4-substituted derivatives of piperidine and method of production thereof

 

(57) Abstract:

The invention relates to new 4-substituted piperidine derivative that is related to ones antagonists neirokinina 2 (NK), which can be used, for example, in the treatment of diseases such as asthma, and the way they are received. 4-Substituted derivatives of piperidine derivatives correspond to the General formula I, where the values of m, D, G, J, L, M have the meanings indicated in the claims. Method of producing compounds of the formula I is the compound of formula I is subjected to condensation with Deaktivierung carbonyl or thiocarbonyl derivative, respectively, followed if necessary by oxidation obtained piperidino derived to obtain the N-oxide, or by alkylation of compounds, where R12- alkyl. 2 C. and 7 C.p. f-crystals, 3 ill., 1 PL.

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The present invention relates to therapeutic compounds, and more specifically, to novel 4-substituted derivatives of piperidine, which are antagonists pharmacological action of one of the endogenous neuropeptide tachykinins known as neurokinin, especially on the receptor neirokinina 2 (NC). New therapeutic heterocycles can be which may have implications for the treatment of those diseases, in which plays a significant role NK-receptor, for example in the treatment of asthma and other closely related conditions. The invention also provides pharmaceutical compositions containing the new therapeutic compounds for use in the treatment of such diseases, methods of their use, and how and intermediate compounds for the production of new therapeutic heterocycles.

Neurokinin mammals are a class of peptide neurotransmitters found in the peripheral and Central nervous systems. Three main neurokinins are Substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB). There are also extended through the terminal nitrogen atom of the form, at least in the case of NKA. Also known at least three types of receptors for the three main neurokinins. Based on the relative selectivity to neurokinin the agonists SP, NKA and NKB, receptors are classified as receptor neirokinina 1 (NK1) receptor neirokinina 2 (NK2) and receptor neirokinina 3 (NK3), respectively. On the periphery of neurokinin SP and NKA are localized in the C-afferent sensory nerve cells, which are characterized by non-mielinizirovannykh nerve endings, known as C-fibers, and are distinguished by villages in the epithelium of the respiratory tract, and thecinema known to cause profound effects that undoubtedly similar to many of the symptoms observed in asthma. Symptoms arising in the selection or the introduction of thekennel in the respiratory tract of mammals include bronchostenosis, increased microvascular permeability, vasodilatation and activation of mast cells. Thus, thecinema involved in the pathophysiological process and hypersensitivity of the respiratory tract, which are observed in asthmatic phenomena; and the blockade highlight thekennel may be useful in the treatment of asthma and related conditions.

It was reported peptide antagonists of NK2. For example, as selective NK2 antagonist described cyclic Hexapeptide known as L-659,877. Known ones and NK2 antagonists, for example, some peptides presented in the European patent applications N 428434, 474561, 512901, 512902, 515240 and 559538. A number of peptide antagonists of NK2 described in International application WO 94/10146.

We have opened a number of new ones NK2 antagonists, which constitute the basis of the present invention. One of the objects of the present invention are 4-substituted derivatives of piperidine, in which the substituent in position 4 of the present is-is derived, presented below in Example 1, which is a potential NK2 antagonist when checking in vitro, which is described below in experiment A, and the functional assessment, described below in experiment B.

In accordance with the present invention offers the claimed Compound which is a compound of formula I (formula below after Examples, together with other formulae referred to by Roman numerals), where:

m takes on the values 2,

D represents a residue of formula Ia, where

Q represents phenyl which may contain one or two substituent selected independently of one another from the group comprising halogen atom,

Qarepresents a hydrogen atom,

R1represents a hydrogen atom or methyl;

R2represents-C(= O)R3where R3represents phenyl, unsubstituted or substituted by one or more atoms of halogen,

hydroxy, (1-4C)alkoxy or (1-4C)alkyl;

G denotes a simple link;

J means oxo or thioxo group;

M stands for-O-, -S - or-NR12;

L means L1;

R12represents a hydrogen atom, a C1-3-alkyl, RaOC(=O)CH2or RbRc=NC (= 0) CH2-;

Rapresi benzyl;

L1represents methylene, trimethylene or tetramethylene;

or N-oxide compounds of formula I at the nitrogen atom piperidino fragment, denoted as ;

or pharmaceutically acceptable salts of these compounds of formula I.

The Quaternary ammonium salt of the compounds of the formula I, in which the nitrogen atom piperidino fragment, denoted as , is a tetravalent ammonium nitrogen atom, where the fourth radical at this atom represents (1-4C)alkyl or benzyl and the associated counterion is a pharmaceutically acceptable anion.

It should be noted that the compound of the formula I contain one or more asymmetrically substituted carbon atoms so that these compounds can be isolated in the form of optically active isomers, racemic and/or diastereoisomeric forms. It should also be noted that the compound of formula I may exist in tautomeric forms, and that this connection may be preformism. It should be understood that the present invention encompasses any racemic, optically active, diastereoisomers, tautomeric, polymorphic or stereoisomeric form, or mixtures thereof, and this form has the properties of antisdale of the racemate or by synthesis from optically active starting materials) and how to determine the properties of the NK2 antagonist using standard experiments, described next. Preferred may be the use of the compounds of formula I in the form that contains, for example, at least 95, 98, or 99% enantiomer excess. In addition, the preferred may be the use of the compounds of formula I, which corresponds to the compound of formula Ic, in the form of containing, such as 95, 98, or 99% enantiomeric excess of the form C (S)-configuration at the centre, which is represented in the formula by an asterisk*.

In the present description, the substituents Ra, Rb, R1, R2and other means the total radicals and have no other values. It should be understood that the General term "(1-3C)alkyl" includes both linear and branched alkyl radicals, and references to individual alkyl radical such as "propyl" only a linear radical ("normal"), and isomeric branched chain, such as "isopropyl" are called separately. Similar techniques are used for other General groups, for example alkoxy groups, alkanoyl groups and other halogen Atoms are fluorine, chlorine, bromine or iodine.

Below for illustration only, but not to exclude other values within the specified ranges, lists the individual values for radicalgenerating values (1-6C) alkyl substituent is methyl, ethyl, propyl, isopropyl and butyl.

Particular values of (1-3C) alkyl substituent is methyl or ethyl.

When D represents the formula Ia, Qarepresents a hydrogen atom, a specific value of the substituent R1is methyl, and the specific value of the substituent R2is-COR3. The specific value of the substituent R3is phenyl, and, more specifically, phenyl, where the aryl (or phenyl) may contain as a substituent one or two atoms of chlorine or fluorine.

The specific value of Q is, for example, phenyl, which may contain one or two substituent selected from the group comprising halogen atom, triptorelin group or methylenedioxy group; more specifically, Q is a 3,4-dichlorophenyl or 3,4-methylidenedioxolan.

The specific value of Q is, for example, a single bond or a methylene group; or a single bond. The specific value of J is, for example, oxo, thioxo, imino, methylimino or ethylimino; and, more specifically, oxo or thioxo. The specific value of M represents a hydroxy, thio or NH; and, more specifically, hydroxy or NR. The specific value of L is, for example, ethylene, CIS-vinile or t the order of the compounds of formula Ic, where: Qbrepresents phenyl which contains one or two substituent, independently from each other selected from the group comprising halogen atom, and G, J, L and M are taking any of the values defined for the corresponding radical in a compound of formula I; or a N-oxide specified with the compounds of formula I at the nitrogen atom of the piperidine, denoted by ; or a pharmaceutically acceptable salt of the compounds of formula I and the N-oxide; or a Quaternary ammonium salt of the compounds of the formula I, in which the nitrogen atom in piperidinium fragment, denoted by , represents a tetravalent ammonium nitrogen atom, where the fourth radical on the nitrogen atom is (1-4C)alkyl or benzyl and the associated counterion is a pharmaceutically acceptable anion.

Another specific group of compounds of formula I are the compounds of formula Ic, where: R12represents a hydrogen atom or (1-3C)alkyl; T and U represents a hydrogen atom; andwis methyl; and their pharmaceutically acceptable salts.

The preferred compounds are (S)-N-[2-(3,4-dichlorophenyl) -4-[4-(2-oxopyrrolidin-1-yl)piperidino] butyl]-N-methylbenzamide; (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(3-methyl-2-oxopyrimidine] butyl] -N-methylbenzamide; and (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxopyrrolidin-1-yl)piperidino] butyl]-N-ethylbenzamide; and their pharmaceutically acceptable salts.

Specific compounds described in the respective Examples.

Pharmaceutically acceptable salt is a salt obtained by use of acid, which gives a physiologically acceptable anion. Pharmaceutically acceptable salts are salts that are formed on the basis of a strong inorganic or organic acids, supplying physiologically acceptable anion, such as, for example, hydrochloric, sulfuric, phosphoric, methansulfonate acid or n - toluensulfonate.

Consider the connection can be obtained by methods which include well-known in the chemistry of the ways to obtain structurally similar heterocyclic compounds.

Such methods and intermediate compounds for obtaining the compounds of formula I or N-oxides of the compounds of formula I in piperidinium the nitrogen atom, denote , or pharmaceutically acceptable salts of the compounds of the formula I or their N-oxides; or Quaternary ammonium salts of the above compounds of formula I, in which piperidinyl the nitrogen atom, denote the I (1-4C)-alkyl or benzyl, and the counterion is a pharmaceutically acceptable anion; which are defined above, are another characteristic of the present invention, and illustrates the following techniques, in which, unless otherwise stated, values are common radicals take the values defined above.

(a) Alkylation of the piperidine of formula II with an aldehyde of the formula IV, reductive alkylation or by using an alkylating agent of formula V, where the Deputy is a leaving group. Typical leaving groups are iodine, bromine, methanesulfonate, p-toluensulfonate, triftorbyenzola and other Alkylation is preferably carried out by conventional reductive alkylation, for example, in accordance with the procedure described in Example 1, by acid catalyzed education in city ammonium salts, followed by recovery of lamborghini.com sodium in an alcohol solvent.

(b) For compounds of formula I, where G is a single bond; J is an oxo or thioxo, respectively; M represents a hydroxy, thio or NP12L takes on the values L1; cyclization of compounds of formula III using Deaktivierung derived carboxylic M carboxylic acids include, for example, 1,1'-carbonyldiimidazole, chloroformiate (such as methylchloroform, ethylchloride or phenylcarbamate) and bicarbonate, as well as phosgene, diphosgene and triphosgene; to Deaktivierung thiocarbonyl derivatives include, for example, 1,1'-thiocarbonyldi-2(1H)-pyridone, 1,1'-thiocarbonyldiimidazole, phenylbarbituric and thiophosgene. The cyclization is usually carried out in an inert solvent, such as chloroform, tetrahydrofuran or toluene, at a temperature from about room temperature to the boiling temperature of the reaction mixture, for example, in accordance with the procedure described in Example 3. If deaktivirovannovo carboxylic acid derivative or deaktivirovannovo thiocarbonyl derivative is the acid chloride of the acid, it may be preferable to conduct the cyclization in the presence of a base as acid acceptor, such as, for example, triethylamine.

(C) For compounds of formula I, which has the formula Ic, the interaction of the amine of formula VIII c with a suitable acid chloride acid. The reaction can be carried out in an inert solvent such as tetrahydrofuran, diethyl ether, toluene, chloroform or methylene chloride, at a temperature in the range from -78 to 100

(g) For compounds of formula I, which has the formula Ic, the interaction of the amine of formula VII with an activated derivative of carboxylic acid. The reaction can be carried out in an inert solvent such as tetrahydrofuran, diethyl ether, toluene, chloroform or methylene chloride, at a temperature in the range from -78 to 100oC, preferably in the range from -20 to 50oC, in the presence of a suitable activating agent, for example, in the presence of hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The reaction can be conducted, for example, in conditions similar to the conditions described in Example 20.

(d) For the N-oxide compounds of formula I in piperidino nitrogen atom, denoted oxidation piperidino the nitrogen atom, denote , using conventional techniques, for example, by oxidation with hydrogen peroxide in methanol, peracetic acid or 3-chloroperoxybenzoic acid in an inert solvent (such as dichloromethane) or dioxirane in acetone. Suitable for carrying out the reaction conditions described in Example 21.

(e) For compounds of formula I, where the substituent R12- represents (1-3C)alkyl, RaOC(=O)CH2or RbRCNC(=O)CH2-, Alcoa by using the appropriate alkylating agent. The alkylation can be carried out in an inert solvent, such as tetrahydrofuran, diethyl ether, toluene or 1,2-dimethoxyethane, at a temperature in the range from -78 to 100oC, preferably in the range from 0 to 50oC, in the presence of a suitable base. The relevant conditions described in Example 22.

(g) Quaternary ammonium salts of the compounds of formula I, alkylation piperidino the nitrogen atom indicated in the compound of formula I , using the appropriate alkylating agent. The alkylation can be carried out in an inert solvent such as tetrahydrofuran, diethyl ether, toluene or 1,2-dimethoxyethane, at a temperature in the range from -78 to 100oC, preferably in the range from 0 to 50oC, in the presence of a suitable base.

In some cases, when carrying out the above methods preferably use of protective groups, or at all stages of the reaction, or at some stage. The protective group can then be removed.

In any of the methods described above, when required to obtain pharmaceutically acceptable salts of the compounds of formula I or pharmaceutically acceptable salt of R-oxide, seeding N-oxide acid, which supplies a physiologically acceptable counterion or by any other known methods.

It should be noted that some of the optional substituents of the considered Compounds can be introduced using standard reactions of aromatic substitution or obtained by conventional modifications of functional groups before or after the above-described methods and, thus, also included in the invention the object "method". Such reactions and modifications of functional groups include, for example, the introduction of a nitro group, or halogen atom, and the restoration of the nitro-groups. Reagents and conditions for such reactions are well known in chemistry.

If the raw materials necessary for carrying out the methods described above, are not commercial products, they can be obtained by methods which are selected from among the standard chemistry of heterocyclic compounds, methods that are similar to the techniques of synthesis of known, structurally similar compounds, as well as from a number of techniques similar to those described above, or the techniques described in the Examples. Original products and methods for their production are also additional object of the present invention.brepresents 3,4-dichlorophenyl described in example 1, stage a) to (e); and obtaining the corresponding optically active alcohol described in Example 2, stage a)-d). The alcohol of formula VI can then be oxidized to the aldehyde of formula IV, for example, using oxalicacid, dimethyl sulfoxide and triethylamine as described in Example 1.W), or using periodinane dessa-Martin (1,1,1-triacetoxy-1,1-dihydro-1,2-benzodioxol-3(1)-he) as described in Example 2.e), or it can be turned into an alkylating agent of formula V using conventional techniques. The aldehyde of formula IV can be converted into the corresponding amine of formula III according to the method similar to the method described in Example 3, stage a)-d). According to the method described in Example 1, an aldehyde of formula IV can be converted into piperidin formula VII; amine of formula III can be obtained by reductive alkylation of an amine of the formula HM-L-NH2using piperidone formula VII in accordance with the procedure described in Example 1.C) or in Example 3, stage a-d).

To get the source piperidone formula II 4-piperidine containing in position 1 protective group, can be used for reset the protective group, for example, by the method of Example 1, stage C)-K). Usually the source piperidine of formula II can be obtained from the 1-protected 4-aminopiperidine or 1-protected 4-piperidone using conventional techniques.

For qualified in the field of specialist it is clear that to obtain the source materials can be used a number of reaction schemes and schemes of reactions leading to the source materials and products of the present invention can be appropriately modified.

Application of the Compounds may be shown by standard tests and clinical trials, including those described below.

Assessment of binding of the receptor neirokinina A (NKA) (Test A)

The ability of Compounds to inhibit the binding of NKA receptor NK2 can be shown by test that uses the NK2 receptor human, expressed in cells erythromelas mice (MEL). In the test used cell membrane MEL (MEL M), which are receptors NK2C high affinity and selectivity. Method of test is described below.

A brief description of the drawings.

Fig. 1: shows the creation of expression vector MA cells of the final product pMEG3 which provides the expression of the human NK2 receptor in cells MEL C88.

Expression of the human NK2 receptor (hNK2R) in MEL cells

Heterogeneous expression of the protein in cells erythromelas mice (MEL) uses a control locus of human globin (LCR) (F. Grosveld et al. , Cell 1987, 51, 975-985). cDNA-s are inserted between the promoter of the human beta-globin second intron of the gene of the human beta-globin, and this expression cassette is then placed down LCR and transfercases in MEL cells (M. Needham et al., Nucl Acids Res., 1992, 20, 997-1003). cDNA of the human NK2 receptor (A. Graham et al., Biochem. Biophys. Res. Commun. 1991, 177, 8-16) RNA extracted from the lung of a person by interacting chain polymerase and DNA sequences. cDNA of the human NK2 receptor subcloning in "Shuttle" the vector (pMEG3), containing the promoter of the beta-globin 3'-part of the gene of the human beta-globin (Fig. 1), cDNA of the human NK2 receptor restrict using Eco 0109 (5' end) and Bam H1 (3' end). Oligonucleotide linker-adaptor containing an internal site Hind III and 3'-end of the website Eco 0109 sew with a fragment of the hNK2R and cDNA. The upper sequence of the oligonucleotide chain = 5'd (GCGCAAGCTTATGGG) (SEQ ID NO:1) and the bottom of the oligonucleotide chain = 5'd(GTCCCCATAAGCTTGCGC) (SEQ 1D NO:2). Their hybridizers and sew with a fragment of the hNK2R using standard methods. After splitting with the product (MEG3/hNK2R) is controlled by restriction mapping and sequencing the junctions of the ends 5' and 3'. Then it transformed into E. coli D5 alpha and standard methods produce plasmid DNA and checked by restriction mapping and sequencing. The Clal fragment/As718, who is the promoter of the beta-globin, human receptor N2 cDNA and fragment 3' beta-globin gene, cut and subcloned in plasmid pGS E (Fig. 2). The final product pMEG3/hKNK-2R cleaved with Clal and ASp718 and cloned directly into the Clal sites and Asp718 (3' LCR) in the expression vector GSE1417. The final product CSE1417/hNK2R (13.9 KB) controlled by restriction mapping. E. coli: DH alpha transform and recombinant plasmids controlled by restriction mapping. Cells MEL, C88 (A. Deisseroth et al., Cell (1978), 15, 55 to 63) is subjected to electroporation (M. Antoniou, Methods Molecular Biology (1991), 7, 421-434) using PVU 1-linearized pGSE1417/hNK2R DNA. Immediately after transfection, the cells were diluted in culture medium to a concentration of 104-105cells/ml and an aliquot of 1 ml was placed in each well of 24-well plate.

24 hours after transfection add G418 concentrations up to 1 mg/ml for selection of stable transfectants. To generate populations of individual clones gather or unite in 7 - 10 days after adding the electoral environment. On pressie cells remain in a state of exponential growth for 4 days and then add dimethylsulfoxide (DMSO) at a concentration of 2% (V/V) to induce differentiation and, therefore, expression. To determine the binding of mRNA and DNA samples taken 4 days after induction. The results indicate that clone #1 expresses hNK2R at a high level (as hNK2R, mRNA, specific DNA binding). This clone scale and are fermented in the usual way if the scale is 20 l/month and use experience A.

The membrane preparations (MEL M) prepared from MEL cells and containing with high affinity receptor NK2 received in accordance with the published Protocol (D. Aharony et al., Neuropeptides, 1992, 23, 121-130) with the following changes:

(1) in homogenizing buffer enter todatetime (1 mm);

(2) the homogenization is carried out in accordance with the published Protocol, but for a shorter period of time - 10 seconds and at a lower speed (residue 10); and

(3) phase equilibrium using KC1/EDTU is not performed.

Usually binding3H-NKA (2.5 nm) with MEL M has a high specificity (88 4%) and linearly dependent on protein concentration, with significant binding is determined up to 26 mg protein/ml Experiments on the equilibrium show binding with high affinity and a high density of receptors p is de [4,5-3H-Leu9] -NKA (typical specific activity 117 Kyu/mmol) was produced using the conventional syntheses described in the Cambridge Research Biochemicals, and has a degree of purity of 95%. Re-analysis by HPLC shows that the ligand is stable under appropriate storage conditions (silanizing vessel with 0.2% mercaptoethanol, argon atmosphere). Also there are no signs of decomposition or metabolism when assessing binding of the receptor. Tests performed using incubation buffer containing 50 mm Tris hydrochloride(hydroxymethyl)aminomethane (Tris HCl) (pH 7.4), 5 mm Mg++, 100 μm of thiorphan, 1 nm3H-NKA, 0.02% (wt./about.) serum bovine albumin (UBA). 30 MMK+and 300 μm of dithiotreitol; the concentration of membrane protein is supported approximately at the level of 0.05-0.025 mg per tube. Nonspecific binding is determined using 1 μm NKA. To each tube add 150 ál of incubation buffer, 20 ál3H-NKA, 20 μl of Compounds suitable NKA or buffer and 125 μl of membrane suspension. The reaction is initiated by addition of the membrane suspension. The tubes are incubated for 60 min at 25oC in shake a bath. The reaction is stopped when the washing test tubes 10 ml ice 50 mlya collection membranes soaked for at least 4 hours at room temperature in 0.01% (vol./about.) polyethylenimine. The filters are placed in scintillation vessels and studied using a scintillation counter Beckman LS 60001, L. binding Constant of Kicalculated by standard methods and usually represents average value for multiple definitions. The value Kican be converted to negative logarithms and represented as-log molar TOi(i.e. the PKi).

At the initial stage of the research the value of the IC50measured for standard connections L-659877, as installed, is set to 30 nm relative to the3H-NKA associated with MEL M. the Selectivity of the Compounds for binding of the receptor NK2 can be shown, for example, binding other receptors using standard estimates, for example, by titration derived SP in the tissues of the drug selective for receptors NK1, or when titration derived NKB in the tissues of the drug, a selective NK3 receptor.

Test on Guinea pigs (Test B)

The following experience as an agonist use or NKA or [ -Ala8] -NKA (4-10), who when describing the experience denoted by AG. The ability of Compounds to inhibit the activity of hypertension in the pulmonary tissue may be demonstrated through functional assessment in Proc. of the arene sharp object on the back of the head. Remove the trachea, cut off the excess fabric and is divided into two segments. Each segment is suspended in the form of a ring between the clamps of stainless steel baths for fabrics with a water jacket (37.5oC) containing a physiological solution of the following composition (mm): NaCl, 119; KCl, 4,6; CaC12, 1.8; MgCl2, 0.5; NaH2PO4, 1; NaHCO325; 11; tiorfan 0.001; and iodometry, 0.005. Saline solution is continuously saturated with a mixture of 95% O2- 5% CO2. The initial tension set on each tissue sample is 1 year, and to add another medication is the tension remain within 0.5-1.5 hours to establish equilibrium. The contractile response was measured on a Grass polygraph through the sensor Grass FT-03.

Tissue reaction provoked over and over again with unit concentration of AG (10 mm) after 30 min with washing to return the voltage to the base values. The concentrations of AG reaches a constant level after two provocations and each connection test for inhibition of the response to AG by adding it to the bath for tissue for 15 min until the third or subsequent exposure to agonist. Contractile response to AG in the presence of the Compound compared to the contractile response, the unity produces a statically significant (p < 0.05) reduction reduction, and calculate, based on the fact that the second contractile response corresponds to 100%.

The activity of selected Compounds evaluated by calculating the apparent dissociation constants (KBfor each studied concentration using the standard equation:

KB= [antagonist][(the ratio of doses-1),

where (the ratio of doses = antilogarithm [(AG - log molar EC50connectionless) - (AG - log molar EC50Connection]. Values of KBcan be converted to negative logarithms and expressed as - log molar KB(i.e. the pKB). For this equation the full curve of the concentration-response for AG obtained in the absence and in the presence of Compounds (a 30-minute incubation period) using paired rings of the trachea. The activity of AG is defined at 50% of their maximum level on each curve. Value EC50transferred to the negative logarithms: log molar EC50. Maximum contractile responses to AG is determined by the representation of the maximal response to AG in the form of a percentage reduction caused by carbachol (30 μm), added after the initial period of the establishment of equilibrium. When using Compounds pornositeleri percent reduction, due carbachol in untreated tissue, which is taken as 100%.

Clinical trials showing the effectiveness of compounds can be carried out using standard methods. For example, the ability of the Compound to prevent or treat the symptoms of asthma or asthmatic conditions can be demonstrated by introducing cold air or allergen and evaluation using standard pulmonary measurements, such as, for example, FEV1(fixed volume of breath for 1 second) and high-flow (fixed lung capacity), analyzed using standard methods of static analysis.

You may notice that the inclusion of compounds in test A or test B is not limited to asthma. These tests demonstrate the General antagonism NKA. In the General case tested Compounds show a statically significant activity in Test a with a value of Ki1 μm and below. For example, the compound described in Example 2, as installed, has a value of Ki4.1 nm. In Test B the value of the pKBis 5 or more. For example, compounds described in Example 2, pKB= 8.7. It should be noted that not always there is a direct correlation between the activity of the Compounds expressed C is>Test Century

As described above, the compounds of the present invention have properties antagonists NKA. Thus, they oppose at least one of the functions of NKA, which are known to include bronchostenosis, increased microvascular permeability, vasodilatation and activation of mast cells. Thus, one of the objects of the present invention is the use of the compounds of formula I; or a N-oxide of the above compounds of formula I according piperidino nitrogen atom, which is indicated ; or pharmaceutically acceptable salts of the above compounds of formula I or named N-oxide; or Quaternary ammonium salts of the above compounds of formula I, in which piperidinyl the nitrogen atom denoted by , represents a tetravalent ammonium nitrogen atom, where the fourth radical when it is (1-4C)alkyl or benzyl and the associated counterion is a pharmaceutically acceptable anion, which is defined above; in the treatment of disease in humans or other mammals in need of such treatment, which involved NKA and requires suppression of its action, for example, in the treatment of asthma and friends diseases. In addition, another object nasto piperidinium the nitrogen atom, which indicated ; or pharmaceutically acceptable salts of the above compounds of formula I or named N-oxide; or Quaternary ammonium salts of the above compounds of formula I, in which piperidinyl the nitrogen atom, denoted by , represents a tetravalent ammonium nitrogen atom, where the fourth radical on it is (1-4C)alkyl or benzyl and the associated counterion is a pharmaceutically acceptable anion, which is defined above; as pharmacological standards for the development and standardization of new models of diseases or tests for use in the development of new therapeutic agents for the treatment of diseases that involve NKA, or tests for their diagnosis.

When used for the treatment of diseases such Connection is usually applied in the form of a corresponding pharmaceutical composition, which contains a compound of formula I; or a N-oxide of the above compounds of formula I according piperidino nitrogen atom, which is indicated ; or a pharmaceutically acceptable salt of these compounds of the formula I or named N-oxide; or a Quaternary ammonium salt of the above compounds of formula I, in which piperidinyl ATOA it is (1-4C)alkyl or benzyl, and the associated counterion is a pharmaceutically acceptable anion, which is defined above; and pharmaceutically acceptable diluent or carrier, and the composition is adapted for the particular route of administration. This song is another object of the present invention. It can be obtained using conventional techniques and using conventional fillers and bonding agents, and can be made in the form of one of the dosing forms. Such forms include, for example, tablets, capsules, solutions or suspensions for oral administration; candles for rectal use, sterile solutions or suspensions for infusion and injection, aerosols or solutions or suspensions for inhalation; or powders together with a pharmaceutically acceptable solid diluents such as lactose, which are intended for use by injection.

Orally usually tablets and capsules, which contain up to 250 mg (and usually from 5 to 100 mg) of the compounds of formula I. When used by inhalation the compounds of formula I are usually assigned to a person with a daily dose of, for example, from 5 to 100 mg, or in one dose or in two to four doses per day. Similarly, for intravenous or% weight./weight. (usually from 0.05 to 5% wt./weight.) the compounds of formula I.

The dose of a compound of formula I, which should be administered to the patient will need to be changed in accordance with principles well known in this field, taking into account the route of administration and the severity of the disease, age and weight of the patient. However, in General, the compound of formula I will be administered to warm-blooded animals (including humans) so that the entered dose was, for example, from 0.01 to 25 mg/kg (usually from 0.1 to 5 mg/kg). It should be understood that typically can be used an equivalent amount of N-oxide, or pharmaceutically acceptable salts or Quaternary ammonium salts of the compounds of formula I.

The present invention is illustrated by the following examples without limiting the invention, in which, unless otherwise stated, we use the following values;

(I) temperatures are given in degrees Celsius (oC); room temperature or ambient temperature corresponds to the temperature of 18-25oC;

(II) organic solvents were dried with anhydrous sodium sulfate; the solvent is evaporated on a rotary evaporator under reduced pressure (600-4000 PA; 4.5-30 mm RT.CT.) p is), carried out on Kieselgel (Merck Kieselhel, Art 9385 company Merck, Germany); silica gel, reversed phase" means the basis, which is applied to octadecylsilane (ODS), with particle diameters 32-74 μm, which is known as "PREP-40-ODS" (Ant 731740-100, firm Bodman Chemicals, Aston, USA); thin layer chromatography (TLC) carried out on 0.25 mm plates of silica gel GHLF (Art 21521, firms Analtech, Newark, DE USA);

(IV) in General, over the course of the reaction is observed by TLC and reaction times are given only for illustration;

(V) melting points are incorrect; (decomp.) indicates decomposition; the melting temperature of the presented materials obtained in accordance with the described methods; polymorphism may result from the selection of materials with different melting temperatures when carrying out any method of obtaining;

(VI) final products are the corresponding spectra of nuclear magnetic resonance and according to TLC are individual products;

(VII) yields are given for illustration only and are not binding in the case careful the method of obtaining; synthesis can be repeated if more product; (VII) the NMR spectra are given values iliyana (TMS), used as internal standard; the spectra were obtained at 300 MHz in CDCl3; to refer to a waveform, use the usual abbreviations; AB-system is the main chemical shift;

(IX) chemical symbols have their usual meaning; used units and designations SI;

(X) a reduced pressure refers to the absolute pressure, expressed in Pascals (PA); high blood pressure refers to the pressure measuring device, which is expressed in bars;

(XI) are the volume ratio of solvent: (./vol.);

(XII) mass spectra obtained by chemical ionization energy of 70 electron volts direct input samples; usually provides one signal that corresponds to the original weight of the connection.

EXAMPLE 1: the Hydrochloride of N-[2-(3,4-Dichlorophenyl)-4-[4-(2-oxo-1,3-oxazolidin-3-yl)piperidino] butyl]-N-methylbenzamide

A solution of N-[2-(3,4 - dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (0,823 g) in methanol (4 ml) are added to a solution of 4-(2-oxo-1,3-oxazolidin-3-yl)piperidine (0.600 g) and acetic acid (0.20 ml) in methanol (8 ml). After 5 minutes add in one portion of Lamborghini sodium (0,220 g) in methanol (4 ml). The reaction mixture is stirred for 3 hours and then rasba the organic extracts are dried, evaporated and chromatographic (eluent dichloromethane:methanol, gradient 98:2, 90:10). The obtained product is dissolved in dichloromethane, precipitated in the form of chlorohydra ethereal solution of hydrogen chloride, evaporated and kept under high vacuum overnight. Get the claimed compound as a white solid (0.88 g).

Mass spectrum: m/z = 504 (M+1). Elemental analysis: Calculated, %: C, 56.96, H 5.92, N, 7.66. C26H31Cl2N31.20 HCl. Found,%: C, 57.02, H 6.05, N, 7.62.

The intermediate compound N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide receive the following way.

a). 1-Bromo-2-(tetrahydropyran-2-yloxy)ethane

To a mechanically stirred solution dihydropyran (1 l) and strongly acidic ion-exchange resin (10.0 g) in hexane (2 l) is added dropwise over 1.5 hours while cooling bath of ice water to maintain the temperature interval 35-40oC add 2-bromoethanol (985). The reaction mixture was stirred over night at room temperature, the mixture is then chromatographic hexane (6 l). The eluate evaporated receive liquid amber, which is distilled from the column in the Game long, 5 cm, collect the product with a boiling point 75-95oC (3300-4700 PA). This product p is 1), the 3.89 (m, 1), 3.77 (m, 1), 3.52 (m, 3), 1.75-1.50 (m, 6).

b). -[2-(Tetrahydropyran-2-iloil)ethyl] 3,4-dichlorophenyl-acetonitrile.

To a solution of sodium hydride (218.0 g of a 55% oil suspension) in tetrahydrofuran (4 l) at 10oC (bath ice/water) is added over 45 minutes a solution of 3,4-dichlorobenzonitrile (893.0 g) in tetrahydrofuran (2 l), the resulting solution was stirred at room temperature for 2 hours. The mixture is cooled with an ice-water bath and added dropwise within 25 minutes, add 1-bromo-2-(tetrahydrofuran-2-yloxy)ethane (1076.0 g) in the form of undiluted oil. The mixture is stirred overnight and divided into 4 parts by volume of 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. The resulting product chromatographic (eluent hexane: dichloromethane, gradient 100:0, 0:100), get the nitrile in the form of oil (932).

Range PMR: 7,47 (m, 4); 7.20 (m, 2), 4,74 (m, 2), 4.08 (m, 2), 3,85 (m, 4), of 3.54 (m, 3), 3,37 (m, 1), of 2.15 (m, 4), 1.77 (m, 4), 1.56 (m, 8).

in). 2-(3,4-Dichlorophenyl)-4-(tetrahydrofuran-2-yloxy)butylamine.

To a solution of the above nitrile (128.3 g) in 95% ethanol (1.1 l) and concentrated solution Amici. The mixture is filtered through diatomaceous earth to remove the catalyst, the filtrate is evaporated. The resulting product chromatographic (eluent methylene chloride: methanol, gradient 100:0, 95:5), receive amine in the form of oil (91 g).

Range PMR: 7.40 (s, 1); 7.38 (s, 1), 7.32 (d, 1, J=2.1),

7.28 (d, 1, J=2.0), 7.07 (DD, 1, J=2.1, 4.9), 7.04 (DD, 1, J=2.1, 4.9), 4.50 (m, 1), 4.43 (m, 1), 3.70 (m, 4), 3.45 (m, 2), with 3.27 (m, 1), 3,17 (m, 1), 2.97-2.75 (m, 6), 2.00 (m, 2), 1.82-1.66 (m, 6), 1.53 (m, 8), 1.18 (ush. C, 4). Mass spectrum: m/z = 318 (M+1).

g). N-[2-(3,4-Dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butyl]benzamide.

To a solution of amine (2.5 g) in methylene chloride (35 ml) is added triethylamine (1.1 ml) and the anhydride of benzoic acid (1.85 g), the resulting solution is stirred for 45 minutes. The mixture was washed with 0.2 G. hydrochloric acid, 1 N. sodium hydroxide and water, then dried and evaporated, get amide as an oil (3.3 g).

Range PMR: 7.63 (m, 4), 7,46 (m, 2), 7.37 (m, 8), 7.09 (m, 2), 6.22 (m, 2), 4.50 (m, 1), 4.43 (m, 1), and 3.8 (m, 5), 3,63 (m, 1), 3.5 (m, 4), 3.36 (m, 1), 3,23 (m, 1), 3.11 (m, 2), 2.06 (m, 2), 1.90-1.77 (m, 4), 1.68 (m, 2), 1.51 (m, 8). Mass spectrum: m/z = 338(M+1)-tetrahydropyranyl].

d). N-[2-(3,4-Dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butyl]-N - methylbenzamide.

To a solution of the above amide (3.3 g) in dimethyl sulfoxide (20 ml) is added powdered potassium hydroxide (1.6 g) and 15 mie organic extracts are dried and evaporated, get amide in the form of an oil (3.1 g).

Mass spectrum: m/z = 353 [(M+1)-tetrahydropyranyl].

e). N-[2-(3,4-Dichlorophenyl)-4-hydroxybutyl]-N-methylbenzamide.

To a solution of the above amide (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 10 N. sodium hydroxide, diluted with water and extracted with methylene chloride. The organic layer is dried and evaporated. The obtained yellow solid is suspended in ether and filtered, to obtain the alcohol as a yellow solid (8.4 g). Mass spectrum: m/z = 352 (M+1).

W). N-[2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methylbenzamide.

To a solution of oxalicacid (2.6 ml) in methylene chloride (60 ml) at a temperature of -78oC add dimethylsulfoxide (4.2 ml) in methylene chloride (30 ml), and then add the alcohol (8.3 g) in dimethyl sulfoxide (6 ml) and methylene chloride (30 ml). The resulting solution was stirred for 30 minutes and then add triethylamine (16.4 ml). Mixture is allowed to warm to room temperature, diluted with methylene chloride, washed with 1 N. hydrochloric acid, saturated aqueous sodium bicarbonate and water, dried and evaporated. The obtained solid is suspended ).

The intermediate 4-(2-oxo-1,3-oxazolidin-3-yl)piperidine was prepared as follows.

C). 1-Benzyloxycarbonyl-4-(2-hydroxyethylamino)piperidine.

1-Benzyloxycarbonyl-4-oxopiperidin (2.5 g) in methanol (7.0 ml) was added to a solution of ethanolamine (1.3 ml) and acetic acid (1.2 ml) in methanol (20 ml). After 5 minutes add in one portion of laborgerate sodium (1.35 g) in methanol (6 ml). After stirring over night the reaction mixture was diluted with aqueous sodium bicarbonate solution, stirred for 30 minutes and extracted with methylene chloride. The combined organic extracts evaporated, diluted with 1 N. hydrochloric acid and washed with dichloromethane. The aqueous phase podslushivaet 1 N. a solution of sodium hydroxide and extracted with methylene chloride. The extracts are dried and evaporated, get amerosport in the form of an oil (1.7 g).

Range PMR (CD3OD): 7.34 (m, 5), 5.10 (s, 2), 4.13 (m, 2), to 3.64 (m, 2), of 2.86 (m, 2), 2,73 (m, 2), to 2.67 (m, 1), 1.90 (m, 2), 1.25 (m, 2); Mass spectrum: m/z = 279 (M+1).

and). 1-Benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine.

The solution amerosport (1.7 g) and 1,1'-carbonyldiimidazole (2.4 g) in chloroform (30 ml) is heated under reflux for 6 hours. The reaction mixture is diluted with methylthiazolidine-3-yl-piperidine as a viscous oil (1.9 g).

Range PMR: 7.35 (m, 5), 5.13 (s, 2), 4.34 (m, 4), 3.89 (m, 1), 3,49 (m, 2), 2.86 (m, 2), 1.78 (m, 2), 1.58 (m, 2). Mass spectrum: m/z = 305 (M+1).

K). 4-(2-Oxo-1,3-oxazolidin-3-yl)piperidine.

The solution described above oxazolidin-3-yl piperidine (1.85 g) and 20% palladium hydroxide on coal (0.340 g) in ethanol is stirred overnight under hydrogen pressure of 1 bar. The reaction mixture is filtered through diatomaceous earth and the filtrate evaporated, to obtain the claimed compound (0.950 g) as a white solid.

Range PMR (CD3OD): 4.35 (m, 2), 3.75 (m, 1), 3.62 (m, 2), 3.20 (m, 2), was 2.76 (m, 2), 1.75 (m, 4); Mass spectrum: m/z = 171 (M+1).

EXAMPLE 2: Hydrochloride (S)-N-[2-(3,4-dichlorophenyl)-4-(2-copersito-1,3 - oxazin-3-yl)piperidinomethyl]-N-methylbenzamide.

According to the method of example 1, replacing 4-[4-(2-oxo-1,3-oxazolidin)piperidine 4-(2-copersito-1,3-oxazin-3-yl)piperidine and N-[2-(3,4-dichlorophenyl)-4-oxobutyl] -N-methylbenzamide the corresponding (S)-enantiomer, get the claimed compound as a white solid.

Mass spectrum: m/z = 518 (M+1); Elemental analysis: Calculated, %: C 56,61, H 6.24, N 7.12. C27H33Cl2N3O31.55 HCl 0.20 (C2H5)2O.

Found, %: C At 56.54, H 6.60, N, 7.38.

(S)-N-[2-(3,4-Dichlorophenyl)-4-oxobutyl] -4-oru 2-(3,4-dichlorophenyl)-4-(tetrahydrofuran-2-yloxy)butylamine (550 g) in methanol (3300 ml) with stirring in one portion of 6.0 N. hydrochloric acid (352 ml), while there is a small heat release. After stirring for 3 hours the reaction mixture is evaporated and the residue diluted with water to a total volume of 3 L. the resulting solution was extracted with ether (2 x 500 ml), alkalinized granulated sodium hydroxide (100 g) and extracted with ethyl acetate (4 x 500 ml). United an ethyl acetate extracts are washed (800 ml saturated sodium chloride solution), dried and evaporated, get alcohol in the form of oil of amber (367 g), which solidified under high vacuum.

Range PMR: 7.39 (d, 1, J= 8.2), 7.28 (d, 1, J= 2.0), 7.04 (DD, 1, J= 8.2, 2.0), 3.65 (m, 1), 3.50 (m, 1), 2.90 (m, 2), a 2.71 (m, 1), 2.25 (m, 2), 1.86 (m, 2).

b). (S)-2-(3.4-Dichlorophenyl)-4-hydroxyethylamine

To a solution of D-tartaric acid (222 g) in methanol (4 l) under stirring and boiling under reflux is added in one portion above amerosport (342 g) in warm methanol (2 l), further washed with methanol (1 liter). The mixture boil. Crystal formation is observed already at a temperature below the boiling point. After 1.5 hours the mixture is gradually cooled to room temperature and stirred for 3 days. The first part of the salt of tartaric acid is filtered off and dried in a vacuum oven techenie 1 hour, driving with 1 l of methanol. The mixture is left to cool slowly to room temperature and stirred for 4 days. The first part of the crystals are filtered and dried, get a solid substance (178.8 g). The methanol filtrate is evaporated to a volume of approximately 3 liters of the resulting suspension is heated to boiling, get a clear solution, which is left under stirring slowly cool to room temperature. Collect the second part of the crystals (43.8 g).

The joint parts of the solid tartratami of amerosport (22.6 g) was dissolved in 1.0 N. the sodium hydroxide (1.5 l) and extracted with methylene chloride (4 x 500 ml). The combined organic extracts washed with brine, dried and evaporated, are optically enriched amerosport in the form of an almost white solid (135.4 g).

So pl. 80 - 82oC. PMR Spectrum (CD3OD): 7.47 (d, 1, J=8.3), 7.42 (d, 1, J = 2.1), 7.17 (DD, J= 8.2, 2.1), 3,47 (m, 1), 3.34 (m, 1), 2.83 (m, 3), 1.92 (m, 1), 1.74 (m, 1). Mass spectrum: m/z = 324 (M+1).

in). Ethyl-(s)-N-[2-(3,4-dichlorophenyl)-4-hydroxybutyl]carbamate.

Ethylchloride (25.5 g) added with stirring dropwise during 20 minutes to a solution of the above amerosport (50.0 g) and triethylamine (24.9 g) in methylene chloride (60 ml), cooled up to gradually warm to room temperature for 4 hours and washed with 1 N. hydrochloric acid, saturated aqueous bicarbona sodium, saturated aqueous sodium chloride. Methylenchloride layer is dried and evaporated, get carbamate as a yellow oil (65.3 g).

Range PMR (CD3OD): 7.44 (d, 1, J=8.3), 7.38 (d, 1, J= 2.1), 7.15 (DD, 1, J= 8.2, 2.1), 3.99 (K, 2, J= 7.1), 3.45 (m, 1), 3,29 (m, 3), 2.97 (m, 1), with 1.92 (m, 1), 1.75 (m, 1), 1.16 (t, 3, J=7.1). Mass spectrum: m/z = 306 (M+1).

g). (S)-N-Methyl-2-(3,4-dichlorophenyl)-4-hydroxyethylamine

The solution of the above carbamate (65.3 g) in tetrahydrofuran (500 ml) is added with stirring dropwise during 30 minutes to a suspension of lithium aluminum hydride (16.0 g) in tetrahydrofuran (200 ml). Adding the temperature of the reaction mixture 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 an ice bath and then added dropwise within 45 minutes, a saturated aqueous solution of sodium sulfate (50 ml). After stirring for 30 minutes the mixture is filtered through diatomaceous earth, the filtrate evaporated, get methylamine as a yellow oil (52.9 g).

Range PMR: 7.37 (d, 1, J= 8.2), 7.27 (d, 1, J=2.0), 7.01 (DD, 1, J= 8.2, 2.1), of 3.69 (m, 1), 3,53 (m, 1), 3,40 (m, 2), was 2.76 (m, 3), 2.45 (m, 3), 1.89 (m, 2). Mass spectrum: m/z = 248 (M+1).

oC. the Reaction mixture is stirred for 3 hours at room temperature and then washed (1 N. hydrochloric acid, brine). The layer of methylene chloride evaporated, receives a yellow oil, which chromatographic (eluent methylene chloride:ethanol, gradient 100:0, 95:5), receive benzamide in the form of a white solid (65.6 g).

So pl. 123-125oC. Mass spectrum: m/z = 352 (M+1); [a]D= -18.3oC (c = 2.46, CH3OH).

e). (S)-N-[2-(3.4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide

The solution of the above alcohol (12.9 g) in methylene chloride (150 ml) candleroom in solution periodinane dessa-Martin (Dss-Martin) (18.6 g) and tert-butanol in methylene chloride (150 ml). After stirring for 5 minutes the reaction mixture was diluted with ether (600 ml) and sodium bicarbonate solution (19.7 g) and pentahydrate sodium thiosulfate (64.5 g) in water. A two-phase system is vigorously stirred until until both layers will not become transparent (approximately 30 minutes). The organic layer was washed with saturated aqueous sodium bicarbonate, dried and evaporated. The crude product chromatographic (eluent methylene chloride: ether, 1:1). The aldehyde is then precipitated with ether and filtered them in the form of a white solid washes the Institute obtained as follows.

W). 1-Benzyloxycarbonyl-4-(3-hydroxypropylamino)piperidine

According to the method of Example 1.C, replacing ethanolamine, 3-amino-1-propanol, get aminopiperidin in the form of butter.

Range PMR (CD3OD): 7,35 (m, 5), 5.10 (s, 2), 4.12 (m, 2), 3,62 (t, 2, J= 6,2), 2.86 (m, 2), 2.71 (m, 2), to 2.65 (m, 1), 1.90 (m, 2), 1,71 (m, 2). Mass spectrum: m/z = 293 (M+1).

C). 1-Benzyloxycarbonyl-4-(2-copersito-1,3-oxazin-3-yl)piperidine.

According to the method of Example 1. and, substituting 1-benzyloxycarbonyl-4- (2-hydroxypropylamino)piperidine 1-benzyloxycarbonyl-4-(3-hydroxypropylamino)piperidine, get oxazin-3-yl piperidine in the form of butter.

Range PMR (CD3OD): 7.35 (m, 5), 5.11 (s, 2), 4.22 (m, 5), 3.24 (m, 2), 2.88 (m, 2), 1.99 (m, 2), 1.69 (m, 4). Mass spectrum: m/z = 319 (M+1).

and). 4-(2-Copersito-1,3-oxazin-3-yl)piperidine

According to the method of Example 1K, substituting 1-benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine 1-benzyloxycarbonyl-4-(2-copersito-1,3-oxazin-3-yl)piperidine, get piperidine with the removed protecting group in the form of a white amorphous solid.

Range PMR (CD3OD): 4.24 (m,2), 4.12 (m, 1), 3.32 (m, 2), 3.22 (m, 2), 2.78 (m, 2), 2,03 (m, 2), 1.79 (m, 4). The mass spectrum; m/z = 185 (M+1).

EXAMPLE 3: Hydrochloride (S)-N-[2-(3,4-dichlorophenyl)-4-[4- (2-Oxymetazoline-1-yl) piperidino]Boo is Yes (0.356 g) and 1,1'-carbonyldiimidazole (of) 0.157 g) in chloroform (6 ml) is refluxed under stirring for 2 hours. The reaction mixture is diluted with methylene chloride, washed with aqueous sodium bicarbonate solution, dried, evaporated and chromatographic (Eluent methylene chloride: methanol, gradient 98:2, 90:10). The obtained product is dissolved in methylene chloride and precipitated as the hydrochloride with ethereal solution of hydrogen chloride, evaporated and kept in a high vacuum over night. Get the claimed compound as a white solid (0.244 g).

Mass spectrum: m/z = 503 (M+1). Elemental analysis:

Calculated, %: C, 55.47, H 6.20, N, 9.65. C26H32Cl2N4O21.70 HCl. 0.20 (C2H5)2O. Found, %: C, 55.47, H 6.35, N 9,44.

The intermediate (S)-N-[4-[4-(2-aminoethylamino)of piperidine] -2- (3,4-dichlorophenyl)butyl]-N-methylbenzamide receive the following way.

a). 1-Benzyloxycarbonyl-4-(2-aminoethylamino)piperidine

A solution of 1-benzyloxycarbonyl-4-oxo-piperidine (12.0 g) in methanol (72 ml) is added to a mixed solution of ethylene diamine (5.2 g) and acetic acid (8.8 ml) in methanol (72 ml). After 15 minutes in one portion add a solution of laborgerate sodium (9.7 g) in methanol (72 ml). After stirring over night the reaction mixture was evaporated. The residue is dissolved in 1 N. hydrochloric acid (100 ml). the aqueous mixture is washed with methylene chloride, alkalinized to pH 10 with 10 n sodium hydroxide solution and extracted with methylene chloride. The organic extracts are dried and evaporated, get diamine in the form of a viscous oil (7.5 g).

Range PMR (CD3OD): 7.35 (m, 5), 5.10 (s, 2), of 4.12 (m, 2), 2,89 (m, 2), 2.70 (m, 5), 1.90 (m, 2). 1.24 (m, 2); Mass spectrum: m/z = 278 (M+1).

b). 1-Benzyloxycarbonyl-4-[(2,2,2-TRIFLUOROACETYL)[2-(2,2,2 - triptoreline)ethyl]amino]piperidine

To a solution of the above diamine (7.5 g) in chloroform (90 ml) is added triperoxonane anhydride (10.5 ml). After stirring over night the reaction mixture was cooled to 0oC, is added dropwise a triethylamine (8.3 g). After one hour the mixture is diluted with methylene chloride, washed with 1 N. hydrochloric acid and aqueous solution of sodium bicarbonate, dried, evaporated and chromatographic (eluent methylene chloride:methanol, 98:2). Get triptoreline piperidine as a white foam (8.9 g).

Range PMR (CD3OD): 7.35 (m, 5), 5.12 (s, 2), 4.28 (m, 2), 3.95 (m, 1), 3.48 (m, 4), 2.90 (m, 2), 1.78 (m, 4). Mass spectrum: m/z= 470 (M+1).

in). 4-[(2,2,2-TRIFLUOROACETYL)[2-(2,2,2-triptoreline)-ethyl]amino]piperidine.

According to the method of Example 1.by replacing 1-benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine 1-benzyloxycarbonyl-4-[(2,2,2-trif the Oh group in the form of a yellow oil.

Range PMR (CD3OD): 3.84 (m, 1), 3.51 (m, 4), 3.12 (m, 4), 2.61 (m, 2), 1.74 (m, 4). Mass spectrum: m/z = 336 (M+1).

g). (S)-N-[2-(3,4-Dichlorophenyl)-4-[4-[(2,2,2-TRIFLUOROACETYL)- [-2-(2,2,2-triptoreline)ethyl]amino]piperidino]butyl-N-methylbenzamide

According to the method of Example 1, replacing 4-(2-oxo-1,3-oxazolidin-3-yl)piperidine 4-[(2,2,2-TRIFLUOROACETYL)[2-(2,2,2-triptoreline)ethyl]amino]piperidine and N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide the corresponding (S)-enantiomer, receive N-benzamide in the form of a viscous oil.

Mass spectrum: m/z = 669 (M+1).

d). (S)-N-[4-[4-(2-Aminoethylamino)piperidino] -2-(3,4-dichlorophenyl) butyl]-N-methylbenzamide

A solution of crude product from example 3.g (2.5 g) in 20% sodium hydroxide (8.5 ml) and methanol (11 ml) is stirred for 1 hour. The reaction mixture is acidified to pH 2 with 1 N. hydrochloric acid and washed 3 times with methylene chloride. Then the aqueous phase is alkalinized to pH 10 with 10 n sodium hydroxide solution and extracted with methylene chloride. The extracts are dried and evaporated, get diamine in the form of a viscous oil (1.8 g).

Mass spectrum: m/z = 477. (M+1).

EXAMPLE 4: Hydrochloride (S)-N-[2-[3,4-Dichlorophenyl)-4-[4-(2-dioxoimidazolidin-1-yl)piperidino] butyl]-N-methylbenzamide

According to the method of Example 3, substituting 1, is within 1.5 hours, get the claimed compound in the form of solids.

Mass spectrum: m/z = 519 (M+1). Elemental analysis:

Calculated, %: C, 53.84, H 5.93, N, 9.51. C26H32Cl2N4OS 1.70 HCl 0.10 (C2H5)2O. Found, %: C, 53.89, H 5.89, N, 9.48.

EXAMPLE 5: Dichlorhydrate (S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(2- oxopyrrolidin-1-yl)piperidino]butyl]-N-methylbenzamide

According to the method of Example 3, substituting (S)-N-[4-[4-(2-aminoethylamino)piperidino] -2-(3,4-dichlorophenyl)butyl] -N - methylbenzamide (S)-N-[4-[4-(3-aminopropylene)piperidino] -2- (3,4-dichlorophenyl)butyl] -N-methylbenzamide get the claimed compound as a white solid.

Mass spectrum: m/z = 527 (M+1): Elemental analysis: Calculated,%: C, 53.14, H 6.14, N 9.00. C27H34Cl2N4O22.60 HCl 0.13(C2H5)2O. Found,%: C, 53.14, H 6.31, N, 9.16.

The intermediate (S)-N-[4-[4-(3-aminopropylene)piperidino] -2- (3,4-dichlorophenyl)butyl]-N-methylbenzamide obtained as follows.

a). 1-Benzyloxycarbonyl-4-(3-aminopropylene)piperidine

According to the method of Example 3. and, replacing Ethylenediamine 1.3-diaminopropane get piperidine as a viscous oil.

Mass spectrum: m/z = 292 (M+1). Range PMR (CD3OD): 7.34 (m, 5), 5.10 (s, 2), 4.13 (m, 2), 2.86 (m, 2), 2,65 (m, filing]amino]piperidine

According to the method of Example 3.b, substituting 1-benzyloxycarbonyl-4-(2-aminoethylamino)piperidine 1-benzyloxycarbonyl-4-(3-aminopropylene)piperidine and adding triethylamine to the solution before adding triperoxonane anhydride at 0oC, get triptoreline piperidine as a viscous oil.

Range PMR (CD3OD): 7.36 (m, 5), 5.14 (s, 2), 4.35 (m, 2), 3,93 (m, 1), the 3.35 (m, 4), and 2.83 (m, 2), 1.87-1.74 (m, 6). Mass spectrum: m/z = 484 (M+1).

in). 4-[(2,2,2-TRIFLUOROACETYL)[3-(2,2,2-triptoreline)-propyl]amino] piperidine

According to the method of Example 1.by replacing 1-benzyloxycarbonyl-4-(2-oxo - 1,3-oxazolidin-3-yl)piperidine 1-benzyloxycarbonyl-4-[2,2,2-TRIFLUOROACETYL- [3-(2,2,2-triptoreline)propyl] amino]-piperidine, get piperidine is removed from position 1 protective group in the form of a viscous oil.

Range PMR (CD3OD): 4.39 (m, 1), 3.98 (m, 1), 3.30 (m, 3), 2.95 (m, 1), 2.82 (m, 1), to 2.65 (m, 2), 2.01 (m, 2), a 1.75 (m, 2), 1.32 (m, 2). Mass spectrum: m/z = 350 (M+1);

g). (S)-N-[2-(3,4-Dichlorophenyl)-4-[4-[(2,2,2-TRIFLUOROACETYL)-[2-(2,2,2 - triptoreline)ethyl]amino]piperidino]-N-methylbenzamide.

According to the method of Example 1, replacing 4-(2-oxo-1,3-oxazoline-3-yl)piperidine 4-[(2,2,2-TRIFLUOROACETYL)[3-(3,2,2-triptoreline)propyl] amino]piperidine and N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-ptx2">

d). (S)-N-[4-[4-(3-Aminopropylene)piperidino] -2-(3,4-dichlorophenyl) butyl]-N-methylbenzamide

According to the method of Example 3E. by replacing (S)-N-[2-(3,4-dichlorophenyl)-4-[4-[(2,2,2- TRIFLUOROACETYL)] 2-(2,2,2-triptoreline)ethyl]amino]piperidino] butyl - N-methylbenzamide N-[2-(3,4-dichlorophenyl)-4-[4-[(2,2,2-TRIFLUOROACETYL)] 2- (2,2,2-triptoreline)propyl] amino] piperidino]butyl-N-methylbenzamide get diamine in the form of a viscous oil.

Mass spectrum: m/z = 491 (M+1).

EXAMPLE 6: Dichlorhydrate (S)-N-[2-(3,4-Dichlorophenyl)-4-[4- (2-dioxopyrimidine-1-yl)piperidino]butyl]-N-methylbenzamide

According to the method of Example 3, substituting 1,1'-carbonyldiimidazole 1,1'-thiocarbonyldiimidazole and substituting (S)-N-[4-[4-(2-aminoethylamino) piperidino]-2-(3,4-dichlorophenyl)butyl] -N-methylbenzamide (S)-N-[4-[4-(3-aminopropylene)piperidino] -2-(3,4-dichlorophenyl) butyl]-N-methylbenzamide and stirring at room temperature instead of boiling, get the claimed compound as a white solid.

Mass spectrum: m/z = 533 (M+1). Elemental analysis: Calculated, %: C 52,67, H 6.01, N 8,96. C27H34Cl2N4OS 2.30 HCl. 0.10 (CH2H5)2O. Found, %: C 52,57, H 6.11, N, 8.84.

EXAMPLE 7: Hydrochloride (S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(3-methyl-2 - dioxopyrimidine-1-yl)piperidino] btil-2-dioxopyrimidine-1-yl)piperidine and N-[2-(3,4 - dichlorophenyl)-4-oxobutyl] -N-methylbenzamide on the corresponding (S)-enantiomer, get the claimed compound as a white solid.

Mass spectrum: m/z = 547 (M+1). Elemental analysis: Calculated, %: C, 55.28, H 6.23, N, 9.08. C28H36Cl2N4OS 1.70 HCl 0.10 (C2H5)2O. Found, %: C, 55.21, H 6.37, N 8.88.

The intermediate 4-(3-methyl-2-dioxopyrimidine-1-yl)piperidine was prepared as follows.

a). 1-Benzyloxycarbonyl-4-(3-methylaminopropyl)piperidine

According to the method of Example 3.and, replacing Ethylenediamine N-methyl-1,3-propandiamine get the claimed compound in the form of a viscous oil.

Mass spectrum: m/z = 306 (M+1). Range PMR (CD3OD): 7.34 (m, 5), 5.10 (s, 2), 4.13 (m, 2), 2.86 (m, 2), 2.70 (m, 5), 2.47 (s, 3), 1.91 (m, 2), 1.73 (m, 2), 1.24 (m, 2).

b). 1-Benzyloxycarbonyl-4-(3-methyl-2-dioxopyrimidine-1 - yl)piperidine

A solution of diamine (3.0 g) and 1,1'-thiocarbonyldiimidazole (1.9 g) in chloroform (70 ml) is boiled for 1.5 hours and stirred overnight at ambient temperature. The reaction mixture is diluted with methylene chloride and washed successively with water, 1 N. hydrochloric acid and aqueous sodium bicarbonate solution. The organic phase is dried, evaporated and chromatographic (eluent methylene chloride: ether, 80: 20). Get thiourea as a yellow t the, ,35 (m, 5), 3.22 (m, 2), is 2.88 (m, 2), 1.92 (m, 2), 1.72-1.55 (m, 4).

in). 4-(3-Methyl-2-dioxopyrimidine-1-yl)piperidine

To a solution of the above piperidine (1.4 g) and anisole (1.4 ml) in methylene chloride (20 ml) at a temperature of 0oC add triftormetilfullerenov. After stirring for 2 hours the reaction mixture was evaporated, dissolved in methanol, passed through a column of a weakly basic ion exchange resin, evaporated and chromatographic (eluent methylene chloride: methanol, gradient 98:2, 90:10). The obtained product is dissolved in dilute hydrochloric acid, extracted with methylene chloride (drop) is alkalinized with sodium hydroxide. The aqueous phase is extracted with methylene chloride and evaporated, get piperidine as a white solid (0.75 g).

Mass spectrum: m/z = 214 (M+1). Range PMR (CD3OD): 5.53 (m, 1), 3.36 (m, 5), 3.29 (m, 2), 3.08 (m, 2), 2,64 (m, 2), 1.94 (m, 2), 1.72-1.53 (m, 4).

EXAMPLE 8: Dichlorhydrate (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxo-1,3-pengertian-1-yl) piperidino]butyl]-N-methylbenzamide

According to the method of Example 1, replacing 4-(2-oxo-1,3-oxazolidin-3-yl)piperidine for 4-(2-oxo-1,3-pengertian-1 - yl)piperidine and N-[2-(3,4-dichlorophenyl)-4-oxobutyl] -N-methylbenzamide to the corresponding (S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl] -N-m(M+1); Elemental analysis:

Calculated, %: C, 55.53, H 6,48, N 8.99. C28H36Cl2N4O22.10 HCl 0.20 (C2H5)2O. Found,%: C, 55.70, H 6.53, N 8.91.

The intermediate 4-(2-oxo-1,3-pengertian-1-yl) piperidine was prepared as follows.

a). 1-Benzyloxycarbonyl-4-(4-aminoethylamino)piperidine

According to the method of Example 3.and, replacing Ethylenediamine 1.4-diaminobutane get the claimed compound in the form of a viscous oil.

Mass spectrum: m/z = 306 (M+1). Range PMR (CD3OD): 7.34 (m, 5), 5.10 (s, 2), 4.13 (m, 2), 2.86 (m, 2), 2.63 (m, 5), 1.90 (m, 2), 1.51 (m, 4), 1.23 (m, 2).

b). 1-Benzyloxycarbonyl-4-(2-oxo-1,3-pengertian-1-yl)piperidine

A solution of diamine (1.6 g) and 1,1'-thiocarbonyldiimidazole (0.94 g) in chloroform (40 ml) is boiled for 1 hour. The reaction mixture is diluted with methylene chloride and washed with water. The organic phase is dried, evaporated and chromatographic (eluent methylene chloride:methanol, gradient 98:2, 90:10). Get urea as a white solid (0.36 g).

Mass spectrum: m/z = 332 (M+1). Range PMR (CD3OD): 7.34 (m, 5), 5.09 (s, 2), is 4.21 (m, 3), 3.25 (m, 2), 3.13 (m, 2), 2.85 (m, 2), 1.58 (m, 6), 1.44 (m, 2).

EXAMPLE 9: (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxo-5,5 - dimethylpyrimidin-1-yl)piperidino]butyl]-N-methylbenzamide 4-(2-oxo-5,5-dimethylpyrimidin - 1-yl piperidine (0.400 g) and acetic acid (0.11 ml) in methanol (8.0 ml). After 5 minutes in one portion add a solution of cyanoborohydride sodium (0.119 g) in methanol (8.0 ml). After stirring over night the reaction mixture was diluted with aqueous sodium bicarbonate solution, stirred for 30 minutes and extracted with methylene chloride. The organic layer is dried, evaporated and chromatographic (eluent methylene chloride: methanol, 95: 5). The oil obtained, which begins to crystallize upon standing, suspended in ether and filtered, to obtain the claimed compound as a white solid (0.720 g).

Mass spectrum: m/z = 545 (M+1). Elemental analysis: Calculated, %: C, 63.84, H 7.02, N, 10.27. C29H38Cl2M4O2.

Found,%: C, 63.95, H 6.95, N 10.15.

The intermediate 4-(2-oxo-5.5'-dimethylpiperidin-1-yl)-piperidine receive the following way.

a). 1-Benzyloxycarbonyl-4-(3-amino-2,2-dimethylpropylene)-piperidine.

According to the method of Example 3.and, replacing Ethylenediamine 2,2-dimethyl-1,3-propandiamine get the claimed compound in the form of a viscous oil.

Range PMR (CD3OD): 7.34 (m, 5), 5.10 (s, 2), 4.08 (m, 2), 2.93 (m, 2), 2.57 (m, 1), 2.46 (s, 2), 2.44 (s, 2), 1.89 (m, 2), 1.27 (m, 2), 0.89 (s, 6).

b). 1-Benzyloxycarbonyl-4-(2-oxo-5,5-dimethylpyrimidin-1-yl) piasau. The reaction mixture is diluted with methylene chloride and washed successively 1 N. hydrochloric acid and aqueous sodium bicarbonate solution. The organic phase is dried, evaporated, triturated in ether and filtered. Get urea as a white solid (1.72 g).

Mass spectrum: m/z = 346 (M+1). Range PMR (CD3OD): 7.34 (m, 5), 5.10 (s, 2), 4.35 (m, 1), to 4.23 (m, 2), 2,87 (m, 6), 1.58 (m, 4), 1.00 (s, 6).

in). 4-(2-Oxo-5,5-dimethylpyrimidin-1-yl)piperidine

According to the method of Example 1.by replacing 1-benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine 1-benzyloxycarbonyl-4-(2-oxo - 5,5-dimethylpyrimidin-1-yl)piperidine receive the specified piperidine as a white solid.

Mass spectrum: m/z = 212 (M+1). Range PMR (CD3OD): 4.28 (m, 1), 3.10 (m, 2), 2.92 (m, 2), 2.89 (m, 2), 2.66 (m, 2), 1.59 (m, 4), 1.03 (s, 6).

EXAMPLE 10: Citrate (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(3- methyl-2-oxopyrrolidin-1-yl)piperidino]butyl-N-methylbenzamide

(S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl] -N-methylbenzamide (0.883 g) in methanol (10.0 ml) was added to a solution of (4-(3-methyl-2-oxopyrrolidin-1 - yl)piperidine (0.498 g) and acetic acid (0.145 ml) in methanol (10.0 ml). After 5 min in one portion add Lamborghini sodium (0.159 g) in methanol (10.0 ml). After peremeschenie 30 minutes and extracted with methylene chloride. The organic layer is separated, evaporated and chromatographic, using as eluent methylene chloride:methanol, 95: 5. The oil obtained (0.970 g) and citric acid (0.352 g) is dissolved in methanol and evaporated. Get a named connection in the form of a glassy product which is triturated with formation of a white solid (1.27 g);

Mass spectrum: m/z = 531 (M+1); Elemental analysis:

Calculated, %: C, 55.53, H 6.11, N, 7.48. C28H36Cl2N4O21.10 C6H8O70.30 H2O; Found, %: C At 55.55, H, 6,04, N 7.46.

The intermediate 4-(3-methyl-2-oxopyrrolidin-N-yl) piperidine receive the following way.

a). 1-Benzyloxycarbonyl-4-(2-oxopyrrolidin-1-yl)piperidine.

A solution of 1-benzyloxycarbonyl-4-(3-aminopropylene)piperidine (10.1 g) and 1,1'-carbonyldiimidazole (6.2 g) in chloroform (250 ml) with stirring, boil for 2 hours. The mixture is washed with water, the organic layer separated and dried, then evaporated the solvent and chromatographic, eluent methylene chloride: methanol, 90:10. Get urea as a white solid (7.4 g).

Mass spectrum: m/z = 318 (M+1); PMR spectrum (CDCl3): 7.35 (m, 5), 5.12 (s, 2), and 4.75 (m, 1), 4,50 (m, 1), 4.26 deaths (m, 2), with 3.27 (m, 2), 3.13 (m, 2), 1.89 (m, 2), and 1.63 (m, is oxycarbonyl-4-(2-oxopyrrolidin-1-yl) piperidine (of 3.06 g) in tetrahydrofuran (88 ml) is added tert.-piperonyl potassium (19.3 ml, 1 M solution in tetrahydrofuran). Then add logmean (2.4 ml) and the reaction mixture is stirred for 30 minutes. Next, the reaction mixture is diluted with methylene chloride, washed with water and chromatographic, eluent methylene chloride: methanol, gradient 98:2, 90:10). The resulting product is triturated with ether, filtered off and get N-methyl derivative as a white solid (2.78 g).

Mass spectrum: m/z = 332 (M+1). Range PMR (CDCl3): 7.34 (m, 5), 5.12 (s, 2), a 4.53 (m, 1), 4.26 deaths (m, 2), 3.21 (m, 2), 3.11 (m, 2), 2.93 (s, 3), 2.86 (m, 2), 1.91 (m, 2), 1.60 (m, 4).

in). 4-(3-Methyl-2-oxopyrrolidin-1-yl) piperidine

According to the method of Example 1. and instead of using 1-benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine 1-benzyloxycarbonyl-4-(3-methyl-2-oxopyrrolidin-1-yl)piperidine, get piperidine as a viscous oil.

Mass spectrum: m/z = 198 (M+1); PMR Spectrum (CD3OD): 4.19 (m, 1), 3.14 (m, 4), 2.98 (m, 2), 2.80 (s, 3), 2.53 (m, 2), 1.82 (m, 2), 1.48 (m, 4).

EXAMPLE 11: Citrate (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(3-ethyl-2-oxopyrrolidin-1-yl) piperidino]butyl]-N-methylbenzamide

According to the method of Example 10 using 4-(3-methyl-2-oxopyrrolidin-1-yl)piperidine instead of 4-(3-methyl-2-oxopyrrolidin-1-yl)piperidine, get called sono, %: C 56,98, H 6.28, N, 7.59. C29H38Cl2N4O21.00 C6H8O7. Found, %: C 56,66, H Of 6.31, N 7.57.

The intermediate 4-(3-ethyl-2-oxopyrrolidin-1-yl)piperidine receive the following way.

a). 1-Benzyloxycarbonyl-4-(3-ethyl-oxopyrrolidin-1-yl)piperidine.

Using the method of Example 10.b and replacing itmean jumatano, when grinding the resulting product is in the air get benzyloxycarbonyl derived in the form of a white solid.

Mass spectrum: m/z = 346 (M+1). Range PMR (CDCl3): 7.34 (m, 5), 5.12 (s, 2), 4.54 (m, 1), 4.26 (m, 2), 3.38 (q, 2, J= 7.1), 3.22 (m, 2), 3.11 (m, 2), 2.86 (s, 2), 1.90 (m, 2), 1.60 (m, 4), 1.10 (t, 3, J= 7.1).

in). 4-(3-Ethyl-2-oxopyrrolidin-1-yl)piperidine

According to the method of Example 1.and instead of using 1-benzyloxycarbonyl-4- (2-oxo-1,3-oxazolidin-3-yl)piperidine 1-benzyloxycarbonyl-4-(3-ethyl-2 - oxopyrrolidin-1-yl) piperidine, get piperidine as a viscous oil.

Mass spectrum: m/z = 212 (M+1); PMR Spectrum (CDCl3): 4.45 (m, 1), 3.38 (q, 2, J = 7.1), 3.17 (m, 6), 2.72 (m, 2), of 2.15 (m, 1), 1.91 (m, 2), 1.62 (m, 4), 1.10 (t, 2. J= 7.1).

EXAMPLE 12: Citrate (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(3-(N,N - dimethylcarbamoyl)-2-oxopyrrolidin-1-yl/piperidino] Buti]-N-methylbenzamide

4-(3-methyl-2-oxopyrrolidin-1-yl)piperidine, get a named connection in the form of a white solid product.

Mass spectrum: m/z = 602 (M+1). Elemental analysis:

Found, %: C 55,48, H 6.16, N, 8.60. C13H41Cl2N5O31.0 C6H8O7. Found, %: C, 55.22, H 6,26, N, 8.65.

The intermediate 4-[3-(N,N-dimethylacetamide)-2-oxopyrrolidin-1-yl] -piperidine receive the following way.

a). 1-Benzyloxycarbonyl-4-(3-carboxymethyl-2-oxopyrrolidin-1-yl) piperidine

1-benzyloxycarbonyl-4-(2-oxopyrrolidin-1-yl)piperidine (15.0 g) is added tert. -piperonyl potassium (52 ml, 1 M solution in tert.-the butanol) and the resulting solution was stirred for 35 minutes. Then add tert.-butylbromide (7.65 ml) and the resulting mixture is stirred over night. The reaction mixture was diluted with tetrahydrofuran (20 ml) and methylene chloride (10 ml) and methylene chloride (10 ml), then added tetrabutylammonium iodide (1.74 g), tert.-piperonyl potassium (52 ml, 1 M solution in tert.-the butanol and tert.-butylbromide (7.65 ml). After stirring over night the reaction mass is diluted with methylene chloride and washed with water. The organic layer is separated and dried, evaporated the solvent in vacuo, the resulting oil is dissolved in 1 N. hydrochloric Kislova in vacuo to remove organic solvents. The resulting aqueous solution is extracted with methylene chloride 2 N. hydrochloric acid to pH 2 and extracted with methylene chloride. The first organic extract is evaporated and get 1-benzyloxycarbonyl-4-(2-oxopyrrolidin-1-yl)-piperidine (7.0 g). The second organic extract washed with water, dried and evaporated. The crude product is triturated with ether and filtered. Get the named compound as a white solid (8.3 g).

Mass spectrum: m/z = 376 (M+1). Range PMR (CDCl3): 7.35 (m, 5), 5.12 (s, 2), 4.48 (m, 1), 4.28 (m, 2), 4.02 (s, 2), 3.35 (m, 2), 3.18 (m, 2), 2.87 (m, 2), 1.97 (m, 2), 1.65 (m, 4).

b). 1-Benzyloxycarbonyl-4-[3-(N, N-dimethylcarbamoyl)-2 - oxopyrrolidin-1-yl]piperidine

A solution of 1-benzyloxycarbonyl-4-(3-carboxymethyl-2-oxopyrrolidin - 1-yl)piperidine (2.00 g), dimethylamine hydrochloride (0.522 g), triethylamine (0.89 ml), 4-dimethylaminopyridine (0.781 g), and hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.23 g) in methylene chloride (55 ml) is stirred over night. The reaction mixture was washed (1 N. hydrochloric acid, aqueous sodium bicarbonate solution), dried and evaporated. The crude product chromatographic (eluent methylene chloride: methanol, gradient 98:2, 80:20), the resulting product is triturated with ether, filtered off the B>): 7.35 (m, 5), 5.12 (s, 2), 4.50 (m, 1), 4,27 (m, 2), 4.12 (s, 2), the 3.35 (m, 2), 3.18 (m, 2), 3.01 (s, 3), 2.95 (m, 2), 2.84 (m, 2), 1.98 (m, 2), of 1.64 (m, 4).

in). 4-/3-(N,N-dimethylacetamide)-2-oxopyrrolidin-1-yl/piperidine

According to the method of Example 1.by using 1-benzyloxycarbonyl-4-[3-(N, N-dimethylcarbamoyl)-2 - oxopyrrolidin-1-yl] piperidine instead of 1-benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine after grinding the resulting product in ether get called piperidine as a white solid.

Mass spectrum: m/z = 269 (M+1). Range PMR (CDCl3): 4.40 (m, 1), 4.12 (s, 2), 3.35 (m,2), 3.24 (m, 2), 3.11 (m, 2), 3.02 (s, 3), 2.95 (s, 3), 2,69 (m, 2), 2.14 (m, 1), 1.98 (m, 2), 1.64 (m, 4).

EXAMPLE 13: Citrate (S)-N-[2-(3,4-dichlorophenyl)-4-/4-(3-N-methylcarbamoylmethyl-2 - oxopyrrolidin-1-yl)piperidino]butyl]-N-methylbenzamide

According to the method of Example 10 using 4-[3-(N-methylcarbamoylmethyl)-2 - oxopyrrolidin-1-yl)piperidine instead of 4-(3-methyl-2 - oxopyrrolidin-1-yl)piperidine, get a named connection in the form of a white solid product.

Mass spectrum: m/z = 588 (M+1). Elemental analysis:

Calculated, %: C, 54.46, H 6.06, N, 8.67. C30H39Cl2N5O31.10 C6H8O70.40 H2O. Found,%: C, 54.49, H 6.10, N 8,64.

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a). 1-Benzyloxycarbonyl-4-[3-(N-methylacetamide)-2 - oxopyrrolidin-1-yl]piperidine

According to the method of Example 12.b using the hydrochloride of methylamine instead of dimethylamine hydrochloride get called amide resin. Mass spectrum: m/z = 389 (M+1). Range PMR (CDCl3): 7.35 (m, 5), 6.59 (m, 1), 5.12 (s, 2), 4.47 (m, 1), 4.28 (m, 2), 3.92 (s, 2), 3.34 (m, 2), 3.16 (m, 2), 2.86 (m, 2), 2.80 (s, 1.5), 2.79 (s, 1.5), 1.96 (m, 2), 1.63 (m, 4).

b). 4-[3-N-Methylcarbamoylmethyl-2-oxopyrrolidin-1-yl]-piperidine.

According to the method of Example 1.and instead of using 1-benzyloxycarbonyl-4-(2-oxo-1,3-oxazolidin-3-yl)piperidine 1-benzyloxycarbonyl-4-[3-(N-methylcarbamoylmethyl)-2-oxopyrrolidin-1-yl) -piperidine, get piperidine in the form of resin.

Mass spectrum: m/z = 255 (M+1). Range PMR (CDCl3): 6.70 (m, 1), 4.38 (m, 1), 3.92 (s, 2), 3.35 (m, 2), 3.23 (m, 2), 3.14 (m, 2), 2.81 (s, 1.5), 2.79 (s, 1.5), 2.72 (m, 2), 2.10 (m, 1), 1.97 (m, 2), 1.64 (m, 4).

EXAMPLE 14: Citrate (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(3-N - benzylcarbamoyl-2-oxopyrrolidin-1-yl)piperidino] butyl]-N-methylbenzamide

According to the method of Example 10 using 4-[3-(N-benzylcarbamoyl)-2-oxopyrrolidin-1-yl)piperidine instead of 4-(3-methyl-2-oxopyrrolidin-1-yl)piperidine, get a named connection in the form of a white solid SUB>N5O31.10 C6H8O70.60 H2O. Found, %: C, 57.65, H 6.00, N, 7.90.

The intermediate 4-[3-(N-benzylcarbamoyl)-2-oxopyrrolidin-1 - yl/piperidine receive the following way.

a). 1-Benzyloxycarbonyl-4-[3-(N-benzylcarbamoyl)-2 - oxopyrrolidin-1-yl]piperidine.

According to the method of Example 12.b using benzylamine instead of dimethylamine hydrochloride and with the exception of the reaction of triethylamine get called amide resin.

Mass spectrum: m/z = 465 (M+1); PMR Spectrum (CD3OD): 7.34 (m, 5), 7.28 (m, 5), 5.10 (s, 2), 4.38 (s, 2), 4.33 (m, 1), 4.22 (m, 2), 3.99 (s, 2), 3.30 (m, 2), 3.20 (m, 2), 2,85 (m, 2), 1.95 (m, 2), 1.60 (m, 4).

b). 4-[3-(N-Benzylcarbamoyl)-2-oxopyrrolidin-1-yl]piperidine

According to the method of Example 1.and instead of using 1-benzyloxycarbonyl-4-(2 - oxo-1,3-oxazolidin-3-yl)piperidine 1-benzyloxycarbonyl-4-[3- (N-benzylcarbamoyl)-2-oxopyrrolidin-1-yl)piperidine, get called piperidine as a viscous oil.

Mass spectrum, m/z = 331 (M+1). Range PMR (CDCl3): 7.29 (m, 5), 4.39 (s, 2), 4.30 (m, 1), 4.00 (m, 2), 3.30 (m, 4), 3.16 (m, 2), 7.23 (m, 2), 1.98 (m, 2), 1.68 (m, 4).

EXAMPLE 15: Citrate (S)-N-[2-(3.4-dichlorophenyl)-4-[4-[3-(ethoxycarbonylmethyl-2 - oxopyrrolidin-1-yl)piperidino one-1-yl)piperidine instead of 4-(3-methyl-2-oxopyrrolidin-1-yl)piperidine, get a named connection in the form of a white solid product.

Mass spectrum: m/z = 603 (M+1). Elemental analysis:

Calculated, %: C, 55.41, H 6.04, N, 6.88. C31H40Cl2N4O41.10 C6H8O7. Found,%: C, 55.28, H 6.11, N 6.86.

The intermediate 4-[3-(ethoxycarbonylmethyl)-2-oxopyrrolidin-1-yl] piperidine receive the following way.

a). 1-Benzyloxycarbonyl-4-[3-(ethoxycarbonylmethyl)-2 - oxopyrrolidin-1-yl]piperidine

A solution of 1-benzyloxycarbonyl-4-(3-carboxymethyl-2-oxopyrrolidin-1 - yl]piperidine (1.51), 2-ethoxy-1 - etoxycarbonyl-1,2-dihydroquinoline (1.64 g) and ammonium bicarbonate (1.43 g) in chloroform (30 ml) is stirred for 4 hours. The reaction mass is diluted with methylene chloride, washed with 1 N. hydrochloric acid (5 times), dried and evaporated. The crude product chromatographic, eluent methylene chloride: methanol, gradient 98:2, 90:10. The resulting product is triturated with ether, receive ester as a white solid (1.25 g).

Mass spectrum: m/z = 404 (M+1). Range PMR (CDCl3): 7.34 (m, 5), 5.11 (s, 2), 4.49 (m, 1), 4.26 (m, 2), 4.18 (square 2, J= 7.1), 4.06 (s, 2), 3.31 (m, 2), 3.17 (s, 2), 2.84 (m, 2), 1.97 (m, 2), 1.64 (m, 4), 1.26 (t 3, J= 7.1).

b). 4-[3-(Ethoxycarbonylmethyl)-2-oxopyrrolidin-1 and the n-3-yl)piperidine 1-benzyloxycarbonyl-4-[3- (ethoxycarbonylmethyl)-2-oxopyrrolidin-1-yl)-piperidine, named get piperidine as a viscous oil.

Mass spectrum: m/z = 270 (M+1). Range PMR (CDCl3: 4.41 (m, 1), 4.19 (q, 2, J= 7.1), 4.07 (s, 2), 3.32 (m, 2), 3.24 (m, 2), of 3.12 (m, 2), 2.70 (m, 2), 2.09 (m, 1), 1.98 (m, 2), 1.63 (m, 4), 1.27 (t, 3, J= 7.1).

EXAMPLE 16: Citrate (S)-N-[2-(3,4-dichlorophenyl)-4-[4- (2-oxopyrrolidin-1-yl)piperidino]butyl]-N-ethylbenzamide

According to the method of Example 10 using 4-(2-oxopyrrolidin-1-yl)piperidine instead of 4-(3-methyl-2-oxopyrrolidin-1-yl)piperidine and (S)-N-[2-(3,4 - dichlorophenyl)-4-oxobutyl] -N-ethylbenzamide instead of N-[2-(3,4 - dichlorophenyl)-4-oxobutyl] -N-methylbenzamide get a named connection in the form of a white solid product.

Mass spectrum: m/z = 531 (M+1). Elemental analysis:

Calculated,%: C, 55.53, H 6.11, N, 7.48. C20H36Cl2N4O21.10 C6H8O70.30 H2O. Found, %: C, 55.51, H 6.19, N, 7.47.

The intermediate (S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl] - N-ethylbenzamide obtained as follows.

a). (S)-N-[2-(3,4-Dichlorophenyl)-4-hydroxybutyl]benzamid.

To a solution of (S)-2-(3,4-dichlorophenyl)-4-hydroxyethylamine (15.0 g) and triethylamine (9.0 ml) d methylene chloride (200 ml) at 0oC add a solution of benzoic anhydride (14.6 g) in methylene chloride (50 ml). After stirring at 0
the layer is dried and evaporated. The crude product chromatographic, eluent methylene chloride: methanol, gradient, 98: 2, 90:10. Get called amide as a pale yellow resin (17.5 g).

Mass spectrum: m/z = 338 (M+1). Range PMR (CDCl3): 7.65 (m, 2), 7.48 (m, 1), 7.38 (m, 3), 7.33 (d, 1, J = 2.1), 7.07 (DD, 1, J= 2.1, 8.2), 6.44 (m, 1, NH), 3,83 (m, 1), 3.70 (m, 1), 3.58-3.41 (m, 2), 3.13 (m, 1), 2.47 (m, 1, OH), 1.99 (m, 1), 1.84 (m, 1).

b) (S)-N-[4-Acetoxy-2-(3,4-dichlorophenyl)butyl]benzamide

To a solution of (S)-N-[2-(3,4-dichlorophenyl)-4-hydroxybutyl]benzamide (17.5 g) and pyridine (8.4 ml) in methylene chloride (400 ml) at 0oC add acetylchloride (4.6 ml). The reaction mass was stirred at room temperature overnight and then washed with water and saturated aqueous solution of copper sulfate (II). The organic layer is separated, dried and evaporated. Receive acetyl derivative as a pale yellow oil.

Mass spectrum: m/z = 380 (M+1). Range PMR (CDCl3): 7.63 (m, 2), 7.48 (m, 1), 7.39 (m, 3), 7.32 (d, 1, J= 2.1), 7.06 (DD, 1, J= 2.1, 8.2), 6.21 (m, 1), 4.03 (m, 1), a 3.87 (m, 2), 3.41 (m, 1), 3.07 (m, 1), 2.09 (m, 1), 1.98 (s, 3), 1.92 (m, 1).

in). (S)-N-[4-Acetoxy-2-(3,4-dichlorophenyl)butyl]-N-ethylbenzamide

(S)-N-[4-Acetoxy-2-(3,4-dichlorophenyl)butyl] benzamide (4.2 g) in tetrahydro who) in tetrahydrofuran (5 ml). The reaction mass is stirred overnight and then evaporated in vacuum, the residue is dissolved in methylene chloride and washed with water. The organic layer is separated, dried, evaporated and chromatographic, eluent methylene chloride: methanol, 10: 1. Get called the N-ethyl derivative in the form of an oil (3.7 g). Mass spectrum: m/z = 408 (M+1).

g). (S)-N-[2-(3,4-Dichlorophenyl)-4-hydroxybutyl]-N-ethylbenzamide

A solution of (S)-N-[4-acetoxy-2-(3,4-dichlorophenyl)butyl]-N-ethylbenzamide (3.7 g) in 1 N. the solution of sodium hydroxide (27 ml), tetrahydrofuran (70 ml), water (20 ml) and methanol (15 ml) is stirred for 3 hours. The reaction mass is evaporated in vacuum, the residue is dissolved in methylene chloride and washed with water. The organic layer is separated, dried and evaporated. Get alcohol in the form of an oil (3.2 g). Mass spectrum: m/z = 366 (M+1),

d). (S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-tilebased

To a solution of oxalicacid (1.3 ml) in methylene chloride (30 ml) at - 78oC add dimethylsulfoxide (2.1 ml) in methylene chloride (10 ml), and then for 5 min add (S)-N-[2-(3,4-dichlorophenyl)-4-hydroxybutyl] -N-ethylbenzamide (3.2 g) in methylene chloride (15 ml). After 15 minutes, add triethylamine (8.2 ml) and allow the reaction mass to warm to room temperature. The mixture is then diluted with Metesky layer is separated, dried, evaporated. The obtained residue chromatographic, eluent methylene chloride:ether: hexane, 2: 1: 1. Get called aldehyde in the form of an oil (2.5 g). Mass spectrum: m/z = 364 (M+1).

EXAMPLE 17: Citrate (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxopyrrolidin-1-yl) piperidino]butyl]-4-fluoro-N-methylbenzamide

To a solution of (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxopyrrolidin-1-yl) piperidino] butyl] -N-methylamine (0.400 g) and pyridine (0.16 ml) in methylene chloride (10 ml) at -30oC add 4-perbenzoate (0.115 ml). The reaction mass allow to warm to room temperature and stirred for 1 h Then the reaction mass is diluted with methylene chloride, washed with aqueous sodium bicarbonate solution and saturated aqueous copper sulfate (II), dried and evaporated. The crude product chromatographic, eluent methylene chloride: methanol, gradient 98:2, 80:10. Pure product (0.350 g) and citric acid (0.126 g) was dissolved in methanol and evaporated. Get the named compound as a glassy mass, which pounded to a white solid (0.450 g).

Mass spectrum: m/z = 535 (M+1). Elemental analysis:

Calculated, %: C, 53.25, H 5.80, N, 7.30. C27H33Cl2FN4O21.10 C6H8O70.10 (C2

a). Tert. -butyl(S)-N-[2-(3,4-dichlorophenyl)-4-hydroxybutyl] -N-methylcarbamate.

To a solution of (S)-N-methyl-[2-(3,4-dichlorophenyl)-4-hydroxyethylamine (25.0 g) in methylene chloride (125 ml) for 30 min added dropwise di-tert.-BUTYLCARBAMATE (21.6 g) in methylene chloride (125 ml). The reaction mass is stirred for 3 h, washed with 0.1 N. hydrochloric acid and aqueous sodium bicarbonate solution, dried and evaporated. The crude product chromatographic, eluent methylene chloride: ether, 2:1. Receive tert.-butyl ether in the form of oil (33.0 g), which eventually crystallizes.

b). Tert.-butyl-(S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylcarbamate.

According to the method of Example 16. d using tert.-butyl-(S)-N-[2-(3,4 - dichlorophenyl)-4-hydroxybutyl] -N-methylcarbamate instead of (S)-N-[2-(3,4 - dichlorophenyl)-4-hydroxybutyl] -N-ethylbenzamide receive the aldehyde in the form of oil, which is used in the next reaction.

in). Tert. -butyl(S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2- oxopyrrolidin-1-yl)piperidino]butyl]-N-methylcarbamate

According to the method of Example 10 using 4-(2-oxopyrrolidin-1-yl) piperidine instead of 4-(3-methyl-2-oxopyrrolidin-1 - yl)piperidine and tert. -butyl(S)-N-[2-(3,4-dichlorophenyl)-4 - oxobutyl]-N-methylbenzamide instead of N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxopyrrolidin-1-yl) piperidino]butyl]-N-methylamine.

To a solution of tert.-butyl-(S)-N-[2-(3,4-dichlorophenyl) -4-[4-(2-oxopyrrolidin-1-yl)piperidino]butyl]-N-methylcarbamate (5.1 g) in methylene chloride (200 ml) add triperoxonane acid (7:7 ml). After 30 minutes, add another portion of triperoxonane acid (7.5 ml) and the resulting mixture is stirred for 4 hours the mixture is Then washed with 1 N. a solution of sodium hydroxide (150 ml), dried and evaporated. Get a named connection in the form of resin (3.8 g). Mass spectrum: m/z = 413 (M+1).

EXAMPLE 18: Citrate (S)-N-[2-(3,4-dichlorophenyl)-4- (2-oxopyrrolidin-1-yl)piperidino]butyl]-4-methyl-N-methylbenzamide

According to the method of Example 17, substituting 4-perbenzoate on p-trouillard, get a named connection in the form of a solid substance.

Mass spectrum: m/z = 531 (M+1). Elemental analysis: Calculated, %: C, 55.63, H 6.18, N, 7.41. C28H36Cl2N4O20.10 (C2H5)2O. 0.30 H2O. Found, %: C, 55.58, H 6.17, N 7.52.

EXAMPLE 19: Citrate (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2- oxopyrrolidin-1-yl)piperidino]butyl]-4-methoxy-N-methylbenzamide

According to the method of Example 17, substituting 4-perbenzoate 4-methoxybenzophenone, get a named connection in the form of a solid substance.

Mass spectrum: m/z = 547 (M+1). UB>2
O 0.70 H2O. Found, %: C At 53.93, H 5.99, N 7.19.

EXAMPLE 20: Citrate (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxopyrrolidin-1-yl)piperidine]butyl]- 4-hydroxy-N-methylbenzamide.

A solution of (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxopyrrolidin-1-yl) piperidino] butyl]-N-methylamine (1.22 g), 4-acetoxybenzoic acid (0.640 g), and hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.682 g) in methylene chloride (30 ml) is stirred over night. The reaction mixture is diluted with methylene chloride, washed with water and aqueous sodium bicarbonate solution, dried and evaporated. The crude product is twice chromatographic, eluent methylene chloride:methanol, gradient 95:5, 80:20. The purified product (0.190 g) and citric acid (0.069 g) was dissolved in methanol and evaporated, get a named connection in the form of a glassy product which is triturated in a white solid (0.220 g).

Mass spectrum: m/z = 533 (M+1). Elemental analysis: Calculated, %: C, 53.40, H 5.86, N, 7.41. C27H34Cl2N4O31.10 C6H8O70.60 H2O. Found, %: C At 53.45, H 6,13, N, 7.26.

EXAMPLE 21: 1-[(S)-N-Benzoyl-3-(3,4-dichlorophenyl)-N-methyl-4 - aminobutyl] -4-(2-oxopyrrolidin-1-yl)piperidine-1-oxide

To a solution of (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2- ocaperidone the 3-chlormadinone acid (0.700 g) in methylene chloride. The reaction mixture was stirred for 1 h and diluted with methylene chloride, washed with aqueous sodium bicarbonate solution, dried and evaporated. The crude product chromatographic, eluent methylene chloride:methanol, gradient 98:2, 70:30. The purified product (0.592 g) and the monohydrate of p-toluenesulfonic acid (0.323 g) dissolved in a mixture of methylene chloride: methanol and evaporated. Get a named connection in the form of a white solid product (0.824 g).

Mass spectrum: m/z = 533 (M+1). Elemental analysis: Calculated, %: C, 56.11, H 6.10, N, 7.54. C27H34Cl2N4O31.10 C7H8O31.10 H2O. Found, %: C 55,85, H 5.96, N 7.33.

EXAMPLE 22: the Hydrochloride of N-[2-(3,4-dichlorophenyl)-4-[4-(3-methyl-2 - Oxymetazoline-1-yl)piperidino]butyl]-N-methylbenzamide

To a suspension of sodium hydride (30 mg, 60% dispersion in oil) in tetrahydrofuran (1 ml) is added N-[2-(3,4-dichlorophenyl)-4-[4- (2-Oxymetazoline-1-yl)piperidino] butyl] -N-methylbenzamide (152 mg) in tetrahydrofuran (2 ml). After 30 minutes add logmean (0.021 ml) and the reaction mixture stirred for 2.5 hours. Then the reaction mixture is diluted with methylene chloride and washed with water. The organic layer is separated, dried and evaporated to obtain an oil which is dissolved in the minimum amount is jut a white solid product (104 mg).

Mass spectrum: m/z = 517 (M+1). Elemental analysis:

Calculated, %: C, 57.83, H 6.42, N 10.05. C27H34Cl2N4O21.2 HCl 0.1 (C2H5)2O. Found,%: C 57,85, H 6.41, N 9.85.

The intermediate N-[2-(3,4-dichlorophenyl)-4-[4-(2-Oxymetazoline-1-yl) piperidino] butyl]-N-methylbenzamide receive according to the method described in Example 3, instead of using N-[2-(3,4-dichlorophenyl)-4-oxobutyl] -N-methylbenzamide (S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide on stage, Z.

THE LIST OF SEQUENCES

(2) Information for SEQ 1D NO:1

(1) the Characteristic sequence:

(A) Length: 15 base pairs

(B) Type: nucleic acid

(C) the Number of chains: one

(D) Topology: linear

(XI) sequence Description SEQ 1D NO:1

GCGCAAGCTT ATGGG

(2) Information for SEQ 1D NO:2

(1) the Characteristic sequence

(A) Length: 18 base pairs

(B) Type: nucleic acid

(C) the Number of chains: one

(D) Topology: linear

(XI) sequence Description SEQ 1D NO: 2

GTCCCCATAA GCTTGCGC

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5

1. 4-Substituted derivatives of piperidine derivatives of the formula I

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where m is 2;

D represents the residue form the hat a hydrogen atom;

R1represents a hydrogen atom or methyl;

R2represents-C(= O)R3where R3represents phenyl, unsubstituted or substituted by one or more atoms of halogen, hydroxy, (1-4C)alkoxy or (1-4C)alkyl;

G denotes a simple link;

J means oxo - or tocograph;

M denotes-O-, -S - or-NR12;

L means L1;

R12represents a hydrogen atom, a C1-3-alkyl, RaOC(=O)CH2or RbRcNC(= O)CH2-;

Rarepresents (1-3C)alkyl;

Rband Rcindependently from each other represent a hydrogen atom, (1-3C)alkyl or benzyl;

L1represents methylene, trimethylene or tetramethylene;

or N-oxide compounds of formula I at the nitrogen atom piperidino fragment, denoted as ;

or pharmaceutically acceptable salts of these compounds of formula I.

2. Connection on p. 1, which has the formula Ic

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where the Deputy Qbis phenyl, substituted by 1 or 2 halogen atoms;

T and U independently of one another represent halogen atom, a hydroxy-group, (1-3C)alkyl or (1-3C)alkoxygroup;

W represents CH3;

G, J, L and M are taking any of the values defined Emaciations acceptable salt of the compounds of formula Ic.

3. Connection on p. 2, where M represents-O-, -S -, or NH; L is trimethylene, and Qbrepresents phenyl substituted by one or two halogen atoms, or N-oxide of the compounds of formula Ic with the nitrogen atom of the piperidine, denoted by ; or a pharmaceutically acceptable salt of the compounds of formula Ic.

4. Connection on p. 2 or 3, where M represents-O - or NH; L is trimethylene and Deputy Qbis 3,4-dichlorophenyl, or N-oxide of the compounds with the nitrogen atom of the piperidine, denoted by ; or a pharmaceutically acceptable salt of the compounds.

5. Connection on p. 1, which is: (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxopyrrolidin-1-yl)piperidino] butyl] -N-methylbenzamide; (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(3-methyl-2-oxopyrrolidin-1-yl)piperidino] -N-methylbenzamide; (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(3-ethyl-2-oxopyrrolidin-1-yl)piperidino] butyl]-N-methylbenzamide or (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxopyrrolidin-1-yl)piperidino] butyl] -N-ethylbenzamide and their pharmaceutically acceptable salts.

6. Connection on p. 1, which is (S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxopyrrolidin-1-yl)piperidino] butyl]-N-methylbenzamide or Neil)-4-[4-(3-ethyl-2-oxopyrrolidin-1-yl)piperidino] butyl] -N-methylbenzamide or its pharmaceutically acceptable salt.

8. The compounds of formula I on p. 1, which represents a pharmaceutically acceptable salt.

9. A method of obtaining a 4-substituted piperidine derivative of the formula

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where G denotes a simple link;

J - oxo - or tocograph;

M means NR12;

L means L1and represents methylene, trimethylene, tetramethylene;

R12is hydrogen or C1- C4-alkyl;

m and D have the meanings specified in paragraph 1 of the formula

and N-oxides of these compounds and nitrogen atom piperidino fragment, designated as a , or pharmaceutically acceptable salts, characterized in that the compound of formula III

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where L, M, D, m have the above values,

is subjected to condensation with Deaktivierung carbonyl or thiocarbonyl compound, followed if necessary by oxidation obtained piperidino connection to obtain the N-oxide and, if necessary, by alkylation of the compounds, where R12means hydrogen.

 

Same patents:

The invention relates to new derivatives of guanidine and their pharmaceutically acceptable salts, used as medicines

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

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where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- amino group, sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, tert

The invention relates to a derivative of oxazolidinone

The invention relates to the field of organic chemistry, specifically to a method for producing 2-(furyl-2)-1,3-oxazolidine formula I

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with astragalina activity

The invention relates to 2-[(dihydro)pyrazolyl-3'-oxymethylene] anilides formula I

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in whichmeans simple or double bond, and the index and the substituents have the following meanings:

n means 0, 1 or 2;

m means 0, 1 or 2 and the substituents R2may be different if m is greater than 1;

X represents a direct bond, O or NRa;

Rameans hydrogen;

R1means halogen or C1-C4alkyl, or, if n is 2, represents optionally associated with two adjacent ring atoms of the hydrocarbon bridge containing 3 or 4 carbon atoms;

R2means nitro, halogen, C1-C4alkyl, C1-C4halogenated or1-C4alkoxycarbonyl;

R3means optionally substituted alkyl, optionally substituted saturated cycle or optionally substituted single or dual core aromatic radical, which together with the carbon atoms may contain as members of the cycle from one to four nitrogen atoms;

R4means hydrogen, optionally substituted alkyl;

The invention relates to new chemical compounds with valuable biological properties, in particular to derive hinolan and naphthyridinone acids with antibacterial activity, as well as to the isoindole derivative as starting compounds for obtaining the derivatives hinolan and naphthyridinone acid

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The invention relates to medicine, namely to addiction
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