hz, 7.8 Hz), 7,01 (d, 1H, J=7.8 Hz), 7.23 percent-to 7.32 (m, 3H), 7,43 (s, 1H), to 7.77 (s, 1H), of 8.47 (d, 1H, J=1.4 Hz), 8,68 (d, 1H, J=1.8 Hz).

Example of getting 129

Synthesis of 1-(tert-butoxycarbonyl)-4-(2,3-dimethoxyaniline)piperidine

1-(tert-Butoxycarbonyl)-4-piperidinol (4,78 g) is subjected to interaction with 2,3-dimethoxyaniline (3,68 g) in accordance with the method described in example receiving 37, receiving specified in the header of the connection.

Exit 18 g (39%).

1H-NMR (400 MHz, CDCl3) δ: 1,29-of 1.42 (m, 2H), 1,45 (s, 9H), 1,97-2,03 (m, 2H), 2,92 (dt, 2H, J=13.5 Hz and 2.2 Hz), 3,38 (dt, 1H, J=13,8 Hz to 4.1 Hz), of 3.77 (s, 3H), 3,82 (s, 3H), 3,99-a 4.03 (m, 2H), 4,17 (m, 1H), 6,27-6,32 (m, 2H), to 6.88 (t, 1H, J=8,4 Hz).

An example of retrieving 130

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(2,3-acid)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-(2,3-dimethoxyaniline)piperidine (673 mg) is subjected to interaction with 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

Yield 613 mg (52%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1.56 to to 1.70 (m, 2H), 1,84 is 1.91 (m, 2H), 2,62 was 2.76 (m, 2H), to 3.58 (TT, 1H, J=11.8 Hz, 3.6 Hz), 3,83 (s, 3H), with 3.89 (s, 6H), 3,93 (s, 6H), 4,08-of 4.25 (m, 2H), 4,35 (s, 2H), 6,56-6,63 (m, 2H), 6,86 (t, 1H, J=8,3 Hz), 7,14 (s, 2H), 7,17 (DD, 1H, J=5,1 Hz, 1.2 Hz), a 7.62 (s, 1H), and 8.50 (d, 1H, J=5,1 Hz).

Example of getting 131

The synthesis of the dihydrochloride of 4-[N-(2,3-acid)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(2,3-acid)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine (613 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

The output 512 mg (88%).

Example 102

Synthesis of trihydrochloride 4-[N-(2,3-acid)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

The dihydrochloride of 4-[N-(2,3-acid)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine (113 mg) is subjected to interaction with 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (59 mg) by the procedure similar to that described in example 2. After transformation product in hydrochloride get mentioned in the title compound as a pale yellow powder.

Yield 21 mg (12%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,76 is 1.96 (m, 4H), 2.00 in to 2.13 (m, 2H), 2,86-3,00 (m, 2H), 3,42-of 3.60 (m, 1H), 3,54 (s, 2H), 3,82 (s, 3H), 3,88 (s, 3H), 3,90 (s, 3H), of 3.97 (s, 6H), to 4.41 (s, 2H), to 6.57 (d, 1H, J=8.0 Hz), 6,62 (d, 1H, J=8,2 Hz), 6,85 (DD, 1H, J=8,4 Hz and 8.4 Hz), 7,11-7,29 (m, 6H), to 7.59 (s, 1H), 7,63 (s, 1H), and 8.50 (d, 1H, J=4.9 Hz), 8,59 (d, 1H, J=4,9 Hz).

Example of getting 132

Synthesis of 1-(tert-butoxycarbonyl)-4-[4-[(triptoreline)phenyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-piperidone (5,00 g) is subjected to interaction with 4-(formatosi)aniline (to 4.23 g) by the procedure similar to that described in example receiving 37, getting mentioned in the title compound as a white powder.

Output with 5.22 g (60%).

1H-NMR (400 MHz, CDCl3) δ: 1,25-1,40 (m, 2H), 1,47 (s, 9H), 1,98-2,8 (m, 2H), 2,83 are 2.98 (m, 2H), 3,34-of 3.43 (m, 1H), 3,97-4,12 (m, 2H), return of 6.58 (d, 2H, J=8,8 Hz), 7,03 (d, 2H, J=8,8 Hz).

Example of getting 133

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[4-(triptoreline)phenyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[4-[(triptoreline)phenyl]amino]piperidine (721 mg) is subjected to interaction with 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

Exit 543 mg (44%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,52-of 1.66 (m, 2H), 1,81 is 1.91 (m, 2H), 2,73-is 2.88 (m, 2H), 3,88-to 3.99 (m, 1H), with 3.89 (s, 3H), 3,93 (s, 6H), 4,15-4,34 (m, 2H), 4,48 (s, 2H), of 6.68 (d, 2H, J=9,2 Hz), 7,07 (d, 2H, J=8,6 Hz), 7,12 (DD, 1H, J=5,2 Hz, 1.3 Hz), to 7.15 (s, 2H), 7,52 (s, 1H), 8,58 (d, 1H, J=5,2 Hz).

Example of getting 134

The synthesis of the dihydrochloride of 4-[N-[4-(triptoreline)phenyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-[4-(triptoreline)phenyl]-N-[[2-(3,4,5-trifloromethyl)pyridine-4-yl]methyl]amino]piperidine (543 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Exit 481 mg (93%).

Example of getting 135

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-(triforma is hydroxy)phenyl)-N-[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[4-[(triptoreline)phenyl]amino]piperidine (721 mg), 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) is treated according to the method similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

The output of 201 mg (16%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,54-to 1.67 (m, 2H), 1,82-1,90 (m, 2H), 2,74-of 2.86 (m, 2H), 3,84-3,91 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 6H), 4,16-4,30 (m, 2H), to 4.52 (s, 2H), to 6.67 (s, 2H), 6,72 (d, 2H, J=9.4 Hz), 7,06 (d, 2H, J=8,4 Hz), to 7.64 (t, 1H, J=2.1 Hz), 8,49 (d, 1H, J=2.2 Hz), 8,68 (d, 1H, J=2.1 Hz).

Example of getting 136

The synthesis of the dihydrochloride of 4-[N-(4-(triptoreline)phenyl]-N-[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-[4-(triptoreline)phenyl]-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]benzyl]amino]piperidine (201 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Yield 185 mg (96%).

Example of getting 137

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[(4-(triptoreline)phenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[4-[(triptoreline)phenyl]amino]piperidine (721 mg) is subjected to interaction with 3-(3,4,5-trimethoxyphenyl)benzylchloride the m (586 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

Yield 1.06 g (86%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1.56 to its 1.68 (m, 2H), 1,83-1,90 (m, 2H), 2.71 to of 2.86 (m, 2H), a 3.87-3,90 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 6H), 4,16-the 4.29 (m, 2H), 4,51 (s, 2H), 6,70 (d, 2H, J=9,3 Hz), 6,70 (s, 2H),? 7.04 baby mortality (d, 2H, J=8.5 Hz), 7,22 (d, 1H, J=7.8 Hz), 7,34-7,44 (m, 3H).

Example of getting 138

Synthesis of the hydrochloride of 4-[N-[4-(triptoreline)phenyl]-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-[(4-triptoreline)phenyl]-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1.06 g) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

The output of 795 mg (84%).

Examples pp. 103 -- 110

The above compound is produced by interaction of amines obtained in examples getting 134, 136 and 138, with derivative chloride obtained in the examples for the preparation of 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride. Outputs and NMR data of their free bases listed below.

ExampleStructureOutputThese NMR (400 MHz, defined as the free base, CDCl3) δ
103 70%1,71-1,90 (m, 4H), 2,15-of 2.23 (m, 2H), 2.95 and-to 3.02 (m, 2H), to 3.58 (s, 2H), 3,76-of 3.85 (m, 1H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,92 (s, 6H), of 3.96 (s, 6H), of 4.54 (s, 2H), 6,66 (d, 2H, J=9,3 Hz), 7,05 (d, 2H, J=8,5 Hz), 7,13 (DD, 1H, J=5,1 Hz, 1.2 Hz), 7,14 (s, 2H), 7,20 (DD, 1H, J=4,9 Hz, 1.2 Hz), 7,22 (s, 2H), 7,53 (s, 1H), to 7.59 (s, 1H), to 8.57 (d, 1H, J=4.9 Hz), 8,59 (d, 1H, J=5,2 Hz).
10448%1,68-of 1.92 (m, 4H), 2.13 and was 2.25 (m, 2H), 2.95 and-a 3.06 (m, 2H), 3,60 (s, 2H), 3.75 to a 3.87 (m, 1H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,91 (s, 6H), 3,93 (s, 6H), to 4.52 (s, 2H), 6,65 (d, 2H, J=9.4 Hz), 6.75 in (s, 2H), 7,05 (d, 2H, J=9,2 Hz), 7,12 (d, 1H, J=5,1 Hz),7,14 (s, 2H),7,52 (s, 1H), 7,76 (s, 1H), 8,51 (d, 1H, J=1.8 Hz), to 8.57 (d, 1H, J=5,1 Hz), to 8.70 (d, 1H, J=2.1 Hz).
10569%1,70-1,89 (m, 4H), 2,10-2,19 (m, 2H), 2,98-is 3.08 (m, 2H)and 3.59 (s, 2H), 3.72 points-a-3.84 (m, 1H), with 3.89 (s, 6H), to 3.92 (s, 6H), to 3.92 (s, 6H), to 4.52 (s, 2H), 6,65 (d, 2H, J=9.4 Hz), 6,76 (s, 2H),? 7.04 baby mortality (d, 2H, J=8.6 Hz), 7,11 (d, 1H, J=5,1 Hz), 7,14 (s, 2H), 7,25-7,33 (m, 1H), 7,37 (DD, 1H, J=7,4 Hz, 7.4 Hz), 7,41-of 7.48 (m, 2H), 7,51 (s, 1H), 8,56 (d, 1H, J=5,1 Hz).
10641%1,73-of 1.93 (m, 4H), 2,12-of 2.26 (m, 2H), 2,93-of 3.07 (m, 2H), 3,53-the 3.65 (m, 2H), 3,74-a-3.84 (m, 1H), 3,88 (s, 9H), 3,90 (s, 3H), of 3.96 (s, 6H), 4,58 (s, 2H), 6,66 (s, 2H), 6,69 (d, 2H, J=9,2 Hz), 7,05 (d, 2H, J=an 8.8 Hz), 7.18 in-7,29 (m, 3H), to 7.59 (W, 1H), to 7.64 (s, 1H), 8,49 (s, 1H), at 8.60 (d, 1H, J=5.3 Hz), 8,67 (d, 1H, J=2.0 Hz).
10728%1,72 is 1.91 (m, 4H), 2,12-of 2.28 (m, 2H), 2,94-3.06 m, 2H), 3,60 (s, 2H), 3,76-3,82 (m, 1H), 3,88 (s, 9H), 3,90 (s, 3H), 3,93 (s, 6H), 4,56 (s, 2H), 6,65 (s, 2H), 6,69 (d, 2H, J=9,2 Hz), 6.75 in (s, 2H), 7,05 (d, 2H, J=8,8 Hz), 7,63 (s, 1H), 7,76 (s, 1H), 8,48 (d, 1H, J=1.8 Hz), 8,51 (d, 1H, J=1.8 Hz), 8,66 (d, 1H, J=2.2 Hz), to 8.70 (d, 1H, J=2.2 Hz).
10878%1,76 is 1.91 (m, 4H), 2,14-of 2.23 (m, 2H), 2,94-3,03 (m, 2H), only 3.57 (s, 2H), 3.75 to-a-3.84 (m, 1H), a 3.87 (s, 9H), 3,90 (s, 3H), of 3.96 (s, 6H), 4,56 (s, 2H), 6,65-6,72 (m, 4H), 7,03 (d, 2H, J=8,8 Hz), 7.18 in-7,24 (m, 4H), 7,33-the 7.43 (m, 3H), to 7.59 (s, 1H), 8,59 (d, 1H, J=4,9 Hz).
1095%1,72-1,90 (m, 4H), 2,12-of 2.21 (m, 2H), 2,94-3,03 (m, 2H)and 3.59 (s, 2H), of 3.73-3,86 (m, 1H), a 3.87 (s, 9H), 3,90 (s, 3H), 3,93 (s, 6H), of 4.54 (s, 2H), 6,66-6,70 (m, 4H), 6.75 in (s, 2H), 7,03 (d, 2H, J=9.0 Hz), 7,21 (d, 1H, J=7,2 Hz), 7,32-7,41 (m, 3H), 7,76 (s, 1H), and 8.50 (d, 1H, J=1.6 Hz), 8,69 (d, 1H, J=1.6 Hz).
11062%1,72-1,89 (m, 4H), 2,08-of 2.20 (m, 2H), 2,97-of 3.07 (m, 2H)and 3.59 (s, 2H), of 3.73-a 3.83 (m, 1H), a 3.87 (s, 9H), with 3.89 (s, 3H), 3,92 (s, 6H), 4,55 (s, 2H), to 6.67 (d, 2H, J=9,3 Hz), 6,69 (s, 2H), 6,76 (s, 2H), 7,02 (d, 2H, J=8.6 Hz), 7,20 (d, 1H, J=7,6 Hz), 7,25-7,47 (m, 7H).

Example of getting 139

Synthesis of 1-(tert-butoxycarbonyl)-4-[[4-(methylthio)phenyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-piperidone (5,00 g) is subjected to interaction with 4-(methylthio)aniline (3.33 g) in accordance with the method described in example receiving 37, receiving specified in the title compound in the form of logo powder.

The output of 3.80 g (49%).

1H-NMR (400 MHz, CDCl3) δ: 1,26-to 1.38 (m, 2H), of 1.46 (s, 9H), 1,98-to 2.06 (m, 2H), 2,41 (s, 3H), 2,88-of 2.97 (m, 2H), 3,36 is-3.45 (m, 2H), 3,48 of 3.56 (W, 1H), 3.96 points-of 4.12 (m, 2H), 6,55 (d, 2H, J=8,8 Hz), 7,21 (d, 2H, J=8,8 Hz).

An example of retrieving 140

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[4-(methylthio)phenyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[[4-(methylthio)phenyl]amino]piperidine (644 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) is treated according to the method similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

Output 671 mg (58%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,50-of 1.66 (m, 2H), 1,81-1,89 (m, 2H), 2.40 a (s, 3H), 2,74-2,87 (m, 2H), 3,88-of 3.94 (m, 1H), 3,90 (s, 3H), of 3.94 (s, 6H), 4,15-the 4.29 (m, 2H), 4,48 (s, 2H), to 6.67 (d, 2H, J=9.0 Hz), 7,11-to 7.18 (m, 1H), 7,16 (s, 2H), 7,22 (d, 2H, J=6.6 Hz), 7,54 (s, 1H), to 8.57 (d, 1H, J=5,1 Hz).

Example of getting 141

The synthesis of the dihydrochloride of 4-[N-[4-(methylthio)phenyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-[4-(methylthio)phenyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine (671 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

The output of 602 mg (94%).

Sample of what I 142

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-(methylthio)phenyl]-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[[4-(methylthio)phenyl]amino]piperidine (645 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) is treated according to the method similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

The output 312 mg (27%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,53-to 1.63 (m, 2H), 1,83-1,89 (m, 2H), 2.40 a (s, 3H), 2,73-to 2.85 (m, 2H), a 3.87-3,91 (m, 1H), 3,88 (s, 3H), 3,90 (s, 6H), 4,16-4,30 (m, 2H), 4,50 (s, 2H), to 6.67 (s, 2H), of 6.71 (d, 2H, J=9,0 Hz), 7,21 (d, 2H, J=9.0 Hz), to 7.64 (s, 1H), 8,48 (d, 1H, J=2.2 Hz), 8,66 (d, 1H, J=2.1 Hz).

Example of getting 143

The synthesis of the dihydrochloride of 4-[N-[4-(methylthio)phenyl]-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-[4-(methylthio)phenyl]-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine (312 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Yield 251 mg (84%).

Example of getting 144

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[(4-methylthio)phenyl]-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-[(4-methylthio)phenyl]the Mino]piperidine (645 mg) is subjected to interaction with 3-(3,4,5-trimethoxyphenyl)benzylchloride (586 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

Yield 1.10 g (95%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,55 by 1.68 (m, 2H), 1,81-1,90 (m, 2H), 2,39 (s, 3H), 2,73-of 2.86 (m, 2H), a 3.87-3,91 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 6H), 4,15-the 4.29 (m, 2H), 4,50 (s, 2H), 6,68-of 6.73 (m, 4H), 7,19-7,24 (m, 3H), 7,33-the 7.43 (m, 3H).

Example of getting 145

Synthesis of the hydrochloride of 4-[N-[4-(methylthio)phenyl]-N-[[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-[4-(methylthio)phenyl]-N-[3-(3,4,5-trifloromethyl)benzyl]amino]piperidine (1.10 g) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Output 866 mg (89%).

Examples 111-118

The above compound is produced by interaction of amines obtained in examples getting 141, 143 and 145, with derivative chloride obtained in the examples for the preparation of 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride. Outputs and NMR data of their free bases listed below.

ExampleStructureOutputThese NMR (400 MHz, defined as the free base, CDCl3) δ
111 40%1,70-1,90 (m, 4H), 2,14-of 2.26 (m, 2H), 2.40 a (s, 3H), 2,94 totaling 3.04 (m, 2H), to 3.58 (s, 2H), 3,76-3,88 (m, 1H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,93 (s, 6H), of 3.96 (s, 6H), a 4.53 (s, 2H), 6,66 (d, 2H, J=9.0 Hz), 7,11-7,24 (m, 8H), 7,54 (s, 1H), to 7.59 (s, 1H), 8,56 (d, 1H, J=5,1 Hz), 8,59 (d, 1H, J=5,1 Hz).
11253%1,66-1,90 (m, 4H), 2,12-of 2.24 (m, 2H), 2.40 a (s, 3H), 2,94 was 3.05 (m, 2H)and 3.59 (s, 2H), of 3.73-3,88 (m, 1H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,92 (s, 6H), 3,93 (s, 6H), 4,51 (s, 2H), 6,65 (d, 2H, J=8,8 Hz), 6.75 in (with, 2H), 7,12 (d, 1H, J=4.9 Hz), 7,14 (s, 2H), 7,21 (d, 2H, J=8,8 Hz), 7,53 (s, 1H), 7,76 (s, 1H), and 8.50 (d, 1H, J=1.9 Hz), 6,55 (d, 1H, J=4.9 Hz), 8,69 (d, 1H, J=1.4 Hz).
11353%1,68-1,89 (m, 4H), 2,10-of 2.20 (m, 2H), 2,39 (s, 3H), 2,98-of 3.07 (m, 2H), to 3.58 (s, 2H), 3.75 to a 3.87 (m, 1H), with 3.89 (s, 6H), to 3.92 (s, 6H), to 3.92 (s, 6H), 4,51 (s, 2H), 6,65 (d, 2H, J=9.0 Hz), 6,76 (s, 2H), 7,11 (d, 1H, J=5,1 Hz), 7,14 (s, 2H), 7,21 (d, 2H, J=8,8 Hz), 7,29 (d, 1H, J=7.4 Hz), 7,37 (DD, 1H, J=7,6 Hz and 7.6 Hz), 7,42-7,49 (m, 2H), 7,52 (s, 1H), 8,54 (d, 1H, J=4,9 Hz).
11450%1,57 is 2.00 (m, 4H), 2,12-of 2.30 (m, 2H), 2,39 (s, 3H), 2,90-3,13 (m, 2H), 3,50-3,74 (m, 2H), 3.75 to 3,86 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 3H), 3,90 (s, 6H), of 3.97 (s, 6H), of 4.57 (s, 2H), 6,66 (s, 2H), 6,70 (d, 2H, J=9.0 Hz), 7,17-7,30 (m, 5H), 7,66 (W, 2H), 8,48 (s, 1H), 8,58-to 8.70 (m, 2H).
11559%1,68-of 1.92 (m, 4H), 2,12-of 2.27 (m, 2H), 2,39 (s, 3H), 2,94-is 3.08 (m, 2H), 3,60 (s, 2H), 3,74-a 3.83 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), 3,93 (s, 6H), 4,55 (s, 2H), 6,66 (s, 2H), 6,69 (who, 2H, J=8,8 Hz), 6.73 x-to 6.80 (m, 2H), 7,20 (d, 2H, J=8,8 Hz), to 7.64 (s, 1H), to 7.77 (W, 1H), 8,48 (s, 1H), and 8.50 (s, 1H), 8,65 (s, 1H), 8,71 (s, 1H).
11685%1,76-of 1.93 (m, 4H), 2,14-of 2.24 (m, 2H), 2,39 (s, 3H), 2,94-3,03 (m, 2H), only 3.57 (s, 2H), 3,76-3,86 (m, 1H), 3,88 (s, 6H), 3,90 (s, 3H), of 3.96 (s, 6H), 4,55 (s, 2H), 6,67-of 6.73 (m, 4H), 7.18 in-7,29 (m, 6H), 7,34 (DD, 1H, J=7,6 Hz and 7.6 Hz), 7,37-7,44 (m, 2H), to 7.59 (s, 1H), 8,59 (d, 1H, J=4,9 Hz).
11753%1,72-1,90 (m, 4H), 2,12-2,22 (m, 2H), 2,39 (s, 3H), 2.95 and was 3.05 (m, 2H)and 3.59 (s, 2H), 3,74-of 3.85 (m, 1H), a 3.87 (s, 3H), 3,88 (s, 6H), to 3.89 (s, 3H), 3,93 (s, 6H), of 4.54 (s, 2H), 6,67-6,70 (m, 4H), 6.75 in (s, 2H), 7,19-of 7.23 (m, 3H), 7,33 (DD, 1H, J=7,4 Hz, 7.4 Hz), of 7.36-7,40 (m, 2H), 7,76 (s, 1H), and 8.50 (d, 1H, J=1.8 Hz), 8,69 (s, 1H).
11883%1,72-1,90 (m, 4H), 2,09-of 2.20 (m, 2H), of 2.38 (s, 3H), 2,97-of 3.06 (m, 2H), to 3.58 (s, 2H), of 3.73-a-3.84 (m, 1H),a 3.87 (s, 3H), 3,88 (s, 3H), with 3.89 (s, 6H), to 3.92 (s, 6H), of 4.54 (s, 2H), 6,66-of 6.71 (m, 4H), 6,76 (s, 2H), 7,18-7,24 (m, 3H), 7,26-of 7.48 (m, 7H).

Example of getting 146

Synthesis of 1-(tert-butoxycarbonyl)-4-[(4-were)amino]piperidine

1-(tert-Butoxycarbonyl)-4-piperidone (5,00 g) and p-toluidine (2,56 g) is treated according to the method similar to that described in example receiving 37, getting mentioned in the title compound as a white powder.

Output 5,79 g (83%).

1H-NMR (400 MHz, CDCl3) δ: 1,25-of 1.36 (m, 2H), of 1.46 (s, 9H), 1,99 e 2.06 (m, 2H), 2,23(s, 3H), 2,86-2,96 (m, 2H), 3,30-of 3.43 (m, 2H), 3.96 points-4,10 (m, 2H), 6,53 (d, 2H, J=8,4 Hz), 6,98 (d, 2H, J=8.0 Hz).

Example of getting 147

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-were)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-were)amino]piperidine (581 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) is treated according to the method similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

The output of 1.00 g (91%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,55-to 1.59 (m, 2H), 1,81-1,90 (m, 2H), of 2.23 (s, 3H), 2,72-of 2.86 (m, 2H), 3,81-of 3.94 (m, 1H), with 3.89 (s, 3H), 3,93 (s, 6H), 4,14-4,30 (m, 2H), of 4.45 (s, 2H), 6,66 (d, 2H, J=8.6 Hz), 7,02 (d, 2H, J=8,2 Hz), 7,13-7,16 (m, 3H), 7,55 (s, 1H), 8,55 (d, 1H, J=8,1 Hz).

Example of getting 148

The synthesis of the dihydrochloride of 4-[N-(4-were)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-were)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]benzyl]methyl]piperidine (1,00 g) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Output 924 mg (97%).

Example of getting 149

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-were)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[(4-were)amino]piperidine (581 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) is treated according to the method similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

Exit 426 mg (39%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,52 is 1.70 (m, 2H), 1,82-1,90 (m, 2H), of 2.23 (s, 3H), 2,72-of 2.86 (m, 2H), of 3.77-3,86 (m, 1H), 3,88 (s, 3H), 3,90 (s, 6H), 4,10-to 4.28 (m, 2H), 4,47 (s, 2H), to 6.67 (s, 2H), 6,70 (d, 2H, J=8.6 Hz), 7,01 (d, 2H, J=8,2 Hz), to 7.67 (DD, 1H, J=2.1 Hz and 2.1 Hz), and 8.50 (d, 1H, J=2.0 Hz), 8,64 (d, 1H, J=2.2 Hz).

Example of getting 150

The synthesis of the dihydrochloride of 4-[N-(4-were)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-were)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine (426 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

400 mg (99%).

Example of getting 151

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-were)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[(4-were)amino]piperidine (581 mg) is subjected to interaction with 3-(3,4,5-trimethoxyphenyl)benzylchloride (586 mg) by the procedure similar to that described in example 9, getting pointed to by the e in the title compound as a pale yellow amorphous substance.

The output of 1.03 g (94%).

1H-NMR (400 MHz, CDCl3) δ: of 1.44 (s, 9H), 1,50-of 1.66 (m, 2H), 1,83-1,90 (m, 2H), of 2.23 (s, 3H), 2,72-to 2.85 (m, 2H), 3,82-to 3.92 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 6H), 4,11-4,30 (m, 2H), 4,47 (s, 2H), of 6.68 (d, 2H, J=8.6 Hz), of 6.71 (s, 2H), 7,00 (d, 2H, J=8,8 Hz), 7.23 percent-7,27 (m, 1H), 7,32-7,44 (m, 3H).

Example of getting 152

Synthesis of the hydrochloride of 4-[N-(4-were)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-were)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1,03 g) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Output 882 mg (97%).

Examples 119-126

The above compound is produced by interaction of amines obtained in examples getting 148, 150 and 152, with derivative chloride obtained in the examples for the preparation of 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride. Outputs and NMR data of their free bases listed below.

ExampleStructureOutputThese NMR (400 MHz, defined as the free base, CDCl3) δ
11966%1,70-to 1.82 (m, 2H), 1,83 is 1.91 (m, 2H), 2.13 and was 2.25 (m, 2H), of 2.23 (s, 3H), 2,96-to 3.02 (m, 2H), only 3.57 (s, 2H), of 3.73-a 3.83(m, 1H), the 3.89 (s, 3H), 3,90 (s, 3H), 3,93 (s, 6H), of 3.96 (s, 6H), 4,50 (s, 2H), only 6.64 (d, 2H, J=8,8 Hz), 7,01 (d, 2H, J=8.5 Hz), 7,13-7,17 (m, 3H), 7,20 (d, 1H, J=4.9 Hz), 7,22 (s, 2H), 7,56 (s, 1H), to 7.59 (, 1H), 8,54 (d, 1H, J=5,1 Hz), 8,59 (d, 1H, J=4,9 Hz).
12041%1,60 is 1.91 (m, 4H), 2,12-of 2.24 (m, 2H), of 2.23 (s, 3H), 2.95 and was 3.05 (m, 2H)and 3.59 (s, 2H), of 3.73-a 3.83 (m, 1H), with 3.89 (s, 3H), with 3.89 (s, 3H), 3,92 (s, 6H), 3,93 (s, 6H), of 4.49 (s, 2H), 6,63 (d, 2H, J=8.6 Hz), 6.75 in (with, 2H), 7,00 (d, 2H, J=8.6 Hz), 7,13-7,16 (m, 3H), 7,55 (s, 1H), 7,76 (s, 1H), and 8.50 (d, 1H, J=1.8 Hz), 8,53 (d, 1H, J=5,1 Hz), to 8.70 (s, 1H).
12169%1,67 and 1.80 (m, 2H), 1,81-1,89 (m, 2H), 2,09-of 2.20 (m, 2H), 2,22 (s, 3H), 2,98-of 3.06 (m, 2H), to 3.58 (s, 2H), 3.72 points-3,81 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 3H), 3,92 (s, 6H), to 3.92 (s, 6H), of 4.49 (s, 2H), 6,63 (d, 2H, J=8,4 Hz), 6,76 (s, 2H), 7,00 (d, 2H, J=8.6 Hz), 7,12-to 7.15 (m, 3H), 7,26-7,32 (m, 1H), 7,37 (DD, 1H, J=7,6 Hz and 7.6 Hz), 7,41-of 7.48 (m, 2H), 7,55 (s, 1H), 8,53 (d, 1H, J=5.0 Hz).
12247%1.55V is 2.00 (m, 4H), 2,12-2,31 (m, 2H), 2,22 (s, 3H), 2,93-3,10 (m, 2H), 3,60 (W, 2H), 3,69-of 3.80 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), of 3.96 (s, 6H), a 4.53 (s, 2H), 6,66 (s, 2H), 6,69 (d, 2H, J=8.6 Hz), 7,00 (d, 2H, J=8.6 Hz), 7,19-7,27 (m, 4H), 7,68 (s, 1H), and 8.50 (s, 1H), at 8.60 (d, 1H, J=4.9 Hz), 8,64 (d, 1H, J=2.2 Hz).
12334%1,67-to 1.98 (m, 4H), 2,10-of 2.38 (m, 2H), 2,22 (s, 3H), 2,85-3,10 (m, 2H), 3,53-to 3.67 (s, 2H), 3,67-with 3.79 (m, 1H), 3,88 (s, 3H), 3,89 (C, 6N), 3,90 (s, 3H), 3,93 (C, 6N), 4,51 (s, 2H), 6,66 (s, 2H), of 6.68 (d, 2H, J=8,8 Hz), 6,76 (s, 2H), 7,00 (d, 2 is, J=8,2 Hz), to 7.67 (s, 1H), to 7.77 (W, 1H), of 8.47 are 8.53 (m, 2H), 8,63 (d, 1H, J=2.0 Hz), to 8.70 (s, 1H).
12491%1,73-of 1.92 (m, 4H), 2,12-of 2.26 (m, 2H), of 2.21 (s, 3H), 2,92-to 3.02 (m, 2H), only 3.57 (s, 2H), 3.72 points-is 3.82 (m, 1H), a 3.87 (s, 3H), 3,88 (C, 6N), 3,90 (s, 3H), 3,95 (C, 6N), a 4.53 (s, 2H), to 6.67 (d, 2H, J=7.8 Hz), 6,70 (2N), of 6.99 (d, 2H, J=8.0 Hz), 7.18 in-7,25 (m, 4H), 7,33 (DD, 1H, J=7,4 Hz, 7.4 Hz), 7,38 (d, 1H, J=7,2 Hz), 7,42 (s, 1H), to 7.59 (s, 1H), 8,58 (d, 1H, J=4,7 Hz).
12574%1,70-of 1.92 (m, 4H), 2,10-of 2.28 (m, 2H), of 2.21 (s, 3H), 2,92-of 3.06 (m, 2H), to 3.58 (s, 2H), 3.72 points-is 3.82 (m, 1H), a 3.87 (s, 3H), 3,88 (s, 6H), to 3.89 (s, 3H), 3,93 (s, 6H), 4,51 (s, 2H), 6,66 (d, 2H, J=8.6 Hz), 6,70 (, 2H), 6.75 in (s, 2H), 7.23 percent (d, 1H, J=7,0 Hz), 7,32 (DD, 1H, J=7,6 Hz and 7.6 Hz), 7,37 (d, 1H, J=7.8 Hz), 7,41 (s, 1H), to 7.77 (s, 1H), 8,49 (s, 1H), 8,69 (s, 1H).
12684%1,71-of 1.88 (m, 4H), 2,08-to 2.18 (m, 2H), of 2.21 (s, 3H), 2,96 totaling 3.04 (m, 2H), to 3.58 (s, 2H), 3,71-a 3.83 (m, 1H), a 3.87 (s, 3H), 3,88 (s, 6H), to 3.89 (s, 3H), 3,92 (s, 6H), to 4.52 (s, 2H), 6,66 (d, 2H, J=8.6 Hz), 6,70 (, 2H), 6,76 (s, 2H), 6,98 (d, 2H, J=8,3 Hz), 7,22-7,47 (m, 8H).

Example of getting 153

Synthesis of 1-(tert-butoxycarbonyl)-4-[[4-(trimetilfenil)phenyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-piperidone (5,00 g) is subjected to interaction with 4-(Cryptor)aniline (3,85 g) by the procedure similar to that described in example receiving 37, getting mentioned in the title compound as white is th powder.

Output 3,30 g (40%).

1H-NMR (400 MHz, CDCl3) δ: 1,30-of 1.41 (m, 2H), 1,47 (s, 9H), 2.00 in 2,07 (m, 2H), 2,88-to 2.99 (m, 2H), 3,32-to 3.52 (m, 1H), 3,83-to 3.89 (m, 1H), 4,00-to 4.14 (m, 2H), 6,59 (d, 2H, J=8,4 Hz), 7,39 (d, 2H, J=8,4 Hz).

Example of getting 154

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[4-(trifluoromethyl)phenyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[[4-(trifluoromethyl)phenyl]amino]piperidine (688 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) is treated according to the method similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

The output of 412 mg (34%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,54 by 1.68 (m, 2H), 1,81-1,90 (m, 2H), 2.77-to 2,90 (m, 2H), with 3.89 (s, 3H), 3,92 (s, 6H), 3,98-4,07 (m, 1H), 4,18-to 4.33 (m, 2H), 4,55 (s, 2H), 6.73 x (d, 2H, J=8,8 Hz), to 7.09 (d, 1H, J=3,7 Hz), 7,13 (s, 2H), 7,44 (d, 2H, J=8,8 Hz), 7,49 (s, 1H), 8,58 (d, 1H, J=5,1 Hz).

Example of getting 155

The synthesis of the dihydrochloride of 4-[N-[4-(trifluoromethyl)phenyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-[4-(trifluoromethyl)phenyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine (412 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Exit 359 mg (91%).

Example the floor is placed 156

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[(4-(trifluoromethyl)phenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[[4-(trifluoromethyl)phenyl]amino]piperidine (689 mg) is subjected to interaction with 3-(3,4,5-trimethoxyphenyl)benzylchloride (586 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

The output 522 mg (44%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,58 is 1.70 (m, 2H), 1,83-1,90 (m, 2H), was 2.76-2,87 (m, 2H), a 3.87 (s, 6H), 3,88 (s, 3H), 3.96 points-4,06 (m, 1H), 4,15-4,30 (m, 2H), 4,58 (s, 2H), of 6.68 (s, 2H), 6,76 (d, 2H, J=8,8 Hz), 7,19 (with, 1H, J=7.4 Hz), 7,33-7,44 (m, 5H).

Example of getting 157

Synthesis of the hydrochloride of 4-[N-[4-(trifluoromethyl)phenyl]-N-[[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-[4-(trifluoromethyl)phenyl]-N-[[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (522 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Yield 460 mg (99%).

Examples 127-132

The above compound is produced by interaction of amines obtained in examples obtain 155 and 157, with derivative chloride obtained in the examples for the preparation of 3, 42 and 48. The obtained free base is then converted into the corresponding hydro is lorida. Outputs and NMR data of their free bases listed below.

ExampleStructureOutputThese NMR (400 MHz, defined as the free base, CDCl3) δ
12772%1,74-of 1.92 (m, 4H), 2,17-of 2.26 (m, 2H), 2,96 totaling 3.04 (m, 2H)and 3.59 (s, 2H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,91 (s, 6H), of 3.96 (s, 6H), 4,60 (s, 2H), 6,72 (d, 2H, J=8,8 Hz), 7,10 (d, 1H, J=4.9 Hz), 7,13 (s, 2H), then 7.20 (d, 1H, J=5,1 Hz), the 7.43 (d, 2H, J=8,8 Hz)to 7.50 (s, 1H), to 7.59 (s, 1H), 8,56 (d, 1H, J=4.9 Hz), 8,58 (d, 1H, J=5,1 Hz).
12851%1,70-1,90 (m, 4H), 2,14-of 2.28 (m, 2H), 2,96-is 3.08 (m, 2H), 3,61 (s, 2H), a 3.87-of 3.96 (m, 1H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,91 (s, 6H), 3,93 (s, 6H), 4,59 (s, 2H), of 6.71 (d, 2H, J=8,8 Hz), 6.75 in (s, 2H), 7,07-7,15 (m, 3H), 7,43 (d, 2H, J=8,8 Hz), 7,49 (s, 1H), 7,76 (s, 1H), 8,51 (d, 1H, J=1.8 Hz), to 8.57 (d, 1H, J=5,1 Hz), to 8.70 (s, 1H).
12959%1,72-of 1.88 (m, 4H), 2,11-of 2.24 (m, 2H), 2,98-3,10 (m, 2H)and 3.59 (s, 2H), a 3.87-3,95 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 3H), 3,90 (s, 6H), to 3.92 (s, 6H), 4,59 (s, 2H), of 6.71 (d, 2H, J=9.0 Hz), 6,76 (s, 2H), 7,08 (d, 1H, J=5,1 Hz), 7,12 (s, 2H), 7,29 (d, 1H, J=7.4 Hz), 7,37 (DD, 1H, J=7,6 Hz and 7.6 Hz), 7,40-7,52 (m, 5H), 8,56 (d, 1H, J=5,1 Hz).
13081%1,78-of 1.94 (m, 4H), 2,15-of 2.27 (m, 2H), 2,94-is 3.08 (m, 2H), to 3.58 (s, 2H) 3,86 (s, 6H), a 3.87 (s, 3H), 3,90 (s, 3H), of 3.96 (s, 6H), 4,63 (s, 2H), 6,67 (s, H), 6,74 (d, 2H, J=8,8 Hz), 7,17-7,24 (m, 4H), 7,34 was 7.45 (m, 5H), to 7.59 (s, 1H), 8,59 (d, 1H, J=5,1 Hz).
13154%a 1.75-1,90 (m, 4H), 2,14-of 2.24 (m, 2H), 2.95 and totaling 3.04 (m, 2H), 3,60 (s, 2H), 3,84-3,88 (m, 1H), 3,86 (m, 1H), a 3.87 (s, 3H), 3,90 (s, 3H), 3,93 (s, 6H), br4.61 (s, 2H), to 6.67 (s, 2H), 6,72-6,77 (m, 4H), 7,18 (d, 1H, J=7.4 Hz), 7,33-the 7.43 (m, 5H), 7,76 (s, 1H), and 8.50 (d, 1H, J=1.9 Hz), 8,69 (d, 1H, J=1.9 Hz).
13267%1,76-of 1.88 (m, 4H), 2,11-2,19 (m, 2H), 2,98-of 3.06 (m, 2H)and 3.59 (s, 2H), 3,86 (s, 6H), a 3.87 (s, 3H), with 3.89 (s, 3H), 3,92 (s, 6H), br4.61 (s, 2H), to 6.67 (s, 2H), 6.73 x (d, 2H, J=8,8 Hz), 6,76 (s, 2H), 7,18 (d, 1H, J=7,3 Hz), 7,29 (d, 1H, J=7,6 Hz), 7,32-7,47 (m, 8H).

Example of getting 158

Synthesis of 1-(tert-butoxycarbonyl)-4-(4-bromophenyl)aminopiperidine

1-(tert-Butoxycarbonyl)-4-piperidone (5,00 g) is subjected to interaction with 4-bromoaniline (4.11 g) by the procedure similar to that described in example receiving 37, getting mentioned in the title compound as a white powder.

Output to 3.09 g (36%).

1H-NMR (400 MHz, CDCl3) δ: of 1.25 to 1.37 (m, 2H), of 1.46 (s, 9H), 1,97-2,05 (m, 2H), 2,86-2,96 (m, 2H), 3.33 and-of 3.42 (m, 2H), 3,47 is 3.57 (m, 1H), 3.96 points-of 4.12 (m, 2H), 6,47 (d, 2H, J=8,8 Hz), 7,24 (d, 2H, J=9.0 Hz).

Example of getting 159

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-bromophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-(4-brave the Il)aminopiperidin (711 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) is treated according to the method similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

The output 607 mg (50%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,50-of 1.64 (m, 2H), 1,81-of 1.88 (m, 2H), 2,74-is 2.88 (m, 2H), 3,86-of 3.94 (m, 1H), with 3.89 (s, 3H), 3,93 (s, 6H), 4,14-4,32 (m, 2H), 4,46 (s, 2H), 6,59 (d, 2H, J=9.1 Hz), 7,10 (d, 1H, J=5,2 Hz), 7,14 (s, 2H), 7,28 (d, 2H, J=9.1 Hz), to 7.50 (s, 1H), to 8.57 (d, 1H, J=5.0 Hz).

Example of getting 160

The synthesis of the dihydrochloride of 4-[N-(4-bromophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-bromophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine (607 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Output 541 mg (93%).

Example of getting 161

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-bromophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-(4-bromophenyl)aminopiperidin (711 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

Yield 347 mg (28%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,52-to 1.67 (m, 2H), 1,80-1,89 (m, 2H), 2,72-2,87 (m, 2H), 3,82-to 3.92 (m, 1H), 3,89 (3H), are 3.90 (s, 6H), 4,14-to 4.33 (m, 2H), 4,50 (s, 2H), 6,63 (d, 2H, J=9,2 Hz), of 6.65 (s, 2H), 7,28 (d, 2H, J=9.4 Hz), to 7.61 (s, 1H), of 8.47 (d, 1H, J=2.0 Hz), 8,67 (d, 1H, J=2.2 Hz).

Example of getting 162

The synthesis of the dihydrochloride of 4-[N-(4-bromophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-bromophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine (347 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

The output of 302 mg (91%).

Example of getting 163

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-bromophenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-(4-bromophenyl)aminopiperidin (711 mg) is subjected to interaction with 3-(3,4,5-trimethoxyphenyl)benzylchloride (586 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

The output of 1.14 g (93%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,52-to 1.67 (m, 2H), 1,80-1,89 (m, 2H), 2,72-of 2.86 (m, 2H), 3,84-3,91 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 6H), 4,11-4,32 (m, 2H), 4,49 (s, 2H), 6,62 (d, 2H, J=9,2 Hz), 6,69 (s, 2H), 7,19 (d, 1H, J=7,6 Hz), 7,25 (d, 2H, J=5.5 Hz), 7,32-7,42 (m, 3H).

Example of getting 164

Synthesis of the hydrochloride of 4-[N-(4-bromophenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-bromophenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1,03 g) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Output 973 mg (84%).

Examples 133-140

The above compound is produced by interaction of amines obtained in examples obtain 160, 162 and 164, with derivative chloride obtained in the examples for the preparation of 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride. Outputs and NMR data of their free bases listed below.

ExampleStructureOutputThese NMR (400 MHz, defined as the free base, CDCl3) δ
13352%1,70-1,90 (m, 4H), 2,14 was 2.25 (m, 2H), 2,94 totaling 3.04 (m, 2H), to 3.58 (s, 2H), of 3.73-a-3.84 (m, 1H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,92 (s, 6H), of 3.96 (s, 6H), to 4.52 (s, 2H), to 6.57 (d, 2H, J=8,8 Hz), 7,10 (d, 1H, J=4,9 Hz), 7,14 (s, 2H), 7,20 (d, 1H, J=4.9 Hz), 7,22 (s, 2H), 7,26 (d, 2H, J=8.5 Hz), 7,51 (s, 1H), to 7.59 (s, 1H), 8,56 (d, 1H, J=4.9 Hz), 8,59 (d, 1H, J=4,9 Hz).
13456%1,68-of 1.88 (m, 4H), 2,12-of 2.24 (m, 2H), 2.95 and totaling 3.04 (m, 2H)and 3.59 (s, 2H), 3.72 points-a-3.84 (m, 1H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,92 (s, 6H), 3,93 (s, 6H), 4,50 (s, 2H), to 6.57 (d, 2H, J=9,2 Hz), 6,74 (s, 2H), 7,09 (Prov., 1H, J=3,9 Hz), 7,13 (s, 2H), 7,26 (d, 2H, J=8,8 Hz)to 7.50 (s, 1H), of 7.75 (s, 1H), and 8.50 (d, 1H, J=2.0 Hz), 8,55 (d, 1H, J=5.0 Hz), 8,69 (d, 1H, J=2.0 Hz).
13565%1,70 is 1.86 (m, 4H), 2,10-of 2.20 (m, 2H), 2,97-is 3.08 (m, 2H)and 3.59 (s, 2H), 3.72 points-is 3.82 (m, 1H), with 3.89 (s, 6H), to 3.92 (s, 6H), to 3.92 (s, 6H), 4,50 (s, 2H), 6,56 (d, 2H, J=9,2 Hz), 6,76 (s, 2H), to 7.09 (d, 1H, J=5,1 Hz), 7,13 (s, 2H), 7.23 percent-7,33 (m, 3H), 7,37 (DD, 1H, J=7.4 Hz), 7,41-of 7.48 (m, 2H), 7,49 (s, 1H), 8,54 (d, 1H, J=5,1 Hz).
13649%1,77-of 1.93 (m, 4H), 2,12-of 2.30 (m, 2H), 2,94-3,10 (m, 2H), 3,60 (s, 2H), of 3.73-a 3.83 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), of 3.96 (s, 6H), 4,55 (s, 2H), is 6.61 (d, 2H, J=9,2 Hz), of 6.65 (s, 2H), 7,19-7,29 (m, 5H), 7.62mm (W, 2H), of 8.47 (d, 1H, J=1.6 Hz), at 8.60 (d, 1H, J=4.9 Hz), 8,66 (d, 1H, J=2.0 Hz).
13750%1,70-of 1.92 (m, 4H), 2,12-of 2.27 (m, 2H), 2,93-of 3.07 (m, 2H), 3,60 (s, 2H), 3,67-4,08 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), 3,93 (s, 6H), of 4.54 (s, 2H), 6,60 (d, 2H, J=9.0 Hz), only 6.64 (s, 2H), 6.73 x-6,80 (m, 2H), 7,25 (s, 2H), to 7.61 (s, 1H), to 7.77 (W, 1H), 8,45 (d, 1H, J=1.7 Hz), and 8.50 (d, 1H, J=1.7 Hz), 8,65 (d, 1H, J=2.0 Hz).
13881%a 1.75-1,90 (m, 4H), 2,17-of 2.24 (m, 2H), 2,94-to 3.02 (m, 2H), only 3.57 (s, 2H), 3.72 points-a 3.83 (m, 1H), 3,88 (s, 3H), 3,88 (s, 6H), 3,90 (s, 3H), of 3.95 (s, 6H), of 4.54 (s, 2H), 6,60 (d, 2H, J=9,2 Hz), 6,69 (s, 2H), 7.18 in-7,27 (m, 6H), 7,32-7,42 (m, 3H), 7,60 (s, 1H), 8,58 (d, 1H, J=4,9 Hz).
13980%1,72-1,90 (m, 4H), 2,3-of 2.21 (m, 2H), 2,94 was 3.05 (m, 2H)and 3.59 (s, 2H), 3.72 points-is 3.82 (m, 1H), a 3.87 (s, 3H), 3,88 (s, 6H), to 3.89 (s, 3H), 3,93 (s, 6H), a 4.53 (s, 2H), 6,60 (d, 2H, J=9.0 Hz), of 6.68 (s, 2H), 6.75 in (s, 2H), 7,19 (d, 1H, J=7,2 Hz), from 7.24 (d, 2H, J=9.0 Hz), 7,31-7,41 (m, 3H), 7,76 (s, 1H), and 8.50 (d, 1H, J=1.8 Hz), to 8.70 (s, 1H).
14078%1,72-of 1.88 (m, 4H), 2,08-to 2.18 (m, 2H), 2,97-of 3.06 (m, 2H), to 3.58 (s, 2H), 3,71-3,82 (m, 1H), a 3.87 (s, 3H), 3,88 (s, 6H), to 3.89 (s, 3H), 3,92 (s, 6H), a 4.53 (s, 2H), 6,59 (d, 2H, J=9,3 Hz), of 6.68 (s, 2H), 6,76 (, 2H), 7,18 (d, 1H, J=7,3 Hz), 7,21-7,47 (m, 9H).

Example of getting 165

Synthesis of 1-(tert-butoxycarbonyl)-4-[(4-chlorophenyl)amino]piperidine

1-(tert-Butoxycarbonyl)-4-piperidone (5,00 g) is subjected to interaction with 4-Chloroaniline (3,05 g) by the procedure similar to that described in example receiving 37, getting mentioned in the title compound as a white powder.

The output of 3.80 g (49%).

1H-NMR (400 MHz, CDCl3) δ: 1,24-to 1.38 (m, 2H), of 1.46 (s, 9H), 1,97-2,05 (m, 2H), 2,86-2,96 (m, 2H), 3,32-of 3.42 (m, 2H), 3,51 (W, 1H), of 6.52 (d, 2H, J=9.0 Hz), 7,11 (d, 2H, J=9.0 Hz).

Example of getting 166

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-chlorophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[(4-chlorophenyl)amino]piperidine (621 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) is treated according to the method similar to that described in example 9, receiving specified in the header with the unity in the form of a light yellow amorphous substance.

Exit 789 mg (69%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,51 by 1.68 (m, 2H), 1,80-1,89 (m, 2H), 2,72-of 2.86 (m, 2H), a 3.87-3,90 (m, 1H), with 3.89 (s, 3H), 3,93 (s, 6H), with 4.64 (s, 2H), only 6.64 (d, 2H, J=9.0 Hz), 7,14 (d, 1H, J=5.3 Hz), to 7.15 (d, 2H, J=9.0 Hz), 7,51 (s, 2H), to 8.57 (d, 2H, J=5,1 Hz).

Example of getting 167

The synthesis of the dihydrochloride of 4-[N-(4-bromophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-bromophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine (789 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Output 673 mg (90%).

Example of getting 168

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-chlorophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[(4-chlorophenyl)amino]piperidine (621 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

The output of 268 mg (24%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), and 1.56 to 1.76 (m, 2H), 1,80-1,90 (m, 2H), was 2.76-and 2.83 (m, 2H), 3,86-3,90 (m, 1H), with 3.89 (s, 3H), 3,90 (s, 6H), 4,15-4,30 (m, 2H), 4,50 (s, 2H), 6,66 (s, 2H), of 6.68 (d, 2H, J=9,2 Hz), 7,15 (d, 2H, J=9.0 Hz), 7,63 (s, 1H), of 8.47 (d, 1H, J=2.0 Hz), 8,66 (d, 1H, J=2.0 Hz).

Example of getting 169

The synthesis of the dihydrochloride of 4-[N-(4-bromophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-bromophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine (268 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

The output of 233 mg (91%).

Example of getting 170

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-chlorophenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[4-chlorophenyl)amino]piperidine (622 mg) is subjected to interaction with 3-(3,4,5-trimethoxyphenyl)benzylchloride (586 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

Yield 1.04 g (92%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,58-to 1.67 (m, 2H), 1,82 is 1.91 (m, 2H), 2,74-of 2.86 (m, 2H), 3,85-to 3.92 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 6H), 4,35-or 4.31 (m, 2H), 4,49 (s, 2H), 6,66 (d, 2H, J=9,2 Hz), 6,70 (s, 2H), 7,12 (d, 2H, J=9.0 Hz), 7,20 (d, 2H, J=7,3 Hz), 7,33-the 7.43 (m, 3H).

Example of getting 171

Synthesis of the hydrochloride of 4-[N-(4-chlorophenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-bromophenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1.04 g) process on m is todica, similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Output 899 mg (97%).

Examples 141-148

The above compound is produced by interaction of amines obtained in examples getting 167, 169 and 171, with derivative chloride obtained in the examples for the preparation of 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride. Outputs and NMR data of their free bases listed below.

70%
ExampleStructureOutputThese NMR (400 MHz, defined as the free base, CDCl3) δ
14166%1,71-1,90 (m, 4H), 2,15-of 2.24 (m, 2H), 2.95 and was 3.05 (m, 2H), to 3.58 (s, 2H), of 3.73-a-3.84 (m, 1H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,93 (s, 6H), of 3.96 (s, 6H), to 4.52 (s, 2H), 6,62 (d, 2H, J=9.0 Hz), 7,10-7,16 (m, 5H), 7,19-from 7.24 (m, 3H), 7,52 (s, 1H), to 7.59 (s, 1H), 8,56 (d, 1H, J=4.9 Hz), 8,59 (d, 1H, J=4,9 Hz).
14267%1,69-1,90 (m, 1H), 2,12 was 2.25 (m, 2H), 2.93 which is a 3.06 (m, 2H)and 3.59 (s, 2H), 3.72 points-a 3.83 (m, 1H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,92 (s, 6H), 3,93 (s, 6H), 4,50 (s, 2H), 6,62 (d, 2H, J=9,2 Hz), 6.75 in (s, 2H), 7,10 (d, 1H, J=5.3 Hz), 7,13 (s, 2H), 7,13 (d, 2H, J=9.0 Hz), to 7.50 (s, 1H), 7,76 (s, 1H), and 8.50 (d, 1H, J=1.8 Hz), 8,55 (d, 1H, J=5,1 Hz), to 8.70 (d, 1H, J=1.8 Hz).
1431,65-of 1.88 (m, 4H), 2,08-of 2.20 (m, 2H), 2,97-of 3.07 (m, 2H)and 3.59 (s, 2H), 3,71-3,82 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 3H), 3,90-3,93 (m, 3H), 4,50 (s, 2H), is 6.61 (d, 2H, J=8,2 Hz), 6,76 (s, 2H), 7,07-7,14 (m, 5H), 7,28 (d, 1H, J=6.6 Hz), 7,37 (DD, 1H, J=7.4 Hz), 7,40-7,47 (m, 2H), 7,50 (s, 1H), 8,54 (d, 1H, J=5,1 Hz).
14457%1,56-of 1.93 (m, 4H), 2,12-of 2.30 (m, 2H), 2,92-3,10 (m, 2H), 3,53-3,68 (m, 2H), 3,70-3,82 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), of 3.96 (s, 6H), 4,56 (s, 2H), 6,64-6,70 (m, 4H), 7,13 (d, 2H, J=9.0 Hz), 7,20-7,30 (m, 3H), 7,63 (W, 2H), 8,48 (s, 1H), at 8.60 (d, 1H, J=5,1 Hz), 8,66 (d, 1H, J=2.2 Hz).
14570%1,71-of 1.92 (m, 4H), 2,12-of 2.27 (m, 2H), 2,94-of 3.07 (m, 2H)and 3.59 (s, 2H), 3,69-3,81 (s, 1H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), 3,93 (s, 6H), of 4.54 (s, 2H), 6,63 of 6.68 (m, 4H), 6.75 in (s, 2H), 7,13 (d, 2H, J=9.0 Hz), a 7.62 (s, 1H), 7,76 (s, 1H), of 8.47 (d, 1H, J=1,8 Hz), and 8.50 (d, 1H, J=1.8 Hz), 8,65 (d, 1H, J=2.0 Hz), to 8.70 (s, 1H).
14678%1,75 is 1.91 (m, 4H), 2,13-of 2.23 (m, 2H), 2,94-to 3.02 (m, 2H), only 3.57 (s, 2H), of 3.73-3,82 (m, 1H), 3,88 (s, 3H), 3,88 (s, 6H), 3,90 (s, 3H), of 3.96 (s, 6H), 4,55 (s, 2H), 6,65 (d, 2H, J=9.0 Hz), of 6.68 (s, 2H), 7,11 (d, 2H, J=8.5 Hz), 7.18 in-7,24 (m, 4H), 7,32-7,42 (m, 3H), to 7.59 (s, 1H), 8,59 (d, 1H, J=4,9 Hz).
14763%1,72-1,89 (m, 4H), 2,12-of 2.21 (m, 2H), 2,94-3,03 (m, 2H)and 3.59 (s, 2H), 3.72 points-is 3.82 (m, 1H), a 3.87 (s, 3H), 3,88 (s, 6H), 3,90 (s, 3H), 3,93 (s, 6H), a 4.53 (s, 2H), only 6.64 (d, 2H, J=9,2 Hz), of 6.68 (s, 2H), 6.75 in (with, 2H), 7,11 (d, 2H), 7,19 (d, 1H, J=7,6 Hz), 7,32-7,40 (m, 3H), 7,76 (s, 1H), and 8.50 (d, 1H, J=1.8 Hz, 8,69 (d, 1H, J=2.2 Hz).
14868%1,72-to 1.87 (m, 4H), 2,08-to 2.18 (m, 2H), 2,97 was 3.05 (m, 2H), to 3.58 (s, 2H), 3,71-3,82 (m, 1H), a 3.87 (s, 3H), 3,88 (s, 6H), to 3.89 (s, 3H), 3,92 (s, 6H), a 4.53 (s, 2H), only 6.64 (dt, 2H, J=9,3 Hz, 2.9 Hz), of 6.68 (s, 2H), 6,76 (s, 2H), 7,10 (dt, 2H, J=9,0 Hz, 2.8 Hz), 7,19 (d, 1H, J=7,6 Hz), 7.24 to 7,47 (m, 7H).

Example of getting 172

Synthesis of 1-(tert-butoxycarbonyl)-4-[(3,4-differenl)amino]piperidine

1-(tert-Butoxycarbonyl)-4-piperidone (5,00 g) is subjected to interaction with 3,4-diftorhinolonom (3,09 g) by the procedure similar to that described in example receiving 37, getting mentioned in the title compound as a white powder.

The output of 4.66 g (62%).

1H-NMR (400 MHz, CDCl3) δ: of 1.24 to 1.37 (m, 2H), of 1.46 (s, 9H), 1,97-2,05 (m, 2H), 2,85-2,96 (m, 2H), 3,26-to 3.36 (m, 1H), 3,38-to 3.52 (m, 1H), 3.96 points-to 4.14 (m, 2H), 6.22 per 6,28 (m, 1H), 6,38 (DDD, 1H, J=12,7 Hz and 6.6 Hz, 2.9 Hz), 6,94 (DD, 1H, J=19.1 Hz, 9.0 Hz).

Example of getting 173

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(3,4-differenl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[(3,4-differenl)amino]piperidine (625 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) is treated according to the method similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

The output 534 mg (47%).

H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,50-1,70 (m, 2H), 1,82-1,90 (m, 2H), 2,73-is 2.88 (m, 2H), 3,90 (s, 3H), of 3.94 (s, 6H), 4,15-4,30 (m, 2H), 4,43 (s, 2H), 6,33-to 6.39 (m, 1H), of 6.52 (DDD, 1H, J=13,6 Hz, 6.4 Hz, 3.1 Hz), 6,98 (DD, 1H, J=19.1 Hz, 9,2 Hz), 7,11 (DD, 1H, J=5.0 Hz, 1.3 Hz), 7,16 (s, 2H), 7,51 (s, 1H), 8,58 (d, 1H, J=5,1 Hz).

Example of getting 174

The synthesis of the dihydrochloride of 4-[N-(3,4-differenl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(3,4-differenl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine (534 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

The output of 442 mg (87%).

Example of getting 175

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(3,4-differenl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[(3,4-differenl)amino]piperidine (625 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) is treated according to the method similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

Yield 350 mg (31%).

Example of getting 176

The synthesis of the dihydrochloride of 4-[N-(3,4-differenl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxide bonyl)-4-[N-(3,4-differenl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine (350 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

The output of 305 mg (92%).

Example of getting 177

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(3,4-differenl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[(3,4-differenl)amino]piperidine (625 mg) is subjected to interaction with 3-(3,4,5-trimethoxyphenyl)benzylchloride (586 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

Yield 1.04 g (92%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,52-of 1.66 (m, 2H), 1,81-1,89 (m, 2H), 2,72-to 2.85 (m, 2H), 3,78 (TT, 1H, J=11.8 Hz, 3.8 Hz), 3,88 (s, 3H), 3,90 (s, 6H), 4,12-4,30 (m, 2H), of 4.45 (s, 2H), 6,36-6.42 per (m, 1H), 6,54 (DDD, 1H, J=a 13.9 Hz, 6.8 Hz, 2.9 Hz), of 6.71 (s, 2H), 6,95 (DD, 1H, J=19.2 Hz, 9,2 Hz), 7,20 (d, 1H, J=7.4 Hz), of 7.36-the 7.43 (m, 3H).

Example of getting 178

Synthesis of the hydrochloride of 4-[N-(3,4-differenl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[(3,4-differenl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (980 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Output 819 mg (94%).

Examples 149-156

These connections receive interaction is the influence of amines, obtained in the examples getting 174, 176 and 178, with derivative chloride obtained in the examples for the preparation of 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride. Outputs and NMR data of their free bases listed below.

ExampleStructureOutputThese NMR (400 MHz, defined as the free base, CDCl3) δ
14967%1,70-1,90 (m, 4H), 2,16-of 2.23 (m, 2H), 2.95 and-3,03 (m, 2H), to 3.58 (s, 2H), 3,64-3,74 (m, 1H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,93 (s, 6H), of 3.96 (s, 6H), of 4.49 (s, 2H), of 6.31-6,37 (m, 1H), 6,51 (DDD, 1H, J=13,9 Hz and 6.6 Hz and 3.1 Hz), of 6.96 (DD, 1H, J=19.2 Hz, 9.8 Hz), 7,11 (d, 1H, J=5,1 Hz),to 7.15 (s, 2H), 7,20 (d, 1H, J=5,1 Hz), 7,22 (s, 2H), 7,52 (s, 1H), to 7.59 (s, 1H), to 8.57 (d, 1H, J=5,1 Hz), 8,59 (d, 1H, J=5,1 Hz).
15047%1,67-to 1.79 (m, 2H), 1,81-1,89 (m, 2H), 2,13-of 2.20 (m, 2H), 2.95 and was 3.05 (m, 2H)and 3.59 (s, 2H), 3,63 of 3.75 (m, 1H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,93 (s, 12H), 4,47 (s, 2H), 6.30-in-6,36 (m, 1H), 6,50 (DDD, 1H, J=a 13.9 Hz, 6,6 Hz, 3.1 Hz), 6.75 in (s, 2H), of 6.96 (d, 1H, J=19,0 Hz, 9.4 Hz), 7,10 (d, 1H, J=4,1 Hz), to 7.15 (s, 2H), 7,51 (s, 1H), of 7.75 (s, 1H), and 8.50 (d, 1H, J=1.8 Hz), 8,56 (d, 1H, J=5,1 Hz), to 8.70 (s, 1H).
15153%1,68-to 1.87 (m, 4H), 2,09-to 2.18 (m, 2H), 2,98-of 3.06 (m, 2H), to 3.58 (s, 2H), 3,63-and 3.72 (m, 1H), with 3.89 (s, 3H), with 3.89 (s, 3H), 3,92 (s, 6H), 3,93 (s, 6H), 4,47 (s, 2H), 6,33-6,5 (m, 1H), 6,50 (DDD, 1H, J=a 13.9 Hz, 6.4 Hz, 2.9 Hz), 6,76 (s, 2H), 6,95 (DD, 1H, J=19.2 Hz, 9.4 Hz), to 7.09 (d, 1H, J=5,1 Hz), to 7.15 (s, 2H), 7,25-7,30 (m, 1H), 7,37 (DD, 1H, J=7,3 Hz and 7.3 Hz), 7,42-7,46 (m, 2H), 7,50 (s, 1H), 8,56 (d, 1H, J=5,1 Hz).
15250%1,72 is 1.96 (m, 4H), 2,12-of 2.28 (m, 2H), 2,94-is 3.08 (m, 2H)and 3.59 (s, 2H), 3,62-and 3.72 (m, 1H), with 3.89 (s, 3H), 3,90 (s, 9H), of 3.96 (s, 6H), to 4.52 (s, 2H), 6,36-to 6.43 (m, 1H), 6,55 (DDD, 1H, J=13,7 Hz and 6.6 Hz, 2.9 Hz), 6,67 (s, 2H), of 6.96 (DD, 1H, J=19.1 Hz, 9,2 Hz), 7,21 (DD, 1H, J=5,1 Hz, 1.2 Hz), 7,24 (s, 2H), to 7.61 (W, 1H), to 7.64 (s, 1H), of 8.47 (d, 1H, J=2.0 Hz), at 8.60 (d, 1H, J=4.9 Hz), 8,67 (d, 1H, J=2.0 Hz).
15361%1,71-1,90 (m, 4H), 2,12 was 2.25 (m, 2H), 2.95 and was 3.05 (m, 2H), 3,57 of 3.75 (m, 1H)and 3.59 (s, 2H), 3,88 (s, 3H), 3,90 (s, 9H), 3,93 (s, 6H), 4,50 (s, 2H), 6,32-to 6.43 (m, 1H), 6,54 (DDD, 1H, J=13,6 Hz, 6.4 Hz, 2.7 Hz), 6,67 (s, 2H), 6.73 x-is 6.78 (m, 3H), of 6.96 (DD, 1H, J=18,9 Hz and 9.6 Hz), 7,63 (s, 1H), 7,76 (s, 1H), 8,46 (s, 1H), and 8.50 (d, 1H, J=1.6 Hz), 8,66 (d, 1H, J=1.8 Hz), to 8.70 (d, 1H, J=2.0 Hz).
15482%1,74-1,90 (m, 4H), 2,13-2,22 (m, 2H), 2.95 and-a 3.01 (m, 2H), only 3.57 (s, 2H), 3,63-to 3.73 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), of 3.96 (s, 6H), 4,51 (s, 2H), 6,34-6,40 (m, 1H), of 6.52 (DDD, 1H, J=14.1 Hz, 6.6 Hz and 3.1 Hz), 6,70 (s, 2H), 6,94 (DD, 1H, J=19.2 Hz, 9.4 Hz), 7,17-7,26 (m, 4H), 7,32-7,42 (m, 3H), to 7.59 (s, 1H), 8,59 (d, 1H, J=5,1 Hz).
15575%1,74-1,90 (m, 4H), 2,13-of 2.21 (m, 2H), 2.95 and totaling 3.04 (m, 2H)and 3.59 (s, 2H), 3,63-and 3.72 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 6H), to 3.89 (s, 3H), 3,93 (s, 6H), of 4.49 (s, 2H), 633-6,39 (m, 1H), of 6.52 (DDD, 1H, J=14,3 Hz and 3.7 Hz, 2.9 Hz), 6,69 (s, 2H), 6.75 in (s, 2H), 6,94 (DD, 1H, J=19.1 Hz, 9.8 Hz), 7,19 (d, 1H, J=7.8 Hz), 7,32-7,41 (m, 3H), 7,76 (s, 1H), and 8.50 (d, 1H, J=1.5 Hz), 8,69 (s, 1H).
15679%1,72-of 1.88 (m, 4H), 2,08-to 2.18 (m, 2H), 2,98 was 3.05 (m, 2H), to 3.58 (s, 2H), 3,62-and 3.72 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 9H), to 3.92 (s, 6H), of 4.45 (s, 2H), 6,33-to 6.39 (m, 1H), 6,51 (DDD, 1H, J=a 13.9 Hz, 6.6 Hz, 3.0 Hz), 6,69 (s, 2H), 6,76 (s, 2H), 6,93 (DD, 1H, J=19.3 Hz, 9.5 Hz), 7,19 (d, 1H, J=7,6 Hz), 7,25-7,47 (m, 7H).

Example of getting 179

Synthesis of 1-(tert-butoxycarbonyl)-4-[(4-forfinal)amino]piperidine

1-(tert-Butoxycarbonyl)-4-piperidone (5,00 g) is subjected to interaction with 4-fornerino (2.66 g) by the procedure similar to that described in example receiving 37, getting mentioned in the title compound as a white powder.

The output of 4.99 g (71%).

1H-NMR (400 MHz, CDCl3) δ: 1,23-of 1.36 (m, 2H), of 1.46 (s, 9H), 1,97-2,05 (m, 2H), 2,84-2,96 (m, 2H), 3,30-3,39 (m, 2H), 3.96 points-to 4.14 (m, 2H), 6,51-to 6.57 (m, 2H), 6,84-6,91 (m, 2H).

Example obtain 180

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-forfinal)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[(4-forfinal)amino]piperidine (589 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) is treated according to the method similar to that described in example 9, receiving specified in the title compound in the form of SV is to-yellow amorphous substance.

The output 702 mg (64%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,48-of 1.64 (m, 2H), 1,81-1,90 (m, 2H), 2,72-to 2.85 (m, 2H), 3,69-3,98 (m, 1H), 3,89 (m, 3H), of 3.94 (m, 6H), 4,16-to 4.28 (m, 2H), 4,43 (s, 2H), 6,66-of 6.73 (m, 2H), 6,91 (DD, 2H, J=9,2 Hz, 9,2 Hz), 7,12-7,16 (m, 3H), 7,53 (s, 1H).

Example of getting 181

The synthesis of the dihydrochloride of 4-[N-(4-forfinal)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-forfinal)-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine (702 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

The output of 561 mg (84%).

Example of getting 182

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-forfinal)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[(4-forfinal)amino]piperidine (589 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) is treated according to the method similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

Yield 190 mg (17%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,50-of 1.73 (m, 2H), 1,82-1,90 (m, 2H), 2.71 to to 2.85 (m, 2H), 3,71 (TT, 1H, J=11.7 Hz, 3.1 Hz), with 3.89 (s, 3H), 3,90 (s, 6H), 4,12-4,30 (m, 2H), of 4.45 (s, 2H), 6,66 (s, 2H), 6.73 x-is 6.78 (m, 2H), 6,91 (DD, 2H, J=9,2 Hz and 8.2 Hz), the 7.65 (s, 1H), 8,49 (d, 1H, J=2.0 Hz), 8,65 (d, 1H, J=2.0 Hz).

P the emer getting 183

The synthesis of the dihydrochloride of 4-[N-(4-forfinal)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-forfinal)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine (190 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Yield 165 mg (91%).

Example of getting 184

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-forfinal)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[(4-forfinal)amino]piperidine (589 mg) is subjected to interaction with 3-(3,4,5-trimethoxyphenyl)benzylchloride (586 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

Yield 1.01 g (92%).

1H-NMR (400 MHz, CDCl3) δ: of 1.44 (s, 9H), 1,51-of 1.65 (m, 2H), 1,82-1,90 (m, 2H), 2,82-2,84 (m, 2H), 3,78 (TT, 1H, J=11.7 Hz, 3.5 Hz), 3,88 (s, 3H), 3,90 (s, 6H), 4,10-4,30 (m, 2H), of 4.45 (s, 2H), 6,68-of 6.73 (m, 4H), 6.89 in (DD, 2H, J=9,2 Hz and 8.2 Hz), 7,21-7,25 (m, 1H), 7,32-7,41 (m, 3H).

Example of getting 185

Synthesis of the hydrochloride of 4-[N-(4-forfinal)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-forfinal)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1.01 g) store the t according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Yield 790 mg (88%).

Examples 157-164

The above compound is produced by interaction of amines obtained in examples getting 181, 183 and 185, with derivative chloride obtained in the examples for the preparation of 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride. Outputs and NMR data of their free bases listed below.

ExampleStructureOutputThese NMR (400 MHz, defined as the free base, CDCl3) δ
15762%1,60-to 1.82 (m, 2H), 1,83 is 1.91 (m, 2H), 2,13-of 2.23 (m, 2H), 2.95 and-3,03 (m, 2H), only 3.57 (s, 2H), 3,64 of 3.75 (m, 1H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,93 (s, 6H), of 3.96 (s, 6H), 4,48 (s, 2H), 6,65-6,70 (m, 2H), 6.90 to (DD, 2H, J=8,8 Hz and 8.8 Hz), 7,13-7,16 (m, 3H), 7,20 (d, 1H, J=5,1 Hz), 7,22 (s, 2H), 7,54 (s, 1H), to 7.59 (s, 1H), 8,55 (d, 1H, J=5,1 Hz), 8,59 (d, 1H, J=4,9 Hz).
15853%1,66-of 1.95 (m, 4H), 2,12-of 2.24 (m, 2H), 2.95 and-of 3.07 (m, 2H), 3,60 (s, 2H), 3,64 is 3.76 (m, 1H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,92 (s, 6H), 3,93 (s, 6H), 4,47 (s, 2H), 6,63-6,70 (m, 1H), 6.75 in (s, 2H), 6.90 to (DD, 1H, J=9,2 Hz and 9.2 Hz), 7,11-7,16 (m, 3H), 7,53 (s, 1H), to 7.77 (s, 1H), and 8.50 (d, 1H, J=2.0 Hz), 8,55 (d, 1H, J=4.9 Hz), to 8.70 (d, 1H, J=5,9 Hz).
159 51%1,64-1,90 (m, 4H), 2,07-of 2.20 (m, 4H), 2,97-is 3.08 (m, 2H)and 3.59 (s, 2H), 3,64 is 3.76 (m, 1H), with 3.89 (s, 6H), to 3.92 (s, 6H), 3,93 (s, 6H), 4,47 (s, 2H), 6,62-6,70 (m, 2H), 6,77 (s, 2H), 6,86-6,93 (m, 2H), 7,11-7,16 (m, 3H), 7,25-7,31 (m, 3H), 7,37 (DD, 1H, J=7,4 Hz, 7.4 Hz), 7,42-7,49 (m, 2H), 7,53 (s, 1H), 8,54 (d, 1H, J=5,1 Hz).
16049%1,74-to 1.98 (m, 4H), 2,10-of 2.30 (m, 2H), 2,90-of 3.12 (m, 2H), 3,53-to 3.73 (m, 3H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), of 3.96 (s, 6H), 4,50 (s, 2H), 6,66 (s, 2H), 6,70-6,76 (m, 2H), 6.90 to (DD, 2H, J=8,8 Hz, 8,8 Hz), 7,19-7,28 (m, 3H), 7,65 (W, 2H), 8,49 (d, 1H, J=1.8 Hz), at 8.60 (d, 1H, J=4.9 Hz), 8,64 (d, 1H, J=2.2 Hz).
16126%1,67-of 1.97 (m, 4H), 2,10-of 2.27 (m, 2H), 2,94-of 3.06 (m, 2H), 3,56-3,68 (m, 3H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), 3,93 (s, 6H), of 4.49 (s, 2H), 6,65 (s, 2H), 6,69-to 6.80 (m, 4H), 6,84-6,93 (m, 2H), to 7.64 (s, 1H), to 7.77 (W, 1H), 8,48 (d, 1H, J=1.7 Hz), and 8.50 (d, 1H, J=1.7 Hz), 8,64 (d, 1H, J=1.9 Hz), to 8.70 (s, 1H).
16283%1,72-of 1.92 (m, 4H), 2,12-of 2.21 (m, 2H), 2,94-to 3.02 (m, 2H), only 3.57 (s, 2H), 3,64-3,74 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), of 3.96 (s, 6H), 4,51 (s, 1H), 6,66-of 6.71 (m, 4H), to 6.88 (DD, 2H, J=8.6 Hz, 8.6 Hz), 7,18-7,27 (m, 4H), 7,34 (DD, 1H, J=7,4 Hz, 7.4 Hz), 7,39 (d, 2H, J=5.4 Hz), to 7.59 (s, 1H), 8,59 (d, 1H, J=5,1 Hz).
16368%1,68-to 1.87 (m, 4H), 2,10-2,22 (m, 2H), 2,94 totaling 3.04 (m, 2H)and 3.59 (s, 2H), 3,65-3,74 (m, 1H), a 3.87 (s, 3H), 3,88 (s, 6H), 3,90 (s, 3H), 3,93 (s, 6H), of 4.49 (s, 2H), 6,66-6,70 (m, 6H), to 6.88 (DD, 2H, J=8,8 Hz, 8,8 Hz), 7,19-7,40 (m, 4H) to 7.77 (s, 1H), 8,49 (d, 1H, J=1.8 Hz), to 8.70 (s, 1H).
16474%1,70-1,90 (m, 4H), 2,08-to 2.18 (m, 2H), 2.95 and was 3.05 (m, 2H), to 3.58 (s, 2H), 3,63-to 3.73 (m, 1H), a 3.87 (s, 3H), 3,88 (s, 6H), to 3.89 (s, 3H), 3,92 (s, 6H), 4,50 (s, 2H), 6,65-6,72 (m, 2H), 6,69 (s, 2H), 6,76 (s, 2H), 6,87 (DD, 2H, J=9,0 Hz, 9.0 Hz), 7,22 (d, 1H, J=7,6 Hz), 7,25-of 7.48 (m, 9H).

Example of getting 186

Synthesis of 1-(tert-butoxycarbonyl)-4-phenylaminopyrimidine

1-(tert-Butoxycarbonyl)-4-piperidone (5,00 g) is subjected to interaction with aniline (2,23 g) by the procedure similar to that described in example receiving 37, getting mentioned in the title compound as a white powder.

The output of 3.77 g (57%).

1H-NMR (400 MHz, CDCl3) δ: 1,25-to 1.38 (m, 2H), 1,47 (s, 9H), 2.00 in 2,07 (m, 2H), 2,87-of 2.97 (m, 2H), 3,38-of 3.53 (m, 2H), 3.96 points-to 4.14 (m, 2H), 6,57-of 6.52 (m, 2H), 6,70 (TT, 1H, J=6.2 Hz, 1.0 Hz), 7,17 (DD, 2H, J=8.6 Hz, 7.2 Hz).

Example of getting 187

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-phenyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-phenylaminopyrimidine (553 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) is treated according to the method similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

The output of 760 mg (71%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,53-to 1.63 (m, 2H), 1,83 is 1.91(m, 2H), was 2.76-2,90 (m, 2H), 3,86-of 3.97 (m, 1H), with 3.89 (s, 3H), 3,93 (s, 6H), 4,14-4,32 (m, 2H), 4,49 (s, 2H), of 6.71-of 6.78 (m, 3H), 7,14 (s, 1H), 7,15 (s, 2H), 7,21 (DD, 2H, J=8,8 Hz, 7.4 Hz), 7,55 (s, 1H), 8,56 (d, 1H, J=5,1 Hz).

Example of getting 188

The synthesis of the dihydrochloride of 4-[N-phenyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-phenyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]amino]piperidine (760 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Output 652 mg (90%).

Example of getting 189

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-phenyl-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-N-phenylaminopyrimidine (553 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) is treated according to the method similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

Yield 222 mg (21%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,52-to 1.67 (m, 2H), 1,82 is 1.91 (m, 2H), 2,74-2,87 (m, 2H), 3,88-3,90 (m, 1H), 3,88 (s, 3H), with 3.89 (s, 6H), 4,14-or 4.31 (m, 2H), 4.53-in (s, 2H), to 6.67 (s, 2H), 6,74-to 6.80 (m, 3H), 7,21 (DD, 2H,, J=8,8 Hz, 7.2 Hz), to 7.67 (s, 1H), and 8.50 (d, 1H, J=5.3 Hz, 2.2 Hz), 8,66 (d, 1H, J=2.1 Hz).

Example of getting 190

The synthesis of the dihydrochloride of 4-[N-phenyl-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]meth is l]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-phenyl-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine (222 mg) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Yield 197 mg (94%).

Example of getting 191

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-phenyl-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-phenylaminopyrimidine (553 mg) is subjected to interaction with 3-(3,4,5-trimethoxyphenyl)benzylchloride (586 mg) by the procedure similar to that described in example 9, getting mentioned in the title compound as a pale yellow amorphous substance.

Yield 1.06 g (100%).

1H-NMR (400 MHz, CDCl3) δ: 1,45 (s, 9H), 1,52 by 1.68 (m, 2H), 1,83-of 1.92 (m, 2H), 2,73-of 2.86 (m, 2H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,94 (TT, 1H, J=11.7 Hz, 3.3 Hz), 4,14-4,30 (m, 2H), to 4.52 (s, 2H), 6,69-of 6.78 (m, 6H), 7,17-7,27 (m, 2H), 7,32-7,42 (m, 3H).

Example of getting 192

Synthesis of the hydrochloride of 4-[N-phenyl-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-phenyl-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1.06 g) is treated according to the method similar to that described in example getting 94, getting mentioned in the title compound as a pale yellow powder.

Output 909 mg (97%).

P is emery 165 to 169

The above compound is produced by interaction of amines obtained in examples getting 188, 190 and 192, with derivative chloride obtained in the examples for the preparation of 3 and 48. The obtained free base is then converted into the corresponding hydrochloride. Outputs and NMR data of their free bases listed below.

ExampleStructureOutputThese NMR (400 MHz, defined as the free base, CDCl3) δ
16553%1,63-of 1.81 (m, 4H), 1,82-of 1.92 (m, 2H), 2,14-of 2.24 (m, 2H), 2.95 and was 3.05 (m, 2H)and 3.59 (s, 2H), 3,80-was 4.02 (m, 1H), with 3.89 (s, 3H), 3,90 (s, 3H), 3,92 (s, 6H), 3,93 (s, 6H), a 4.53 (s, 2H), 6,69-6,77 (m, 5H), 7,13-7,17 (m, 3H), 7,20 (DD, 2H, J=7,6 Hz and 7.6 Hz), 7,55 (s, 1H), 7,76 (s, 1H), 8,51 (d, 1H, J=1.8 Hz), 8,55 (d, 1H, J=5,1 Hz), to 8.70 (s, 1H).
16650%1,85-2,04 (m, 4H), 2,20-2,40 (m, 2H), 2,92-of 3.25 (m, 2H), 3,60-of 3.77 (m, 3H), 3,88 (s, 3H), with 3.89 (s, 6H), 3,90 (s, 3H), of 3.97 (s, 6H), 4,59 (s, 2H), to 6.67 (s, 2H), 6,72-for 6.81 (m, 4H), 7,17-7,30 (m, 4H), 7,68 (s, 1H), and 8.50 (s, 1H), to 8.62 (d, 1H, J=4.9 Hz), 8,65 (d, 1H, J=2.0 Hz).
16743%1,72-of 1.92 (m, 4H), 2,13-of 2.26 (m, 2H), 2.95 and totaling 3.04 (m, 2H)and 3.59 (s, 2H), 3,78-4,01 (m, 1H), 3,88 (s, 9H), 3,90 (s, 3H), 3,93 (s, 6H), 4,56 (s, 2H), 6,66 (s, 2H), 6,70-of 6.78 (m, 5H), 7,19 (DD, 2H, J=8,2 Hz and 8.2 Hz), 7,66 (s, 1H), to 7.77 (s, 1H), and 8.50 (d, 1H, J=2.3 Hz), 8,51 (d, 1H,J=2.2 Hz), 8,65 (d, 1H, J=1.9 Hz), to 8.70 (d, 1H, J=2.2 Hz).
16882%a 1.75-of 1.92 (m, 4H), 2,14-of 2.23 (m, 2H), 2,94-a 3.01 (m, 2H), only 3.57 (s, 2H), 3,80-of 3.94 (m, 1H), a 3.87 (s, 3H), 3,88 (s, 6H), 3,90 (s, 3H), of 3.96 (s, 6H),of 4.57 (s, 2H), 6,67-6,77 (m, 5H), 7,15-7,27 (m, 5H), 7,34 (DD, 1H, J=7,4 Hz, 7.4 Hz), 7,39 (d, 1H, 7,6 Hz), 7,42 (s, 1H), to 7.59 (s, 1H), 8,59 (d, 1H, J=5,1 Hz).
16965%1,72 is 1.91 (m, 4H), 2,13-2,22 (m, 2H), 2.95 and-3,03 (m, 2H)and 3.59 (s, 2H), 3,79-4,00 (m, 1H), a 3.87 (s, 3H), a 3.87 (s, 6H), 3,90 (s, 3H), 3,93 (s, 6H), 4,56 (s, 2H), 6,66-6,77 (m, 7H), 7,18 (DD, 2H, J=7,4 Hz, 7.4 Hz), from 7.24 (d, 1H, J=7.4 Hz), 7,33 (DD, 1H, J=7,4 Hz, 7.4 Hz), 7,38 (d, 1H, J=7,6 Hz), 7,41 (s, 1H), 7,76 (s, 1H), and 8.50 (d, 1H, J=1.6 Hz), 8,69 (d, 1H, J=2.2 Hz)

Examples get 193-203

These connections receive, using the methodology described in the examples of the preparation 1-3. Structure and NMR data are shown below.

An example of receivingStructureThese NMR (400 MHz, CDCl3) δ
193br4.61 (s, 2H), 7,25 (d, 1H, J=1.2 Hz), 7,41-7,52 (m, 3H), of 7.75 (d, 1H, J=0.8 Hz), 7,98-8,02 (m, 2H), 8,69 (d, 1H, J=4,9 Hz).
194a 3.87 (s, 3H), 4,60 (s, 2H), 7,01 (d, 1H, J=8,4 Hz), was 7.08 (t, 1H, J=7.4 Hz), 7,24 (DD, 1H, J=5,1 Hz and 1.4 Hz), 7,38 (dt, 1H, J=7,4 Hz, 1.8 Hz), to 7.77 (DD, 1H, J=7,6 Hz, 1.8 Hz), to 7.84 (s, 1H), 8,69 (d, 1H, J=5,1 Hz).
195are 3.90 (s, 3H), 4,60 (s, 2H), 6.87 in-7,03 (1H, m), 7,39 (t, 1H, 7.8 Hz), 7,50-7,66 (m, 2H), 7,73 (s, 1H), 8,68 (d, 1H, J=5,1 Hz)
196of 1.45 (t, 3H, J=7.0 Hz), of 4.12 (q, 2H, J=7.0 Hz), 4,59 (s, 2H), 6,99 (d, 2H, J=8,8 Hz), 7,18 (d, 1H, J=5,1 Hz), 7,20-7,29 (m, 1H), 7,68 (s, 1H), 7,95 (d, 2H, J=8,8 Hz), 8,63 (d, 1H, J=5,1 Hz).
197of 3.95 (s, 3H), of 4.00 (s, 3H), 4,60 (s, 2H), of 6.96 (d, 1H, J=8,4 Hz), 7,21 (d, 1H, J=4,1 Hz), 7,53 (DD, 1H, J=8,4 Hz, 2.0 Hz), to 7.67 (d, 1H, J=2.0 Hz), of 7.70 (s, 1H), 8,65 (d, 1H, J=5,1 Hz).
198br4.61 (s, 2H), 7,14-7,21 (m, 1H), 7,21-of 7.23 (m, 2H), 7,35-7,42 (m, 1H), 7,80 (s, 1H), 7,98 (1H, dt, J=8.0 Hz, 2.0 Hz), 8,73 (d, 1H, J=5,1 Hz).
199br4.61 (s, 2H), 7,13 (1H, dt, J=8,4 Hz, 2.8 Hz), 7,28 (1H, d, J=5.0 Hz), 7,40-7,79 (m, 1H), 7,70-7,79 (m, 3H), 8,69 (d, 1H, J=5.0 Hz).
2004,60 (s, 2H), 7,13-7,20 (m, 2H), 7,25 (1H, d, J=5,1 Hz), of 7.70 (s, 1H), 7.95 is-8,03 (m, 2H), 8,66 (d, 1H, J=5,1 Hz).
201br4.61 (s, 2H), 7,21-7,30 (m, 2H), 7,69 (s, 1H), 7,73-7,76 (m, 1H), 7,85-a 7.92 (m, 1H), 8,76 (d, 1H, J=4,9 Hz).
202br4.61 (s, 2H), 6,86-6,91 (m, 1H), 7,31 (1H, d, J=5,1 Hz), 7,51-to 7.59 (m, 2H), 7,71 (s, 1H), 8,69 (d, 1H, J=5,1 Hz).
203br4.61 (s, 2H), 7,26 (d, 1H, J=4.9 Hz), was 7.45 (d, 2H, J=8,4 Hz), 7,72 (s, 1H), 7,95 (d, 2H, J=8,4 Hz), 8,68 (s, 1H, J=4,9 Hz).

Example of getting 204

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[(2-phenylpyridine-4-yl)methyl]amino]piperidine

4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (612 mg) is subjected to interaction with 4-chloromethyl-2-phenylpyridine (204 mg) by the procedure similar to that described in example 9, receiving specified in the header of the connection.

Exit 407 mg (43%).

Example of getting 205

The synthesis of the dihydrochloride of 4-[N-(4-methoxyphenyl)-N-[(2-phenylpyridine-4-yl)methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[(2-phenylpyridine-4-yl]methyl]amino]piperidine (407 mg) is treated according to the method similar to that described in example getting 94, receiving specified in the header of the connection.

The output of 365 mg (95%).

Example of getting 206

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[[2-(2-methoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) is subjected to interaction with 4-chloromethyl-2-(2-methoxyphenyl)pyridine (234 mg) by the procedure similar to that described in example 9, receiving specified in the header is connected to the E.

The output of 237 mg (72%).

Example of getting 207

The synthesis of the dihydrochloride of 4-[N-(4-methoxyphenyl)-N-[[2-(2-methoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[[2-(2-methoxyphenyl)pyridine-4-yl]methyl]amino]piperidine (360 mg) is treated according to the method similar to that described in example getting 94, receiving specified in the header of the connection.

The output of 365 mg (65%).

Example of getting 208

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[[2-(3-methoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) is subjected to interaction with 4-chloromethyl-2-(3-methoxyphenyl)pyridine (234 mg) and then condense according to the method similar to that described in example 9, receiving specified in the header of the connection.

Yield 550 mg (theoretical output).

Example of getting 209

The synthesis of the dihydrochloride of 4-[N-(4-methoxyphenyl)-N-[[2-(3-methoxyphenyl)pyridine-4-yl]methyl]amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[[2-(3-methoxyphenyl)pyridine-4-yl]methyl]amino]piperidine (550 mg) is treated according to the method similar to that described in example getting 94, receiving specified in the header of the connection.

The output 436 g (85%).

Example of getting 210

Sint is C 1-(tert-butoxycarbonyl)-4-[N-[[2-(4-ethoxyphenyl)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine

4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) is subjected to interaction with 4-chloromethyl-2-(4-ethoxyphenyl)pyridine (248 mg) by the procedure similar to that described in example 9, receiving specified in the header of the connection.

The output of 515 mg (99%).

Example of getting 211

The synthesis of the dihydrochloride of 4-[N-[[2-(4-ethoxyphenyl)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-[2-(4-ethoxyphenyl)pyridine-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine (515 mg) is treated according to the method similar to that described in example getting 94, receiving specified in the header of the connection.

The output 418 mg (80%).

Example of getting 212

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[[2-(3,4-acid)pyridine-4-yl]methyl]-[N-(4-methoxyphenyl)amino]piperidine

4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) is subjected to interaction with 4-chloromethyl-2-(3,4-acid)pyridine (264 mg) by the procedure similar to that described in example 9, receiving specified in the header of the connection.

Yield 600 mg (theoretical output).

Example of getting 213

The synthesis of the dihydrochloride of 4-[N-[[2-(3,4-acid)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-[[2-(34-acid)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine (600 mg) is treated according to the method similar to that described in example getting 94, receiving specified in the header of the connection.

The output of 416 mg (77%).

Example of getting 214

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[[2-(2-forfinal)pyridine-4-yl]methyl]-[N-(4-methoxyphenyl)amino]piperidine

4-(p-Anisidino)-(tert-butoxycarbonyl)piperidine (306 mg) is subjected to interaction with 4-chloromethyl-2-(2-forfinal)pyridine (222 mg) by the procedure similar to that described in example 9, receiving specified in the header of the connection.

Yield 530 mg (theoretical output).

Example of getting 215

The synthesis of the dihydrochloride of 4-[N-[[2-(2-forfinal)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-[[2-(2-forfinal)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine (530 mg) is treated according to the method similar to that described in example getting 94, receiving specified in the header of the connection.

The output of 423 mg (85%).

Example of getting 216

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[[2-(3-forfinal)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine

4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (153 mg) is subjected to interaction with 4-chloromethyl-2-(3-forfinal)pyridine (111 mg) by the procedure similar to that described in example 9, receiving specified in the header connection./p>

Yield 270 mg (theoretical output).

Example of getting 217

The synthesis of the dihydrochloride of 4-[N-[[2-(3-forfinal)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-[[2-(3-forfinal)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine (270 mg) is treated according to the method similar to that described in example getting 94, receiving specified in the header of the connection.

Exit 193 mg (70%).

Example of getting 218

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[[2-(4-forfinal)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine

4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) is subjected to interaction with 4-chloromethyl-2-(4-forfinal)pyridine (222 mg) by the procedure similar to that described in example 9, receiving specified in the header of the connection.

Yield 550 mg (theoretical output).

Example of getting 219

The synthesis of the dihydrochloride of 4-[N-[[2-(4-forfinal)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-[[2-(4-forfinal)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine (550 mg) is treated according to the method similar to that described in example getting 94, receiving specified in the header of the connection.

The output of 439 mg (88%).

Example 220

Synthesis of 1-(tert-butoxide the Nile)-4-[N-[[2-(3,4-differenl)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine

4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) is subjected to interaction with 4-chloromethyl-2-(3,4-differenl)pyridine (240 mg) by the procedure similar to that described in example 9, receiving specified in the header of the connection.

Yield 590 mg (theoretical output).

Example of getting 221

The synthesis of the dihydrochloride of 4-[N-[[2-(3,4-differenl)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-[[2-(3,4-differenl)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine (590 mg) is treated according to the method similar to that described in example getting 94, receiving specified in the header of the connection.

The output of 483 mg (93%).

Example of getting 222

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[[2-(3,5-differenl)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine

4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) is subjected to interaction with 4-chloromethyl-2-(3,5-differenl)pyridine (240 mg) by the procedure similar to that described in example 9, receiving specified in the header of the connection.

Yield 530 mg (theoretical output).

Example of getting 223

The synthesis of the dihydrochloride of 4-[N-[[2-(3,5-differenl)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine

1-(tert-Butoxide is of IMT-4-[N-[[2-(3,5-differenl)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine (530 mg) is treated according to the method similar to that described in example getting 94, receiving specified in the header of the connection.

The output 418 mg (81%).

Example of getting 224

Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[[2-(4-chlorophenyl)pyridine-4-yl]methyl]-[N-(4-methoxyphenyl)amino]piperidine

4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) is subjected to interaction with 4-chloromethyl-2-(4-chlorophenyl)pyridine (238 mg) by the procedure similar to that described in example 9, receiving specified in the header of the connection.

Yield 600 mg (theoretical output).

Example of getting 225

The synthesis of the dihydrochloride of 4-[N-[[2-(4-chlorophenyl)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine

1-(tert-Butoxycarbonyl)-4-[N-[[2-(4-chlorophenyl)pyridine-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine (600 mg) is treated according to the method similar to that described in example getting 94, receiving specified in the header of the connection.

Exit 447 mg (86%).

Examples 170-202

The above compound is produced by interaction of amines obtained in the examples get 96, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223 and 225, with derivative chloride obtained in the examples get 3, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202 and 203. The obtained free base is then converted into the corresponding hydrochloride. Outputs and NMR data of their free bases listed below.

ExampleStructureOutputThese NMR (400 MHz, defined as the free base, CDCl3) δ17047%1,67 and 1.80 (m, 2H), 1,83 is 1.91 (m, 2H), 2,10-2,19 (m, 2H), 2.93 which is 3.00 (m, 2H), 3,54-the 3.65 (m, 1H), of 3.56 (s, 2H), of 3.73 (s, 3H), with 3.89 (s, 3H), 3,93 (s, 6H), of 4.45 (s, 3H), 6.73 x (d, 2H, J=9.4 Hz), 6,78 (d, 2H, J=9.4 Hz), 7,14-7,21 (m, 2H), 7,15 (s, 2H), 7,38-7,49 (m, 3H), EUR 7.57 (s, 1H), 7,68 (s, 1H), of 7.97 (d, 1H, J=1.0 Hz), to 7.99 (d, 1H, J=1.6 Hz), 8,54 (d, 1H, J=5,1 Hz), 8,61 (d, 1H, J=5,1 Hz).17155%of 1.62 and 1.80 (m, 2H), 1,84-of 1.93 (m, 2H), 2,10-of 2.20 (m, 2H), 2,93-to 3.02 (m, 2H), 3,53-3,66 (m, 1H), of 3.56 (s, 2H), of 3.73 (s, 3H), 3,90 (s, 3H), of 3.96 (s, 6H), of 4.44 (s, 2H), 6,65-6,83 (m, 4H), 7,14-7,30 (m, 4H), of 7.36-to 7.50 (m, 3H), to 7.59 (s, 1H), to 7.67 (s, 1H), to 7.93 (d, 2H, J=7.0 Hz), 8,54-8,61 (m, 2H).17254%1,67-of 1.92 (m, 4H), 2,08-of 2.20 (m, 2H), 2,92-a 3.01 (m, 2H), 3,52-the 3.65 (m, 1H), 3,55 (s, 2H), and 3.72 (s, 3H), of 4.38 (s, 2H), 6,72 (d, 2H, J=9,2 Hz), 6,78 (d, 2H, J=9.0 Hz), 7,18 (DD, 2H, J=4,9 Hz, 4.9 Hz), of 7.36-7,50 (m, 6H), to 7.67 (s, 1H), 7,68 (s, 1H), to 7.93 (DD, 2H, J=8,4 Hz, 1.2 Hz), 7,98 (DD, 2H, J=8.6 Hz, 1.4 Hz), to 8.57 (d, 1H, J=5,1 Hz), at 8.60 (d, 1H, J=5,1 Hz).173100%1,66-to 1.79 (m, 2H), 1,82 is 1.91 (m, 2H), 2,09-of 2.20 (m, 2H), 2,93-3,03 (m, 2H), of 3.56 (s, 2H), 3,56-3,59 (m, 1H), of 3.73 (s, 3H), of 3.80 (s, 3H), with 3.89 (s, 3H), 3,93 (s, 6H), of 4.45 (s, 2H), 6.73 x (d, 2H, J=9,3 Hz), 6,78 (d, 2H, J=9,3 Hz), 6,98 (d, 1H, J=8.5 Hz), 7,07 (t, 1H, J=7.6 G is), to 7.15 (s, 2H), 7,15-7,19 (m, 2H), 7,33-7,38 (m, 1H), EUR 7.57 (s, 1H), 7,66-7,74 (m, 2H), 8,53 (d, 1H, J=5,1 Hz), 8,61 (d, 1H, J=4,9 Hz).17494%1,70-1,80 (m, 2H), 1,83 is 1.91 (m, 2H), 2,11-to 2.18 (m, 2H), 2,92-a 3.01 (m, 2H), of 3.56 (s, 2H), 3,57-the 3.65 (m, 1H), of 3.73 (s, 3H), 3,74 (s, 3H), 3,90 (s, 3H), of 3.96 (s, 6H), of 4.44 (s, 2H), of 6.71 (d, 2H, J=9.0 Hz), 6,78 (d, 2H, J=9.0 Hz),of 6.96 (d, 1H, J=8,3 Hz), 7,05 (dt, 1H, J=7,3 Hz, 1.0 Hz), 7,14 (d, 1H, J=5,2 Hz), 7,20 (d, 1H, J=5,2 Hz), 7,22 (2H, s), 7,32-7,37 (m, 1H), to 7.59 (s, 1H), 7,71 to 7.75 (m, 2H), 8,56 at 8.60 (m, 2H).17598%1,67 and 1.80 (m, 2H), 1,83-1,90 (m, 2H), 2,10-2,19 (m, 2H), 2,94-3,03 (m, 2H), 3,50-to 3.67 (m, 1H), of 3.56 (s, 2H), of 3.73 (s, 3H), 3,74 (s, 3H), 3,79 (s, 3H), of 4.44 (s, 2H), 6,70 (d, 2H, J=9,3 Hz), 6,78 (d, 2H, J=and 9.3 Hz), of 6.96 (d, 1H, J=8,3 Hz), 6,98 (d, 1H, J=8,8 Hz),? 7.04 baby mortality (DD, 1H, J=7,6 Hz, 1.0 Hz), 7,07 (DD, 1H, 7,6, J=1.0 Hz), 7,12-7,19 (m, 2H), 7,32-7,39 (m, 2H), 7,70 to 7.75 (m, 4H), 8,58 (d, 1H, J=5,1 Hz), 8,61 (d, 1H, J=4,9 Hz).176100%1,68-to 1.79 (m, 2H), 1,82-1,90 (m, 2H), 2,10-2,19 (m, 2H), 2,90-a 3.01 (m, 2H), of 3.56 (s, 2H), 3,56-to 3.58 (m, 1H), of 3.73 (s, 3H), with 3.89 (s, 3H), 3,91 (s, 3H), 3,93 (s, 6H), of 4.45 (s, 2H), 6.73 x (d, 2H, J=9,3 Hz), 6,78 (d, 2H, J=9,3 Hz), 6,93-6,99 (m, 1H), 7,15 (s, 2H), 7,16-7,20 (m, 2H), 7,37 (t, 1H, J=7.8 Hz), 7,52-to 7.59 (m, 3H), to 7.67 (s, 1H), 8,54 (d, 1H, J=5,1 Hz), at 8.60 (d, 1H, J=5,1 Hz).177100%1,68-to 1.79 (m, 2H), 1,83-of 1.92 (m, 2H), 2,11-of 2.16 (m, 2H), 2.91 in-to 3.02 (m, 2H), of 3.56 (s, 2H), 3,55-the 3.65 (m, 1H), of 3.73 (s, 3H), 3,88 (s, 3H), 3,90 (s, 3H), of 3.96 (s, 6H), 4,43 (s, 2H), 6,72 (d, 2H, J=9,3 Hz), 6,7 (d, 2H, J=9,3 Hz), to 6.95 (DD, 1H, J=8,3 Hz, 2.7 Hz), 7,16-7,21 (m, 2H), 7,22 (s, 2H), 7,35 (t, 1H, J=7.8 Hz), of 7.48 (d, 1H, J=7.8 Hz), 7,53 (t, 1H, J=2.7 Hz), to 7.59 (s, 1H), 7,65 (s, 1H), 8,55 at 8.60 (m, 2H).178100%1,65-to 1.79 (m, 2H), 1,82-1,90 (m, 2H), 2,09-2,19 (m, 2H), 2,92-3,00 (m, 2H), 3,50-3,66 (m, 1H), of 3.56 (s, 2H), of 3.73 (s, 3H), of 3.73 (s, 3H), 3,88 (s, 3H), with 3.89 (s, 3H), of 4.44 (s, 2H), 6,72 (d, 2H, J=9,3 Hz), 6,78 (d, 2H, J=9,3 Hz), 6,92-6,98 (m, 2H), 7,16-7,21 (m, 2H), 7,34 (d, 1H, J=7.8 Hz), 7,38 (d, 1H, J=8.5 Hz), 7,46-to 7.59 (m, 4H), of 7.65 (s, 1H), to 7.67 (s, 1H), to 8.57 (DD, 1H, J=5,1 Hz, 0.7 Hz), at 8.60 (d, 1H, J=5,1 Hz).17976%the 1.44 (t, 3H, J=7,1 Hz), 1,70-1,80 (m, 2H), 1,82 is 1.91 (m, 2H), 2,10-2,19 (m, 2H), 2,90-to 3.02 (m, 2H), 3,54 (s, 2H), of 3.73-of 3.78 (m, 1H), of 3.73 (s, 3H), 3,88 (s, 3H), 3,93 (s, 6H), 4.09 to (q, 2H, J=7,1 Hz), 4,45 (, 2H), 6.73 x (d, 2H, J=9,2 Hz), 6,78 (d, 2H, J=9,2 Hz), 6,97 (d, 2H, J=8,8 Hz), 7,10-to 7.18 (m, 2H), 7,15 (s, 2H), EUR 7.57 (s, 1H), to 7.61 (s, 1H), 7,92 (d, 2H, J=8,8 Hz), charged 8.52-8,58 (m, 2H).18093%of 1.43 (t, 3H, J=6.8 Hz), 1,68 and 1.80 (m, 2H), 1,82-of 1.92 (m, 2H), 2,10-2,19 (m, 2H), 2,90-a 3.01 (m, 2H), of 3.56 (s, 2H), 3,57-to 3.64 (m, 1H), of 3.73 (s, 3H), 3,90 (s, 3H), of 3.96 (s, 6H), 4,08 (q, 2H, J=6.8 Hz), 4,42 (, 2H), 6,72 (d, 2H, J=9.0 Hz), 6,78 (d, 2H, J=9,3 Hz), to 6.95 (d, 2H, J=8,8 Hz), 7,11 (d, 1H, J=5,1 Hz), 7,20 (d, 1H, J=5,1 Hz), 7,22 (s, 2H), 7,58 to 7.62 (m, 2H), 7,87 (d, 2H, J=8,8 Hz), charged 8.52 (d, 1H, J=a 5.1 Hz), 8,58 (d, 1H, J=5,1 Hz).181100%of 1.43 (t, 3H, J=7,1 Hz)of 1.44 (t, 3H, J=7,1 Hz), 1,67-of 1.78 (m, 2H), 1,82-1,90 (m, 2H), 2,09-to 2.18 (m, 2H), 2,92-300 (m, 2H), 3,54 (s, 2H), 3,55-the 3.65 (m, 1H), of 3.73 (s, 3H), 4,08 (q, 2H, J=7,1 Hz), 4.09 to (q, 2H, J=6.8 Hz), 4,42 (s, 2H), of 6.71 (d, 2H, J=9.0 Hz), 6,78 (d, 2H, J=9.0 Hz), 6,93-7,00 (m, 4H), 7,10-7,14 (m, 2H), 7,60 (s, 2H), 7,88 (s, 2H), 7,88 (d, 2H, J=8,8 Hz), to 7.93 (d, 2H, J=8,8 Hz), charged 8.52 (d, 1H, J=5,1 Hz), 8,56 (d, 1H, J=4,9 Hz).182100%1,68-to 1.79 (m, 2H), 1,82-1,90 (m, 2H), 2,10-2,19 (m, 2H), 2,90-a 3.01 (m, 2H), 3,55 (s, 2H), 3,56-3,59 (m, 1H), of 3.73 (s, 3H), with 3.89 (s, 3H), 3,93 (s, 6H), of 3.94 (s, 3H), 3,99 (s, 3H), of 4.45 (s, 2H), 6,76 (d, 2H, J=9.5 Hz), 6,78 (d, 2H, J=9.5 Hz), 6,94 (d, 1H, J=8,3 Hz),to 7.15 (s, 2H), 7,16-7,19 (m, 2H), 7,49-7,66 (m, 4H), 8,54 (d, 1H, J=4.9 Hz), to 8.57 (d, 1H, J=5,1 Hz).183100%1,68-of 1.78 (m, 2H), 1,82 is 1.91 (m, 2H), 2,10-to 2.18 (m, 2H), 2.93 which is 3.00 (m, 2H), of 3.56 (s, 2H), 3,56-3,62 (m, 1H), of 3.73 (s, 3H), 3,90 (s, 3H), 3,93 (s, 3H), of 3.96 (s, 6H), of 3.97 (s, 3H), 4,43 (s, 2H), 6,72 (d, 2H, J=9,3 Hz), 6,78 (d, 2H, J=9,3 Hz), 6,92 (d, 1H, J=8,3 Hz), 7,12 (d, 1H, J=5,1 Hz), 7,20 (d, 1H, J=5,1 Hz), 7,22 (s, 2H), 7,42 (d, 1H, J=8,5 Hz, 2.2 Hz), 7,58-7,63 (m, 3H), 8,53 (d, 1H, J=4.9 Hz), 8,58 (d, 1H, J=5,1 Hz).18489%1,67-to 1.79 (m, 2H), 1,84-1,90 (m, 2H), 2,10-2,19 (m, 2H), 2,93-a 3.01 (m, 2H), 3,50-the 3.65 (m, 1H), 3,55 (s, 2H), of 3.73 (s, 3H), of 3.94 (s, 3H), of 3.97 (s, 3H), 3,99 (s, 3H), 4,43 (s, 2H), 6,72 (d, 2H, J=9,3 Hz), 6,78 (d, 2H, J=9,3 Hz), 6,92 (d, 1H, J=8.6 Hz), 6,94 (d, 1H, J=8,3 Hz), 7,14 (d, 1H, J=5.6 Hz), to 7.15 (d, 1H, J=6.4 Hz), the 7.43 (DD, 1H, J=8.6 Hz, 2.0 Hz), to 7.50 (DD, 1H, J=8,3 Hz, 1.9 Hz), 7,60-7,63 (m, 3H), 7,66 (d, 1H, J=2.2 Hz), 8,53 (d, 1H, J=5,1 Hz), to 8.57 (d, 1H, J=4,9 Hz).185 100%1,68-to 1.79 (m, 2H), 1,82-1,90 (m, 2H), 2,10-of 2.20 (m, 2H), 2,93-a 3.01 (m, 2H), only 3.57 (s, 2H), 3,57-the 3.65 (m, 1H), of 3.73 (s, 3H), with 3.89 (s, 3H), 3,93 (s, 6H), to 4.46 (s, 2H), 6.73 x (d, 2H, J=7,3 Hz), 6,78 (d, 2H, J=the 7.3 Hz), 7,11-7,19 (m, 2H),7,15 (s, 2H), 7,22-7,29 (m, 2H), 7,34-7,40 (m, 1H), 7,58 (s, 1H), 7,73 (s, 1H), 7,94 (t, 1H, J=8,3 Hz), 8,54 (d, 1H, J=5,1 Hz)8,64 (d, 1H, J=4,9 Hz).18688%1,68-to 1.79 (m, 2H), 1,83-of 1.92 (m, 2H), 2,09-of 2.16 (m, 2H), 2,93-a 3.01 (m, 2H), of 3.56 (s, 2H), 3,56-3,62 (m, 1H), of 3.73 (s, 3H), 3,90 (s, 3H), of 3.96 (s, 6H), of 4.44 (s, 2H), of 6.71 (d, 2H, J=9,3 Hz), 6,77 (d, 2H, J=and 9.3 Hz), 7,10-7,16 (m, 1H), 7,17-7,26 (m, 3H), 7,22 (s, 2H), 7,32-7,38 (m, 1H), to 7.59 (s, 1H), 7,73 (s, 1H), 7,92 (dt, 1H, J=8.0 Hz, 2.0 Hz), 8,57-8,61 (m, 2H).187100%of 1.66 and 1.80 (m, 2H), 1,83-of 1.93 (m, 2H), 2,10-of 2.20 (m, 2H), 2,92-to 3.02 (m, 2H), 3,53-the 3.65 (m, 1H), only 3.57 (s, 2H), of 3.73 (s, 3H), of 4.44 (s, 2H), of 6.71 (d, 2H, J=9.0 Hz), 6,78 (d, 2H, J=9,3 Hz), 7,10-to 7.18 (m, 2H), 7,19-7,29 (m, 4H), 7,32-7,40 (m, 2H), 7,73 (s, 2H), to $ 7.91 (DD, 1H, J=8,1 Hz, 1.4 Hz), 7,95 (DD, 1H, J=7,6 Hz, 1.5 Hz), at 8.60 (d, 1H, J=4.9 Hz), 8,64 (d, 1H, J=5,1 Hz).188F96%1,67 and 1.80 (m, 2H), 1,82-of 1.92 (m, 2H), 2,10-of 2.20 (m, 2H), 2.91 in-a 3.01 (m, 2H), of 3.56 (s, 2H), 3,56-3,61 (m, 1H), of 3.73 (s, 3H), with 3.89 (s, 3H), 3,93 (s, 6H), to 4.46 (s, 2H), 6.73 x (d, 2H, J=9,3 Hz), 6,78 (d, 2H, J=and 9.3 Hz), 7,06-7,19 (m, 2H), 7,15 (s, 2H), 7,20-7,26 (m, 1H), 7,38 was 7.45 (m, 1H), 7,56 (s, 1H), 766-7,78 (m, 3H), 8,54 (d, 1H, J=5,1 Hz), 8,61 (d, 1H, J=4,9 Hz).18992%1,65-of 1.78 (m, 2H), 1,79-of 1.92 (m, 2H), 2.21 are of 2.26 (m, 2H), 2,90-a 3.01(m, 2H), of 3.56 (s, 2H), 3,56-3,63 (m, 1H), of 3.73 (s, 3H), 3,90 (s, 3H), of 3.96 (s, 6H), of 4.44 (s, 2H), 6,72 (d, 2H, J=9,3 Hz), 6,78 (d, 2H, J=9,3 Hz), was 7.08 (dt, 1H, J=8,3 Hz, 1.7 Hz), 7.18 in-7,40 (m, 2H), 7,22 (s, 2H,), 7,37-the 7.43 (m, 1H), 7,56-7,72 (m, 4H), 8,55 at 8.60 (m, 2H).19055%1,66-to 1.79 (m, 2H), 1,80 is 1.91 (m, 2H), 2,10-of 2.20 (m, 2H), 2,88-a 3.01 (m, 2H), 3,50-3,66 (m, 1H), of 3.56 (s, 2H), of 3.73 (s, 3H), of 4.45 (s, 2H), 6,72 (d, 2H, J=8.5 Hz), 6,79 (d, 2H, J=9.0 Hz),? 7.04 baby mortality-7,13 (m, 2H), 7,19-7,25 (m, 2H), 7,35-7,46 (m, 2H), 7,62-7,79 (m, 6H), to 8.57 (d, 1H, J=5,1 Hz), 8,61 (d, 1H, J=4,9 Hz).191100%1,68-to 1.79 (m, 2H), 1,82 is 1.91 (m, 2H), 2,10-2,19 (m, 2H), 2,92-3,00 (m, 2H), 3,55 (s, 2H), 3,56-3,63 (m, 1H), of 3.73 (s, 3H), with 3.89 (s, 3H), 3,93 (s, 6H), of 4.45 (s, 2H), 6.73 x (d, 2H, J=9,3 Hz), 6,78 (d, 2H, J=and 9.3 Hz), 7,11-7,19 (m, 4H), to 7.15 (s, 2H), EUR 7.57 (s, 1H), 7,63 (s, 1H), 7,92 shed 8.01 (m, 2H), 8,54 (d, 1H, J=5,1 Hz), 8,58 (d, 1H, J=5,1 Hz).192100%1,68-to 1.79 (m, 2H), 1,83-of 1.92 (m, 2H), 2,11-2,19 (m, 2H), 2,93-a 3.01 (m, 2H), of 3.56 (s, 2H), 3,57-3,62 (m, 1H), of 3.73 (s, 3H), 3,90 (s, 3H), of 3.96 (s, 6H), 4,43, (s, 2H), 6,72 (d, 2H, J=9,3 Hz), 6,78 (d, 2H, J=9,3 Hz), 7,10-7,22 (m, 4H), 7,22 (s, 2H), 7,54-7,66 (m, 2H), 7,88-7,94 (m, 2H), 8,55 (d, 1H, J=4.9 Hz), 8,58 (d, 1H, J=4,9 Hz).19390%of 1.66 and 1.80 (m, 2H), 1,83 is 1.91 (m, 2H), 2,10-2,19 (m, 2H), 2,92-3,00 (m, 2H), 3,50-3,66 (m, 1H), 3,55 (s, 2H), of 3.73 (s, 3H), of 4.44 (s, 2H), 6,72 (d, 2H, J=9,3 Hz), 7,78 (d, 2H, J=9,3 Hz), 7,09-7,20 (m, 6H), 7,62 (s, 1H), 7,63 (s, 1H), 7,89-of 8.00 (m, 4H), 8,55 (d, 1H, J=5,1 Hz), 8,58 (d, 1H, J=4,9 Hz). 19436%1,68 and 1.80 (m, 2H), 1,82-1,90 (m, 2H), 2,11-2,19 (m, 2H), 2.91 in-2,99 (m, 2H), 3,55 (s, 2H), 3,56-3,62 (m, 1H), of 3.73 (s, 3H), with 3.89 (s, 3H), 3,93 (s, 6H), of 4.45 (s, 2H), 6.73 x (d, 2H, J=9,3 Hz), 6,78 (d, 2H, J=and 9.3 Hz), to 7.15 (s, 2H), 7,16-7,26 (m, 3H), EUR 7.57 (s, 1H), 7.62mm (s, 1H), 7,71 (W, 1H), 7,80-of 7.90 (m, 1H), 8,54 (d, 1H, J=5,1 Hz), 8,58 (d, 1H, J=4,9 Hz).195100%1,60-1,80 (m, 2H), 1,82 is 1.91 (m, 2H), 2,12-2,19 (m, 2H), 2.91 in-3,00 (m, 2H), of 3.56 (s, 2H), 3,56-to 3.64 (m, 1H), of 3.73 (s, 3H), 3,90 (s, 3H), of 3.96 (s, 6H), of 4.45 (s, 2H), 6,72 (d, 2H, J=9.0 Hz), 6,78 (d, 2H, J=9.0 Hz), 7,17-7,24 (m, 4H), 7,25-7,27 (m, 1H), 7,60 (s, 2H), 7,65 (W, 1H), to 7.77-to 7.84 (m, 1H), 8,53-8,61 (m, 2H).196100%1,66-to 1.79 (m, 2H), 1,82 is 1.91 (m, 2H), 2,09-of 2.20 (m, 2H), 2,90-3,00 (m, 2H), 3,50-the 3.65 (m, 1H), 3,55 (s, 2H), of 3.73 (s, 3H), of 4.44 (s, 2H), 6,72 (d, 2H, J=9,3 Hz), 6,79 (d, 2H, J=9,3 Hz), 7.18 in-7,28 (m, 4H), 7,60 (s, 1H), 7.62mm (s, 1H), 7,63-to 7.68 (m, 1H), 7,70 to 7.75 (m, 1H), to 7.77-7,89 (m, 2H), 8,55 (d, 1H, J=4.9 Hz), 8,58 (d, 1H, J=5,1 Hz).197100%1,68 and 1.80 (m, 2H), 1,82-1,90 (m, 2H), 2,10-of 2.21 (m, 2H), 2,90-3,00 (m, 2H), of 3.56 (s, 2H), 3,56-3,63 (m, 1H), of 3.73 (s, 3H), with 3.89 (s, 3H), 3,93 (s, 6H), 4,56 (s, 2H), 6.73 x (d, 2H, J=9,3 Hz), 6,78 (d, 2H, J=and 9.3 Hz), for 6.81-6.87 in (m, 1H), 7,15 (s, 2H), 7,18 (d, 1H, J=4, 2 Hz), 7,22-7,26 (m, 1H), 7,51-to 7.59 (m, 3H), of 7.65 (s, 1H), 8,54 (d, 1H, J=4.9 Hz), 8,59 (d, 1H, J=5,1 Hz)198100%1,65-to 1.79 (m, 2H), 1,80-of 1.94 (m, 2H), 2,22 was 2.25 (m, 2H), 2,90-3.05 m, 2H), of 3.56 (s, 2H), 3,56-the 3.65 (m, 1H), of 3.73 (s, 3H), 3,90 (s, 3H), of 3.96 (s, 6H), of 4.44 (s, 2H), 6,72 (d, 2H, J=9,2 Hz), 6,78 (d, 2H, J=9,2 Hz), 6,80-6,94 (m, 2H), 7,22 (s, 2H), 7,19-7,28 (m, 1H), 7,45-7,51 (m, 2H), to 7.59 (s, 1H), 7.62mm (s, 1H), 8,56 (d, 1H, J=4.9 Hz), 8,59 (d, 1H, J=5,1 Hz).199100%1,67-to 1.79 (m, 2H), 1,82-of 1.92 (m, 2H), 2,12-of 2.20 (m, 2H), 2,92-to 2.99 (m, 2H), 3,50-the 3.65 (m, 1H), of 3.56 (s, 2H), of 3.73 (s, 3H), of 4.45 (s, 2H), 6,72 (d, 2H, J=9.0 Hz), 6,79 (d, 2H, J=9,3 Hz), 6,80-to 6.88 (m, 2H), 7.23 percent-7,27 (m, 2H), of 7.48 (DD, 2H, J=8,8 Hz, 2.2 Hz), 7,55 (DD, 2H, J=8,8 Hz, 2.2 Hz), 7,63 (s, 1H), 7,65 (s, 1H), to 8.57 (d, 1H, J=4.9 Hz), at 8.60 (d, 1H, J=4,9 Hz).20084%1,68-1, 80 (m, 2H), 1,83-of 1.92 (m, 2H), 2,10-of 2.21 (m, 2H), 2.91 in-3,00 (m, 2H), of 3.56 (s, 2H), 3,57-3,62 (m, 1H), of 3.73 (s, 3H), with 3.89 (s, 3H), 3,93 (s, 6H), of 4.45 (s, 2H), 6.73 x (d, 2H, J=9,3 Hz), 6,78 (d, 2H, J=9,3 Hz), to 7.15 (s, 2H), 7,17 (d, 1H, J=4.9 Hz), 7,20 (d, 1H, J=5,1 Hz), the 7.43 (d, 2H, J=8,3 Hz), EUR 7.57 (s, 1H), 7,65 (s, 1H), to 7.93 (d, 2H, J=8,3 Hz), 8,54 (d, 1H, J=4.9 Hz), 8,59 (d, 1H, J=5,1 Hz).20172%1,65-of 1.78 (m, 2H), 1,82 is 1.91 (m, 2H), 2,10-of 2.16 (m, 2H), 2.91 in-to 3.02 (m, 2H), of 3.56 (s, 2H), 3,56-to 3.64 (m, 1H), of 3.73 (s, 3H), 3,90 (s, 3H), of 3.96 (s, 6H), 4,43 (s, 2H), 6,72 (d, 2H, J=9,3 Hz), 6,78 (d, 2H, J=and 9.3 Hz), 7,17-7,21 (m, 1H), 7,22 (2H, s), 7,41 (d, 2H, J=8.7 Hz), of 7.48 (d, 1H, J=7.8 Hz), to 7.59 (s, 1H), 7,63 (s, 1H) 7,87 (d, 2H, J=8.7 Hz), 8,56 (d, 1H, J=4.9 Hz), 8,58 (d, 1H, J=5,1 Hz).20294%1,67-of 1.88 (m, 2H), 1,83-1,90 (m, 2H), 2,10-2,17 (m, 2H), 2,92-to 2.99 (m, 2H), 3,50-the 3.65 (m, 1H), 3,55 (s, 2H), of 3.73 (s,3H), of 4.44 (s, 2H), 6,72 (d, 2H, J=9.0 Hz), 6,78 (d, 2H, J=9,3 Hz), 7,17-7,22 (m, 2H), 7,39 was 7.45 (m, 4H), 7,63 (s, 1H), 7,65 (s, 1H), 7,88 (d, 2H, J=8.6 Hz), to 7.93 (d, 2H, J=8.5 Hz), 8,56 (d, 1H, J=4.9 Hz), 8,59 (d, 1H, J=4,9 Hz).

Example of getting 226

Synthesis of 4-[N-[3-(3,4,5-trimethoxyphenyl)benzyl]-N-[4-(methylsulphonyl)phenyl]amino]piperidine

Hydrochloride 4-[N-[3-(3,4,5-trimethoxyphenyl)benzyl]-N-[4-(methylthio)phenyl]amino]piperidine (52 mg, obtained in example getting 145) dissolved in dichloromethane (1 ml) and to the resulting solution at 0°add 3-chloroperbenzoic acid (69 mg). After the mixture is allowed to warm to room temperature and 3-hour stirring, add a saturated solution of sodium bicarbonate. After separation of the organic layer the aqueous layer was extracted with chloroform. The combined organic layers washed with saturated salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained pale-yellow oil is used in the next stage without purification.

Example 203

The synthesis of the dihydrochloride of 4-[N-[3-(3,4,5-trimethoxyphenyl)benzyl]-N-[4-(methylsulphonyl)phenyl]amino]-1-[2-(3,4,5-trimethoxyphenyl)pyridine-4-yl]methyl]piperidine

The crude 4-[N-[3-(3,4,5-trimethoxyphenyl)benzyl]-N-[4-(methylsulphonyl)phenyl]amino]piperidine obtained in example getting 226 expose sanitatio with 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (29 mg) by the procedure similar to that described in example 2. After transformation of the obtained free base in the corresponding dihydrochloride receive specified in the title compound as a pale yellow powder.

Yield 23 mg (26% in two stages).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,70-of 1.97 (m, 4H), 2,16-of 2.28 (m, 2H), 2.95 and totaling 3.04 (m, 2H), 2,99 (s, 3H)and 3.59 (s, 2H), 3,82 (s, 3H), a 3.87-of 3.97 (m, 1H), 3,90 (s, 3H), 3,91 (s, 3H), 3,92 (s, 3H), 3.96 points (s, 9H)and 4.65 (s, 2H), 6,59 (s, 1H), 6.75 in (d, 2H, J=9,3 Hz), 7,19-7,30 (m, 7H), 7,39 (DD, 1H, J=7,6 Hz and 7.6 Hz), 7,60 (s, 1H), 7,68 (d, 2H, J=9.0 Hz), at 8.60 (d, 1H, J=4,9 Hz).

Example 204

Synthesis of trihydrochloride 4-[N-(4-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]-1-[[2-(3-methoxyphenyl)pyridine-4-yl]methyl]piperidine

The dihydrochloride of 4-[N-(4-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine (139 mg, see example getting 98) is subjected to interaction with 4-chloromethyl-2-(3-methoxyphenyl)pyridine (70 mg, see example getting 195) according to the method similar to that described in example 2, obtaining mentioned in the title compound in the form of trihydrochloride.

Yield 131 mg (66%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,70-of 1.95 (m, 4H), 2.05 is was 2.25 (m, 2H), 2,90-is 3.08 (m, 2H), 3,45-3,68 (m, 3H), and 3.72 (s, 3H), 3,88 (s, 3), 3,90 (s, 9H), to 4.46 (s, 2H), 6,70-6,85 (m, 4H), of 6.96 (d, 1H, J=8,3 Hz), 7,21 (W, 1H), 7,38 (t, 1H, J=7.8 Hz), 7,55 (t, 1H, J=7.8 Hz), to 7.59 (s, 1H), 7,63 to 7.75 (m, 2H), and 8.50 (s, 1H), 8,62 (the Il, 1H).

Example 205

Synthesis of 4-[N-(4-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]amino]-1-[[2-(3,4-acid)pyridine-4-yl]methyl]piperidine

The dihydrochloride of 4-[N-(4-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine (139 mg, see example getting 98) is subjected to interaction with 4-chloromethyl-2-(3,4-acid)pyridine (80 mg, see example getting 197) according to the method similar to that described in example 2, obtaining mentioned in the title compound in the form of trihydrochloride.

Yield 139 mg (67%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,70-of 1.95 (m, 4H), 2.05 is-of 2.20 (m, 2H), 2,90 was 3.05 (m, 2H), 3.45 points-of 3.60 (m, 3H), of 3.73 (s, 3H), 3,88 (s, 3H), with 3.89 (s, 6H), of 3.94 (s, 3H), of 4.00 (s, 3H), of 4.46 (s, 2H), 6,65 (s, 2H), 6,74-PC 6.82 (m, 4H), 6,94 (d, 1H, J=8,3 Hz), 7,15 (W, 1H), 7,52 (W, 1H), 7,58-7,71 (m, 3H), and 8.50 (s, 1H), to 8.57 (d, 1H, J=5,2 Hz), 8,62 (W, 1H).

Example 206

Synthesis of trihydrochloride 4-[N-(4-forfinal)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]-1-[[2-(3-methoxyphenyl)pyridine-4-yl]methyl]piperidine

The dihydrochloride of 4-[N-(4-forfinal)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine (135 mg, see example getting 183) is subjected to interaction with 4-chloromethyl-2-(3-methoxyphenyl)pyridine (70 mg, see example getting 195) according to the method similar to that described in example 2, obtaining specified in the header of the connection is as trihydrochloride.

The output 178 mg (92%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,73-of 1.95 (m, 4H), 2,10-of 2.25 (m, 2H), 2.93 which was 3.05 (m, 2H), only 3.57 (s, 2H), 3,64 (W, 1H), 3,88 (s, 3H), with 3.89 (s, 9H), 4,51 (s, 2H), 6,66 (s, 2H), 6,70-6,76 (m, 2H), 6.90 to (t, 2H, J=8,3 Hz), of 6.96 (d, 1H, J=8,3 Hz), 7,21 (W, 1H), 7,38 (t, 1H, J=8.0 Hz), 7,54 (d, 1H, J=7.8 Hz), 7,58 (s, 1H), 7,65 (s, 1H), 7,74 (W, 1H), and 8.50 (s, 1H), 8,61 (d, 1H, J=5,1 Hz), 8,65 (W, 1H).

Example 207

Synthesis of trihydrochloride 4-[N-(4-forfinal)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]-1-[[2-(3,4-acid)pyridine-4-yl]methyl]piperidine

The dihydrochloride of 4-[N-(4-forfinal)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine (135 mg, see example getting 183) is subjected to interaction with 4-chloromethyl-2-(3,4-acid)pyridine (80 mg, see example getting 197) according to the method similar to that described in example 2, obtaining mentioned in the title compound in the form of trihydrochloride.

Yield 195 mg (96%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,70-of 1.95 (m, 4H), 2,10-of 2.24 (m, 2H), 2,94-to 3.09 (m, 2H), only 3.57 (s, 2H), 3,64 (W, 1H), 3,88 (s, 3H), with 3.89 (s, 6H), of 3.94 (s, 3H), of 4.00 (s, 3H), 4,51 (s, 2H), 6,65 (s, 2H), 6,69-of 6.78 (m, 2H), 6,86-6,97 (m, 3H), 7,16 (d, 1H, J=4.9 Hz), 7,51 (d, 1H, J=8.5 Hz), 7,60-of 7.70 (m, 3H), and 8.50 (s, 1H), 8,58 (d, 1H, J=4.9 Hz), 8,65 (s, 1H).

Example 208

Synthesis of trihydrochloride 4-[N-(3,4-differenl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]-1-[[2-(3-methoxyphenyl)pyridine-4-yl]methyl]piperidine

The dihydrochloride of 4-[N-(3,4-differenl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine (160 mg, see example getting 176) is subjected to interaction with 4-chloromethyl-2-(3-methoxyphenyl)pyridine (80 mg, see example getting 195) according to the method similar to that described in example 2, obtaining mentioned in the title compound in the form of trihydrochloride.

Yield 130 mg (57%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,73-1,90 (m, 4H), 2,01-of 2.24 (m, 2H), 2,92 was 3.05 (m, 2H), only 3.57 (s, 2H), 3,67 (W, 1H), 3,88 (s, 3H), with 3.89 (s, 3H), 3,90 (s, 6H), to 4.52 (s, 2H), 6,36-6.42 per (m, 1H), 6,50 return of 6.58 (m, 1H), 6,67 (s, 2H), 6,93-7,01 (m, 2H), 7,20 (W, 1H), 7,38 (t, 1H, J=7.8 Hz), 7,52 to 7.62 (m, 2H), 7,62-7,72 (m, 2H), 8,48 (W, 1H), 8,61 (W, 1H), 8,66 (d, 1H, J=2.0 Hz).

Example 209

Synthesis of 4-[N-(4-methylthiophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]-1-[[2-(3-methoxyphenyl)pyridine-4-yl]methyl]piperidine

The dihydrochloride of 4-[N-(4-methylthiophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridine-5-yl]methyl]amino]piperidine (121 mg, see example getting 143) is subjected to interaction with 4-chloromethyl-2-(3-methoxyphenyl)pyridine (55 mg, see example getting 195) according to the method similar to that described in example 2, obtaining specified in the header of the connection.

Yield 71 mg (44%).

1H-NMR (400 MHz, defined as the free base, CDCl3) δ: 1,72 of-1.83 (m, 4H), 2,12-of 2.20 (m, 2H), is 2.37 (s, 3H), of 2.97 (d, 2H, J=10,8 Hz), 56 (s, 2H), 3.75 to-3,81 (m, 1H), 3,86 (s, 3H), a 3.87 (s, 6H), of 4.54 (s, 2H), 6,64-6,69 (m, 3H), 6,94 (DD, 1H, J=7.8 Hz, 1.9 Hz), 7,17-7,26 (m, 4H), 7,35 (t, 1H, J=7.8 Hz), 7,51-7,66 (m, 4H), of 8.47 (s, 1H), 8,59 (d, 1H, J=4.6 Hz), 8,63 (s, 1H).

Example test 1

(inhibitory effect on cell adhesion)

The test is carried out according to the method similar to that described Ross et al. (J. Biol. Chem.,267, 8537-8543 (1992)). More specifically, after cultivation in a 48-hole tablet endothelial cells of the umbilical vein of a person (HUVEC) until confluent growth to add TNFα. 5 hours after the specified add add U937, representing macrophage/historically leukocyte, fluorescently labeled RCN (product of Sigma-Aldrich Co., Ltd.), in number 1×106cells per well. After staying tablet at rest at room temperature for one hour't even U937 wash and are lysed in 1% Triton X-100 to measure the remaining fluorescence intensity (wavelength excitation 480 nm; the wavelength dimension 530 nm). HUVEC and U937 were cultured in EGM-2 (product of Sanko Junyaku K.K.) and RPMI1640 containing 10% FCS (fetal calf serum), respectively. Each investigational agent is added to HUVEC after addition of TNFα and U937 24 hours before the start of testing on cell adhesion. The degree of inhibition is determined in accordance with equation (a-C)/(a-b)×100(%)where And is the number of U937 cells adhered to HUVEC stimulated TNF without adding ISS is ebimage agent, In equal to the number of U937 cells adhered to HUVEC, not stimulated TNFα without adding the investigational agent and is equal to the number of U937 cells adhered to HUVEC stimulated TNFα with the addition of the investigational agent. The results presented in the table. As control compounds were simultaneously evaluated the investigational compound 1 described in patent application laid Japan No. 9-143075, and dilazep described in patent application laid Japan No. 11-92382.

ExampleIC50(µm)
30,3
50,2
70,3
100,04
130,03
160,3
190,3
230,03
290,03
360,2
400,2
420,07
670,09
880,07
890,09
1110,08
1570,09
The analyzed connection 110
Dilazep>10

As mentioned above, the compound of the present invention differs in that the cyclic amine contains phenylpyridine or biphenylene groups at both ends of the molecule.

Inhibitory effect on cell adhesion compounds of cyclic amine containing peredelnye groups at its both ends obtained in example getting 91, determined in accordance with the above methodology. In the result, this compound did not show inhibitory effect on cell adhesion even at concentrations as high as 10 ám.

Below are examples of specific compositions.

Example compositions 1(the drug in the form of capsules)
The compound obtained in example 1330 mg
Microcrystalline cellulose30 mg
Lactose57 mg
Magnesium stearate3 mg
The total number of120 mg

The above ingredients are mixed according to the method known in the field per se, and then placed in gelatin capsules, receiving the drugs in the form of capsules.

Example composition 2(the drug in pill form)
Obedinenie, obtained in example 1330 mg
Starch44 mg
Starch (for gluing)5.6 mg
Magnesium stearate0.4 mg
Calcium carboxymethylcellulose20 mg
The total number of100 mg

The above ingredients are mixed according to the method known in the field per se, getting drugs in tablet form.

An example of the composition 3(drug injection)

The compound obtained in example 13 (100 mg) and sodium chloride (900 mg) dissolved in distilled water (80 ml) for injection and the resulting solution was added distilled water to total amount 100 ml of the Obtained diluted solution is sterilized by filtration and then divided into doses and placed into 10 vials, after which the ampoule sealed, receiving drugs for injection.

Industrial applicability

As indicated above, the compounds (1) in accordance with the present invention show inhibitory effect against cell adhesion, and cell infiltration, and can be useful as drugs for the prevention or treatment of Allergy, asthma, rheumatism, arteriosclerosis, inflammatory disease, Sjogren syndrome, etc.

1. The cyclic connection is about Amin, represented by the following General formula (1):

where each of R1, R2and R3independently represents a hydrogen atom, a halogen atom, a hydroxy-group, With1-C8alkoxygroup;

each of W1and W2independently represents N or CH;

X represents O, NR4, CONR4or NR4CO;

R4represents a hydrogen atom, a C1-C8alkyl, C3-C6quinil, unsubstituted or substituted phenyl, unsubstituted benzyl, unsubstituted of indanyl, where the substituent(s) represents phenyl(comply) with a 1 to 3 groups or atoms selected from C1-C8of alkyl, C1-C8alkoxy, C1-C8alkoxy substituted by 1-3 halogen atoms, C1-C8-allylthiourea,1-C8alkylsulfonyl, halogen atom, triptorelin group and C1-C3alkylenedioxy; and

each of l, m and n represents the number 0 or 1, its pharmaceutically acceptable salt or hydrate.

2. The compound according to claim 1, where W2represents N.

3. Drug, possess inhibitory effect on cell adhesion and/or cell infiltration, containing as active ingredient a compound according to any one of claims 1 and 2.

4. Drug medium is in according to claim 3 for the treatment of diseases, selected from allergies, asthma, inflammation, rheumatic diseases, arteriosclerosis and Sjogren syndrome.

5. Pharmaceutical composition having inhibitory effect on cell adhesion and/or cell infiltration, containing a compound according to any one of claims 1 and 2, and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to claim 5 for the treatment of diseases selected from allergies, asthma, inflammation, rheumatic diseases, arteriosclerosis and Sjogren syndrome.

Priority points and features:

30.08.2001 according to claims 1-6, variations in the definitions of the radicals R1, R2and R3, W1and W2, R4, l, m and n;

26.10.2001 according to claims 1-6, variations in the definitions of the radicals R1, R2and R3, W1and W2, R4, l, m and n;

28.03.2002 according to claims 1-6, variations in the definitions of the radicals R1, R2and R3, W1and W2, R4, l, m and n;

10.07.2002 according to claims 1-6, variations in the definitions of the radicals R1, R2and R3, W1and W2, R4, l, m and n.



 

Same patents:

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes derivatives of 1H-imidazole-4-carboxamide of the formula (I): wherein R represents phenyl, 2-pyridinyl, 3-pyridinyl that can be substituted; R1 means phenyl, 5-membered aromatic heterocyclic ring comprising one nitrogen atom (N) as a heteroatom that can be substituted; R2 means hydrogen atom (H), (C1-C8)-alkyl; R3 represents (C2-C8)-alkyl, (C1-C8)-alkoxy-group, (C3-C8)-cycloalkyl, benzyl group, aromatic ring that can be substituted; R4 means hydrogen or halogen atom, cyano-group, sulfamoyl, methanesulfonyl, methylsulfanyl or (C1-C4)-alkyl. Also, invention describes methods for synthesis of these compounds and pharmaceutical compositions. Derivatives of 1H-imidazole-4-carboxamide are effective agonists, partial agonists or antagonists of cannabinoid CB1-receptors that can be useful in treatment of psychic and neurological diseases and other diseases with involving cannabinoid neurotransmission.

EFFECT: valuable biological and medicinal properties of compounds and pharmaceutical compositions.

11 cl, 1 tbl, 113 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 4-phenyltetrahydroisoquinoline of the general formula (I): wherein R1, R2, R3 and R4 mean independently of one another hydrogen (H), fluorine (F), chloride (Cl), bromine (Br) atoms, CaH2a+1 wherein one or more atoms H are substituted with F, -NR11R12 or -SOj-R15 wherein a = 1-8; R11 and R12 mean independently of one another H, CeH2e+1 or CrrH2rr-1 wherein e = 1-4; rr = 3, 4, or in common with nitrogen atom to which they are bound form a cycle chosen from group consisting of pyrrolidinyl, piperidinyl, N-methylpiperazinyl, piperazinyl or morpholine; j = 1 or 2; R15 means CkH2k+1 wherein k = 1-8; R5 means CpH2p+1 or CssH2ss-1; p = 1-8; ss = 3-8; R6 means H; R7, R8 and R9 mean independently of one another mean -SOwR23, -NR32COR30, NR32CSR30, -NR32SObbR30, H, F, Cl, Br, -OH, -NH2, CeeH2ee+1, -NR40R41, -CONR40R41 or -COOR42 wherein w = 0, 1 or 2; bb = 2 or 3; R23 means NR25R26 wherein R25 and R26 mean independently of one another H or CzH2z+1, CzzH2zz-1 wherein z = 1-8; zz = 3-8 wherein in CzH2z+1 and CzzH2zz-1 one or more H atoms are substituted with fluorine atom and one or more CH2-groups are substituted with -C(=O) or NR27 wherein R27 means H or CaaH2aa+1 wherein aa = 1-4; or R25 and R26 in common with nitrogen atom to which they are bound form 5-, 6- or 7-membered cycle; R30 means H, CccH2cc+1, CyyH2yy-1, pyrrolydinyl, piperidinyl wherein in their cycles CH2-group can be substituted with oxygen atom (O) or -NR33; R32 and R33 mean independently of one another H or ChH2h+1 wherein cc = 1-8; yy = 3-8; h = 1-8 wherein in the group ChH2h+1 one or more hydrogen atoms are substituted with fluorine atom, and in the groups CccH2cc+1 and CyyH2yy-1 one or more hydrogen atoms can be substituted with fluorine atom, and CH2-group can be substituted with O or -NR31 wherein NR31 means H, methyl, ethyl, acetyl or -SO2CH3; or R30 means 6-membered heteroaryl with 1-4 nitrogen atoms, 0 or 1, S-atoms or 0, or 1 O-atom that represents unsubstituted or substituted with up to three substitutes chosen from group consisting of F, Cl, Br, J, CooH2oo+1 wherein one or more hydrogen atoms can be substituted with fluorine atom, -NO2 or -NR70R71 wherein oo = 1-8; R70 and R71 mean independently of one another H, CuuH2uu+1 or -COR72 wherein uu = 1-8; R72 means H, CvvH2vv+1 wherein vv = 1-8; ee = 1-8; R40 and R41 mean independently of one another H, CttH2tt+1 or -C(NH)NH2 wherein tt = 1-8 and wherein in the group CttH2tt+1 one or more CH2-groups can be substituted with NR44 wherein R44 means CggH2gg+1 wherein gg = 1-8; R42 means H or ChhH2hh+1 wherein hh = 1-8 being, however, two substitutes from group R7, R8 and R9 can't mean -OH simultaneously, and at least one residue from R7, R8 and R9 must be chosen from group consisting of -CONR40R41, -OvSOwR23, -NR32COR30, -NR32CSR30 and -NR32SObbR30. Also, invention relates to using above given compounds for preparing a medicinal agent. Also, invention considers a medicinal agent representing inhibitor of sodium-proton exchange of subtype III (NHE3) based on proposed compounds. Invention provides synthesis of novel compounds, a medicinal agent based on thereof for aims of treatment of such diseases as nervous system ischemia, insult and brain edema, in treatment of snore, shock, impaired respiratory impulse, as purgative agents, as agents against extoparasites, for prophylaxis of gall stones formation, as anti-atherosclerotic agents, agents against diabetes mellitus later complications, cancer diseases, fibrous diseases, endothelial dysfunction, hypertrophies and hyperplasia of organs and others.

EFFECT: valuable medicinal properties of compounds and medicinal agents.

21 cl, 15 tbl, 221 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of quinoline of the formula (I): wherein R1 and R2 are chosen independently from hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, alkylcarbonyl, cycloalkylcarbonyl, phenyl, unsubstituted benzyl or benzyl substituted with halogen atom, cyano-group, trifluoromethyl, alkyl, alkoxy-group, benzylcarbonyl, pyridinyl, furyl, thiophenyl, indanyl, phenyl-SO2-, pyridinyl-SO2-, thiophenyl-SO2; or R1 and R2 in common with atom N to which they are added form piperidino-group, pyrrolidinyl, morpholinyl, azepanyl, 3,4-dihydro-1H-isoquinolinyl, and wherein heterocyclic ring is optionally substituted with one or some substitutes chosen independently from alkyl and alkoxy-group; R3 represents hydrogen atom, alkyl; R4 represents hydrogen atom; A in common with nitrogen atom that is added to quinoline ring represents pyrrolidinyl, azepanyl, and ring A is optionally substituted with one-three substitutes chosen independently from alkoxy-group, hydroxyalkyl, alkoxyalkyl. Also, invention describes methods of synthesis of quinoline derivatives of the formula (I). Proposed compounds can be used as components of pharmaceutical formulations in treatment or prophylaxis of arthritis, cardiovascular diseases, diabetes mellitus, renal insufficiency, disorders in food eating and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 122 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of quinazoline of the general formula (I): , wherein R1 represents -O-R4 or -N(R5)(R6); R2 represents alkyl; R3 represents hydrogen atom; R4 represents hydrogen atom, alkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, pyridinylalkyl substituted with cyano-group or halogen atom, cycloalkylalkyl; R5 and R6 are chosen independently from hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, arylcarbonyl, alkoxyalkyl, hydroxyalkyl, pyridinyl, furanylcarbonyl, or R5 and R6 in common with nitrogen atom (N) to which they are added form a 5-10-membered heterocyclic ring that comprises optionally the second heteroatom chosen from nitrogen or oxygen atoms and wherein heterocyclic ring is substituted optionally with one or some substitutes chosen independently from alkyl or alkoxy-group; A represents 5-7-membered heterocyclic ring comprising nitrogen atom added to quinazoline ring, and optionally the second heteroatom that is chosen from oxygen, sulfur or nitrogen atoms and wherein ring A is substituted optionally with one or some substitutes chosen independently from alkoxy-, hydroxy-group, hydroxyalkyl, alkoxyalkyl, and their pharmaceutically acceptable salts and esters. Also, invention relates to a method for synthesis of compounds of the formula (I) and to pharmaceutical composition possessing antagonistic activity with respect to neuropeptide Y. Invention provides synthesis of novel biologically active compounds and pharmaceutical compositions based on thereof possessing antagonistic activity with respect to neuropeptide Y.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 34 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for improved synthesis of pharmacologically active compound of the formula (A): Method involves the following steps: (a) interaction of compound of the formula (I): with alkaline metal nitrite in the presence of suitable acid to yield compound of the formula (VII): (b) coupling compound of the formula (VII) with compound of the formula (VI): to yield compound of the formula (V): and (c) removal of protection from compound of the formula (V) to yield compound of the formula (A). Compound of the formula (A) possesses property of antagonist of R2T receptors, high metabolic stability and bioavailability. Also, invention relates to a novel intermediate substance of the formula (I) and methods for its synthesis, and to novel intermediate substances used in its synthesis.

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

12 cl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts wherein rings A and B represent optionally substituted benzene rings; R1 represents alkyl, hydroxyl, thiol, carbonyl, sulfinyl, unsubstituted or substituted sulfonyl group and others; R2 represents hydrogen atom, hydroxyl, amino-group, alkyl, unsubstituted or substituted carbonyl group or halogen atom; Z represents oxygen atom or group -N(R3)- wherein R3 and R4 represent hydrogen atom or alkyl group under condition that N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidineamine is excluded. Compounds of the formula (I) or their salts possess antagonistic activity with respect to tachykinin NK1-receptors and can be used in medicine in treatment and prophylaxis of inflammatory, allergic diseases, pain, migraine, diseases of central nervous system, digestive organs and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

18 cl, 138 tbl, 527 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (U): or its pharmaceutically acceptable salt wherein X is chosen from -NR1, sulfur atom (S); Y1 and Y2 represent oxygen atom (O); Z represents O; m = 0 or 1; A is chosen from a direct bond, (C1-C6)-alkyl; R1 is chosen from hydrogen atom (H), alkyl; R3 and R6 are chosen independently from H, alkyl, halogenalkyl, heteroalkyl, cycloalkyl, aryl, cycloalkyl-alkyl, cycloalkyl-heteroalkyl, heterocycloalkyl-alkyl, alkylaryl, heteroaryl, arylalkyl, aryl-heteroalkyl, heteroaryl-alkyl, heteroaryl-heteroalkyl or heterocycloalkyl; R4 is chosen from H, alkyl; R5 represents a bicyclic or tricyclic group comprising two or three ring structure wherein each of that comprises from 3 to 7 ring atoms chosen independently from cycloalkyl, aryl, heterocycloalkyl or heteroaryl wherein each ring structure is joined with the next ring structure through a direct bond, through -O-, through -S-, through (C1-C6)-alkyl, through (C1-C6)-heteroalkyl, through (C1-C6)-alkynyl, through carboxy-(C1-C6)-alkyl, or it is condensed with the next ring structure wherein heteroalkyl represents heteroatom-substituted alkyl comprising one heteroatom chosen from N, O and S. Also, invention describes compounds of formulae (Ib), (Ic) and (Id) given in the invention description, pharmaceutical composition and using these compounds in preparing a medicine for using in treatment of disease or state mediated by one or more enzymes representing metalloproteinase. Represented compounds are useful as inhibitors of metalloproteinases and especially as inhibitors of MMP12.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

17 cl, 3 tbl, 17 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I): wherein X represents -NR1; Y1 and Y2 represent oxygen atom (O); Z is chosen from -SO2N(R6), -N(R7)SO2; m = 1 or 2; A is chosen from a direct bond, (C1-C6)-alkyl; R1 represents hydrogen atom (H); each R2 and R3 is chosen independently from H, alkyl, aryl, alkylaryl, arylalkyl; each R4 is chosen independently from H, (C1-C3)-alkyl; R6 is chosen from H, alkyl, aryl, heteroaryl, alkylaryl, alkyl-heteroaryl, arylalkyl, heteroaryl-alkyl; R2 and R6 can join to form a ring comprising up to 7 ring atoms, or R3 and R6 can join to form a ring comprising up to 7 ring atoms, or R4 and R6 can join to form a ring comprising up to 7 ring atoms; R5 represents monocyclic, bicyclic or tricyclic group comprising one or two ring structures wherein each of that comprises up to 7 ring atoms chosen independently from cycloalkyl, aryl, heterocycloalkyl or heteroaryl and possibly substituted; when R5 represents bicyclic group then each ring structure is bound with the next ring structure through a direct bond, through -O-, through (C1-C6)-alkyl or condensed with this next ring structure; R7 is chosen from (C1-C6)-alkyl. Also, invention describes compound of the formula (II) given in the description, pharmaceutical compositions and using compound of the formula (I) or the formula (II) in preparing a medicine for using in treatment of disease or state mediated by one or more enzymes and representing metalloproteinase. Represented compounds are useful as inhibitors of metalloproteinases and especially as inhibitors of MMP12.

EFFECT: valuable medicinal and biochemical properties of inhibitors and pharmaceutical compositions.

20 cl, 3 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anthranilic acid amides with a by-side heteroarylsulfonyl chain. Invention describes compounds of the formula (I): wherein R1 means compounds of formulae: or wherein A means -CnH2n- wherein n = 0, 1, 2, 3, 4 or 5; D means a bond or -O-; E means -CmH2m- wherein m = 0, 1, 2, 3, 4 or 5; R8 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon atoms or -CpH2p-R14 wherein p = 1, 2, 3, 4 or 5; R14 means phenyl or heteroaryl wherein phenyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting fluorine (F), chlorine (Cl), bromine (Br) and iodine (J) atom, alkyl with 1, 2, 3 or 4 carbon atoms; R9 means hydrogen atom or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms; R10 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon toms, phenyl, naphthyl or heteroaryl wherein phenyl, naphthyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R11 means cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl, furyl, pyridyl, pyrazinyl wherein phenyl, furyl, pyridyl, pyrazinyl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms; R12 means alkyl with 1, 2, 3 or 4 carbon atoms, alkynyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl or heteroaryl; R13 means -CpH2p-R14 wherein p = 0, 1, 2, 3, 4 or 5; R15 means cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms; R2 means hydrogen atom; R3 means heteroaryl wherein heteroaryl is unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R4, R5, R6 and R7 mean independently of one another hydrogen atom, F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms, and their pharmaceutically acceptable salts also. Also, invention describes pharmaceutical composition containing compounds of the formula (I) possessing the effect blocking Kv1.5-channel. Proposed compounds can be used in treatment and prophylaxis of diseases mediated by K+-channel.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

20 cl, 4 tbl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula: or their pharmaceutically acceptable salts wherein Ra - R8a mean phenyl; R8b means pyridyl, or R8 means naphthyl; R1 means hydrogen atom; R2 - R9, R10, R11 mean substituted phenyl; R9, R10, R11 mean substituted pyridyl or pyrimidyl; R9, R10, R11 mean substituted pyridyl-N-oxide or pyrimidyl-N-oxide; R12, R13 mean substituted oxazolyl, naphthyl, fluorenyl, compounds of formulae , or ; R3 means hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C6)-alkyl; R8 means phenyl; R8 means phenyl-(C1-C6)-alkyl, or R8 means thienyl-(C1-C6)-alkyl; R4, R5, R7 and R13 mean independently hydrogen atom or (C1-C6)-alkyl; R6 means hydrogen atom or (C1-C6)-alkyl; R8 means 1-3 substitutes that mean independently hydrogen atom, halogen atom, (C1-C6)-alkoxyl or -CF3; R8a means 1-3 substitutes that mean independently hydrogen atom, halogen atom, -CF3, -CF3O, -CN; R14 means phenyl, -NHCOCF3 and imidazolyl; R8b means 1-3 substitutes that mean independently hydrogen atom or halogen atom; R9 and R10 mean independently (C1-C6)-alkyl, halogen atom, -NR17R18, -OH, -CF3 and -OCH3; R11 means R9, hydrogen atom, phenyl, -NO2, -CN, -CH2F, -CHF2, -CHO, -CN=NOR17, pyridyl, pyridyl-N-oxide, pyrimidinyl, pyrazinyl, -N(R17)CONR18R19, -NHCONH-(chloro-(C1-C6)-alkyl), -NHCONH-((C3-C10)-cycloalkyl-(C1-C6)-alkyl), -NHCO-(C1-C6)-alkyl, -NHCOCF3, -NHSO2N-((C1-C6)-alkyl)2, -NHSO2-(C1-C6)-alkyl, -N(SO2CF3)2, -NHCO2-(C1-C6)-alkyl, (C3-C10)-cycloalkyl, -SR20, -OSO2-(C1-C6)-alkyl, -SO2CF3, hydroxy-(C1-C6)-alkyl, -CONR17R18, -CON(CH2CH2-O-CH3)2, -OCONH-(C1-C6)-alkyl, -Si(CH3)3 or -B(OC(CH3)2)2; R12 means (C1-C)-alkyl or R14-phenyl; R14 means 1-3 substitutes that mean independently hydrogen, (C1-C6)-alkyl, -CF3, -CO2R17, -CN, (C1-C6)-alkoxyl and halogen atom; R15 and R16 mean independently hydrogen atom and (C1-C6)-alkyl, or R15 and R16 mean in common (C2-C5)-alkylene group and in common with carbon atom to which they are bound form (C3-C6)-spiran ring; R17, R18 and R19 mean independently hydrogen atom or (C1-C6)-alkyl; R20 means (C1-C6)-alkyl. Also, invention describes pharmaceutical compositions containing these compounds and using novel compounds as CCR5 antagonists in treatment of HIV infection, arthritis, asthma, cerebrospinal sclerosis and other diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

29 cl, 30 tbl, 31 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I): or its pharmaceutically acceptable salts or esters hydrolyzed in vivo and possessing properties of selective inhibitor of cyclin-dependent kinases, such as CDK-2, and inhibiting proliferation of cells. Compounds can be used in preparing medicinal agents used in treatment of cancer diseases. In compounds of the formula (I) R1 represents halogen atom; p = 0 or 1; R2 represents sulfamoyl or group B-E-; q = 0 or 1 wherein p + q = 1; R3 represents hydrogen atom, (C1-C6)-alkyl wherein R3can be substituted optionally at carbon atom with one or some M; R4 represents (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl wherein R4 can be substituted optionally with one or some M; or R3 and R4 taken with nitrogen atom to which they are bound form heterocyclic ring substituted optionally at carbon atom with one or some M wherein if indicated heterocyclic ring comprises group -NH then nitrogen atom can be substituted optionally with group chosen from Q; B is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein B can be substituted optionally at carbon atom with one or some D and wherein indicated heterocyclic group comprises group -NH- then nitrogen atom can be substituted optionally with group chosen from G; E represents -S(O)r- or -N(Ra)SO2- wherein Ra represents hydrogen atom or (C1-C6)-alkyl and r = 2; D is chosen independently from halogen atom, nitro-, cyano-, hydroxy-, amino-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N-(C1-C6)-alkylamino-, N,N-((-C1-C6)-alkyl)2-amino-, (C1-C6)-alkanoylamino-group, (C1-C6)-alkyl-S(O)a wherein a = 0-2, wherein D can be substituted optionally at carbon atom with one or some V; M is chosen independently from halogen atom, nitro-, cyano-, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N,N-((C1-C6)-alkyl)2-amino-group, (C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl or heterocyclic group wherein M can be substituted optionally at carbon atom with one or some P; P, X and Y are chosen independently from hydroxy-group, methyl, methoxy-, dimethylamino-group; G and Q are chosen independently from (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkoxycarbonyl wherein Q can be substituted optionally at carbon atom with one or some X. Also, invention relates to methods for synthesis of compounds, preparing pharmaceutical compositions based on thereof and to a method for inhibition of proliferation of cells.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions, improved method of inhibition, improved method of synthesis of compounds.

15 cl, 2 sch, 133 ex

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention describes compound of the formula (I): wherein B represents oxygen atom (O) or -NR1; J represents 5-membered heteroaromatic ring representing group of the formula (J-1): optionally substituted with 1-2 radicals R5 wherein Q represents -NR5; each X, Y and Z represents independently nitrogen atom (N), -CH or - CR5; B1 represents O; R2 represents hydrogen atom (H) or (C1-C6)-alkyl optionally substituted with one halogen atom, or (C2-C6)-alkynyl; or R1 and R2 taken in common form a binding chain consisting of 2-3 members and comprising at least one carbon atom, optionally comprising one carbon atom as -C(=O), optionally substituted with R3 wherein R3 represents (C1-C2)-alkyl; each R represents independently H, (C1-C6)-alkyl, halogen atom or -CN; each R5 represents independently (C1-C6)-halogenalkyl or halogen atom, or each ring is substituted with one R6; each R6 represents independently halogen atom; n represents a whole number 1 or 2. Also, invention describes a composition used for control of insects and comprising the biologically effective dose of compound of the formula (I) and at least one additional component chosen from group comprising surface-active substances, solid and liquid diluting agents, and methods for control of insects with using compositions based on compounds of the formula (I) and compounds of the formula (I). Proposed compounds of the formula (I) possess insecticide activity and can be used in agriculture.

EFFECT: valuable insecticide properties of compounds and compositions.

11 cl, 26 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of quinoline of the formula (I): wherein R1 and R2 are chosen independently from hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, alkylcarbonyl, cycloalkylcarbonyl, phenyl, unsubstituted benzyl or benzyl substituted with halogen atom, cyano-group, trifluoromethyl, alkyl, alkoxy-group, benzylcarbonyl, pyridinyl, furyl, thiophenyl, indanyl, phenyl-SO2-, pyridinyl-SO2-, thiophenyl-SO2; or R1 and R2 in common with atom N to which they are added form piperidino-group, pyrrolidinyl, morpholinyl, azepanyl, 3,4-dihydro-1H-isoquinolinyl, and wherein heterocyclic ring is optionally substituted with one or some substitutes chosen independently from alkyl and alkoxy-group; R3 represents hydrogen atom, alkyl; R4 represents hydrogen atom; A in common with nitrogen atom that is added to quinoline ring represents pyrrolidinyl, azepanyl, and ring A is optionally substituted with one-three substitutes chosen independently from alkoxy-group, hydroxyalkyl, alkoxyalkyl. Also, invention describes methods of synthesis of quinoline derivatives of the formula (I). Proposed compounds can be used as components of pharmaceutical formulations in treatment or prophylaxis of arthritis, cardiovascular diseases, diabetes mellitus, renal insufficiency, disorders in food eating and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 122 ex

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (1): and their salts wherein values R1, k, Ar, n, j, Y, R and R2 are determined in the invention claim. Novel compounds are able to modulate activity of chemokine receptors. Also, invention relates to using indicated compounds for treatment of human immunodeficiency virus or feline immunodeficiency virus and to a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 100 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of quinazoline of the general formula (I): , wherein R1 represents -O-R4 or -N(R5)(R6); R2 represents alkyl; R3 represents hydrogen atom; R4 represents hydrogen atom, alkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, pyridinylalkyl substituted with cyano-group or halogen atom, cycloalkylalkyl; R5 and R6 are chosen independently from hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, arylcarbonyl, alkoxyalkyl, hydroxyalkyl, pyridinyl, furanylcarbonyl, or R5 and R6 in common with nitrogen atom (N) to which they are added form a 5-10-membered heterocyclic ring that comprises optionally the second heteroatom chosen from nitrogen or oxygen atoms and wherein heterocyclic ring is substituted optionally with one or some substitutes chosen independently from alkyl or alkoxy-group; A represents 5-7-membered heterocyclic ring comprising nitrogen atom added to quinazoline ring, and optionally the second heteroatom that is chosen from oxygen, sulfur or nitrogen atoms and wherein ring A is substituted optionally with one or some substitutes chosen independently from alkoxy-, hydroxy-group, hydroxyalkyl, alkoxyalkyl, and their pharmaceutically acceptable salts and esters. Also, invention relates to a method for synthesis of compounds of the formula (I) and to pharmaceutical composition possessing antagonistic activity with respect to neuropeptide Y. Invention provides synthesis of novel biologically active compounds and pharmaceutical compositions based on thereof possessing antagonistic activity with respect to neuropeptide Y.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 34 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of bipiperidine of the formula (I): , wherein X means a direct bond, -CH2-, -CH2-CH2- or -CHR9-; R1 means optionally R10- and/or R11-substituted phenyl, optionally R10- and/or R11-substituted heteroaryl, N-oxide of optionally R10- and/or R11-substituted heteroaryl or optionally R10- and/or R11-substituted naphthyl; R2 has one of values given for R1, or it means optionally R10-substituted (C1-C6)-alkyl, optionally R10-substituted (C3-C6)-cycloalkyl, optionally R10-substituted adamantyl; R3 has one of values given for R1; each radical among R4, R5, R6 and R7 means hydrogen atom; R8 means hydrogen atom or (C1-C6)-alkyl; R9 means (C1-C6)-alkyl or (C3-C6)-cycloalkyl; R10 represents from 1 to 4 substitutes chosen independently from (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C2-C6)-alkoxyalkyl, (C1-C6)-halidealkyl, (C3-C6)-cycloalkyl, phenyl, heteroaryl, heteroaryl N-oxide, fluorine, chlorine, bromine, iodine atoms, hydroxyl, groups -OR9, -CONH2, -CONHR9, -CONR9R9, -COOH, -CF3, -CHF2, -CN, -NH2, -NHR9, -NHC(O)R9, -NR9C(O)R9; R11 represents two adjacent substitutes that form anellated 4-7-membered nonaromatic ring optionally comprising up to two heteroatoms chosen independently from nitrogen oxygen and sulfur atoms; Y means a direct bond, -C(O)-, -S(O2)-, -CH2-. Proposed compounds can be in free form as a salt. Compounds of the formula (I) and their salts possess antagonistic activity with respect to CCR5-receptors and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 6 tbl, 83 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to derivatives of 2-aminonicotine amide of the formula (I): , to methods of their synthesis and a pharmaceutical composition based on thereof inhibiting activity of receptor tyrosine kinase vessel endothelial growth factor (VEGF) and to corresponding method for inhibition of activity of VEGF-receptor tyrosine kinase. It is suggested that this activity will allow offering the curative effect in proliferative diseases associated with angiogenesis, in particular, in treatment of tumors, retinopathy or age degeneration of yellow (corneal) spot.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 42 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: organic chemistry, medicine, oncology, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel tricyclic compounds, their pharmaceutically acceptable salts and solvates useful for inhibition of activity of farnesyl-protein-transferase. Invention describes compound of the formula (1.0): or its pharmaceutically acceptable salt or solvate wherein one among a, b, c and d means nitrogen atom (N) or -N+O-, and other a, b, c and d mean carbon atom and wherein each carbon atom comprises radical R1 or R2 bound to indicated carbon atom; or all a, b, c and d mean carbon atom wherein each carbon atom comprises radical R1 or R2 bound to indicated carbon atom; broken line (- - -) means optional binds; X means N or -CH when optional bond is absent, and it means carbon atom (C) when optional bond presents; when optional bond between carbon atom 5 and carbon atom 6 presents then only a single substitute A presents bound with carbon atom 5, and only a single substitute B presents bound with carbon atom 6, and A and B fifer from hydrogen atom (H); if optional bind between carbon atom 5 and carbon atom 6 is absent then two substitutes A present bound with carbon atom 5, and two substitutes B bound with carbon atom 6 wherein at least one of two substitutes A or one among two substitutes B mean H and wherein at least one of two substitutes A or one of two substitutes B has value distinct from H, and other radical are described in the invention claim. Also, invention disclosed a pharmaceutical composition comprising such compounds, a method for inhibition of anomalous growth of cells and methods for treatment of proliferative diseases as cancer.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

52 cl, 2 tbl, 505 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I): or its pharmaceutically acceptable salts or esters hydrolyzed in vivo and possessing properties of selective inhibitor of cyclin-dependent kinases, such as CDK-2, and inhibiting proliferation of cells. Compounds can be used in preparing medicinal agents used in treatment of cancer diseases. In compounds of the formula (I) R1 represents halogen atom; p = 0 or 1; R2 represents sulfamoyl or group B-E-; q = 0 or 1 wherein p + q = 1; R3 represents hydrogen atom, (C1-C6)-alkyl wherein R3can be substituted optionally at carbon atom with one or some M; R4 represents (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl wherein R4 can be substituted optionally with one or some M; or R3 and R4 taken with nitrogen atom to which they are bound form heterocyclic ring substituted optionally at carbon atom with one or some M wherein if indicated heterocyclic ring comprises group -NH then nitrogen atom can be substituted optionally with group chosen from Q; B is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein B can be substituted optionally at carbon atom with one or some D and wherein indicated heterocyclic group comprises group -NH- then nitrogen atom can be substituted optionally with group chosen from G; E represents -S(O)r- or -N(Ra)SO2- wherein Ra represents hydrogen atom or (C1-C6)-alkyl and r = 2; D is chosen independently from halogen atom, nitro-, cyano-, hydroxy-, amino-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N-(C1-C6)-alkylamino-, N,N-((-C1-C6)-alkyl)2-amino-, (C1-C6)-alkanoylamino-group, (C1-C6)-alkyl-S(O)a wherein a = 0-2, wherein D can be substituted optionally at carbon atom with one or some V; M is chosen independently from halogen atom, nitro-, cyano-, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N,N-((C1-C6)-alkyl)2-amino-group, (C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl or heterocyclic group wherein M can be substituted optionally at carbon atom with one or some P; P, X and Y are chosen independently from hydroxy-group, methyl, methoxy-, dimethylamino-group; G and Q are chosen independently from (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkoxycarbonyl wherein Q can be substituted optionally at carbon atom with one or some X. Also, invention relates to methods for synthesis of compounds, preparing pharmaceutical compositions based on thereof and to a method for inhibition of proliferation of cells.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions, improved method of inhibition, improved method of synthesis of compounds.

15 cl, 2 sch, 133 ex

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