Derivatives of piperidine derivatives or their pharmaceutically acceptable salts, method of production thereof, pharmaceutical compositions on their basis and intermediate compounds

 

(57) Abstract:

Derivatives of piperidine derivatives of General formula I,

< / BR>
where R2, R3each represents hydrogen or R2- N and R3- HE;

R4is phenyl, furyl, pyridyl, 1,3,4-oxadiazol-2-yl or 2-imidazolyl, possibly substituted with halogen, hydroxy, alkyl, alkoxyl, Rk, Rk- alkyl, -NR1Rm, R1, Rm- H, alkyl, S(O)nRN, RN- alkyl;

n = 0, 1, or 2, or R2and R4together with biradicals X1and the carbon atom to which they are attached, may form spirocyclohexane ring - Spiro(isobenzofuran-1/3H/-4'-piperidin) or oxaspiro(isobenzofuran-1/3H/-4'-piperidin), R3- H,

or their pharmaceutically acceptable salts exhibit the properties of the antagonist of PKA. 6 C. and 10 C.p. f-crystals, 3 ill.,table 1.

The present invention relates to new aryl-substituted with the heterocyclic compounds, and more particularly to a new 1-substituted 4-arylpiperazines, pharmacological effect which manifests itself in antagonism to one or more endogenous neuropeptide to tachykinins known under the name of neurokinins, in particular the receptor neirokinina 2 (NC). New aryl-substituted heterocycles applicable in the x diseases going with the participation NK receptor, for example, for the treatment of asthma and related conditions. The invention provides pharmaceutical preparations containing the new aryl-substituted heterocycles and intended for use in the treatment of these conditions, the ways in which such drugs, as well as ways and intermediate compounds for new aryl-substituted heterocycles.

Neurokinin mammal form a class of peptide neurotransmitters, which can be detected in the peripheral and Central nervous system. The three most important neurokinin include substance P (BP), neurokinin A (NKA) and neurokinin B (LCI). There are also elongated in the N-end forms at least for NSV. These three neurokinin know at least three types of receptors. Taking into account their relative selectivity manifested in the predisposition to neurokinin BP, NSV and LCI, respectively, the receptors are classified as respectively neurokinin 1 (NK), neurokinin 2 (NC) and neurokinin 3 (NK) receptor. On the periphery of the BP and the NSA localized in the C-remote sensory neurons, characterized by semilinearity nerve endings, known as C-fibers, and their secretion of origin is located in the epithelium of the Airways, and, as you know, tachykinin have a noticeable effect, between which and observed many asthmatics the symptoms is possible to draw a clear parallel. Action from the selection or administration of tachykinins in the air path of a mammal is manifested in bronchostenosis, increased microvascular permeability, vasodilation and activated mastocytes. Thus, tachykinin involved in the pathophysiology and hyperreactivity Airways observed in asthmatics, therefore blocking the action of tachykinins released can be used for the treatment of asthma and related conditions. There are reports of peptide NK the antagonists. For example, a cyclic Hexapeptide, known under the designation L-659877, reportedly, is a selective NK antagonist.

There are also reports about the ones NK the antagonists, for example in the application for a European patent, publication number (EPA) 428434 and EPA 474561 (duplicate of U.S. patent 5236921). EPA 428434 reveals a series of 4-substituted piperidino and piperazinediones, in which 4-Deputy consists of a carbon atom that is attached to certain aryl radical and which may also be attached to the second Deputy (selected from hydroxy-, oxo - ecomonday radical (specifically claimed connection) presented 4-benzylpiperidine. In EPA 474561 (and its equivalents) with a publication date - March 1992, the number of detected ones NK antagonists includes a group of 4,4-disubstituted piperidinedione that /a/ the first 4-assistant selected from phenyl, pyridyl or tanila, which is unsubstituted or substituted one or more times by one of the substituents, independently selected from hydrogen, halogen, hydroxy-group, (1 - 4C)alkoxygroup, trifloromethyl and (1 - 4C)alkyl, and /b/ the second 4-Deputy chosen from a long list radicals, recommended hydroxy-, acetoxy - (1-6C)alkylcarboxylic, or /c/ second Deputy forms a double bond with the carbon to which it is attached, and with the adjacent atom of the heterocycle. The compound N-/4-(4-acetylamino-4-phenylpiperidine)-2-(3,4-dichlorophenyl)butyl/N - methylbenzamide (in the form of a racemate or in form of any enantiomer) is defined in EPA 474561 as especially recommended. Accordingly, (S)-isomer identified as the preferred enantiomer encrypted as SR 48968 (see below). The only example in EPA 474561 compounds in which the 4-Deputy gets a value that meet the above paragraph /c/, is the example 41: N-/2-(3,4-dichlorophenyl)-4-/4-(3-triptoreline)-1,2,3,6 - tetrahydropyridine/butyl/N-methyl who neproizvodnykh with character substitution different from that disclosed in EPA 428434 and EPA 474561, which formed the basis of our invention. One of the aspects of the opening includes monosubstituted piperidinedione, in which only 4-Deputy presents aryl or heteroaryl group (see definition below). For example, we have found that 4-phenylpiperidines, disclosed below in example 1 is effective NK antagonist in vitro selection below (Test A) and the functional analysis below (Test B). After our opening, but before may 24, 1993, i.e. before the date of the patent application in the UK 9310713.4 on the basis of which is a stated priority for this application) in EPA 512901, EPA 512902 and EPA 515240 (duplicates including patents Canada (CA), respectively CA 2067877; CA 2067834 and CA 2067924, for each date of publication - November 4, 1992 ) were disclosed additional nematodirinae antagonists tachykinin. Original description EPA 512901 includes differing in the structure of several compounds, including 4,4-disubstituted piperidinedione, in which the first 4-Deputy presents aryl group defined above under the paragraph /a/ for EPA 474561, and the second Deputy takes the values defined above /b/ and /c/ for EPA 474561. the tel takes values according to the above for EPA 474561 /a/, however, any examples of such compounds in EPA 512901 is not given. The only examples of compounds containing a single substituent in the 4-position of piperidine are 4-benzylpiperidine (recommended in EPA 428434 radical), in which the aryl group is separated from piperidino cycle. In EPA 512901 the only examples of compounds with aryl-substituent in the 4-position (phenyl) piperidino are in the same position and the second Deputy (hydroxy-, acetoxy-, acetylamino, as recommended in EPA 474561). In EPA 515240 revealed another series of compounds similar in its structure to the compounds disclosed in 428434, including 4-substituted piperidinedione, in which the 4-Deputy presents the heteroatom (or replaced by heteroatoms, optionally substituted aryl group.

In the publication, closely related to the object of the invention EPA 474561, the authors provide pharmacological data for SR 48968 and other similar structure connections /Edmonds-Alt X. and others, Bioorganic and Medicinal Chemistry Letters(1993), 3(5), 925 - 930, just "Edmonds-Alt (1993)"/ (published April 19, 1993). According to Edmonds-Alt (1993) connection of SR 48968 manifests itself as NK antagonist with inhibition constant (Kiin the in vitro analysis of binding similar to following A Test (in which try on /3H/-NCA and recombinant human NK receptor). In the work of Edmonds-Alt (1993) disclosed in addition 4-phenylpiperidines described below in example 1, to which is given a value of Kiabove 100 nm. After may 24, 1993 (the date of priority of the present application) in EPA 559538 (and its equivalents, including CA 2090785 with a publication date in September 1993 and earlier Hungarian counterpart HU 9300580, published on may 28, 1993) among disclosed in whole connection is indicated by the extra 4-arylpiperazines. Included in EPA 559538 4-arylpiperazines disclosed and claimed in General as intermediate compounds to obtain the corresponding compounds in which the nitrogen piperidinium stereoselectivity; a value of /d/, is defined for a "4-aryl" radical selected from the group comprising phenyl (which is unsubstituted or substituted one or more times by the Deputy, is independently selected from hydrogen, halogen, hydroxy-group, (1-3C)alkyl, (1-3C)alkoxygroup and trifloromethyl, (3-7C)cycloalkyl, pyridyl or thienyl; the only example is provided only for 4-phenylpiperidines. In addition, EPA 559538 indicated that such 4-arylpiperazines, in particular 4-phenylpiperidine activity reported in Edmonds-Alt (1993) benzamide (see example 1 of this specification) in EPA 559538 indicated that phenylacetamide, namely: N-/2-(3,4-dichlorophenyl)-4-(4-phenylpiperidine)butyl/-N-methyl-3 - isopropoxyaniline has a high affinity for neurokinin receptors, but such activity has benzamide derivatives, substituted benzamide or 4-fluoro-1-naphthylamide given as examples are not marked, with the exception of activity as antagonists of substance P. in Any of the above descriptions is not given examples (saturated) piperidinedione, monosubstituted in the 4-position substituted phenyl group or heteroaryl group.

In accordance with the invention provides the compound of the invention represented by the compound of formula I (formula I, as well as other formulas, denoted by Roman numerals in this description are listed immediately after the examples), in which R2and R3each represents hydrogen or R2is hydrogen, and R3the hydroxy - group; R4represents aryl or heteroaryl, which may be substituted by aryl, Arailym, heteroaryl or heteroaryl Deputy and in which the aromatic or heteroaromatic part can be Zam is ormatie, nitro, hydroxy-group, (1-5C)alkoxygroup, (1-5C)alkanoyloxy, NRARB, NRCRDC(=NRG)NRERF, COORK, CONRLRM, mercaptopropyl, S(O)nRN, (1-5C)alkyl and (1-5C)of alkanoyl, where NRARBcontains from zero to seven carbon atoms and each of RAand RBindependently represents hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl or NRARBforms pyrrolidino-, piperidino, morpholino, thiomorpholine (or its S-oxide) or piperazinil (and piperazinil can be substituted in 4-position stands or ethyl), and each of these cyclic groups may be optionally substituted by one or more methyl substituents; RCis hydrogen or (1-5C)alkyl and RDis (1-5C)alkanoyl, aroyl or heteroaryl, or RDrepresents a group of formula C(=J)NRERFin which J is oxygen, sulfur, NRGor CHRH; NRERFcontains from zero to seven carbon atoms and each of REand RFindependently represents hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, or NRERFforms pyrrolidino-, piperidino, morpholino, thiomorpholine (or its S-oxide) or piperazinil (and pipel optionally substituted by one or more methyl substituents; or REis hydrogen or (1-5C)alkyl and RFtogether with RGforms an ethylene or trimethylene group; RGrepresents hydrogen, (1-5C)alkyl or together with RFforms an ethylene or trimethylene group; RHrepresents a cyano, a nitro-group or SO2RI; where RIis (1-5C)alkyl or phenyl; RKrepresents hydrogen, (1-5C)alkyl, aryl, heteroaryl, arylmethyl or heteroaromatic; NRLRMcontains from zero to seven carbon atoms and each of RLand RMindependently represents hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, or NRLRMforms pyrrolidino-, piperidino, morpholino, thiomorpholine (or its S-oxide) or piperazinil (and piperazinil can be substituted in 4 - position stands or ethyl), and any of these cyclic groups may be optionally substituted by one or more methyl substituents; RNrepresents (1-6C)alkyl, (3-6C)cycloalkyl, aryl or heteroaryl; h= 0, 1, or 2; and heteroaromatic nitrogen may be substituted by (1-5C)alkyl and moreover (1-5C)alkyl, (1-5C)alkoxygroup, (1-5C)alkanoyl or part of R4may be substituted by a hydroxy-group, (1-5C)alkoxygroup or one or neskolko alkoxygroup and the carbon alkanol cannot be substituted by chlorine, bromine or iodine;

or R3is hydrogen, and R2and R4together with biradicals X1and 4-carbon piperidinium to which they are attached, form spirits, in which R4- phenyl, coupled with R2ortho-replacement biradicals X1and phenyl (R4may be in turn substituted by a Deputy selected from halogen, (1-3C)alkyl, (1-3C)alkoxygroup, hydroxy-group, (1-3C)ancilliary, (1-3C)alkylsulfonyl and (1-3C)alkylsulfonyl; biradical X1represents a methylene, carbonyl or sulfonyl; R2is oxygraph or aminogroup formula-NRQwhere RQis hydrogen or (1-3C)alkyl;

with the exception of compounds in which R2and R3each represents hydrogen and R4represents unsubstituted phenyl;

or pharmaceutically acceptable salt of the compounds of formula I.

Specific compounds of formula 1 represented by compounds in which R2and R3represent hydrogen and

R4represents aryl or heteroaryl, which can be substituted by aryl, Arola, heteroaryl or heteroaryl and in which the aromatic or heteroaromatic part may be the trifloromethyl, nitro, hydroxy-group, (1-5C)alkoxygroup, (1-5C)alkanoyloxy, NRARB, NRCRDC(=NRG)NRERF, COORK, CONRLRM, S(O)nRN, (1-5C)alkyl and (1-5C)of alkanoyl, where NRARBcontains from zero to seven carbon atoms and each of RAand RBindependently represents hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, or NRARBforms pyrrolidino-, piperidino, morpholino, thiomorpholine (or its S-oxide) or piperazinil (and piperazinil can be substituted in 4-position stands or ethyl); RCis hydrogen or (1-5C)alkyl; RDis (1-5C)alkanoyl, aroyl or heteroaryl, or RDrepresents a group of formula C(=J)NRERFin which J is oxygen, sulfur, NRGor CHRH; NRERFcontains from zero to seven carbon atoms and each of RE, RFindependently represents hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, or NRERFforms pyrrolidino-, piperidino, morpholino, thiomorpholine (or its S-oxide) or piperazinil (and piperazinil can be substituted in 4-position stands or ethyl); or REis hydrogen or (1-5C)alkyl, and RFtogether with RGabout the P> form a methylene or trimethylene group; RHrepresents a cyano, a nitro-group or SO2RJwhere RJis (1-5C)alkyl or phenyl; RKrepresents hydrogen, (1-5C)alkyl, arylmethyl or heteroaromatic; NRLRMcontains from zero to seven carbon atoms and each of RLand RMindependently represents hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, or NRLRMforms pyrrolidino-, piperidino, morpholino, thiomorpholine (or its S-oxide) or piperazinil (and piperazinil can be substituted in 4-position stands or ethyl); RNrepresents (1-6C)alkyl, (3-6C)cycloalkyl, aryl or heteroaryl; h= 0, 1, or 2, and heteroaromatic nitrogen may be substituted by (1-5C)alkyl, and additionally, (1-5C)alkyl, (1-5C)alkoxygroup, (1-5C)alkanoyl or part of R4may be substituted by a hydroxy-group, (1-3C)alkoxygroup or one or more halogen atoms, provided that the carbon associated with nitrogen or oxygen, does not have a hydroxy - or alkoxygroup and carbon of alkanoyl not substituted by chlorine, bromine or iodine;

or pharmaceutically acceptable salts of these compounds.

You must specify that the compounds of formula I contain one or more asymm the economic and/or diastereomeric form. Some compounds are able to demonstrate polymorphism. It must be emphasized that the present invention is directed to any racemic, optically active, diastereomers, polymorphic or stereoisomeric form, or mixtures thereof, if these forms have properties antagonist HK2. Specialists are well known methods for producing optically active forms (for example, separation of the racemic form or by synthesis from optically active starting products) and detection properties of the antagonist HK2 standard methods, which are below. It may be preferable to use the compound of the formula I in the form, characterized by a content of, for example, at least 95%, 98% or 99% enantiomeric excess shape having (S)-configuration in the centre specified in the formula 1 asterisk (*).

In this description RA, RB, R4etc. denote the generic radicals and do not accept any other values. You must specify that the generic term "(1-5C)alkyl" includes alkyl radicals with a straight or branched chain, but reference to an individual radical such as "propyl" embraces only the radical with a straight chain ("normal"), the isomers of branched-chain, such as "isopropyl" appears the dust, alkanoyl etc., Aryl refers to a phenyl radical or an ortho-fused bicyclic carbocyclic the radical with nine or ten atoms in the cycle, in which at least one aromatic cycle. Heteroaryl denotes a radical attached via a carbon monocyclic aromatic cycle in a loop containing five or six atoms, including carbon and one to four heteroatoms selected from the group comprising: oxygen, sulphur and nitrogen, and also coming from them radicals in the form of ortho-condensed bicyclic heterocycles eight or ten atoms in the cycle, in particular besprovodnye or radicals formed by or of propylene, trimethylene and tetramethylene with monoheterocycles, as well as their stable N-oxides. Aroyl and heteroaryl refer respectively to kilcarbery and heteroarylboronic.

Pharmaceutically acceptable salt is a salt formed from the acid, producing a physiologically acceptable anion.

Below lists the specific values of the radicals and substituents, and ranges, which do not exclude other defined values or other values within defined ranges for the radicals and substituents. To the, Anil, pyrrolyl, pyridyl or pyrimidinyl, and 1,3,4-oxadiazol-2-yl, 2-imidazolyl or benzo/d/isoxazol-3-yl. A specific value for a possible substituent on the aromatic or heteroaromatic carbon in R4include, for example, halogen: fluorine or chlorine; a cyano, trifluoromethyl, hydroxy-group, (1-5C)alkoxygroup: a methoxy group or ethoxypropan; for (1-5C)alkanoyloxy: acetoxy; NRARB: an amino group, methylaminopropyl or dimethylaminopropyl; NRCRD: acetaminoph; C(=NRG)NRERF: imidazolin-2-yl; for COORK: carboxypropyl, methoxycarbonyl or benzyloxycarbonyl and etoxycarbonyl; CONRLRM: carbarnoyl, N,N-dimethylcarbamoyl or pyrrolidinecarbonyl, and N-methylcarbamoyl; S(O)nRN: metalcorp, b or methylsulphonyl; for (1-5C)alkyl; methyl, ethyl, propyl, butyl, isopropyl or 2-methylpropyl, and tert-butyl; (1-5C)of alkanoyl: formyl, acetyl and propionyl. Specific values for the substituent at the heteroaromatic nitrogen in R4include, for example, methyl or ethyl. Specific values for the substituent in the (1-5C)alkyl, (1-5C)alkoxygroup or (1-5C)alkanoyl, or part of R4in the particular groups of compounds of formula I includes those compounds in which R2and R3each represents hydrogen and R4is, for example, phenyl which may be substituted by fluorine, chlorine, hydroxy-group, a methoxy group, acetoxypropionyl, amino group, acetaminophe, methoxycarbonyl, carbamoyl, stands, ethyl or acetyl, more specifically, R4represents phenyl, substituted hydroxy-group.

Another specific group of compounds of formula I includes those compounds in which R2is hydrogen, R3the hydroxy - group, located in the TRANS-position is obtained relative to R4; and R4represents phenyl which may be substituted by a methoxy group, a hydroxy-group, methylthiourea or methylsulfinyl, or pharmaceutically acceptable salts of these compounds.

Another specific group of compounds of formula I includes those compounds in which R3is hydrogen, and R2and R4together with biradicals X1and 4-carbon piperidinium to which they are attached, form spirocyclic system, where R4represents phenyl which is connected with R2ortho-replacement biradicals X1and phenyl (R4may be, in turn, to have a Deputy selected from metoxygroup, hydroxylgroups, or pharmaceutically acceptable salts of these compounds.

According to another characteristic of the invention provides a pharmaceutical preparation containing videopreteen compound of formula I or its pharmaceutically acceptable salt and pharmaceutically acceptable diluent or carrier.

The present invention also provides a compound of formula I or its pharmaceutically acceptable salt intended for use in medicine, in particular for the treatment of diseases associated with the participation of the NCA, and in which it is desirable to show the antagonistic action of such compounds, for example, for the treatment of asthma and related disorders.

In addition, the present invention provides a method of using vysokorejtingovykh compounds of the formula I or their pharmaceutically acceptable salts for the preparation of drugs intended for the treatment of diseases associated with the participation of the NCA, and in which it is desirable to show the antagonistic action of these compounds, for example, for the treatment of asthma and related disorders.

Additional selected aspects of the invention is based on the unexpectedly high results (and disclose CLASS="ptx2">

Accordingly, as a favorite aspect of the invention provides a compound of formula I (or (RS) - or, preferably, (S)-form in the center indicated in the formula I by an asterisk ( * ) in which R2and R3each represents hydrogen and R4represents phenyl, substituted methylthiourea or methylsulfinyl (in the form of mixtures of optical isomers or in the form of a single isomer, or its pharmaceutically acceptable salt. As an additional favorite aspect of the invention provides the above compound of formula I or its pharmaceutically acceptable salt intended for use in medicine, in particular for the treatment of diseases associated with the participation of the Agency, and which preferably inhibits the actions of the NSA, for example, in the treatment of asthma or related disorders. And another one chosen aspect of the invention provides a pharmaceutical preparation containing the above compound of formula I or its pharmaceutically acceptable salt and pharmaceutically acceptable diluent or carrier.

As another favorite aspect of the invention provides a compound of formula I (or (RS) - or, preferably, (S)-form in the center shown in the formula I associate ITIL), or its pharmaceutically acceptable salt. As an additional favorite aspect of the invention provides the above compound of formula I or its pharmaceutically acceptable salt intended for use in medicine, in particular for the treatment of diseases associated with the participation of the Agency, and which preferably inhibits the actions of the NSA, for example, for the treatment of asthma or related disorders. And another elected aspect of the invention provides a pharmaceutical preparation containing the above compound of the formula or its pharmaceutically acceptable salt and pharmaceutically acceptable diluent or carrier.

Typical compounds of formula I described in the accompanying examples. The examples of the compounds (or (RS) - or, preferably, (S)-form in the center shown in the formula I by an asterisk ( * ) and their pharmaceutically acceptable salts are another aspect of the invention. Of the above-mentioned examples of the compounds recommended compounds of examples 9, 13, 14, 15, 16 and 17 (especially examples 14, 15 and 16) or their pharmaceutically acceptable salts.

Pharmaceutically acceptable salts of the compounds of formula I include salts formed a strong inorganic or organic is, methane sulfonic acid or p-toluensulfonate.

The compound of the formula I can be obtained by methods including the method used by professional chemists for the synthesis of analogous structure of heterocyclic compounds. Such methods and intermediate compounds for the synthesis of compounds of formula I are further features of the invention and are illustrated by the following techniques, in which the generic radicals agree to the above values, unless otherwise specified.

(a) Alkylation of the appropriate piperidine of formula II with an aldehyde of the formula III reductive alkylation or alkylating agent of the formula IV, in which V represents the outgoing group. Alkylation recommend regular restorative alkylation, for example, as shown in example 1 of the method, i.e., acid catalyzed formation in silu salt ammonia with subsequent restoration by cyanoborohydride sodium in an alcohol solvent. Reductive alkylation can be carried out in an acceptable solvent, such as methanol, tetrahydrofuran or acidified water using a suitable reducing agent, such as, for example, cyanoborohydride is their formula I it is convenient to allocate in the form of a salt with the acid, for example in the form of hydrochloride.

(b) For compounds of formula I in which R2and R3each represents hydrogen, hydronaut double bond in the compound corresponding to the compound of formula I, but in which R2and R3together with the existing carbon-carbon bond forming a double bond. The hydrogenation is usually carried out at atmospheric pressure over palladium on coal as a catalyst in acidic solution in a lower alcohol. The resulting product is convenient to allocate in the form of its salt with an acid, such as hydrochloride, for example by the method of example 1.

Perhaps it may be desirable during the whole or some segment of the above processes apply protective groups, which can then be removed with the formation of the final compound.

And at the final stage, any of the following methods, if you want to get a pharmaceutically acceptable salt of the compounds of formula I, spend the reaction of the compounds of formula I with the acid, producing a physiologically acceptable counterion, or use any other conventional method.

If necessary, the original products are not available by industry, you can get methods, which are selected from standard is whether the methods similar to the above, or as shown in the examples methods. Original products and methods of obtaining them are additional aspects of the invention.

In General, the source compound of formula II can be obtained from 4-piperidone by the method similar to the method of example 2, the following sequence of transformations. The nitrogen cycle protects conventional protecting group, for example by benzyloxycarbonyl. Received piperidin process ORGANOMETALLIC reagent, for example, a compound of formula R4L; or R4MgBr. The resulting tertiary alcohol is subjected to hydrolysis (for example, the use of triperoxonane acid and triethylsilane in an inert solvent, such as dichloromethane). The removal of the nitrogen protecting groups are piperidine of formula II. Or it may be preferable to degidrirovanii tertiary alcohol with subsequent hydrogenation of the resulting double bond. Some compounds of formula II can be successfully obtained catalyzed by palladium attach heteroaryl groups according to the method similar to the method of example 9.g. - 9.i. For certain compounds, in which R4- heteroaryl, it may be preferable application of the derived philsaga Deputy in the usual manner, for example, using the methods of examples 7 and 8. If necessary, the introduction of the group R4target substituent can be carried out and other transformations. For example, conventional reagent allylthiourea can be converted into the corresponding alkylsulfonyl, including the use of the reagent for chiral oxidation allylthiourea can be converted into a chiral alkylsulfonyl. 4-Hydroxypiperidine formula Va (which can be obtained in a sequence of transformations, similar to the above, but without hydrogenolysis) can be alkylated initial product of the formula III or IV according to the method similar to the method described above for method (a), with the initial product of the formula V (see, for example, the method of example 1.h.).

I believe that certain compounds of formula II (and their synthetic precursors) are novel compounds and constitute a further aspect of the invention.

The intermediate aldehyde of formula III can be synthesized according to scheme I and example 1, parts a.-g. Alkylation of the anion of 3,4-dichlorobenzonitrile 1-bromo-2-(2-tetrahydropyranyl-hydroxy)ethane (conveniently be obtained from 2-bromoethanol and dihydropyran in the presence of a CA is an appropriate amine of the formula VII, which can be allerban benzoic anhydride in the presence of an appropriate base with the formation of the amide of formula VIII. The alkylation of the amide methyliodide with subsequent hydrolysis of the acetal get the alcohol of formula IX, the oxidation of which can be obtained intermediate compound of formula III. Or the alcohol of formula IX in the usual way can be turned into an alkylating agent of the formula IV.

The intermediate compound of formula III or IV, in which the center is marked with*has absolute (S)-configuration, can be obtained from the corresponding compounds of formula IX, which can be synthesized from racemic compounds of formula VII according to scheme II and according to the methods of example 9. Hydrolysis of the acetal of the formula VII leads to the amine of formula X. the Formation of salts with D-tartaric acid followed by crystallization, recrystallization and processing water base receive (S)-enantiomer of compounds of formula x by Treatment with etelcharge.com with subsequent recovery of the resulting carbamate receive (S)-enantiomer of compounds of formula XI. Treatment of amine with benzoyl chloride leads to (S)-enantiomer of compounds of formula IX, which can be oxidized, for example: oxychlorides, dimethylsulfonium the compounds of formula III or can be converted into (S)-enantiomer of compounds of formula IV.

As it is obvious to the specialist to get the original compounds are the different sequences of transformations, and the sequence of transformations leading to the original compounds and to the products of the invention may be modified based on the appropriate method of synthesis and availability of certain radicals.

The applicability of the compounds of the invention or their pharmaceutically acceptable salts (hereinafter also go under the General name of "connection") can be shown by standard tests and clinical studies, including those listed Edmonds-Alt (1993) and in the above EPA, for example: EPA 428434 or EPA 474561 (or U.S. patent 5236921) which are listed below.

Analysis of the binding neirokinina And (NCA) receptor (Test)

The ability of the compounds of the invention to show the antagonism of the binding of NKA in NK receptor can be shown in the analysis using the human NK receptor expressed in cells of the mouse erythroleukemia (MEL) using MEI cell membranes (MELM), which has high affinity and selectivity NK receptors. The analysis consists in the following.

Brief explanations of the charts

Fig. 1 illustrates constructionone MEI klitora GSE1417/h NK2R.

In Fig. 3 shows the expression of human HK2 receptor in cells MEL C88.

Expression of human HK2 receptor (cncr) in MEL cells. Expression of heterologous protein in cells of the mouse erythroleukemia (MEL) proceeds with the application area of locus of control (OLK) human globin (F. Grosveld, and others , Cell (1987) 51, 975-985). cDNA is inserted between the promoter of the human beta-globin second intron of the gene of the human beta-globin, the resulting tape is then put in a downstream direction from OLK and transfection in MEL cells (M. Needham and others, Nucl.Acids Res. (1992) 20, 997-1003). cDNA of human NK receptor (A. Graham and others, Biochem Biophys. Res. Commun. (1991) 177, 8-16) was isolated from the human lung RNA polymerase-cableway reaction and DNA sequencing. cDNA of human NK receptor subcloning in vector service (MEG3), containing the promoter of the beta-globin 3'-part of the gene of the human beta-globin (Fig. 1). cDNA of human NK receptor restriction in the presence of Eco 0109 (5'end) and Bam H1 (3'end). Oligonucleotide likereceptor containing internal Hind III site and the 3'end Eco 0109 site are ligated with cncr cDNA fragment. The sequence of the oligonucleotide upper thread = 5'd (GCGCAAGCTTATGGG) (AFTERBIRTH. N 1), and oligonucleotide lower thread = 5'd in the presence of Hind III clone this fragment into the Hind III Bam HI sites in polylinker vector-dropship rmes. The construct (MEG3/h NK2R or pMEG3/cncr) check restriction mapping and sequencing the 5'-end and 3'end joints cDNA/vector. The resulting construct is then transformed into E. coli DH5 alpha, standard methods produce plasmid DNA and test DNA restriction mapping and DNA sequencing. Clal/Asp718 the cassette containing the promoter of the beta-globin, human cDNA NK receptor and the 3'fragment of the beta-globin gene, is subjected to cutting and subcloning in a downward direction from OLK plasmid pGSE1417 (Fig. 2). Construct pMEG3/h KNK-2R break down in the presence of Clal and As p718 and clone directly into the Clal and As p718 sites (3' OLK) in the expression vector GSE1417. Construct GSE1417/h NK2R (13,9 K. O.) check restriction kadrirovaniem. E. coli DH5 alpha transform, and recombinant plasmids check restriction mapping. Cells MEL C88 (A. Deisseroth, etc. , Cell (1978) 15, 55 to 63) is subjected to electroporation (M. Antonion, Methods Molecular Biology (1991) 7, 421-434) in the presence of the translated Pvul in linear form pGSE1417/DNA human NK receptor. Immediately after transfection, the cells were diluted in culture medium to a concentration of 104and 105cells / ml and aliquot 1 ml is transferred into each well of the tablet in 24 wells. For selection ustoichivost or combine with the formation of populations in seven to ten days after addition of the selective environment. Fig. 3 illustrates the strategy used for the selection transfection cell lines MEl /human NK receptor. To study the expression of cells within four days stand under conditions of exponential growth, and then to induce differentiation, and hence the expression add dimethylsulfoxide (DMSO) to a final concentration of 2% (vol./vol.). Later, 4 days after induction for analysis on the binding of mRNA and NSV selected samples. The results show that the clone N 1 expresses cncr at the highest level (as cncr mRNA and specific binding NCA). This clone reproduced, currently produced by normal fermentation in a volume of 20 liters per month and is available for use in Test A.

Membrane preparations (MEL M), prepared from MEL cells containing NK receptors with high affinity, obtained according to the published method (D. Aharony and others , Neuropeptides (1992) 23, 121-130) with the following minor changes: (1) in the homogenization buffer is enabled todatetime (1 mm); (2) homogenization are published by technique, but more a short time of 10 seconds and at a slower rate (10 times slower) and (3) the stage of balancing EXT is (88 + 4%) and linearly dependent on protein concentration, moreover detectable binding was already at a concentration of 26 ág protein/ml Equilibrium competition experiments showed binding with high affinity and a high density of receptors with values of KD= 1187 nm, Bmax= 2229 of fmole/mg protein.

Radioligand3H-neurokinin A (3H-HKA) /4,5-3H-Leu9/-HKA (typical specific activity - 117 C/mmol) were obtained from custom synthesis from Cambridge research Biochemicals with a purity of 95%. Repeated HPLC analysis showed that the ligand is stable when properly stored (silanizing vessels with 0.2% mercaptoethanol, under argon). In addition, no signs of destruction or metabolism is not mentioned in the analysis of receptor binding.

The analysis is performed using incubation buffer containing 50 mm Tris HCl (pH of 7.4), 5 mm Mo++, 100 μm of thiorphan, 1 nm3H-HKA, 0,02% (wt./about. ) BSA, 30 mm K+and 300 μm of dithiotreitol; the concentration of membrane protein support of 0.05 - 0.025 mg per tube. Nonspecific binding is determined in the usual way with 1 μm NSV. In each tube upload the following: 150 ál of incubation buffer, 20 ál3H-HKA, 20 µl connection, NSV or buffer as needed and 125 μl of membrane water bath. The reaction is stopped by adding in test tubes 10 ml ice 50 mm Tris HCl with application to collect membrane system for collecting cells Brandela, which uses filters Whatman IG/In, soak at least 4 hours at room temperature in 0.01% (wt./about.) polyethylenimine. Filters put in acquired scintillation vessels and read in acquired scintillation counter Beckman model LS6000LL. The binding constant (Ki) calculated by standard methods, and usually record the average of several measurements. The value of Ki can be turned into a negative logarithms and expressed as-Iog molar Ki (i.e. pK).

At the beginning of the application of this analysis IR50defined for the default connection 1-659,877, was found equal to 30 nm relative to the3H-HKA binding MEL M. Selectivity of connections linking the HK2 receptor may be shown by determining its binding to other receptors using standard analyses, such as analysis, which uses trithiolane derived BP in tissue preparation, selective to NK receptors, or analysis that uses trithiolane derived LCI in tissue preparation, selective to NK receptors.

The and, or /-ala8/-HKA(4-10). Selected agonist forth in the description designated as AG. The ability of the compounds of the invention act as an antagonist to the action of AG in the lung tissue can be shown using functional analysis to the trachea of the Guinea pig, which is carried out as follows.

Male Guinea pigs kill a strong punch. The trachea is removed, freed from excess tissue and divided into two segments. Each segment is suspended in the form of rings between brackets stainless steel tub for fabrics with a water jacket (37,5oC) containing physiological salt solution of the following composition (mm): NaCl 119, KCl 4,6, CaCl21,8, MgCl20,5 NaH2PO41, NaHCO325, glucose 11, tiorfan 0.001 and indomethacin 0,005 continuously passing gas (95% O2- 5% CO2). The initial voltage applied to each fabric is 1 g and his support during the whole period of equilibrium (0.5 to 1.5 hours) before adding another drug. The contractile response was measured on a polygraph grass by means of force sensors grass.

Fabric is supported in a state of stress when the same concentration of AG (10 nm), with a break of 30 Minogue constant level after two treatments AG, and each connection test for the inhibition of responses to the effect of AG addition in bath tissue for 15 minutes until the third or subsequent exposure to agonist. Contractile response to AG in the presence of the compound compared with the reaction that occurs when the second impact AG (no connection). The percentage inhibition of control when the connection creates a statistically significant (p < 0.05) decrease in the compression ratio, and calculate, taking as 100% the second contractile response.

Effectiveness of selected compounds is determined by calculating the apparent dissociation constants (KBfor each tested concentration using the standard equation:

KB= (antagonist) : (ratio of doses-1),

/where the ratio of doses = log(AG - log molar EC50connectionless) - (AG - log molar EC50connection)/. Values of KBcan be turned into a negative logarithms and expressed as log molar KB(since pKB). For this test received full curves the concentration-response for AG in the absence and presence of compound (incubation period of 30 min) using paired tracheal rings. The effectiveness of the AG determined on each curve at 50% of Ararat in the form of - log molar EC50. The maximum contractile response to AG determine the expression of the maximum response to AG in the form of a percentage reduction caused by carbachol (30 μm), added after the initial period of establishing equilibrium. When the connection is created statistically significant (p<0.05) decrease in the maximum response to AG, calculate the percentage of inhibition relative to the magnitude of the reduction under carbachol raw paired tissue which is taken for 100%.

Analysis of difficult abdominal breathing (shortness of breath) in Guinea pigs (Test)

The activity of compounds of the invention as antagonist NSV at NK receptor can also be shown in vivo in laboratory animals, for example, a device for this purpose a conventional aerosol test on Guinea pigs, created Snyder and others to identify antagonists of leukotrienes (Snyder D. W., N. J. Liberati and M. M. McCarthy Aerosol model in consciousness Guinea pigs for the detection of peptide antagonists of leukotrienes. J. Pharmacol. Meth (1988) 19, 219). The use of transparent plastic cameras previously described by Snyder and others , allowing you to capture Guinea pigs for impact only on their heads spray agonistica experience. Using an ultrasonic atomizer DeVilbiss model 25 in coming into the camera airflow at a rate of 2 l/min is served in the form of an aerosol thekennady NC-selective agonist, namely /-ala8- NKA(4-10), 3 TO 10-5M/.

Guinea pigs (275 - 400 g) fixed in about 16 hours before the start of the experiments. At various times prior to exposure to aerosol agonist is administered p. O. or centuries connection, studied for the ability to block the action (ala8- NKA(4-10), or media (10% PEG in saline solution). All animals pre-treated with atropine (10 mg/kg, W. B., 45 minutes pre-treatment), indomethacin (10 mg/kg), W. B., 30 minutes pre-treatment), propranolol (5 mg/kg, W. B., 30 minutes pre-treatment) and Tirana (1 mg/ml aerosol within 5 minutes, 15 minutes pre-treatment).

The impact of aerosol agonist initially leads to increased rate of breathing, with subsequent reduction with the first signs of a slight participation in breathing abdominal muscles. As the duration of the effect respiratory rate continues to fall, breathing becomes difficult with a large participation of the abdominal muscles. Clearly identifiable end that is m abdominal muscles. Using the stopwatch for each animal to determine the time (in seconds) from the beginning of exposure of the aerosol to that endpoint. Upon reaching the endpoint animals usually in collapse and don't come in after called the agonist ease breathing. Animals inhale aerosol agonist to a maximum of 780 seconds.

Differences between the group receiving the drug, and a control group treated with the appropriate media, compared using t-test t-test for unpaired observations.

Using the standard methods can be carried out clinical studies designed to demonstrate the effectiveness of compounds of the invention. For example, the ability of compounds to prevent or treat the symptoms of asthma or asthma conditions can be shown by using exposure inhaled cold air or allergen and the determination of results of standard pulmonary measurements, such as, for example: OPV1(the amount of force output per second) and PEEL (forced vital capacity) with subsequent analysis of the results of standard methods of statistical analysis.

You must specify that Pravitelstva General antagonism to the NCA. In General, compounds of the invention, subjected to the tests showed statistically significant activity in the Test And with the values of Ki in 1 μm or much less. For example, the compounds described in the examples 1, 2, 6, 7, 9, 10, 13 and 24 are characterized by nanomolar Ki values, respectively, in 2, 6, 9, 2, 8, 21, 1, 2, 13, 3 and 3.5. In the Test for compounds of the invention, as a rule, receive a value of KB5 or more. For example, compounds described in the examples 1, 2, 6, 7, 9, 10, 13 and 24 obtained values of KBaccordingly 8, 8,3, 8,5, 7,1, 8,6, 8, 8,6 and 8.2. It should be noted that it may not always be a direct correlation between the activity of the compounds defined in the form of Ki in Test A, and the values obtained by other methods of analysis, such as values of KBobtained in Test B. No unwanted side effects after the introduction of Test C compounds of the invention are not marked.

Unexpectedly very good results in Test after oral administration for two hours before exposure to agonist, obtained for the compounds of selected aspects of the invention compared with the compound of example 1 shown in table. 1.

As indicated above, the compounds of formula I or their pharmaceutically acceptable salts have properties nausea, as you know, bronchostenosis, increased microvascular permeability, vasodilation and activation of mastocytes. One of the features of the invention is the use of compounds of the formula I or their pharmaceutically acceptable salts for the treatment of diseases of the human or other mammal in need of such treatment, and the disease proceeds with the participation of the NSA and it is desirable to create antagonism of the action of the NCA. Among such diseases include asthma and related disorders. In addition, another characteristic of the invention consists in the use of the compounds of formula I or its salt as pharmacological standard designed for the creation and standardization of new disease models or analyses used to create new medicines for the treatment of diseases involving the NSA, or tests to diagnose such diseases.

When used for treatment of the above diseases, the compound of the invention is usually administered in the form of a corresponding pharmaceutical preparation containing the compound of formula I or its pharmaceutically acceptable salt according to the above definition, as well as pharmaceutically acceptable rasheedawiest as another characteristic of the invention. The drug can be obtained by conventional techniques, fillers and binders, and can be one of the many dosage forms. Such forms include, for example: tablets, capsules, solutions or suspensions for oral administration; candles for rectal administration; sterile solutions or suspensions for administration by intravenous or intramuscular injection or by injection; aerosol or sprayable solutions or suspensions for administration by inhalation or powder in a mixture with a pharmaceutically acceptable solid diluents such as lactose, for the introduction of insufflating.

For oral administration is convenient to use tablets or capsules, containing up to 250 mg (usually 5 to 100 mg) of the compounds of formula I. When introduced by inhalation the compounds of formula I is administered to a person in the range of daily doses, for example, 5 to 100 mg a single dose or daily dose divided into two to four doses. Similarly, for intravenous or intramuscular injection or injection convenient to use sterile solution or suspension containing up to 10% wt./wt. (usually 0.05 to 5% wt./wt.) the compounds of formula I.

The dose of injected compounds of formula I necessarily modifies the of atrasta patient. However, as a rule, the compound of formula I is introduced warm-blooded animal (such as man) so that he receives a dose in the range, for example, 0.01 to 25 mg/kg (typically 0.1 - 5 mg/kg). You must specify that, as a rule, can be used an equivalent amount of pharmaceutically acceptable salts of the compounds of formula I.

The invention is further illustrated by the following not limiting examples in which, unless otherwise specified:

(I) temperatures are given in degrees Celsius (oC) operations are conducted at room temperature or ambient temperature, i.e. in the temperature range 18 - 25oC;

(II) organic solutions are dried over anhydrous magnesium sulfate, evaporation of the solvent is carried out in a rotary evaporator under reduced pressure (600 - 4000 Pascal, a 4.5 - 30 mm Hg) with a bath temperature of up to 60oC;

(III) chromatography means pressure chromatography on silica gel, chromatography with reversed phase means chromatography on coated octadecylsilane (UDF) media diameter particles 32 - 74 microns, known under the code of "PREP-40-ODS" (Art. 731740 - 100 firm Bodman chemicals, Aston, PCs PA, USA), thin-layer chromatography (TLC) carried out for the purpose of illustration;

(V) melting points are not corrected and (decomp.) indicates decomposition; the melting point correspond obtained in this way products; in some preparative cases when selecting products with different melting temperatures may occur polymorphism;

(VI) final products have satisfactory spectra of proton nuclear magnetic resonance (NMR);

(VII) the output is shown only for illustrative purposes and are not necessarily the most that can be achieved by careful design of the way; if necessary to obtain large amounts of product operation repeat;

(VIII) when given, NMR data is presented in the form of Delta values for major characteristic of protons in parts per million (h /m) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz using as solvent a fully deuterated dimethyl sulfoxide (DMSO-o6); use conventional abbreviations for designation of a waveform; for AB spectra are directly observable shifts; constant doubling (I) are given in Hz; if there is a designation of Ar, it is obedenytsy C;

(X) low pressure are given as absolute pressures in Pascals (PA), high blood pressure is given in the form of instrument pressure in bars;

(XI) the ratio of the solvents are given in volume: volume (vol./vol.);

(XII) mass spectra (MS) were obtained at an electron energy of 70 electron volts in the chemical mode of ionization (HI) with direct effects on the sample; where indicated ionization carried out by electron impact (PI) or fast atom bombardment (the Belarusian library Association); the m/z values; usually indicated only ions of appropriate parental masses.

Example 1. N-/2-(3,4-Dichlorophenyl)-4-(4-phenylpiperidine)butyl/N-methylbenzamide hydrochloride.

A solution of N-/2-(3,4-dichlorophenyl)-4-(4-phenyl-1,2,3,6-tetrahydropyridine-1-yl) butyl/N-methylbenzamide (0.28 g) in methanol (10 ml) is treated with a methanol solution of hydrogen chloride (2 ml), then add 10% (wt. /Mac. ) palladium on coal (0.03 g). The reaction mixture hydronaut 2.5 hours at room temperature. At the end of this period the reaction mixture was treated with an additional amount of 10% palladium on coal (0.03 g) and hydrogenation continued for another 16 hours. The reaction mixture is filtered through diatomaceous earth and evaporated. Pamesa ethyl acetate, methanol, ether and hexane, washed with a mixture of ether and hexane, and after drying under vacuum to obtain the title compound in the form of white matter (0.11 g) so pl. 142-148oC; NMR (CD3OD): 1.8 - 2.4m (m, 6), 2,6 - 3,2 (m, 9), of 3.5 - 3.9 (m, 4), 7-7,6 (m, 13); MS: m/z = 495 (M+1). Analysis for C29H32Cl2N2O HCl H2O: calculated: C 63,33, H 6,41, N 5,09; found: C 63,46, 6,12 H, N 5,13.

The intermediate N-/2-(3,4-dichlorophenyl)-4-(4-phenyl-1,2,3,6-tetrahydropyridine-1-yl)butyl/N-methylbenzamide obtained as follows.

a. 2-Tetrahydropyran-2-laxitive. To stir with a mechanical stirrer solution dihydropyran (1000 ml) and a strong acid resin (10 g) in hexane (2000 ml) for 1.5 hours in a cooling water bath added dropwise 2-bromoethanol (985), keep the temperature in the range of 35 - 40o. After stirring over night at room temperature the reaction mixture chromatographic using as eluent hexane. Evaporation of the hexane get amber liquid that is distilled through a column Vigra diameter of 2 inches (5 cm) with the selection of the product, wikipaedia in the range of 75 - 95oC (3300-4700 PA). By repeated distillation of the resulting product is obtained in the form of a simple oil ether (1195,5 g); so bales. 80 - 90oC (2666 P is lorganisation. To a solution of sodium hydride (218 g of a 55% suspension in oil) in tetrahydrofuran (4 l) at 10oC in a bath of ice water for 45 minutes, was added 3,4-dichlorobenzonitrile (893 g) in tetrahydrofuran (2 l) and the resulting solution was stirred for 2 hours at room temperature. The mixture is cooled in a bath of ice water, and within 25 minutes added in the form of pure oil 2-tetrahydropyran-2-ioxithalamate (1076 g). The mixture is stirred over night at room temperature and divided into four portions with 2 liters Each portion was diluted with a saturated solution of ammonium chloride (3 l) and extracted with ether (500 ml). The combined organic layers washed with aqueous ammonium chloride, dried and evaporated. Chromatographytandem obtained product with elution by the mixture hexane-dichloromethane (gradient 100:0, 0:100) are obtained in the form of oil nitrile (932 g); NMR: 7,47 (m, 4), 7,2 (m, 2), of 4.57 (m, 2), 4,08 (m, 2), 3,85 (m, 4), of 3.54 (m, 3), 3,37 (m, 1), of 2.15 (m, 4), or 1.77 (m, 4), and 1.56 (m, 8).

c. 2-(3,4-Dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butylamine. To a solution of the obtained nitrile (128,3 g) in 95% ethanol (1.1 l) and concentrated ammonium hydroxide (550 ml) was added Raney Nickel (25 g). The mixture hydronaut 1.5 days at room temperature in hydrogen atmosphere (3.65 bar). To remove Catalca with elution with a mixture of dichloromethane-methanol (gradient 100:0, 95:5) are obtained in the form of oil amine (91 g); NMR: 7,4 (s, 1), 7,38 (s, 1), 7,32 (d, 1, J = 2,1), 7,28 (d, 1, J = 2), 7,07 (LW. d, 1, J = 2,1, 4,9),? 7.04 baby mortality (LW. d, 1, J = 2,1, 4,9), and 4.5 (m, 1), 4,43 (m, 1), and 3.7 (m, 4), of 3.45 (m, 2), with 3.27 (m, 1), 3,17 (m, 1), 2,97 is 2.75 (m, 6), 2 (m, 2), 1,82 - of 1.66 (m, 6), of 1.53 (m, 8), of 1.18 (broad s, 4); MS: m/z = 318 (M + 1).

d. N-/2-(3,4-Dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butyl/benzamid. To a solution of 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butylamine (2.5 g) in dichloromethane (35 ml) is added triethylamine (1.1 ml) and benzoic anhydride (1.85 g) and the resulting solution was stirred for 45 minutes. The mixture is washed with 0.2 G. hydrochloric acid, 1 N. sodium hydroxide and water, dried and after evaporation receive in the form of oil amide (3,3 g); NMR: 7,63 (m, 4), 7,46 (m, 2), 7,37 (m, 8), to 7.09 (m, 2), to 6.22 (m, 2), and 4.5 (m, 1), 4,43 (m, 1), and 3.8 (m, 5), 3,63 (m, 1), 3,5 (m, 4), to 3.36 (m, 1), 3,23 (m, 1), 3,11 (m, 2), to 2.06 (m, 2), 1,9 - to 1.77 (m, 4), by 1.68 (m, 2) and 1.51 (m, 8), ; MS: m/z = 338 /(M + 1) - tetrahydropyranyl/.

e. N-/2-(3,4-Dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butyl/N - methylbenzamide. To a solution of N-/2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2 - yloxy)butyl/benzamide (3,3 g) in dimethyl sulfoxide (20 ml) is added powdered potassium hydroxide (1.6 g) and after 15 minutes add logmean (1 ml). After 1 hour the mixture is diluted with water (330 ml) and extracted with dichloromethane. The combined organic extracts are dried and after evaporation of poluchautsia/-N-methylbenzamide. To a solution of N-/2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butyl/N - methylbenzamide (10.5 g) in tetrahydrofuran (100 ml) is added 6 N. hydrochloric acid (50 ml) and the resulting solution stirred overnight. The mixture is neutralized 1 N. sodium hydroxide, diluted with water and extracted with dichloromethane. The organic layer is dried and evaporated. The obtained yellow solid is suspended in ether and after filtration get alcohol in the form of a white solid (8,4 g); MS: m/z = 352 (M + 1).

g. N-/2-(3,4-Dichlorophenyl)-4-oxobutyl/-N-methylbenzamide. The solution oxalicacid (878 mg) in dichloromethane (5 ml) cooled to -78oC and treated with dropwise addition of a solution of dimethyl sulfoxide (595 mg) in dichloromethane (2 ml). The resulting mixture was stirred for 15 minutes at -78oC and treated with dropwise addition of a solution of N-/2-(3,4-dichlorophenyl)-4-hydroxybutyl/-N-methylbenzamide (1.22 g) in a mixture of dichloromethane (10 ml) with dimethyl sulfoxide (2 ml). The mixture is stirred for 1 hour at -78oC, treated with triethylamine (1.75 g), warmed to room temperature and stirred for 1 hour. The mixture is then transferred into water and extracted with dichloromethane. The organic extract was washed with water and brine, dried, filtered through activated silica m m/z = 350 /(M + 1),35Cl2/.

h. N-/2-(3,4-Dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidine)butyl/N - methylbenzamide. A solution of 4-hydroxy-4-phenylpiperidine (1,99 g) in methanol (20 ml) cooled to 0oC and adding acetic acid to establish a pH of 8. To the resulting solution was added N-/2-(3,4-dichlorophenyl)-4-oxobutyl/-N-methylbenzamide (3.57 g) in methanol (20 ml) and the resulting reaction mixture is treated with cyanoborohydride sodium (0,765 g). After heating to room temperature the reaction mixture is stirred for 16 hours and treated with a saturated solution of sodium bicarbonate. The solution is extracted with dichloromethane, dried over anhydrous sodium sulfate and evaporated. Purification of the obtained product by elution with a mixture of dichloromethane-methanol (90:10) receive piperidine (2,42 g): NMR (CDCl3): 1,5-2,5 (m, 10), 2,68 (wide bandwidth, 4), 3,47 (s, 3), 3,5 is 3.57 (m, 1), 6,8 - 7,5 (m, 13); MS: m/z = 511 (M+1). The resulting product is used in the next stage without additional purification.

i. N-/2-(3,4-Dichlorophenyl)-4-(4-phenyl-1,2,3,6-tetrahydropyridine-1 - yl)butyl/N-methylbenzamide. The mixture of the alcohol obtained in the previous phase (example 1.h.) (2.5 g) and conc. hydrochloric acid (20 ml) is heated for 2 hours at 100oC. the Reaction mixture is cooled to room temperature, re is on anhydrous sodium sulfate and evaporated. Purification of the obtained product by chromatography with elution with a mixture of methanol-dichloromethane (1: 12) get tetrahydropyridine (0,81 g); NMR (CD3OD): 1,5-1,9 (wide band, 3), 2,3 (wide bandwidth, 1), 2,7 - 2,4 (m, 3), was 2.76 (s, 2), 3.04 from (s, 3), 3,14 (wide bandwidth, 1), and 3.8 to 3.7 (m, 2), between 6.08 (d, 1, J = 18), 6,9 - 7,6 (m, 13); MS: m/z = 493 (M + 1). The resulting product is used in the next stage without additional features.

Example 1 (alternative method of obtaining). The title compound obtained as follows.

A solution of 4-phenylpiperidine (0,48 g) in methanol (18 ml) is treated with add 18 drops of acetic acid and then a solution of N-/2-(3,4-dichlorophenyl)-4-oxobutyl/-N-methylbenzamide (1.04 g) in methanol (20 ml). The mixture is treated with cyanoborohydride sodium (0.28 g) and stirred for 16 hours at room temperature. The mixture is treated with water and evaporated. The residue is diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer is dried over anhydrous sodium sulfate and evaporated. Chromatography with elution with a mixture of dichloromethane-methanol (95:5) receive oil (1.6 g). The resulting product is converted into the corresponding hydrochloride in the following way. The oil was dissolved in dichloromethane (6 ml), treated with ethereal races what filtrowanie sediment obtain the title compound (0.98 in); so pl. 102 - 141oC (decomp.). The resulting product is identical to the 4-phenylpiperidines described above in example 1.

Example 2. N-/2-(3,4-Dichlorophenyl)-4-/4-(2-methoxyphenyl) piperidino/butyl/N-methylbenzamide hydrochloride.

By the method similar to the method of example 1 (alternative method), conducting the reaction between 4-(2-methoxyphenyl)piperidine (0,19 g) and N-/2-(3,4-dichlorophenyl)-4-oxobutyl/-N methylbenzamide (0.35 g) and get the crude product. Transformation of the obtained product in hydrochloride get the title compound in the form of white matter (0,42 g) so pl. 85 - 100oC (decomp. ); NMR (CD3OD): 1,29 - 1,38 (wide band, 2), 2,05 (wide band, 5) and 2.2 (broad band, 1), and 2.7 (s, 2), 2,7 - 3,3 (wide band, 5), 3,4 - 3,7 (wide band, 2), of 3.7 - 3.9 (broad band, 5), 6,9 - 7 (m, 3), 7,15 - 7,24 (m, 4), of 7.36 was 7.45 (m, 4), 7,56 to 7.62 (m, 1); MS: m/z = 509 (M + 1). Analysis for C30H34Cl2N2O20,75 H2O: calculated: C 62,61, H 6,39, N to 4.87; found: C 62,73, H is 6.78, N 4,76.

The intermediate 4-(2-methoxyphenyl)piperidine obtained in the following way.

a. 1-Benzyloxycarbonyl-4-piperidone. The suspension of the hydrochloride of 4-piperidone (11,96 g) in tetrahydrofuran (150 ml) cooled to 0oC and treated with benzylchloride (14,3 ml). The reaction mixture is about hours. The reaction mixture was extracted with ethyl acetate, the organic layer washed with water, dried and after evaporation receive piperidine as a pale yellow oil (20,58 g); NMR (CDCl3): 2,45 (t, 4, J = 6), with 3.79 (t, 4, J = 6), by 5.18 (s, 2), 7,32 - 7,38 (m, 5); MS: m/z = 234 (M + 1). The resulting product is used in the next stage without additional purification.

b. 1-Benzyloxycarbonyl-4-hydroxy-4-(2-methoxyphenyl)piperidine. A solution of anisole (2,19 g) in tetrahydrofuran (50 ml) cooled to -78oC and treated with tert-butyllithium (12 ml, 1.7 M solution in pentane). The resulting reaction mixture is heated to -15oC and stirred for 45 minutes. The reaction mixture was again cooled to -78oC and treated with a solution of 1-benzyloxycarbonyl-4-piperidone (4,67 g) in tetrahydrofuran (5 ml). The reaction mixture is heated to -15oC, stirred for 1 hour, then allowed to warm to ambient temperature and stirred for 72 hours. The reaction mixture was diluted with water and extracted several times with ethyl acetate. The combined organic layers are dried and after evaporation obtain the crude product. Chromatography with elution by the mixture hexane-ethyl acetate (2:1) receive the mixture of alcohol with the original product (2,98 g); NMR (CDCl3): 1,95 - 2,04 (m, 4), 2,9 (wide band, 2), 3,9 the sustained fashion cleanup.

c. 1-Benzyloxycarbonyl-4-(2-methoxyphenyl)piperidine. A solution of 1-benzyloxycarbonyl-4-hydroxy-4-(2-methoxyphenyl)piperidine (2,59 g) in dichloromethane (45 ml) is treated triperoxonane acid (8.6 g) and then triethylsilane (17.5 g). The resulting brown reaction mixture is stirred for 5 minutes and then transferred into a saturated solution of sodium bicarbonate. The bicarbonate solution is extracted with dichloromethane. The dichloromethane solution is dried and after evaporation receive deshydrogenase (2.1 g); NMR (CDCl3): 1,55 - of 1.66 (m, 2), 1,78 - 1,82 (sh. lane 2), only 2.91 (m, 2), 3,11 (m, 1), 3,8 and is 3.82 (s, 3), 4,32 (sh. band, 2), 5,12 is 5.28 (m, 2), at 6.84 (d, 4, J = 9), 6,87 - to 6.95 (m, 1), 7,11 - 7,25 (m, 2), 7,29 - 7,38 (m, 5); MS: m/z = 326 (M + 1). The resulting product is used in the next stage without additional purification.

d. 4-(2-Methoxyphenyl)piperidine. A solution of 1-benzyloxycarbonyl-4-(2-methoxyphenyl)piperidine (0,67 g) in ethanol (10 ml) is treated with cyclohexene (4,2 ml) and then 10% palladium on coal (0,13 g). After boiling for 2 hours, the reaction mixture was cooled to room temperature, diluted with ether and extracted with 1 N. hydrochloric acid. The aqueous layer was alkalinized with sodium bicarbonate and extracted with dichloromethane. The organic layers dried over anhydrous sodium sulfate and after isarene the,83 (doublet t, 2, J1= 12, J2= 2), 3,02 - 3,2 (m, 3), 3,82 (s, 3), 6,85 (d, 1, J = 8), 6,9 (m, 1), 7,15 - 7,26 (m, 2); MS: m/z = 192 (M + 1). The resulting product is used in the next stage without additional purification.

Example 3. N-/2-(3,4-Dichlorophenyl)-4-/4-(4-methoxyphenyl) piperidino/butyl/N-methylbenzamide hydrochloride.

By the method similar to the method of example 1 (alternative method), but using 4-(4-methoxyphenyl)piperidine obtained N-methylbenzamide. Chromatographytandem obtained product by elution with a mixture of dichloromethane-methanol (19:1) and conversion into the hydrochloride obtained the title compound in the form of white matter with so pl. 167 - 169oC; NMR (CD3OD): 1,92 - 2,05 (m, 3), 2,24 (sh. lane 1), and 2.79 (s, 3), 2,8 - 3,3 (m, 4), 3,3 - 3,6 (m, 3), of 3.7 - 3.9 (m, 4), to 6.88 (m, 2), 7 (d, 1, J = 8), 7,16 - 7,22 (m, 4), 7,37 was 7.45 (m, 4), EUR 7.57 - to 7.64 (m, 1); MS: m/z = 525 (M + 1). Analysis for C30H34Cl2N2O2HCl 0,75 H2O : calculated: C 62,13, H to 6.43, N a 4.83; found: C 62,39, H 6,2, N 4,82.

The intermediate 4-(4-methoxyphenyl)piperidine obtained in the following way.

a. 1-Benzyloxycarbonyl-4-hydroxy-4-(4-methoxyphenyl) piperidine. To obtain alcohol 4-bromoanisole treated by the method similar to the method of example 2, except that the reaction mixture is not heated above -78wasp, 2), and 3.2 (wide band, 2), and 3.8 (m, 3), 4,1 (wide band, 2), a 5.1 (s, 2), 6.87 in - 6,9 (m, 2), 7,25 to 7.4 (m, 7); MS: m/z = 324 (M - 18). The resulting product is used in the next stage without additional purification.

b. 1-Benzyloxycarbonyl-4-(4-methoxyphenyl)piperidine. 1-Benzyloxycarbonyl-4-hydroxy-4-(4-methoxyphenyl)piperidine treated by the method similar to the method of example 2.c. The resulting product chromatographic with elution by the mixture hexane-ethyl acetate (3: 1) and get deshydrogenase; NMR (CDCl3): 2,61 (m, 1), 2,81 (wide band, 2), of 3.78 (s, 3), 4,32 (wide band, 2), of 5.15 (s, 2), at 6.84 (d, 2, J = 7), and 7.1 (d, 2, J = 8), 7,31 - 7,38 (m, 5); MS: m/z = 326 (M + 1). The resulting product is used in the next stage without additional purification.

c. 4-(4-Methoxyphenyl)piperidine. A solution of 1-benzyloxycarbonyl-4-(4-methoxyphenyl)piperidine (0,42 g) in ethanol (5 ml) is treated with 10% palladium on coal (0.04 g) and hydronaut 16 hours at atmospheric pressure. The reaction mixture is filtered through diatomaceous earth and after evaporation receive in the form of a colorless oil of 4-(4-methoxyphenyl)piperidine (0,22 g); NMR (CDCl3): 1,59 - 1,71 (m, 2), of 1.85 (d, 2, J = 12), 2,71 - 2,81 (doublet t, J = 12), 3,19 - 3,23 (wide band, 2), 3,79 (s, 3), 6,83 - 6,87 (m, 2), 7,12 - 7,26 (m, 2); MS: m/z = 192 (M + 1). The resulting product is used in the following stateissued hydrochloride.

By the method similar to the method of example 1 (alternative method), but using 4-(3-methoxyphenyl)piperidine obtained N-methylbenzamide. Chromatography of the resulting product by elution with a mixture of dichloromethane-methanol (19:1) and conversion into the hydrochloride get the title compound in the form of white matter (0.25 g) with so pl. 172 - 176oC; NMR (CD3OD): 1,85 - 2,14 (wide band, 3), 2,15 - 2,36 (wide bandwidth, 1), 2,6 - 2,95 (wide bandwidth, 4), 2,9 - 3,3 (m, 4), 3,4 - 3,7 (m, 2), of 3.7 - 3.9 (broad band, 1), of 3.96 (s, 3), 6,78 - 6,83 (m, 3), of 6.99 (d, 1, J = 7), a 7.1 to 7.3 (m, 3), of 7.36 - the 7.43 (m, 4), 7,56 - 7,63 (m, 1); MS: m/z = 525 (M + 1). Analysis for C30H34Cl2- N2O2HCl 0.5 H2O: calculated: C 63,11, H 6,35, N 4,91; found: C 63,01, H, 6,21, N 4,8.

The intermediate 4-(3-methoxyphenyl)piperidine obtained in the following way.

a. 1-Benzyloxycarbonyl-4-hydroxy-4-(3-methoxyphenyl)piperidine. The alcohol obtained by the method similar to the method of example 2, but without heating the reaction mixture above -78oC and using 3-bromoanisole instead of anisole. The product is contaminated source piperidine (2:1 according to NMR); NMR (CDCl3): 1,72 - 1,77 (wide band, 2), 2,04 (wide band, 2), 3,25 (wide band, 2), and 3.8 (s, 3), 4 - 4,25 (wide band, 2), a 5.1 (s, 2), 6,83 (m, 2), 7,02 to 7.4 (m, 2), 7,26 - 7,39 (m, 6); MS: m/z = 324 (M is carbonyl-4-(3-methoxyphenyl)piperidine. 1-Benzyloxycarbonyl-4-hydroxy-4-(3-methoxyphenyl)piperidine (1,79 g) is treated according to the method similar to the method of example 2.c. Chromatography of the crude product by elution with a mixture of hexane with ethyl acetate (2:1) receive deshydrogenase (1.29 g); MS: m/z = (M + 1). NMR of this product is complex. The resulting product is used in the next stage without additional purification.

C. 4-(3-Methoxyphenyl)piperidine. Use a technique similar to the technique of example 3.c. The hydrogenation of 1-benzyloxycarbonyl-4-(3-methoxyphenyl)piperidine (0,42 g) in the presence of 10% palladium on coal obtained as a pale yellow oil of 4-(3-methoxyphenyl)piperidine (0,19 g); NMR (CDCl3): 1,64 - to 1.77 (m, 2), 1,85 (wide band, 2), is 2.74 (m, 2), 3,21 - 3,25 (wide band, 2), and 3.8 (s, 3), 6.73 x - 6,83 (m, 3), 7,21 - of 7.25 (t, 1, J = 8); MS: m/z = 192 (M + 1). The resulting product is used in the next stage without additional purification.

Example 5. N-/2-(3,4-Dichlorophenyl)-4-/4-(4-hydroxyphenyl) piperidino/butyl/N-methylbenzamide hydrochloride.

By the method similar to the method of example 1 (alternative method), but using 4-(4-hydroxyphenyl)piperidine obtained N-methylbenzamide. The chromatography product by elution with a mixture of dichloromethane-methanol (9: 1) and PEPs.): NMR (CD3OD): 1,8 - 2,14 (sh. band, 4), 2,1 - 2,2 (wide band, 2), of 2.7 - 3.1 (m, 8), of 3.5 - 3.7 (broad band, 2), 3,81 - of 3.85 (m, 2), 6,7 (d, 2, J = 8), 6,9 - 7,2 (m, 5), 7,3 - 7,44 (m, 4.5), and 7.5 and 7.6 (m, 1.5); MS: m/z = 511 (M + 1). Analysis for C29H32Cl2N2O2HCl 0.5 H2O: calculated: C 62,53, H x 6.15, N of 5.03; found: C 62,53, H 6,2, N 4,95.

The intermediate 4-(4-hydroxyphenyl)piperidine obtained in the following way.

a. 4-Benzyloxyphenol. A solution of 4-bromophenol (17.3 g) in dimethylformamide (200 ml) is treated with potassium carbonate (15.2 g) and then benzylbromide (17.1 g, 11.9 ml). After stirring 16 hours at ambient temperature the reaction mixture was diluted with water and hexane. The aqueous layer was extracted with a mixture of hexane-ether (5:1). The organic extracts washed with water, 1 N. sodium hydroxide and brine, dried and after evaporation receive in the form of a white solid substance brobinson (23,4 g); NMR (CDCl3): to 5.03 (s, 2), 6,85 (LW. d, J1= 5, J2= 2), 7.3 to 7.4 (m, 7); MS: m/z = 263 (M + 1). The resulting product is used in the next stage without additional purification.

b. 1-Benzyloxycarbonyl-4-hydroxy-4-(4-benzyloxyphenyl)piperidine. A solution of 4-benzyloxyphenol (6.6 g) in tetrahydrofuran (125 ml) cooled to -78oC and treated with n-butyllithium (10 ml of 2.5 M solution in externe (5 ml) and the reaction mixture is stirred 1 hour at -78oC and 2 hours at 0oC. the resulting solution was treated with water (10 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried and after evaporation receive the crude product by chromatography with elution by the mixture hexane-isopropanol (9:1) get two fractions (1,91 and of 4.05 g each). The first fraction according to NMR is a mixture (1:1) alcohol and the source of the ketone, the second fraction contains alcohol (yield 39%); NMR (CDCl3): 1,74 (d, 2, J = 13), 2,04 (wide bandwidth, 1), of 3.32 (m, 2), 4.09 to (wide band, 2), of 5.05 (2), 5,14 (s, 2), of 6.96 (m, 2), 7,29 - 7,49 (m, 12); MS: m/z = 450 (M + 18).

c. 1-Benzyloxycarbonyl-4-(4-benzyloxyphenyl)piperidine. 1-Benzyloxycarbonyl-4-hydroxy-4-(4-benzyloxyphenyl) piperidine treated by the method similar to the method of example 2.C. Chromatography of the resulting product with elution by the mixture hexane-ethyl acetate (2:1) receive deshydrogenase contaminated corresponding alkene (3,48 g); MS: m/z = 402 (M + 1). The NMR spectrum of this product is complex. The resulting product is used in the next stage without additional purification.

d. 4-(4-Hydroxyphenyl)piperidine. Treatment 1-benzyloxycarbonyl-4-(4-benzyloxyphenyl)piperidine (0.65 g) by the method similar to the method of example 3. c. , (wide band, 2), 2,9 - 3 (wide band, 2), of 6.66 (d, J = 8), of 6.99 (d, 2, J = 8); MS: m/z = 178 (M + 1). The resulting product is used in the next stage without additional purification.

Example 6. N-/2-(3,4-Dichlorophenyl)-4-/4-(2-hydroxyphenyl)piperidino/butyl/N - methylbenzamide hydrochloride.

By the method similar to the method of example 1 (alternative method), but using 4-(2-hydroxyphenyl)piperidine, receive N-methylbenzamide. Chromatography of the resulting product by elution with a mixture of dichloromethane-methanol (19:1) and conversion into the hydrochloride get the title compound (0.33 g) as a white substance with so pl. 225 - 228oC; NMR (CD3OD): 1,9 - 2,1 (wide band, 5), 2,3 (wide band, 2), and 2.79 (s, 3), 3,6 (wide band, 2), 3,81 - of 3.85 (m, 2), 6,79 (m, 2), 7 - of 7.3 (m, 5), and 7.3 - 7.5 (m, 4,5), 7,6 (m, 1.5); MS: m/z = 511 (M + 1). Analysis for C29H32Cl2N2O2HCl 0.5 H2O: calculated: C 62,53, H x 6.15, N of 5.03; found: C 62,58, H 6,13, N 4,94.

The intermediate 4-(2-hydroxyphenyl)piperidine obtained in the following way.

a. 2-Benzyloxyphenol. A solution of 2-bromophenol (17.3 g) in dimethylformamide (200 ml) is treated with potassium carbonate (15.2 g) and then benzylbromide (17.1 g, 11.9 ml). After stirring 3 hours at room temperature, the reaction mixture was diluted with water is Assalom, dried and after evaporation receive the product as a colourless oil (22,94 g). Fractional distillation of the resulting oil under reduced pressure get brobinson (16,52 g), so Kip. 110 - 145oC (1333 PA); NMR (CDCl3): of 5.17 (s, 2), 6,65 (LW. so 1, J = 8, J = 1), 6,92 - of 6.96 (LW. D. 1, J = 8, J = 1), 7,19 - 7,26 (m, 1), 7,33 - 7,42 (m, 3), 7,46 - 7.5 (m, 2), 7,55 (LW. d, 1, J = 9, J = 2). The resulting product is used in the next stage without additional purification.

b. 1-Benzyloxycarbonyl-4-hydroxy-4-(2-benzyloxyphenyl)piperidine. Crude hydroxy obtained by the method similar to the method of example 5.b., but using 2-benzyloxyphenol. Chromatography of the resulting product with elution hexane-isopropanol (9:1) receive hydroxy; NMR (CDCl3): 2,04 (m, 4), 3,4 (wide band, 2), 4 - 4,1 (wide band, 3), 5,13 - 5,16 (m, 4), of 6.96 - 7,02 (m, 2), 7,22 - 7,27 (m, 3), 7,3 - 7,41 (m, 9); MS: m/z = 418 (M1).

C. 1-Benzyloxycarbonyl-4-(2-benzyloxyphenyl)piperidine. 1-Benzyloxycarbonyl-4-hydroxy-4-(2-benzyloxyphenyl)piperidine treated by the method similar to the method of example 2.with. Chromatography of the resulting product with elution by the mixture hexane-ethyl acetate receive piperidine (1,67 g, contaminated with impurity); NMR (CDCl3): 1,6 - of 1.64 (m, 2), 1,84 (wide band, 2), 2,89 (wide pgct used in the next stage without additional purification.

d. 4-(2-Hydroxyphenyl)piperidine. Treatment 1-benzyloxycarbonyl-4-(2-benzyloxyphenyl)piperidine according to the method similar to the method of example 3.S., receive in the form of a brown solid of 4-(2-hydroxyphenyl)piperidine (0.36 g); NMR (CDCl3): 1.7 to 1.9 (m, 4), 2.77 - to of 2.86 (m, 2), 2,99 totaling 3.04 (m, 1), 3,23 (d, 2 J = 12), 4,17 (s, 2), 6,72 (d, 1, J = 8), at 6.84 (t, 1, J = 7), 7,05 (m, 1); MS: m/z = 178 (M + 1). The resulting product is used in the next stage without additional purification.

Example 7. N-/2-(3,4-Dichlorophenyl)-4-/4-(5-methyl-1,3,4-oxadiazol - 2-yl)piperidino/butyl/N-methylbenzamide hydrochloride.

By the method similar to the method of example 1 (alternative method), but using 4-(5-methyl-1,3,4-oxadiazol-2 - yl)piperidine obtained the title compound in the form of white matter with so pl. 121 - 124oC; NMR to 7.61 - 7,19 (m, 8), 3,82 of 3.75 (m, 2), 3,07, 2,77 (2s, 3, N-CH3), of 2.51 (c, 3), a 2.4-2 (broad m, 8); MS: m/z = 529 (M + 1 + 28), m/z = 501 /(M + 1),35Cl2/. Analysis for C26H30Cl2N4O2HCl 0,25 H2O: calculated: C 57,57, H 5,85, N 10,33; found: C 57,53, H 6,01, N 10,06.

Intermediate piperidine obtained in the following way.

a. Ethyl ester of 1-(benzyloxycarbonyl)-4-piperidinecarboxylic acid. A solution of ethyl ester of 4-piperidinecarboxylic acid (14,71 g) and three is rmat (17,91 g). The resulting mixture is heated for 1 hour at 0oC, then warmed to room temperature and stirred for 12 hours. The mixture was washed with 1 N. hydrochloric acid and brine, dried, filtered and after evaporation obtain a pale yellow oil (26,4 g). Purification of the oil by chromatography and elution with a mixture of dichloromethane-methanol (95:5) receiving urethane in the form of a colorless syrup (22,15 g); NMR: 7,35 (m, 5), 5,07 (s, 2), 4,06 (K, 2, J = 7), 3,91 (broad d, 2, J = 13.3-inch), 2,95 (wide band, 2), 2,53 (m, 1), equal to 1.82 (broad d, 2, J = 13.3-inch), of 1.41 (m, 2), of 1.18 (t, 3, J = 7).

b. 1-Benzyloxycarbonyl-4-piperidinecarboxylate. A solution of ethyl ester 1-(benzyloxycarbonyl)-4-piperidinecarboxylic acid (2.5 g) and hydrazine hydrate is added (0.65 g) in ethanol (30 ml) is boiled for 16 hours. Add an extra amount of hydrazine hydrate is added (1.29 g) and the mixture boiled for a further 24 hours. Then the reaction mixture is cooled and evaporated. The residue is diluted with dichloromethane and washed successively with water and brine. The organic extract is dried, filtered and evaporated. The solid residue is suspended in ether, filtered and after drying receive carbohydrazide (1,69 g) as a white substance with so pl. 123 - 125oC; NMR: 7,35 (m, 5), of 5.11 (s, 2), 4,21 (wide band, 2), 2,82 (wide band, 2 in), 2.25 (m, 1), 1,85 - 1,6 (m, 4); MS: m/z = 308 (M + 1 + 28).

c. 1-Benzyloxy the razida (0.66 g) and hydrochloride of ethylacetamide (0.35 g) in ethanol (5 ml) is boiled for 3 hours, then cooled to room temperature and the solvent evaporated. The residue is dissolved in dichloromethane and washed with water and brine, dried and after evaporation receive (oxadiazolidine-2-yl)piperidine (0.66 g) as a white substance with so pl. 129 - 131oC; NMR (CDCl3): 8,66 (s, 1), 7,35 (m, 5), to 5.13 ( s, 2), 4,21 to 4.5 (m, 2), 4.04 the (K, 2, J = 7), 3,1 (m, 1), 2,89 (m, 2), to 1.98 (s, 3), 1,8 - 1,6 (m, 4), of 1.28 (t, 3, J = 7). Analysis for C18H25N3O4. Calculated: C 62,23, H 7,25, N 12,1; found: C 62,03, H 7,11, N 12.

d. 1-Benzyloxycarbonyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)piperidine. A solution of 1-benzyloxycarbonyl-4-(5-ethoxy-5-methyl-1,3,4 - oxadiazoline-2-yl)piperidine (200 mg) in toluene (5 ml) containing pyridine (0.25 ml), boiled for 20 hours. The mixture is cooled to room temperature and the solvent evaporated. Purification of the residue by chromatography with elution with a mixture of chloroform-methanol-ammonium hydroxide (98:2:1) receive the derived 1,3,4-oxadiazole (0,143 g) as a clear oil; NMR (CDCl3): to 7.35 (m, 5), to 5.13 (s, 2), 4,16 (broad d, 2, J = 12,8), was 3.05 (m, 1), and 2.5 (s, 3), 2,04 (m, 2) and 1.83 (m, 2).

e. 4-(5-Methyl-1,3,4-oxadiazol-2-yl)piperidine. A solution of 1-benzyloxycarbonyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)piperidine (0.18 g) in ethanol (5 ml) hydronaut 2 hours under hydrogen pressure of 1 bar in the presence of 10% palladium on mind and after evaporation of the solvent receive piperidine as a white crystalline substance (0,98 g); so pl. 64 - 66oC; NMR (CDCl3): 3,17 (m, 2), 2,98 (m, 1), 2,75 (LW. t, 2, J = 2,6, 12), of 2.51 (s, 3), a 2.01 (m, 2), a 1.75 (m, 2); MS: m/z = 196 (M + 1 + 28).

Example 8. N-/2-(3,4-Dichlorophenyl)-4-/4-(4-ethoxycarbonylmethyl - 2-yl)piperidino/butyl/N-methylbenzamide.

By the method similar to the method of example 1 (alternative method), but using 4-(4-ethoxycarbonylmethyl-2-yl)piperidine obtained the title compound in the form of white matter with so pl. 96 - 102oC; NMR: 7,6 - 7,05 (m, 9), 4,3 (K, 2, J = 7,2), of 3.78 (m, 2), 3.04 from, 2,77 (2s, 3, N-CH3), 2,2 - of 1.75 (m, 8), of 1.34 (t, 3, J = 7,2); MS: m/z = 557 / (M + 1),35Cl/, m/z = 585 / (M + 1 + 28),35Cl/, m/z = 559 / (M + 1),37Cl). Analysis for C29H34Cl2N4O30.5 H2O: calculated: C 61,48, H 6,23, N of 9.89; found: C 61,69; H 6,75, N 9,59.

Source piperidine obtained in the following way.

a. 1-Benzyloxycarbonyl-4-cyanopiperidine. A solution of 4-cyanopiperidine (5 g) in 10% aqueous sodium bicarbonate solution (100 ml) cooled to 0oC and treated with dropwise addition of benzylchloride (9.3 g). The resulting mixture was warmed to room temperature and stirred for 16 hours. A two-phase mixture is extracted with ethyl acetate. The organic extracts washed with water and brine, combined, dried, filtered and evaporated. Cleaning I piperidine as a clear oil (for 9.64 g); MC: m/z = 245 (M + 1); NMR (CDCl3): to 7.35 (m, 5), to 5.13 (s, 2), 3,71 (m, 2), 3,44 (m, 2), of 2.81 (m, 1), 1,88 - 1,6 (m, 4).

b. 1-Benzyloxycarbonyl-4-piperidinecarboxylate. To a solution of hydroxylamine hydrochloride (0.34 g) in water (5 ml) is added sodium carbonate (0.26 g) and then a solution of 1-benzyloxycarbonyl-4-cyanopiperidine (1 g) in ethanol (10 ml). The resulting mixture is boiled for 3 hours. Add additional hydroxylamine hydrochloride (0.34 g) and sodium carbonate (0.26 g) and boiling continued for another 14 hours. The mixture is cooled and evaporated. Semi-solid residue is suspended in dichloromethane, filtered and dried solid product is obtained carboxamide (0.7 g) as a white substance with so pl. 111 - 113oC; NMR: 8,83 (s, 1), 7,35 (m, 5), 5,33 (broad s, 2), 5,07 (s, 2), was 4.02 (broad d, 2, J = 13,1), and 2.8 (wide band, 2), 2,19 (m, 1), 1,69 (broad d, 2, J = 11), 1,55 - of 1.42 (m, 2); MS: m/z = 278 (M + 1).

C. 1-Benzyloxycarbonyl-4-piperidinecarboxylic O((EE/Z)- 2-ethoxycarbonylphenyl)oxime. A solution of 1-benzyloxycarbonyl-4 - piperidinecarboxylate (1.5 g) and ethylpropyl (0,633 g) in methanol (15 ml) is boiled for 16 hours, then evaporated. Purification by chromatography obtained amber syrup with elution with a mixture of dichloromethane-ethyl acetate (2:1) receive vinyloxy in the form of a mixture of isomers (1.68 g); NMR (CDCl3 is, 1) and 1.83 (broad m, 2), and 1.54 (broad m, 2), 1,25 (m, 3).

d. 1-Benzyloxycarbonyl-4-(4-ethoxycarbonylmethyl-2-yl)piperidine. A solution of 1-benzyloxycarbonyl-4-piperidinecarboxylic-O-((E/Z)-2 - ethoxycarbonylphenyl)oxime (1.68 g) in mesitylene (50 ml) is boiled for 3 hours. The solvent is evaporated and purification of the residue chromatographic with elution with a mixture of chloroform-methanol-ammonium hydroxide (970:30:1) receive a derivative of imidazole in the form of a brown foam (0.85 grams); NMR: of 7.75 (d, J = 2,1), 7,35 (m, 5), 5,09 (s, 2), 4,21 (K, 2, J = 7,1), Android 4.04 (broad d, 2, J = 13,2), only 2.91 (m, 3), a 1.88 (m, 2), of 1.62 (m, 2), of 1.24 (t, 3, J = 7,1); MS: m/z = 386 (M + 1 + 28).

e. 4-(4-Ethoxycarbonylmethyl-2-yl)piperidine. A solution of 1-benzyloxycarbonyl-4-(4-ethoxycarbonylmethyl-2-yl)piperidine (0,82 g) in ethanol (20 ml) hydronaut 1 hour under hydrogen pressure in 3,45 bar in the presence of 10% palladium on coal. The mixture is filtered through diatomaceous earth and the filter cake washed with ethanol. Evaporation of the filtrate receive a derivative of piperidine as a white foam (0.51 g), NMR: the 7.65 (s, 1), 4,18 (K, 2, J = 7,1), 2,99 (broad d, 2, J = 12,2), a 2.75 (m, 1), to 2.55 (m, 2), and 1.8 (broad d, 2, J = 12,6), of 1.57 (m, 2), 1,25 (t, 3, J = 7,1), MS: m/z = 252 (M + 1 + 28).

Example 9. (S)-N/2-(3,4-Dichlorophenyl)-4-/4-(3-pyridyl)piperidine/ butyl/N-methylbenzamide hydrochloride.

By the method similar to the IU shall henyl)-4-oxobutyl/-N-methylbenzamide. Chromatography of the crude product by elution with a mixture of dichloromethane-methanol (9:1) followed by conversion into the hydrochloride get the title compound (0,253 g) as a white substance with so pl. 70 - 140oC (decomp.); NMR: 1.8 - 2.4m (m, 6), by 2.73 (s, 3), is 2.8 - 3.2 (broad, 5), 7-7,2 (m, 3), and 7.4 (s, 4), of 7.5 to 7.7 (m, 2), and 7.9 (m, 1), and 8.2 (broad s, 1), and 8.7 (d, 2, J = 5); MS: m/z = 496 (M + 1). Analysis for C28H31ClN3O 2,2HCl3H2O: calculated: C 53,94, H of 6.31, N 6,74; found: C 53,53, H 6,16, N of 6.65.

(S)-N/2-(3,4-Dichlorophenyl)-4-oxobutyl/-N-methylbenzamide obtained as follows.

a. 2-(3,4-Dichlorophenyl)-4-hydroxyethylamine. To stir with a mechanical stirrer a solution of 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butylamine (550 g) in methanol (3300 ml) in one portion add 6 N. hydrochloric acid (352 ml), which leads to a little heat. After stirring 3 hours, the reaction mixture is evaporated and the residue diluted with water to a volume of 3 L. the resulting solution was extracted with ether (2 times 500 ml), alkalinized pellets of sodium hydroxide (100 g) and extracted with ethyl acetate (4 x 500 ml). United an ethyl acetate extracts are washed with 800 ml of saturated solution of sodium chloride, dried and after evaporation receive alcohol (367 g) as an amber oil, which hardens the

b. (S)-2-(3,4-Dichlorophenyl)-4-hydroxyethylamine. To stir with a mechanical stirrer a solution of D-tartaric acid (222 g) in methanol (4 l) at boiling one portion of the type obtained in the previous phase of aminoplast (342 g) in warm methanol (2 l) and washed with additional methanol (1 liter). The mixture boil. Before boiling begin to appear crystals. After boiling for 1.5 hours, the solution is gradually cooled to room temperature and stirred for 3 days. The first batch of salts of tartaric acid is collected by suction and, after drying in a vacuum oven at 60oC receive the product (232 g). The resulting product is transferred in boiling methanol (13.5 l) and continue boiling for 1 hour with distillation 1 l of methanol. The mixture is left to slowly cool to room temperature and stirred for 4 days. The first batch of crystals are collected by filtration with suction and, after drying receive 178,8 g of solid product. The methanol filtrate is evaporated almost to a volume of 3 L. the Resulting suspension is again heated to boiling with the formation of a clear solution, with stirring, gradually leave to cool to room temperature. Collect a second batch of crystals (43,8 g). United party split tartratami military organic extracts washed with brine, dried and after evaporation are optically enriched amine (135,4 g) in the form of snow-white matter with so pl. 80 - 2oC; NMR (CD3OD): 7,47 (d, 1, J = 8), 7,42 (d, 1, J = 2,1), 7,17 (LW. d, 1, J = 8,2, 2,1), 3,47 (m, 1), to 3.34 (m, 1), and 2.83 (m, 3), with 1.92 (m, 1), of 1.74 (m, 1), MS: m/z = 324 (M + 1).

c. Ethyl-(S)-N/2-(3,4-dichlorophenyl)-4-hydroxybutyl/carbamate. To a cooled to -30oC and mixed with a mechanical stirrer, the solution obtained at the previous stage of amerosport (50 g) and triethylamine (24,9 g) in dichloromethane (600 ml) dropwise over 20 minutes add ethylchloride (25,5 g). During the addition the internal temperature maintained within the range of -20 to 25oC. Then the reaction mixture is gradually leave for 4 hours to warm to room temperature and washed with 1 N. hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The separated dichloromethane phase is dried and after evaporation receive carbamate (65,3 g) as a yellow oil; NMR (CD3OD): 7,44 (d, 1, J = 8,3), 7,38 (d, 1, J = 2,1), 7,15 (LW. d, 1, J = 8,3, 2,1), 3,99 (K, 2, J = 7,1), of 3.45 (m, 1), 3,29 (m, 3), of 2.97 (m, 1), with 1.92 (m, 1), a 1.75 (m, 1), of 1.16 (t, 3, J = 7,1); MS: m/z = 306 (M + 1).

d. (S)-N/2-(3,4-Dichlorophenyl)-4-hydroxybutyl/-N-methylamine. To stir with a mechanical stirrer suspension lydialydia carbamate (65,3 g) in tetrahydrofuran (500 ml). During the addition the internal temperature rises to 45oC. the Reaction mixture is boiled for 1 hour, then cooled to room temperature and stirred over night. The mixture is cooled in a bath of ice and added dropwise within 45 minutes was added a saturated aqueous solution of sodium sulfate (50 ml). After stirring 30 minutes, the mixture is filtered through diatomaceous earth and evaporation of the filtrate get methylamine (52,9 g) as a yellow oil; NMR: 7,37 (d, 1, J = 8,2), 7,27 (d, 1, J = 2), 7,01 (LW. d, 1, J = 8,2, 2,1), of 3.69 (m, 1), 3,53 (m, 1), 3,4 (m, 2), was 2.76 (m, 3), a 2.45 (m, 3), 1,89 (m, 2); MS: m/z = 248 (M + 1).

e. (S)-N/2-(3,4-Dichlorophenyl)-4-hydroxybutyl/-N-methylbenzamide. To stir with a mechanical stirrer, the solution obtained at the previous stage amine (52,9 g) and triethylamine (54 g) in dichloromethane (1 l), cooled in a bath of ice with maintaining the internal temperature in the range of 5 to 8oC, are added dropwise within 45 minutes, benzoyl chloride (31.5 g) in dichloromethane (200 ml). The reaction mixture is stirred 3 hours at room temperature and then washed with 1 N. hydrochloric acid and brine. Evaporation of the separated dichloromethane layer receives a yellow oil by chromatography with elution with a mixture of dichloromethane-methanol (gradient 100:0, 95:5) receive benzamide (65, is l)-4-oxobutyl/-N-methylbenzamide. Obtained in the previous phase of alcohol (12.9 g) in dichloromethane (150 ml) via cannula was added to the solution periodinane dess-Martin (18.6 g) and tert-butanol (4.5 ml) in dichloromethane (150 ml). After stirring 5 minutes, the reaction mixture was diluted with ether (600 ml) and sodium bicarbonate solution (19.7 g) and sodium thiosulfate (pentahydrate, 64,5 g) in water (825 ml). A two-phase system is intensively stirred until complete lightening both layers (about 30 minutes). The separated organic layer was washed with saturated aqueous sodium bicarbonate, dried and evaporated. Chromatography of the crude product by elution with a mixture of dichloromethane-ether (1:1) receive the aldehyde (9.7 g) as a white solid after precipitation and filtration of the ether.

The intermediate 4-(3-pyridyl)piperidine obtained in the following way.

g. 1-Benzyloxycarbonyl-1,2,3,6-tetrahydropyridine. To a cooled to 0oC a solution of 1,2,3,6-tetrahydropyridine (5 g) in dichloromethane (200 ml), add triethylamine (10.1 ml) and then benzylchloride (10.3 ml). The reaction mixture is stirred 1 hour at 0oC, diluted with dichloromethane, washed with diluted hydrochloric acid and sodium bicarbonate solution, dried and evaporated. By distillation of a crude product is obtained which further 5.15 (s, 2), and 5.8 (2 broad peak 2), and 7.4 (m, 5); MS: m/z = 218 (M + 1).

h. 1-Benzyloxycarbonyl-4-(3-piperidyl)-1,2,3,6-tetrahydropyridine. To a solution of 1-benzyloxycarbonyl-1,2,3,6-tetrahydropyridine (8.69 g) in dimethyl sulfoxide (50 ml) is added 3-bromopyridine (6,32 g), triethylamine (5.6 ml) and palladium (II) acetate (0,49 g). The reaction mixture is heated for 16 hours at 100oC, cooled to room temperature, diluted with water and extracted with ether. The organic layer is washed with water, the combined organic layers are dried and after evaporation obtain the crude product. The product is distilled under reduced pressure and the volatile components, Athanasius at 120oC (66,7 PA), are removed. Chromatography of the residue with elution by the mixture hexane-ethyl acetate (1: 1) receive the product connection (0,714 g); NMR (CDCl3): 1,7 (broad s, 2), 2,16 (broad m, 1), of 3.5 - 3.7 (m, 2), 4,9 - 5,1 (LW. m, 2), and 5.2 (m, 2), 7-7,5 (m, 8), 8,5 (m, 2); MS: m/z = 295 (M + 1).

i. 4-(3-Pyridyl)piperidine. A solution of 1-benzyloxycarbonyl-4-(3-pyridyl)-1,2,3,6-tetrahydropyridine (0,714 g) in ethanol (50 ml) hydronaut 16 hours under hydrogen pressure 3.44 bar in the presence of 10% palladium on coal (0.1 g). Removal of the catalyst the reaction mixture was filtered through diatomaceous earth and evaporation of the resulting filtrate get piperidine (0,393 g); I-4-/(3R*, 4R*)-3-hydroxy-4-phenylpiperidine/butyl-N-methylbenzamide hydrochloride.

A solution of (3R*, 4R*)-3-hydroxy-4-phenylpiperidine (0.16 g) in methanol is treated with acetic acid (6 drops), cooled to 0oC and treated with a solution of N-/2-(3,4-dichlorophenyl)-4-oxobutyl/-N-methylbenzamide (0.28 g) in methanol (5 ml) and then cyanoborohydride sodium (0.08 g). After stirring 16 hours at room temperature, the reaction mixture was evaporated and dissolved again in dichloromethane. The resulting solution was washed with solutions of sodium carbonate and sodium chloride, dried and after evaporation obtain the crude product. The resulting product is converted into the hydrochloride by dissolving in dichloromethane and handling of anhydrous hydrogen chloride in ether. After dilution with ether and stirring for 2 hours the precipitate was separated and receive the title compound (0.36 g) as a white substance with so pl. 105 - 141oC; MS: m/z = 511 (M + 1); NMR: 1.8 - to 2.2 (m, 4), and 2.5 (s, 3), 4,1 (sh. strip, 1), 6,98 to 7.7 (m, 13). Analysis for C29H32Cl2N2O2HClH2O: calculated: C 61,54, H 6,23, N of 4.95; found: C 61,63, H 6,24, N 5.

The intermediate (3R*, 4R*)-4-hydroxy-4-phenylpiperidine obtained as follows.

a. 1-Benzyloxycarbonyl-4-hydroxy-4-Hairdryer is mesh cooled to -6oC. the Reaction mixture is treated with benzylchloride (9,62 g) added in portions of 1 ml, stirred for 3 hours, diluted with chloroform (100 ml), washed with 1 N. hydrochloric acid and extracted with chloroform. The organic layers washed with brine, dried and evaporation obtain the crude product. Chromatography with elution with a mixture of methanol-dichloromethane (1: 30) get benzyloxycarbonylation (9.4 g); MS: m/z = 312 (M +1 ); NMR: 1,6 (d, 1, J = 10), 1,77 - 1,89 (m, 2), 3,91 (m, 2), 5,09 (s, 2), 7,18 - of 7.48 (m, 10).

b. 1-Benzyloxycarbonyl-4-phenyl-1,2,3,6-tetrahydropyridine. A solution of 1-benzyloxycarbonyl-4-hydroxy-4-phenylpiperidine (8,89 g) in concentrated hydrochloric acid is heated for 15 minutes at 100oC. After cooling to room temperature the reaction mixture is neutralized with sodium bicarbonate solution (77 g in 250 ml water) and extracted with dichloromethane. The organic layers washed with brine, dried over anhydrous potassium carbonate, and after evaporation of get the cheese product. Chromatography with elution with a mixture of methanol-dichloromethane (1: 99) receive in the form of a viscous liquid tetrahydropyridine (6.3 g); MS: m/z = 294 (M + 1); NMR: 2,07 - of 2.36 (m, 2), 4 (m, 2), 5,12 (two peaks, 2), 7,26 - of 7.69 (m, 10).

c. (3R*, 4R*)-1-Benzyloxycarbonyl-3-hydroxy-4-phenylpiperidine. A solution of 1-benzyloxy the Lex borane-tetrahydrofuran (3.75 ml 1 M solution in tetrahydrofuran). The reaction mixture is stirred 16 hours at ambient temperature, diluted with methanol (50 ml) and treated with 3 N. sodium hydroxide (1.25 ml). The resulting reaction mixture is cooled to 0oC and treated with 30% hydrogen peroxide solution (of 0.58 ml). After boiling for 2 hours, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers are dried and after evaporation obtain the crude product (0.88 g). Chromatography with elution by the mixture hexane-ethyl acetate (3:1) to obtain TRANS-1-benzyloxycarbonyl-3-hydroxy-4-phenylpiperidine (0.31 g); MS: m/z = 312 (M + 1); NMR: 1,54 - 1,72 (m, 2), 3,51 (m, 1), was 4.02 (m, 1), 4,17 (m, 1), a 4.86 (d, 1, J = 5), a 5.1 (s, 2), 7,17 - 7,37 (m, 10).

d. (3R*, 4R*)-3-hydroxy-4-phenylpiperidine. A solution of (3R*, 4R*)-1-benzyloxycarbonyl-3-hydroxy-4-phenylpiperidine (0.3 g) in methanol (30 ml) hydronaut 2 hours at atmospheric pressure in the presence of 10% palladium on coal (0.03 g). The reaction mixture is filtered through diatomaceous earth and after evaporation receive (3R*, 4R*)-3-hydroxy-4-phenylpiperidine (0.2 g); MS: m/z = 178 (M + 1); NMR: 1,44 is 1.58 (m, 2), 2,23 - 2,5 (m, 9), 4,39 (wide bandwidth, 1), 7,13 - 7,29 (m, 5).

Example 11. N/(2R)-(3,4-Dichlorophenyl)-4-/(3S, 4S)-3-hydroxy-4-phenylpiperidine what W (3S, 4S)-3-hydroxy-4-phenylpiperidine (about 80% of S, S-isomer) and (R)-N-/2-(3,4-dichlorophenyl)-4-oxobutyl/-N-methylbenzamide obtained the title compound (approximately 80% of S, S-isomer); MS: m/z = 511 (M + 1); NMR (DMSO-d6+ CF3COOD): 1,9 - 2,2 (sh. lane 4), was 2.76 (s, 3), 3,74 (sh. strip, 1), 3,98 (sh. strip, 1), 7,02 - 7,72 (m, 13). Analysis for C29H32Cl2N2O2H2O: calculated: C 61,54, H 6,23, N of 4.95; found: C 61,75, H 6,2, N 4,89.

Intermediate (3S, 4S)-3-hydroxy-4-phenylpiperidine (about 80% of S,S-isomer) is obtained as follows.

a. (3S, 4S)-1-Benzyloxycarbonyl-3-hydroxy-4-phenylpiperidine. A solution of N, N'-bis(monoisopropanolamine)-N,N-N-N'-tetramethylethylenediamine/ brand name R-Alpin-Baramin/ (1 g) in 20 ml of tetrahydrofuran is treated with efratom boron TRIFLUORIDE (0,59 ml) and stirred for 1.5 hours at room temperature. Stirring is stopped and the precipitate allowed to settle. The supernatant taken by syringe and added to a 1-benzyloxycarbonyl-4-phenyl-1,2,3,6-tetrahydropyridine (1,41 g). The resulting reaction mixture is left for 16 hours at -25oC. At the end of this period the reaction mixture is heated to room temperature, stirred for 16 hours, treated with methanol (0,49 ml), then 3 N. the camping is heated for 1 hour at 60oC, cooled to room temperature, diluted with 100 ml ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate. The organic layers are dried and after evaporation obtain the crude product. Chromatography with elution with a mixture of ethyl acetate-hexane (1:4) to obtain the target product (0.32 g); MS: m/z = 312 (M + 1); NMR (DMSO-d6+CF3COOD): 1,62 - of 1.73 (m, 2), 2,56 (sh. strip, 1), 2,55 (sh. lane 1), of 3.57 (m, 1), 4.09 to (d, 1, J = 13), 4,25 (d,d, 1, J = 12, J = 4), to 5.13 (s, 2), 7,16 - 7,41 (m, 10).

The analysis of the obtained product liquid chromatography high pressure column with particles of silica gel (10 μm) as a carrier derivative of cellulose, hydroxy-group which is converted into N-3,5-dimethylphenylcarbamate group (Chiralcel OD obtained from J. So Waker Inc)/Chiralcel-brand name products firm Daicel chemical industries, with elution with a mixture of ethanol-hexane (1:7) showed that the product in 81% consists of one of the possible optical isomers. The resulting product is used in the next stage without further purification and characterization.

b. (3S, 4S)-3-Hydroxy-4-phenylpiperidine. To retrieve the target piperidine (0.18 g) of (3S, 4S)-1-benzyloxycarbonyl-3-hydroxy-4-phenylpiperidine (0.3 g) is treated according to the method of example 10, MS: m/z = ="ptx2">

(R)-N-/2-(3,4-Dichlorophenyl)-4-oxobutyl/-N-methylbenzamide obtained by oxidation of (R)-N-/2-(3,4-dichlorophenyl)-4-hydroxybutyl/-N-methylbenzamide, which in turn is obtained by separating isomers of N-/2-(3,4-dichlorophenyl)-4-hydroxybutyl/-N-methylbenzamide. The division performed preparative liquid chromatography high-pressure column size 50 mm x 50 cm, containing particles of silica gel (10 μm) as a carrier derivative of cellulose, in which the hydroxy-group into a 4-methylbenzoate group (Chiralcel OJ received from j. So Waker Inc.) /Chiracel - brand name (see above) with elution by the mixture hexane-ethanol (3:1) at a flow rate of 54 ml/min and UV detection at 230 nm.

Example 12. N/(2S)-(3,4-Dichlorophenyl)-4-/(3S, 4S)-3-hydroxy-4-phenylpiperidine/butyl/N-methylbenzamide hydrochloride.

By the method similar to the method of example 10, but using (3S, 4S)-3-hydroxy-4-phenylpiperidine (about 80% of S, S-isomer) and (S)-N/2-(3,4-dichlorophenyl)-4-oxobutyl/-N-methylbenzamide obtained the title compound (approximately 80% of S,S-isomer); MS: m/z = 511 (DMSO-d6+ Cl3COOD): 1,8 - 2,4 (m, 4), is 2.74 (s, 3), 3,4 - 3,7 (m, 3), 6,91 - to 7.68 (m, 8), of 9.55 (two peaks, 1). Analysis for C29H32Cl2N2O2HCl H2O: calculated: C 61,54, 6 H,S)-N/2-(3,4-dichlorophenyl)-4-hydroxybutyl/-N-methylbenzamide, obtained by separation of the isomers N-/2-(3,4-dichlorophenyl)-4-hydroxybutyl/-N-methylbenzamide. The division carry out preparative liquid chromatography high pressure according to the method of example 11.b.

Example 13. N-/2-(3,4-Dichlorophenyl)-4-/4-(2-methylthiophenyl)piperidine/butyl/N-methylbenzamide hydrochloride.

The title compound obtained by the method similar to the method of example 1 (alternative method), but using 4-(2-methylthiophenyl)piperidine. Chromatography with elution with a mixture of dichloromethane-methanol and subsequent conversion into the hydrochloride obtained white substance with so pl. 98 - 118oC; MC: 541; NMR (CD3OD): of 1.9 - 2.3 (m, 6), and 2.4 (s, 1), 2,7 - 2,8 (two, 3), 2,9 - 3,4 (wide band, 6), of 3.5 - 3.9 (m, 4), 7 (m, 4), and 7.3 and 7.6 (m, 8), and 7.5 and 7.6 (m, 2). Analysis for C30H34Cl2NO21,0 HCl 1,0 H2O: calculated C 60,45, H 6,26, 4,7 N; found: C 60,43, H 5,91, N 4,63.

The intermediate 4-(2-methylthiophenyl)piperidine obtained in the following way.

a. 1-Benzyloxycarbonyl-4-hydroxy-4-(2-methylthiophenyl)piperidine. A solution of 2-bromothioanisole (1,05 g) in 20 ml of anhydrous tetrahydrofuran cooled to -78oC and treated with 2 ml of 2.5 M hexane solution of n-utillity. Upon completion of addition, the reaction mixture peremeshivaete stirring 30 minutes at -78oC, the reaction mixture was left to warm up to the 6oC and treated with 10 ml of water. After extraction with ethyl acetate, drying and evaporation of the organic layer get the crude product. Purification of the obtained product by chromatography with elution by the mixture hexane-ethyl acetate (6:4) to obtain the target compound (0.27 g); MS: 358; NMR: 1,9 - 2,1 (W, 4), and 2.5 (s, 3), 3,4 (W, 2), 4,1 (W, 2), a 5.1 (s, 2), and 7.1 - 7.5 (m, 9).

b. 1-Benzyloxycarbonyl-4-(2-methylthiophenyl)piperidine. To a solution of 1-benzyloxycarbonyl-4-hydroxy-4-(2-methylthiophenyl)piperidine (2,89 g) in dichloromethane (80 ml) is added 6.2 ml triperoxonane acid, then of 25.7 ml of triethylsilane and the mixture is stirred for 16 hours. At the end of this period, the volatile components distilled off under reduced pressure and the obtained residue chromatographic. The elution by the mixture hexane-ethyl acetate (3:1) to obtain the target compound (2,02 g); MS: 342 (M + 1); NMR: 1,5 - 1,6 (W, 2), 1,8 - 1,9 (m, 2), a 2.45 (s, 3): 2,8 - 2,9 (m, 2), 3,1 - 3,2 (m, 1), 4,3 (W, 2), a 5.1 (s, 2), and 7.1 to 7.2 (m, 2), a 7.2 to 7.3 (m, 2), 7.3 to 7.4 (m, 5).

c. 4-(2-Methylthiophenyl)piperidine. A mixture of 1-benzyloxycarbonyl-4-(2-methylthiophenyl)piperidine (0.34 g) and thioanisole (0,58 ml) is treated triperoxonane acid (5 ml), then heated for 30 minutes at 60oC. At the end of this period the reaction mixture is stryrofoam with ethyl acetate to obtain the crude product. Purification of the obtained product column chromatography with elution with a mixture of dichloromethane-methanol (19: 1) containing 5% triethylamine, to obtain the target compound (0,13 g); MS: 208 (M + 1); NMR: 1.4 to 1.8 m (K, q, J1= 25, J2= 12,2), 1,8 - 1,9 (m, 2), the 2.46 (s, 3), 2,8 - 2,9 (d, t, J1= 12, J2= 2,7, 2), 3,1 - 3,2 (m, 1), 3,3 (W., 2), 4 (W., 1), a 7.1 to 7.3 (m, 4).

Example 14. (S)-N/2-(3,4-Dichlorophenyl)-4-/4-(2- methylsulfinylphenyl)piperidino/butyl/N-methylbenzamide hydrochloride.

The title compound obtained by the method similar to the method of example 1 (alternative method), but using 4-(2-methylsulfinylphenyl)piperidine and (S)-N/2-(3,4-dichlorophenyl)-4-oxobutyl/-N-methylbenzamide, chromatography with elution with a mixture of dichloromethane-methanol and subsequent conversion into the hydrochloride get a white substance with so pl. 71 - 144oC; MS: 557; NMR (CD3OD): of 1.9 - 2.3 (m, 6), and 2.4 (s, 1), 2,7 - 2,8 (two, 3), 2,9 - 3,4 (W., 6), of 3.5 - 3.9 (m, 4), 7 (m, 4), and 7.3 and 7.6 (m, 2). Analysis for C30H34Cl2NO2SH2O: calculated: C 60,45, H 6,26, N 5,7; found: C 60,43, H 5,91, N 4,63.

The intermediate 4-(2-methylsulfinylphenyl)piperidine obtained in the following way.

a. 1-Benzyloxycarbonyl-4-(2-methylsulfinylphenyl)piperidine. A solution of 1-benzyloxycarbonyl-4-(2-methylthiophenyl)drank)-3-phenyloxazolidine (2.5 g) (Vishwakarma and others, Org. Syn., 66, 203 - 210). The reaction mixture is left to warm up for 1 hour to room temperature and the solvent evaporated. Chromatographytandem residue by elution with a mixture of ethyl acetate with methanol (9:1) to obtain the target compound (1,71 g); MS: 358; NMR: 1,6 - 1,9 (m, 4), and 2.7 (s, 3), 2,8 - 3 (W., 3), 4.4 to 4.5 (W., 2), and 5.2 (s, 2), 7,2 - 7,3 (m, 1), 7.3 to 7.4 (m, 5), of 7.4 - 7.5 (m, 2), 8 (m, 1).

b. 4-(2-Methylsulfinylphenyl)piperidine). A solution of 1-benzyloxycarbonyl-4-(2-methylsulfinylphenyl)piperidine (1.66 g) in 8 ml triperoxonane acid is boiled for 45 minutes. At the end of this period the reaction mixture is evaporated and the residue treated with toluene. After evaporation of the solvent the residue is treated another operation of toluene and the process is repeated. The final residue is dried under reduced pressure, and after purification by chromatography with elution with a mixture of dichloromethane-methanol-triethylamine (19:1:1) to obtain the target compound (0.87 g); MS: 224; NMR: 1,6 - 2,4 (m, 4), 2.7m (two peaks, 3), 2,9 - 3,2 (m, 3), 3,3 - 3,5 (m, 2), 5,3 - 5,7 (W., 1), the 7.4 - 7.5 (m, 3), 7,9 - 8 (m, 1).

Example 15. (S)-N/2-(3,4-Dichlorophenyl)-4-/4-(4-methylthiophenyl) piperidine/butyl/N-methylbenzamide hydrochloride.

The title compound obtained by the method similar to the method of example 1 (alternative method), but used is the use of a mixture of dichloromethane-methanol and subsequent conversion into the hydrochloride get a white substance with so pl. 73 - 92oC (decomp. ); MS: 541; NMR (CD3OD): 1.8 - to 2.2 (m, 6), and 2.4 (s, 1), and 2.7 (s, 3), 2,6 - 3,2 (m, 6), of 3.4 to 3.8 (m, 4), 6,9 (d, J= 7, 1), 7,1 - 7,2 (m, 6), and 7.3 (m, 5), 7.5 (m, 1). Analysis for C30H34Cl2NO2SH2O: calculated: C 60,45, H 6,26, 4,7 N; found: C 60,23, H 5,85, N 4,7.

The intermediate 4-(4-methylthiophenyl)piperidine obtained in the following way.

a. 1-Benzyloxycarbonyl-4-hydroxy-4-(4-methylthiophenyl)piperidine. The target compound obtained by the method similar to the method of example 13.a., but using 4-bromoanisole; MS: 358; NMR: 1,7 (d, J = 13, 2), 2 (W, 2), and 2.5 (s, 3), 3,2 (W., 2), 4,1 (W., 2), a 5.1 (s, 2), of 7.2 to 7.4 (m, 9).

b. 1-Benzyloxycarbonyl-4-(4-methylthiophenyl)piperidine. By the method similar to the method of example 13, but using 1-benzyloxycarbonyl-4-hydroxy-4-(4-methylthiophenyl)piperidine obtained the title compound in the form of contaminated mixture, giving the expected MS: 342; NMR: 1,6 (W., 2), and 1.8 (W., 2), and 2.6 (m, 1), 2,9 - 3 (W., 2), 4,4 (W., 2), and 7.1 to 7.4 (m, 4). In addition, this will show additional peaks belonging impurities. The resulting product is used without further purification.

c. 4-(4-Methylthiophenyl)piperidine. The target compound obtained by the method similar to the method of example 13.c. but using 1-benzyloxycarbonyl-4-(4-methylthiophenyl)piperidine; MS: 208; I SHALL/P> Example 16. (S)-N/2-(3,4-Dichlorophenyl)-4-/4-(4- methylsulfinylphenyl)piperidino/butyl/N-methylbenzamide hydrochloride.

The title compound obtained by the method similar to the method of example 1 (alternative method), but using 4-(4-methylsulfinylphenyl)piperidine and (S)-N/2-(3,4-dichlorophenyl)-4-oxobutyl/-N-methylbenzamide. Chromatography with elution with a mixture of dichloromethane-methanol and subsequent conversion into the hydrochloride get a white substance with so pl. 94 - 125oC; MS: 557; NMR (CD3OD): 1.8 to 2.3 (m, 6), and 2.8 (s, 6), 2,8 - 3,3 (W., 6), 3,4 - 3,9 (m, 4), of 7.9 to 7.7 (m, 12). Analysis for C30H34Cl2NO2S1,5H2O: calculated: C 58,02, H 6,17, N 4,51; found: C 57,74, H 6, N 5,01.

The intermediate 4-(4-methylsulfinylphenyl)piperidine obtained in the following way.

a. 1-Benzyloxycarbonyl-4-(4-methylsulfinylphenyl)piperidine. The target compound obtained by the method similar to the method of example 14.a., but using 4-(4-methylthiophenyl)piperidine. Chromatography with a mixture of ethyl acetate-methanol to obtain white solid; MS: 358; NMR: 1.6 to 1.7 (m, 2), to 1.86 (d, J = 12,2), 2,7 - 2,8 (m, 4), 2,9 (W., 2), 4,3 (W., 2), and 5.2 (s, 2), of 7.2 to 7.7 (m, 9).

b. 4-(4-Methylsulfinylphenyl)piperidine. By the method similar to the method of example 14.b., but using/SUB> = 12, J2= 4, 2), and 1.9 (d, J = 12,2), 2,5 (s, 1), 2,6 - 2,8 (m, 6), of 3.25 (d, J = 12, 2), and 7.4 (d, J = 8,2), 7,6 (t, d, J1= 8, J2= 2,2).

Example 17. (S)-N/2-(3,4-Dichlorophenyl)-4-/4-(2- hydroxyphenyl)piperidino/butyl/N-methylbenzamide hydrochloride.

The title compound obtained by the method similar to the method of example 1 (alternative method), but using 4-(2-hydroxyphenyl)piperidine and (S)-N/2-(3,4-dichlorophenyl)-4-oxobutyl/-N-methylbenzamide. Chromatography with elution with a mixture of dichloromethane-methanol and subsequent conversion into the hydrochloride get a white substance with so pl. 205 - 210oC; MS: 511; NMR (CD3OD): 1.7 to 2.3 (m, 6), and 2.7 (s, 1), 2,8 - 3,1 (m, 6), 3,2 - 3,8 (m, 5), 6,7 - 6,8 (m, 2), 7 (t, J = 7, 3), 7,2 (W., 2), 7,4 (W., 2), 7,4 (sh. 4), some of 7.5 to 7.7 (m, 2), and 9.5 (s, 10), and 10.5 (s, 1). Analysis for C29H32Cl2N2O20,75 H2O: calculated: C 62,04, H is 6.19, N 4,99; found: C 62,24, H x 6.15, N 5,08.

The intermediate 4-(2-hydroxyphenyl)piperidine obtained in the following way.

a. Benzyl-2-brompheniramine ether. To a suspension of potassium carbonate (15.2 g) in 200 ml of dimethylformamide containing 2-bromophenol (14.9 g), add benzylbromide (17.1 g). After stirring 3 hours, the reaction mixture was diluted with water and extracted with hexane. The hexane layer is washed with water, 1 N. solution HYDR what estcoy oil by fractional distillation under reduced pressure to get a clean simple ester; so Kip. 110 - 145oC (133 PA); MS: 269; NMR: 5,2 (s, 2), 6.8 or 6.9 (d, t, J1= 7,5, J2= 1,3, 1), 6,9 - 7 (d, d, J1= 8, J2= 1,3, 1), 7,2 - 7,4 (m, 7), 7.5 (m, 2), and 7.5 and 7.6 (d, d, J1= 8, J2= 1,6).

b. 1-Benzyloxycarbonyl-4-hydroxy-4-(2-benzyloxyphenyl)piperidine. A solution of benzyl-2-pomperaug ether (3.5 g) in 50 ml of anhydrous tetrahydrofuran cooled to -78oC and treated with 5.3 ml of 2.5 M solution of n-utility in hexane, followed by addition of a solution of 1-benzyloxycarbonyl-4-oxopiperidine (3.1 g) in 3 ml of anhydrous tetrahydrofuran. After stirring for 1 hour at -78oC the reaction mixture is heated to 0oC, stirred for 2 hours and allowed to warm to room temperature. The addition of water, extraction with ethyl acetate, drying over magnesium sulfate and evaporation obtain the crude product. Purification of the obtained product with elution by the mixture hexane-isopropanol (9: 1) get in the form of a white solid target compound (2.86 g); MS: 418; NMR: 2 (W., 4), 3,3 - 3,4 (W., 2), 3,9 - 4,1 (s, 3), 5,1 (two, 4), 6,9 - 7 (m, 2), 7,2 - 7,3 (m, 2), 7.3 to 7.4 (m, 10).

c. 1-Benzyloxycarbonyl-4-(2-benzyloxyphenyl)piperidine. The target compound obtained by the method similar to the method of example 13, but using 1-benzyloxycarbonyl-4-hexan-ethyl acetate (2: 1) receive contains a mixture of the target compound: MS: 402; NMR: 1.5 and 1.7 (m, 2), and 1.8 (d, J = 12,2), 2,9 (W., 2), 3,2 (m, 1), 4,3 (W., 2), 5 - 5,2 (m, 4), 6,9 - 7 (m, 2), and 7.1 to 7.2 (m, 2), 7.3 to 7.4 (m, 10). In addition, the NMR spectrum there are additional signals that belong impurities. The resulting product is used in the next stage without additional purification.

d. 4-(2-Hydroxyphenyl)piperidine. To a solution of 1-benzyloxycarbonyl-4-(2-benzyloxyphenyl)piperidine (1.22 g) in 20 ml of tetrahydrofuran added as catalyst, 10% palladium on coal (0.12 g) and hydronaut 16 hours at atmospheric pressure. The target compound is obtained after filtration and evaporation. Obtained 0.36 g solid; MS: 178; NMR: as 1.8 - 1.9 (m, 4), 2,7 - 2,8 (m, 2), 3 (m, 1), and 3.2 (d, J = 12,2), 5,4 (W., 2), 6,7 (d, J = 8,1), 6,8 (t, J = 7,1), 7, and 7.1 (m, 1) and 7.1 (d, J = 7,2).

Example 18. (S)-N/2-(3,4-Dichlorophenyl)-4-/4-(3- hydroxyphenyl)piperidine/butyl/N-methylbenzamide hydrochloride.

The title compound obtained by the method similar to the method of example 1 (alternative method), but using 4-(3-hydroxyphenyl)piperidine and (S)-N/2-(3,4-dichlorophenyl)-4-oxobutyl/-N-methylbenzamide. Chromatographytandem with a mixture of dichloromethane-methanol and subsequent conversion into the hydrochloride get a white substance with so pl. 178 - 182oC; MS: 511; NMR (CD3OD): 1.8 to 2.3 (m, 6), and 2.8 (s, 3), 2,8 - 3,3 (m,B>2
O20.5 H2O: calculated: C 65,54, H x 6.15, N of 5.03; found: C 62,19, H 6,1, N 5.

The intermediate 4-(3-hydroxyphenyl)piperidine obtained in the following way.

a. Benzyl-3-brompheniramine ether. By the method similar to the method of example 17.a., but using 3-Bromphenol, get the target compound as a white solid; MS: 263; NMR: 5 (s, 2), 6,9 (m, 1), 7 to 7.2 (m, 3), 7.3 to 7.4 (m, 5).

b. 1-Benzyloxycarbonyl-4-hydroxy-4-(3-benzyloxyphenyl)piperidine. By the method similar to the method of example 17, but using benzyl-3-pomperaug ether, the obtained target compound. Purification of the obtained product by chromatography with elution by the mixture hexane-isopropanol (9:1) target connection (2,44 g) are obtained in the form of a solid; MS: 400 (M - 18); NMR: 1.6 to 1.7 (m, 3), 2 (W., 2), and 3.3 (m, 2), 4,1 (W., 2), 5 (C, 2), 5,1 (, 2) and 6.9 (m, 1), 7 (m, 1), and 7.1 (m, 2), 7,2 - 7,5 (m, 11).

C. 1-Benzyloxycarbonyl-4-(3-benzyloxyphenyl)piperidine. The target compound obtained by the method similar to the method of example 13.b., but using 1-benzyloxycarbonyl-4-hydroxy-4-(3-benzyloxyphenyl)piperidine. Purification of the obtained product by chromatography with elution by the mixture hexane-ethyl acetate (3:1) get contaminated by the impurity of the target compound; MS: 402; NMR: 1.5 to the positive signals, owned by impurities. The resulting product is used in the next stage without additional purification.

d. 4-(3-Hydroxyphenyl)piperidine. By the method similar to the method of example 17. d. but using 1-benzyloxycarbonyl-4-(3-hydroxyphenyl)piperidine obtained target compound; MS: 178; NMR: 1.6 to 1.7 (m, 2), 1,8 - 1,9 (m, 2), 2 to 2.4 (m, 4), 2,5 - 2,6 (m, 1), 2,7 - 2,8 (l, K, J1= 12, J2= 2,6, 1), 3,2 (W., d, J = 12.1) is, by 6.6 and 6.7 (m, 1), 6,7 - 6,8 (m, 1), 7 (d, J= 0,5, 1), 7,1 - 7,2 (t, J = 7,7, 1).

Example 19. (S)-N/2-(3,4-Dichlorophenyl)-4-/4-(4-hydroxyphenyl)piperidino/butyl/N-methylbenzamide hydrochloride.

The title compound obtained by the method similar to the method of example 1 (alternative method), but using 4-(4-hydroxyphenyl)piperidine and (S)-N/2-(3,4-dichlorophenyl)-4-oxobutyl/-N-methylbenzamide. Chromatography with a mixture of dichloromethane-methanol and subsequent conversion into the hydrochloride obtained white substance with so pl. 144 - 160oC; MS: 511; NMR (CD3OD): 1.8 - to 2.2 (m, 6), and 2.7 (s, 3), 2,8 - 3,3 (m, 5). 3,4 - 3,9 (m, 3), 6,7 (d, J= 8, 2), 7 - 7,2 (m, 5), and 7.3 and 7.6 (m, 5); (C = 1,06, methanol). Analysis for C29H32Cl2N2O2HCl 0.5 H2O: calculated: C 62,54, H x 6.15, N of 5.03; found: C 62,16, H 6,2, N 4,74.

The intermediate 4-(4-hydroxyphenyl)piperidine obtained in the following OBR is eat 4-bromophenol, in the form of a white solid substance obtained target compound; MS: 263; NMR: 5 (s, 2), 6,8 (l, d, J1= 7, J2= 2,2, 2), 7,3 - 7,4 (m, 7).

b. 1-Benzyloxycarbonyl-4-hydroxy-4-(4-benzyloxyphenyl)piperidine. By the method similar to the method of example 17.b., but using benzyl-4-pomperaug ether obtained target compound. Purification of the obtained product by chromatography with elution by the mixture hexane-isopropanol (9:1) get in a solid target compound (2,44 g); MS: 418; NMR: 1,7 (d, J= 13, 2), 1,9 - 2 (W., 2), and 3.3 (W., 2), 4,1 (W., 2), of 5.05 (s, 2), 5,14 (s, 2), 6,9 - 7 (m, 2), and 7.3 - 7.5 (m, 12).

c. 1-Benzyloxycarbonyl-4-(4-benzyloxyphenyl)piperidine. By the method similar to the method of example 13. b., but using 1-benzyloxycarbonyl-4-hydroxy-4-(4-benzyloxyphenyl)piperidine obtained target compound. Purification of the obtained product by chromatography with elution by the mixture hexane-ethyl acetate (3: 1) receive contains a mixture of the target compound; MS: 402; NMR: 1,5 (m, 2), 1.8 m (W., 2), and 2.6 (m, 1), 2,9 (W., 2), 4,4 (W., 2), 5-5,2 (C, 4) and 6.9 (m, 2), and 7.1 (m, 1), 7,2-7,5 (m, 11). The NMR spectrum there are additional signals that belong impurities. The resulting product is used in the next stage without additional purification.

d. 4-(4-Hydroxyphenyl)piperidine. For me the, obtained the title compound; MS: 178; NMR: 1.3 to 1.5 (m, 2), and 1.6 (d, J = 11,2), of 2.3 - 2.5 (m, 3), 3 (d, J = 12,2), and 6.6 (d, J =8,2), 7 (d, J = 8,2).

Example 20. N-/2-(3,4-Dichlorophenyl)-4-/4-(2,4-dihydroxyphenyl)piperidine/butyl/N - methylbenzamide hydrochloride.

The title compound obtained by the method similar to the method of example 1 (alternative method), but using 4-(2,4-dihydroxyphenyl)piperidine. Chromatography with a mixture of dichloromethane-methanol and subsequent conversion into the hydrochloride obtained white substance with so pl. 184-190oC; NMR (CD3OD): 1,8 - 2 (m, 5), 2 - 2,1 (W., 1), and 2.6 (s, 2), 2,6 - 3,2 (m, 7), 3,3 - 3,5 (m, 2), of 3.7 - 3.8 (m, 2) and 6.1 (m, 2), 6,7 (m, 1), 6,9 (m, 1), 7, and 7.1 (m, 2), 7,2 - 7,6 (m, 7). Analysis for C29H32Cl2N2O3HCl H2O: calculated: C 59,85, H 6, N to 4.81; found: C 59,7, H of 5.89, N 4,73.

The intermediate 4-(2,4-dihydroxyphenyl)piperidine obtained in the following way.

a. 2,4-Dimensionamento. By the method similar to the method of example 17.a., but using 4-bromoresorcinol and two equivalents of benzylbromide and potassium carbonate obtained in the form of a white solid target compound; MS: 369; NMR: 5 (s, 2), a 5.1 (s, 2), 6,47 (l, d, J1= 8, J2= 2,6, 1), and 6.6 (d, J = 2,7, 1), 7,2 -7,5 (m, 11).

b. 1-Benzyloxycarbonyl-4-hydroxy-4-(2,4-dibenzylidene)piperidine. On Metodii. Purification of the obtained product by chromatography with elution by the mixture hexane-isopropanol (9:1) target connection (2,44 g) are obtained in the form of an oil; MS: 524; NMR: 1,8-2,1 (m, 4), 3,3 (W, 2), a 3.9 (s, 1), 4 - 4,1 (W., 2), to 5.03 (s, 2), 5,09 (s, 2), to 5.13 (s, 2), and 6.5 (d, e, J1= 9, J2= 2,4, 1), 6,7 (d, J = 2,4, 1) and 7.1 (d, J = 8,1), 7,2 - 7,5 (m, 18).

c. 1-Benzyloxycarbonyl-4-(2,4-dibenzylidene)piperidine. The target compound is obtained according to the method of example 13.b., but using 1-benzyloxycarbonyl-4-hydroxy-4-(2,4-dibenzylidene)piperidine. The resulting product was then purified by chromatography with elution by the mixture hexane-ethyl acetate (3:1) to obtain containing a mixture of target compound; MS: 508; NMR: 1.5 and 1.7 (m, 2), 1,7 - 1,9 (W., 2), and 2.8 (m, 2), 3 (m, 2), a 4.3 and 4.4 (W., 2), 5 (C, 2), of 5.05 (s, 2), to 5.17 (s, 2), is 6.54 (d, d, J1= 8, J2= 2,4, 1), 6 (d, J = 2,2), 7 (d, J= 8, 1), 7,2 - 7,4 (m, 15). In addition, the NMR spectrum is observed additional peaks belonging impurities. The resulting product is used in the next stage without additional purification.

d. 4-(2,4-Dihydroxyphenyl)piperidine. The target compound obtained by the method similar to the method of example 17.d., but using 1-benzyloxycarbonyl-4-(2,4-dihydroxyphenyl)piperidine; MS: 194; NMR: 1.5 and 1.7 (m, 2), 1.7 to 1.9 (m, 2), 2,7 - 2,8 (m, 2), 2,9 - 3 (m, 1), 3 - 3,1 (m, 2), 6,2 (m, 2), to 6.88 (d, J = 8, 1).

The title compound obtained by the method similar to the method of example 1 (alternative method), but using 4-(2,5-acid)piperidine. Chromatography with elution with a mixture of dichloromethane-methanol (9: 1) and subsequent conversion into the hydrochloride get a white substance with so pl. 85 - 110oC (decomp.); MS: 555; NMR (CD3OD): 1,9 - 2,2 (m, 6), and 2.8 (s, 3), is 2.8 - 3.2 (m, 6), 3,5 - 3,6 (m, 3 in), 3.75 (s, 3), 3,79 (s, 3), 3,8 - 3,9 (m, 1), 6,7 - 6,8 (m, 2) and 6.9 (d, J= 9, 1), 7 - 7,2 (m, 3), of 7.4 - 7.5 (m, 4), to 7.6 (m, 1). Analysis for C31H36Cl2N2O3HCl for 1.5 H2O: calculated: C 60,15, H 6,51, N a 4.53; found: C 60,23, 6,12 H, N 4,51.

The intermediate 4-(2,5-acid)piperidine obtained in the following way.

a. 1-Benzyloxycarbonyl-4-hydroxy-4-(2,5-acid)piperidine. The title compound is obtained according to methods analogous to the methods 13.a., but using 2,5-dimethoxyphenol. The resulting product is crystallized from a mixture of ethyl acetate with hexane to obtain white matter; MC: 372; NMR: 1,9 - 2 (m, 4), 3,4 (W., 2), 3,76 (s, 3), 3,86 (s, 3), 4,1 (W., 2) and 4.2 (C, 1), 5,1 (s, 2), 6,7 - 6,8 (m, 3), of 7.2 to 7.4 (m, 5).

b. 1-Benzyloxycarbonyl-4-(2,5-acid)piperidine. By the method similar to the method of example 13. b., but using 1-benzyloxycarbonyl-4-hydroxy-4-(2,5-dimethoxyphenyl hexane-ethyl acetate receive contains a mixture of the target compound; MS: 556; NMR: a 1.5 - 1.6 (m, 2), and 1.8 (d, J = 12, 2), 2,9 (m, 2), 3,1 (m, 1), 4,3 (m, 2), 5,1 (, 1), 6,7 - 6,8 (m, 3), 7,2 - 7,8 (m, 5). In addition, the NMR spectrum there are additional signals corresponding impurities. The resulting product is used in the next stage without additional purification.

c. 4-(2,5-Acid)piperidine. The title compound obtained by the method similar to the method of example 17.S., but using 1-benzyloxycarbonyl-4-(2,5-acid)piperidine; MS: 222; 1,6 (l, K, J1= 12, J2= 3,9, 2), 1,7 - 1,8 (m, 3), 2,7 - 2,8 (d, t, J1= 12, J2= 2,5, 2), 3 - 3,1 (m, 1), 3,1 (d, J = 12, 2), and 3.7 (s, 3), and 3.8 (s, 3), of 6.65 (d, d, J1= 9, J2= 3,1), 6,8 (m, 2).

Example 22. N-/2-(3,4-Dichlorophenyl)-4-/4-(2,5-dihydroxyphenyl)piperidine/butyl/N - methylbenzamide hydrochloride.

The title compound obtained by the method similar to the method of example 1 (alternative method), but using 4-(2,5-dihydroxyphenyl)piperidine. Chromatography with a mixture of dichloromethane-methanol-triethylamine (19:1:1), and subsequent conversion into the hydrochloride get a white substance with so pl. 168 - 175oC; MS: 527; NMR (CD3OD): 1.8 - to 2.2 (m, 6), and 2.7 (s, 2), 2,7 - 3,3 (m, 7), of 3.4 to 3.8 (m, 4), 6,4 - 6,6 (m, 3), 6,9 - 7,2 (m, 3), and 7.3 and 7.6 (m, 5). Analysis for C29H32Cl2N2O3HCl H2About: Vici the following way.

a. 4-(2,5-Dihydroxyphenyl)piperidine. A solution of 1-benzyloxycarbonyl-4-(2,5-acid)piperidine (0.54 g) (receipt see example 21.b.) in 10 ml of dichloromethane is cooled to 0oC and treated with a solution trichromate bar in dichloromethane (1M, 9 ml). After stirring 1 hour at 0oC, the reaction mixture was left to warm to room temperature. At the end of this period the reaction mixture was cooled to 0oC and neutralized with methanol. The resulting solution was evaporated and then treated with an additional quantity of methanol. After evaporation receive the product as yellow solid (0,42 g); MC: 194; NMR: 1,6 - 1,9 (m, 4), 3 (m, 2), 3,3 (W., 2), 6,4 - 6,5 (m, 2), and 6.6 (d, J= 8, 1), 8,3 - 8,8 (m, 3).

Example 23. N-/2-(3,4-Dichlorophenyl)-4-(Spiro/isobenzofuran-1(3H), 4'-piperidine/-1'-yl)butyl/N-methylbenzamide hydrochloride.

The title compound obtained by the method similar to the method of example 1 (alternative method), but using Spiro/isobenzofuran-1(3H), 4'-piperidine/. Chromatography with elution with a mixture of dichloromethane-methanol and subsequent conversion into the hydrochloride get a white substance with so pl. 120-126oC: MC: 523; NMR (CD3OD): 1,9 (W., 3), of 1.9 - 2.3 (m, 3), and 2.8 (s, 3), 2.8 to 3.5 (W., 5), 3,5 (m 2), and 3.8 (m, 2), a 5.1 (s, 2), 7 (W. , 1), 7,2 - 7,6 1,24, H OF 5.82, N 4,76.

Intermediate Spiro/isobenzofuran-1(3H), 4'-piperidine/obtained as follows.

a. 1'-Benzyloxycarbonyl-3-oxaspiro/isobenzofuran-1(3H),4'-piperidine/. A solution of N-methylbenzamide (0,38 g) in 200 ml of anhydrous tetrahydrofuran cooled to -78oC and treated with tert-butyllithium (30 ml, 1.7 M). Upon completion of addition, the reaction mixture is left to warm to 0oC, stirred at this temperature for 1 hour and then cooled to -78oC. After treatment with a solution of 1-benzyloxycarbonyl-4-piperidone (of 5.83 g) in 2 ml of tetrahydrofuran, the reaction mixture was stirred for 40 minutes at -78oC and then neutralized with 300 ml of saturated solution of ammonium chloride. Extraction with ethyl acetate, washing the organic layer with brine, drying over magnesium sulfate and evaporation obtain the crude product. The resulting product is partially purified column chromatography with elution with a mixture of ethyl acetate-hexane (6: 4), and obtaining the target compound (5,25 g); MS: 238 (M -99); NMR; 1.6 to 1.7 (m, 2), 2 - 2,1 (m, 2), 3,4 (W., 2), 4 - 4,1 (W., 2), and 5.2 (s, 1), 7,2 - 7,44 (m, 5), 7.5 (m, 1), and 7.7 (m, 1), and 7.9 (m, 1).

b. 3 Oxaspiro/isobenzofuran-1(3H), 4'-piperidine/. The target compound obtained by the method similar to the method of example 17, but using the .4 (d, J = 7,1). 7.5 (l, t, J1= 7,5, J2= 0,9, 1), and 7.7 (m, 1), and 7.9 (m, 1).

c. Spiro/isobenzofuran-1(3H),4'-piperidine/. The solution sociallyengaged (7.5 ml, 1 M in ether), diluted with 35 ml of tetrahydrofuran, cooled to 0oC and added to a suspension of 3-oxaspiro/isobenzofuran-1(3H), 4'-piperidine/ (0,38 g) in 40 ml of anhydrous tetrahydrofuran containing ether boron TRIFLUORIDE (6.9 ml). The reaction mixture was left to warm to room temperature and then boiled for 3 hours. At the end of this period the reaction mixture is cooled with ice and treated with 5% HCl (8 ml) and then water (8 ml). After concentration under reduced pressure, the reaction mixture was treated with concentrated HCl (8 ml), boiled, cooled down to room temperature, the addition of sodium hydroxide solution set pH 5 and extracted with ether. The aqueous layer was alkalinized with sodium hydroxide to pH 11 and extracted with two portions of dichloromethane. The dichloromethane layer is dried and after evaporation obtain the target compound (0.28 g), which is used in the next stage without further purification; MS: 190; NMR: 1.7 to 1.9 (m, 4), 2,9 - 3,1 (m, 4), a 5.1 (s, 2), a 7.1 to 7.3 (m, 4).

Example 24. N-/2-(3,4-Dichlorophenyl)-4-(3-oxaspiro/isobenzofuran-1(3H), 4'-piperidine/-1-yl/butyl/N-methylbenzene what native method), but the use of 3-oxaspiro/isobenzofuran-1(3H), 4'-piperidine/ (receipt see example 23). The transformation into the hydrochloride get a white substance with so pl. 163 - 168oC; MS: 537; NMR (CD3OD); 2 (W, 3), 2,3 (m, 1), and 2.6 (m, 2), and 2.8 (s, 2), 3 (m, 2), 3,2 - 3,4 (m, 3), of 3.5 - 3.9 (m, 5). Analysis for C30H30Cl2N2O3HCl 0.5 H2O: calculated: C 61,81, H of 5.53, N to 4.81; found: C 61,55, H 5,54, N 4,91.

Example 25. N-/2-(3,4-Dichlorophenyl)-4-/4-(4-N-methylcarbamoylmethyl)piperidin/butyl/N-methylbenzamide hydrochloride.

The title compound obtained by the method similar to the method of example 1 (alternative method), but using 4-(4-N-methylcarbamoyl)piperidine. Chromatography with a mixture of dichloromethane-methanol and subsequent conversion into the hydrochloride get a white substance with so pl. 247 - 249oC; MS; 552; NMR (CD3OD): 2 to 2.3 (m, 6), 2,7 - 3,5 (m, 3), of 3.5 - 3.9 (m, 4), 7 (Sch. , 1), 7,2 (m, 2), and 7.3 and 7.6 (m, 7), and 7.8 (d, J = 8,2). Analysis for C31H35Cl2N3O2HCl H2O: calculated: C 61,34, H of 6.31, N 6,92; found: C 61,43, 6,12 H, N 6,93.

The intermediate 4-(4-N-Methylcarbamoyl)piperidine obtained in the following way.

A. 4-Bromobenzoate. A mixture of 4-bromobenzoyl acid (5 g) and thionyl chloride (15 ml) is stirred for 16 hours at room temperature, to the reduction mixture is diluted with chloroform and evaporated. The residue is treated with toluene, evaporated and this process was repeated three times. The product is obtained in the form of solids (5,63 g); MS: 221; NMR 7,5 (m, 2), of 7.9 to 8.1 (m, 2).

b. 4-Bromo-N-Methylbenzamide. A solution of 4-bromobenzonitrile (5.6 g) in 50 ml of tetrahydrofuran is cooled to 0oC and treated with an aqueous methylamine (40%, 5 ml). Upon completion of addition, the reaction mixture is left to warm to room temperature and stirred for 16 hours. At the end of this period the reaction mixture is diluted with water, extracted with ethyl acetate and the organic layer washed with 10% HCl and then with sodium carbonate. After drying over magnesium sulfate and evaporation receive a white solid: (with 4.64 g); MS: 214; NMR: 3 (d, J = 5, 3); 6,2 (W., 1), and 7.5 and 7.6 (m, 2), and 7.6 to 7.7 (m, 2).

c. 1-Benzyloxycarbonyl-4-hydroxy-4-(4-N-methylcarbamoyl)piperidine. By the method similar to the method of example 17, but using 4-bromo-N-methylbenzamide obtained target compound. Purification of the obtained product column chromatography with elution by the mixture hexane-ethyl acetate (1:1) to obtain the target compound; MS: 369; NMR: 1,7 (m, 2), 2 (W., 2), 2,2 (s, 1), 3 (d, J = 5, 3), 3,3 (W., 2), 4,1 (W., 2) and 6.2 (d, J = 4,1), 5,1 (c, 2), 7.3 to 7.4 (m, 5), 7.5 (d, J = 8, 2), 7.7 (d, J = 8, 2).

d. 4-(4-N-Methylcarbamoylmethyl)-1,2,3,6-tetracarboxylic acids are added 8 ml of triethylsilane and the mixture is boiled for 16 hours. By the end of the specified period of volatile components distilled off under reduced pressure and the resulting residue is suspended in hexane to obtain the target compound (0.3 g) as a solid substance in a mixture with an admixture; MS: 219; NMR: 1.7 to 1.9 (m, 2), and 1.9 (W., 2), and 2.8 (m, 3), 2,9 - 3 (m, 4), and 7.3 (d, J = 4,2), and 7.5 and 7.6 (m, 2). See additional peaks corresponding to impurities.

e. 4-(4-N-Methylcarbamoyl)piperidine. A mixture of 4-(4-N-Methylcarbamoylmethyl)-1,2,3,6-tetrahydropyridine (0.3 g), thioanisole (0.58 ml), methanol (15 ml), concentrated HCl (0.25 ml) and platinum oxide (5 mg) hydronaut 16 hours under hydrogen pressure of 3.4 bar. At the end of this period the reaction mixture is filtered through diatomaceous earth, evaporated and purified by chromatography. By elution with a mixture of dichloromethane-triethylamine (8:2,0,5) obtain the target compound as yellow solid (0,19 g); MS: 219; NMR: 1,2 (m, e, 2), of 1.5 - 1.8 (m, 2), to 2.5 - 2.7 (m, 3), 2.7 (l, t, J = 4, 2), 3 (d, J = 12, 2), and 7.3 (d, J = 8, 2), 7,76 (d, J = 8, 2 ), at 8.36 (W., 1).

Example 26. (S)-N/2-(3,4-Dichlorophenyl)-4-/4-(2-forperiod-3-yl) piperidino/butyl/N-methylbenzamide hydrochloride.

The title compound obtained by the method similar to the method of example 1 (alternative method ), but using 4-(2-forperiod-3-yl)piperidine and (S)-N/2-UP>o
C; MS: 514; NMR (CD3OD): 1,9-2,3 (W., 6), 2,7 - 3,2 (m, 9), 3,4 - 3,9 (m, 4), 7 to 7.2 (m, 3), 7.3 to 7.4 (m, 5), and 7.6 (m, 2), 7,8 - 7,9 (t, J = 8, 1) and 8.1 (d, J = 4, 1). Analysis for C28H30Cl2FN3O HCl 0.5 H2O: calculated: C 60,06, H 5,76, N 7,5; found, C 60,13, H 6,06, N 7,02.

The intermediate 4-(2-forperiod-3-yl)piperidine obtained in the following way.

a. 1-Benzyloxycarbonyl-4-hydroxy-4-(2-forperiod-3-yl)piperidine. To a solution of Diisopropylamine lithium (0,31 mol) in 300 ml of anhydrous tetrahydrofuran was added at -78oC solution of 2-herperidin (24.6 ml) in 40 ml of anhydrous tetrahydrofuran. The reaction mixture is left to warm to -50oC, again cooled to -74oC and added dropwise a solution of literotica cases (55.5 g) and 1-benzyloxycarbonyl-4-oxopiperidine cases (55.5 g) in 300 ml of anhydrous tetrahydrofuran. The addition carried out in such a way that the temperature of the reaction mixture remained below -70oC. Upon completion of addition, the reaction mixture is left to warm to -30oC and then treated with water. The organic layer is separated and the aqueous layer was extracted with two portions of ether. The combined organic layers are dried and after evaporation obtain the crude product. Purification of the obtained product column chromatography receive cityboy-4-hydroxy-4-(2-forperiod-3-yl)piperidine (3.3 grams) in 50 ml of dichloromethane is cooled to 0oC and treated with 10 ml of pyridine followed by the addition of thionyl chloride (0.8 ml). After stirring 16 hours at room temperature, the reaction mixture was diluted with water and treated with sodium bicarbonate solution. Extraction with two portions of dichloromethane, drying the organic layer over sodium sulfate and evaporation obtain the crude product. The title compound is obtained by purification of the obtained product by chromatography with elution by the mixture hexane-ethyl acetate (4:1). Obtained 2.35 g of target compound; MS: 313; NMR: 2,5 (W., 2), and 3.7 (t, J= 5,6, 2), 4,1 - 4,2 (d, d, J1= 5,6, J2= 2,7, 2), and 5.2 (s, 2), 6 (W., 1), to 7.2 (m, 1), 7.3 to 7.4 (m, 5), and 7.6 to 7.7 (m, 1) and 8.1 (d, d, J1= 3,4, J2= 1,4, 1).

c. 1-Benzyloxycarbonyl-4-(2-forperiod-3-yl)piperidine. To a solution of 1-benzyloxycarbonyl-4-(2-forperiod-3-yl)-1,2,3,6 - tetrahydropyridine (2,04 g) in 50 ml of ethanol is added platinum oxide (0,22 g) and the mixture hydronaut 16 hours under hydrogen pressure of 3.4 bar. At the end of this period the reaction mixture was filtered through a layer of diatomaceous earth and evaporation of the filtrate obtain the target compound (2 g) as a white solid; MS: 315; NMR: 1,6 (W., 2), 1,8 - 1,9 (d, J= 14, 2), 2,8 - 3,1 (m, 3), 4,3 (W., 2), a 5.1 (s, 2), and 7.1 to 7.2 (m, 1), of 7.2 to 7.4 (m, 5), and 7.6 (m, 1) and 8.1 (m, 1).

d. 4-(2-forperiod-3-yl)belong 30 minutes and evaporated. The resulting residue is dissolved in chloroform and evaporated. After repeating this process three times to receive in the form of oil target compound (0.64 g); MS: 181; NMR: 1,6 - 2,1 (m, 4), 3 and 3.4 (m, 5), 7,2 - 7,5 (m, 2), 7,8 - 7,9 (m, 4), and 8.1 (m, 1), 8,2 - 8,8 (W., 2).

Example 27. (S)-N/2-(3,4-Dichlorophenyl)-4-/4-(2-pyridyl) piperidine/butyl/N-methylbenzamide hydrochloride.

The title compound obtained by the method similar to the method of example 1 (alternative method), but using 4-(2-pyridyl)piperidine and (S)-N/2-(3,4-dichlorophenyl)-4-oxobutyl/-N-methylbenzamide. The transformation into the hydrochloride get a white substance with so pl. 200 - 202oC; MS: 496; NMR; 2,14 (sh. , 8), and 2.7 (s, 3), 3,4 - 3,9 (m, 8), the 6.9 to 7.7 (m, 12), 8,16 (m, 1), 8,68 (m, 1), 10,4 (W., 1). Analysis for C28H31Cl2N3O 2HCl 0.5 H2O: calculated: C 58,14, H of 5.92, N 7,26; found: C 58,0, H 5,9, N 7,56.

The intermediate 4-(2-pyridyl)piperidine obtained in the following way.

a. 1-Benzyloxycarbonyl-4-hydroxy-4-(2-pyridyl)piperidine. To a solution of 2-bromopyridine (1,58 g) in 50 ml of anhydrous tetrahydrofuran was added at -78oC tert-utility (6.5 ml, 1.7 M) and the reaction mixture is stirred 1 hour at -78oC. Upon expiration of the specified period, add a solution of 1-benzyloxycarbonyl-4-oxopiperidine (2,34 g) in 20 ml betw anatoy temperature, add aqueous solution of ammonium chloride and the resulting mixture extracted with ethyl acetate. The organic layer is washed with sodium chloride, dried over magnesium sulfate and after evaporation obtain the crude product. The target compound (1 g) is obtained by purification by chromatography with elution by the mixture hexane-ethyl acetate (1:1); MS: 313; NMR: 6,63 (m, 3), was 1.94 (m, 2), 3,37 (m, 2), of 4.13 (m, 2).

b. 1-Benzyloxycarbonyl-4-(2-pyridyl)-1,2,3,6-tetrahydropyridine. To a solution of 1-benzyloxycarbonyl-4-hydroxy-4-(2-pyridyl)piperidine (0.8 g) in 20 ml of dichloromethane are added at 0oC pyridine (2 ml) and then thionyl chloride (0,22 ml). The reaction mixture was left to warm to room temperature and stirred for 16 hours. At the end of this period the reaction mixture is diluted with water and extracted twice with ethyl acetate. The organic layer is washed with copper sulfate solution, dried over magnesium sulfate and concentrated under reduced pressure to get crude product. Purification of the obtained product column chromatography with elution by the mixture hexane-ethyl acetate (1:1) to obtain the target compound (0,48 g); MS: 295; NMR: to 2.67 (m, 2), 3,74 (m, 2), 4,2 (m, 2), is 5.18 (s, 2), and 6.6 (m, 1), 7,18 (m, 1), was 7.36 (m, 6), to 7.68 (m, 1), 8,56 (m, 1).

c. 4-(2-Pyridyl)piperidine. The target compound obtained by the method similar to the method of example 17.c. but using 1-benzyloxycarbonyl-4-(2-Unit.

Example 28

This example illustrates representative pharmaceutical dosage forms, which can be used for therapeutic or prophylactic injection of the compounds of formula I or its pharmaceutically acceptable salts (hereinafter referred to as "Compound X").

(I) Tablets 1 mg/tablet

"Compound X" - 100,0

Lactose is 77.5

Povidone - 15,0

Croscarmellose sodium to 12.0

Microcrystalline cellulose - 92,5

Magnesium stearate- 3,0 - ------- - 300,0

(II) Tablets 2 mg/tablet

"Compound X" - 20

Microcrystalline cellulose - 410

Starch - 50

The glycolate natricinae - 15

Magnesium stearate- 5 - ----- - 500

(III) Capsule mg/capsule

"Compound X" - 10,0

Colloidal silicon dioxide is 1.5

Lactose - 465,5

Pregelatinization starch - 120,0

Magnesium stearate- 3,0 - ----- - 600,0

(IV) Aerosol mg/pot

"Compound X" - 20

Oleic acid - 10

Trichloronitromethane - 5000

DICHLORODIFLUOROMETHANE - 10000

Dichlorotetrafluoroethane - 5000

You must specify that the above pharmaceutical preparations may vary in accordance with well known pharmaceutical methods, depending on various m metering aerosol spray.

Formula:

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Scheme I

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Scheme II

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Sequence listing

(2) Information for TH. N 1:

(1) sequence Characteristics:

(A) Length: 15 base pairs

(B) Type: nucleic acid

(C) Number of threads: one

(D) Topology: linear

(XI) sequence Description, TH. N 1:

GCGCAAGCTT ATGGG

(2) Information for LAST. N 2:

(1) sequence Characteristics:

(A) Length: 18 base pairs

(B) Type: nucleic acid

(C) Number of threads: one

(D) Topology: linear

(XI) a Description of the PLACENTA. N 2:

GTCCCCATAA GCTTGCGC

1. Derivatives of piperidine derivatives of General formula I

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where R2and R3each represents hydrogen or R2is hydrogen and R3represents a hydroxy-group:

R4represents phenyl, furyl, pyridyl, 1,3,4-oxadiazol-2-yl, 2-imidazolyl, each of which may have one or more of the substituents at the carbon atom, selected from halogen,hydroxy, (1-5C)alkyl, (1-5C)alkoxy, -COORkwhere Rkis (1-5C)alkyl, -CONRLMMwhere RLand RMrepresent hydrogen or (1-5C)alkyl, -S(O)nRN
R3represents hydrogen, with the exception of compounds in which R2and R3each represents hydrogen;

R4represents unsubstituted phenyl,

or their pharmaceutically acceptable salts.

2. The compound of formula I under item 1, in which the substituent in R4represents fluorine, chlorine, hydroxy-group, methoxy, ethoxy, methoxycarbonyl, etoxycarbonyl, carbarnoyl, N,N-dimethylcarbamoyl, N-methylcarbamoyl, methylthio, methylsulfinyl, methylsulphonyl, methyl, ethyl, propyl, butyl, isopropyl, 2-methylpropyl, tertbutyl.

3. The compound of formula I under item 1, in which R2and R3each represents hydrogen and R4represents phenyl substituted by fluorine, chlorine, hydroxy-group, a methoxy group, methoxycarbonyl, stands or acetyl.

4. The compound of formula I on p. 3 in which R4represents phenyl, substituted hydroxy-group.

5. The compound of formula I under item 1, in which R2is hydrogen, R3the hydroxy - group, in Transorientale relative to R4and R4a small town is CLASS="ptx2">

6. The compound of formula I under item 1, in which R3represents hydrogen, and R2and R4together with biradicals X1and the carbon atom to which they are attached, form spirocyclohexane ring - Spiro(isobenzofuran-1(3H)-4'-piperidine) or oxaspiro(isobenzofuran-1-(3H)-4'-piperidine).

7. The compound of formula I under item 1, in which the substituted piperidinophenyl choose from 4-phenylpiperidine-, 4-(2-methoxyphenyl)piperidine-, 4-(3-methoxyphenyl)piperidine-, 4-(4-methoxyphenyl)piperidino-, 4-(2-hydroxyphenyl)piperidino-, 4-(3-hydroxyphenyl)piperidine-, 4-(4-hydroxyphenyl)piperidino-, 4-(5-methyl-1,3,4-oxadiazol-2-yl)piperidino-, 4-(4-ethoxycarbonylmethyl-2-yl)piperidino-, 4-(3-pyridyl)piperidine-, 4-(2-pyridyl)piperidine-,4-(2-perperidis-3-yl)piperidine-,(3R*,4R*)-3-hydroxy-4-phenylpiperidine-, (3S, 4S)-3-hydroxy-4-phenylpiperidine-, 4-(2-methylthiophenyl)piperidine-, 4-(4-methylthiophenyl)piperidine-, 4-(2-methylsulfinylphenyl)piperidino-, 4-(4-methylsulfinylphenyl)piperidino-, 4-(2,4-dihydroxyphenyl)piperidine-, 4-(2,5-acid)piperidino-, 4-(2,5-dihydroxyphenyl)piperidine, Spiro(isobenzofuran-1/3H/-4'-piperidine)-1'-yl, 3-oxaspiro(isobenzofuran-1/3H/-4'-piperidine)-1'-yl and 4-(4-N-methylcarbamoylmethyl)piperidinium.


R4represents phenyl, substituted methylthiourea or methylsulfinyl,

or their pharmaceutically acceptable salts.

9. Connection on p. 8, in which the substituted piperidinophenyl the compounds of formula I are selected from 4-(4-methylthiophenyl)piperidine-, 4-(2-methylsulfinylphenyl)piperidino - and 4-(4-methylsulfinylphenyl)piperidino.

10. A derivative of piperidine derivatives of General formula I

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where R2and R3each represents hydrogen;

R4represents pyridyl,

or its pharmaceutically acceptable salt.

11. Connection on p. 10, in which R4is 3-pyridyl.

12. Sol according to any one of paragraphs.1 - 11, obtained with the acid, forming a physiologically acceptable anion.

13. The method of obtaining the piperidine derivatives of General formula I or their pharmaceutically acceptable salts according to any one of paragraphs.1 - 12, characterized in that carry out the alkylation of the appropriate piperidine of formula II

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where R2, R3and R4have the meanings given in paragraph 1,

the aldehyde of formula III

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under conditions of reductive alkylation or alkylating agent of the formula IV

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where Y represents the group that you want,
acceptable salt interaction of compound I with an acid, giving a physiologically acceptable anion, or in any other usual way.

14. The compound of formula I or its pharmaceutically acceptable salt according to any one of paragraphs.1 - 12 with the properties of antagonists NKA.

15. Derivatives of piperidine of General formula II

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where R2and R3each represents hydrogen,

R4choose from 2-methylthiophenyl, 2-methylsulfinylphenyl, 4-methylthiophenyl, 4-methylsulfinylphenyl and 3-pyridyl,

or their acid additive salt.

16. The pharmaceutical composition exhibiting properties antagonist NKA containing a pharmaceutically acceptable carrier or diluent and, as active ingredient an effective amount of a compound according to any one of paragraphs.1 - 12 or its pharmaceutically acceptable salt.

 

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The invention relates to new derivatives of benzimidazole with valuable properties, in particular a derivative of benzimidazole of General formula (I)

< / BR>
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< / BR>
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