Derivatives of piperidine and method for their preparing

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): in free form or as a salt wherein Ar1 means phenyl substituted with one or some halogen atoms; Ar2 means phenyl or naphthyl that can be unsubstituted or substituted with one or some substitutes chosen from the group comprising halogen atom, cyano-, hydroxy-, nitro-group, (C1-C8)-alkyl, (C1-C8)-halogenalkyl, (C1-C8)-alkoxy-group or (C1-C8)-alkoxycarbonyl; R1 means hydrogen atom or (C1-C8)-alkyl optionally substituted with hydroxy-,(C1-C8)-alkoxy-, acyloxy-group, -N(R2)R3, halogen atom, carboxy-group, (C1-C8)-alkoxycarbonyl, -CON(R4)R5 or monovalence cyclic organic group; each among R2 and R3 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R2 means hydrogen atom and R3 means acyl or -SO2R6, or R and R3 in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; each among R4 and R5 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R4 and R in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; R6 means (C1-C8)-alkyl, (C1-C8)-halogenalkyl or phenyl optionally substituted with (C1-C8)-alkyl; n means 1, 2, 3 or 4 under condition that when Ar1 means para-chlorophenyl and R1 means hydrogen atom then Ar2 doesn't mean phenyl or para-nitrophenyl. Compounds of the formula (I) possess the inhibitory CCR-3 activity and can be used in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

7 cl, 47 ex

 

The invention relates to organic compounds, their preparation and use as pharmaceutical agents.

One of the objects of the invention are the compounds of formula

in free form or in salt form, where

Ar1denotes phenyl, substituted by one or more halogen atoms,

Ar2denotes phenyl or naphthyl, which is unsubstituted or substituted by one or more substituent selected from the series comprising halogen, cyano, hydroxy, nitro, C1-C8alkyl, C1-C8haloalkyl,1-C8alkoxy or1-C8alkoxycarbonyl,

R1denotes hydrogen or C1-C8alkyl, optionally substituted hydroxy, C1-C8alkoxy-, alloctype, -N(R2R3, halogen, carboxypropyl, C1-C8alkoxycarbonyl, -CON(R4R5or a monovalent cyclic organic group,

R2and R3each independently of one another denotes hydrogen or C1-C8alkyl, or R2denotes hydrogen and R3denotes acyl or - SO2R6or R2and R3together with the nitrogen atom to which they are attached, form a 5 - or 6-membered heterocyclic group,

R4and R5each independently on the UGA denotes hydrogen or C 1-C8alkyl, or R4and R5together with the nitrogen atom to which they are attached, form a 5 - or 6-membered heterocyclic group,

R6stands With1-C8alkyl, C1-C8haloalkyl or phenyl, optionally substituted C1-C8-alkyl, and

n denotes 1, 2, 3,or 4

provided that when Ar1denotes the pair-Porvenir and R1denotes hydrogen, then Ar2does not denote a phenyl or para-nitrophenyl.

Concepts that are used in the present description have the following meanings:

"C1-C8alkyl" in the context of the present description denotes1-C8alkyl straight or branched chain, which may represent, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl with straight or branched chain hexyl straight or branched chain heptyl straight or branched chain or octyl straight or branched chain. Preferably1-C8alkyl denotes a1-C4alkyl.

"C1-C8alkoxy" in the context of the present description represents C1-C8alkoxygroup straight or branched chain, which may indicate, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentox is a straight or branched chain, hexyloxy straight or branched chain, heptyloxy straight or branched chain or octyloxy straight or branched chain. Preferably1-C8alkoxy denotes a1-C4alkoxy.

"C1-C8haloalkyl" in the context of the present description denotes1-C8alkyl, as defined above, substituted by one or more halogen atoms, preferably one, two or three halogen atoms.

"Acyl" in the context of the present description denotes alkylsulphonyl, for example With1-C8alkylsulphonyl, where C1-C8the alkyl may be one of the above1-C8alkyl groups, optionally substituted by one or more halogen atoms; cycloalkylcarbonyl, for example With3-C8cycloalkylcarbonyl, where C3-C8cycloalkyl can represent, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; 5 - or 6-membered heterocalixarenes bearing in the ring one or two heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, such as fullcarbon or pyridylcarbonyl; arylcarbamoyl, for example With6-C10arylcarbamoyl, such as benzoyl; or aralkylamines, for example With6-C10aryl-C1-C4alkylsulphonyl, this is AK benzylcarbamoyl or phenylethylamine. Preferably the acyl denotes a1-C4alkylsulphonyl.

"Acyloxy" in the context of the present description denotes alkylcarboxylic, for example With1-C8alkylcarboxylic, where C1-C8the alkyl may be one of the above1-C8alkyl groups, optionally substituted by one or more halogen atoms; cycloalkylcarbonyl, for example With3-C8cycloalkylcarbonyl, where C3-C8cycloalkyl may denote, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; 5 - or 6-membered geterotsiklicheskikh that lays in the ring one or two heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, such as shrinkability or pyridylcarbonyl; arylcarboxylic, for example With6-C10arylcarboxamide, such as benzoyloxy; or aralkylamines, for example With6-C10aryl-C1-C4alkylcarboxylic, such as benzylcarbamoyl or phenylethylenediamine. Preferably acyloxy represents C1-C4alkylcarboxylic.

"Halogen" in the context of the present description denotes fluorine, chlorine, bromine or iodine; preferably fluorine, chlorine or bromine.

In Ar1the phenyl group may be substituted by one, two sludge is three, preferably one or two halogen atoms, which are preferably selected from fluorine atoms and chlorine. When a substituent is present one halogen atom, it is preferably in the para-position relative to the indicated carbonyl group. When the substituents are two or three of halogen atom, preferably one of them is in the para-position relative to the indicated carbonyl group and at least one other is in the ortho-position relative to the indicated carbonyl group.

If Ar2denotes a substituted phenyl, it may, for example, be substituted by one, two, three, four, or five, preferably one, two or three, the above substituents. Ar2may, for example, to designate a monosubstituted phenyl, a Vice which preferably is halogen, cyano, nitro or1-C4alkoxygroup, which is preferably in the ortho - or meta-position relative to the specified-CH=CH-group. In another embodiment, Ar2may denote, for example, disubstituted phenyl, the substituents which are preferably selected from the group comprising halogen, cyano, hydroxy, nitro, C1-C4alkoxy, C1-C4alkyl and C1-C4haloalkyl, particularly preferred substituents are the two who are two halogen atom (identical or different halogen atoms), two1-C4alkoxygroup, two1-C4alkyl groups, two With1-C4haloalkylthio group, one halogen and one cyano, one halogen and one With1-C4alkoxygroup, one halogen and one nitrogroup, one halogen and one hydroxy-group, one halogen and one With1-C4haloalkyl, one cyano, one With a1-C4alkoxygroup, one hydroxy-group and one With1-C4alkyl or a hydroxy - and one With a1-C4alkoxygroup. In another embodiment, Ar2may denote, for example, tizamidine phenyl, the substituents which are preferably selected from the group including halogen, hydroxy, C1-C4alkoxy and C1-C4alkoxycarbonyl, particularly preferred substituents are three halogen atom (the same atoms or two or three different halogen atom), or two1-C4alkoxygroup and one halogen, hydroxy or With the1-C4alkoxycarbonyl. In another embodiment, Ar2may denote, for example, pentamidine phenyl, substituents which preferably are halogen atoms, especially fluorine. Especially preferred groups Ar2are tianfei primarily meta-tianfeng, and disubstituted phenyl, one of the Vice which is1-C4alkoxygroup, site is preferably located in the ortho-position to the-CH=CH-group, and the second Deputy, preferably located in the para-position relative to the1-C4alkoxygroup is1-C4alkoxy, halogen, cyano or1-C4alkyl.

R1that represents optionally substituted C1-C8alkyl, preferably represents optionally substituted C1-C4alkyl, especially With1-C4alkyl or substituted methyl or ethyl. When R1substituted cyclic organic group, the latter may denote a carbocyclic or heterocyclic group, for example With3-C15carbocyclic group, or a 5-7 membered heterocyclics group bearing one or more, preferably one, two or three ring heteroatoms selected from the group comprising nitrogen, oxygen and sulfur. With3-C15the carbocyclic group may, for example, to denote a cycloaliphatic group having 3-8 carbon atoms, preferably5- or6cycloalkyl, such as cyclopentyl, Methylcyclopentane or cyclohexyl. In another embodiment, a3-C15the carbocyclic group may denote, for example, With1-C8aromatic group such as phenyl which can be unsubstituted or substituted C1-C8the alkyl, C1-C8alkoxygroup, halogen, cyano what Ruppel, -CON(R4R5, -SO2N(R4R5or C1-C8alkylsulfonamides, where R4and R5have the above values. Heterocyclic group may bear in the ring, one atom of nitrogen, oxygen, or sulfur, or can carry two nitrogen atom or one oxygen atom and one or two nitrogen atom, or one sulfur atom and one or two nitrogen atom. The heterocyclic group preferably represents a heterocyclic aromatic group, especially a 5 - or 6 - membered heterocyclic group such as furyl, imidazolyl, thiazolyl or pyridyl. In the most preferred compounds, R1stands With1-C4alkyl, substituted hydroxy-group, phenyl, or 5 - or 6 - membered heterocyclic aromatic group bearing one or two ring heteroatoms selected from the group comprising nitrogen, oxygen and sulphur.

Preferred compounds of formula I in free form or in salt form are compounds in which

Ar1denotes phenyl, substituted by fluorine or chlorine in the para-position relative to the indicated carbonyl group and optionally additionally substituted by halogen in the ortho-position relative to the indicated carbonyl group,

Ar2denotes phenyl, monosubstituted Deputy, selected from the series comprising halogen, qi is but nitro and C1-C4alkoxy, phenyl, substituted by two identical or different substituents selected from the series comprising halogen, cyano, hydroxy, C1-C4alkoxy, C1-C4alkyl, C1-C4haloalkyl and nitro, or phenyl substituted with three identical or different substituents selected from the series comprising halogen, hydroxy, C1-C4alkoxy and C1-C4alkoxycarbonyl,

R1denotes hydrogen, C1-C4alkyl or C1-C4alkyl, substituted hydroxypropoxy,3-C8cycloalkyl, phenyl, phenyl substituted With1-C4alkylsulfonamides, or 5 - or 6-membered heterocyclic aromatic group bearing one or more ring heteroatoms selected from the series comprising nitrogen, oxygen and sulfur, and

n denotes 1 or 2.

Also preferred compounds of formula I in free form or in salt form are compounds in which

Ar1denotes phenyl, substituted by fluorine or chlorine in the para-position relative to the indicated carbonyl group,

Ar2denotes phenyl, substituted in the ortho-position relative to the specified-CH=CH-group1-C4alkoxygroup and substituted in the para-position relative to the1-C4alkoxygroup by cyano, ha is igenom or 1-C4alkoxygroup,

R1stands With1-C4alkyl, substituted hydroxy-group, phenyl, phenyl substituted With1-C4alkylsulfonamides, or 5 - or 6-membered heterocyclic aromatic group bearing one or two ring heteroatoms selected from the series comprising nitrogen, oxygen and sulfur, and

n denotes 1.

Compounds represented by the formula, have the ability to form acid additive salts, especially pharmaceutically acceptable acid salt additive. Pharmaceutically acceptable acid additive salts of the compounds of formula include salts of inorganic acids, such as halogen acids such as hydrofluoric acid, hydrochloric acid, Hydrobromic acid or uudistoodetena acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example aliphatic monocarboxylic acids such as formic acid, acetic acid, triperoxonane acid, propionic acid and butyric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, aromatic carboxylic acids, such as benzoic acid, para-chlorbenzene sour is a, diphenylhexane acid or triphenylarsine acid, aromatic hydroxy acids such as ortho-hydroxybenzoic acid, para-hydroxybenzoic acid, 1-hydroxynaphthalene-2-carboxylic acid or 3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids, such as methanesulfonate acid or benzolsulfonat acid. These salts can be obtained from compounds of the formula using known processes of salt formation.

Compounds of formulas that contain acid, for example, carboxyl groups may also form salts with bases, especially with pharmaceutically acceptable bases, which are well known in the art; such salts may include metal salts, especially alkali metal salts or alkaline-earth metals, for example salts of sodium, potassium, magnesium or calcium, or salts with ammonia or pharmaceutically acceptable organic amine, or heterocyclic bases, such as ethanolamines, benzylamine or pyridine. These salts can be obtained from compounds of the formula I by known processes of salt formation.

When R1has a value other than hydrogen, the carbon atom to which R1attached in the formula, is asymmetric, and in this case, the compounds exist in individual optically active isomeric forms or their mixtures is her for example in the form of racemic or diastereoisomeric mixtures. Under the scope of the invention fall as the individual optically active R - and S-isomers and their mixtures, e.g. racemic or diastereoisomeric mixture.

Specific preferred compounds according to the invention are compounds described in the examples, especially examples 4, 9, 10, 15, 18, 19, 20, 21, 23, 24, 25, 28, 29, 30, 37, 38, 40, 42, 43, 44 and 45.

The invention relates also to a method for producing compounds of formula stipulating

(I) (a) interactions of the compounds of formula

with the compound of the formula

or amide forming derivatives, where Ar1, Ar2, R1and n have the above values, or

(B) interaction of the compounds of formula III or its amide forming derivative with the compound of the formula

where Ar1, R1and n have the above meanings and Z represents the solid phase substrate, chemically associated with the indicated nitrogen atom, and the removal of formed product from the substrate by replacing Z by hydrogen; and

(II) isolation of the product in free form or in salt form.

According to variant (A) of the method, Obedinenie formula II may be in free form or in salt form. Option (A) how can osushestvljali by known methods, for example, by reacting the compounds of formula II with galogenangidridy, primarily with the acid chloride of the acid of formula III, using well-known processes of the formation of amides. Typically, the compound of formula II in free form or in salt form is subjected to interaction with the free carboxylic acid of the formula III, for example, using known processes, such as interaction in the presence of a tertiary amine and a connecting peptide agent, such as Fofanova salt tetrafluoroborate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium or diisopropylcarbodiimide; this reaction is carried out in an inert organic solvent, for example, halogenated hydrocarbon such as dichloromethane; as a rule, the reaction temperature is 0 to 40°preferably represents the ambient temperature.

According to another implementation variant (A) of the method the compound of formula II, preferably in salt form, is subjected to the interaction with the amide forming derivatives of the acids of formula III, representing tiefer formula

where Ar2has the above values. The reaction may be accomplished using known procedures or analogously to the methods described in the examples. It can be done in the presence of a tertiary base, such is AK N-methylmorpholin. The reaction is generally carried out in an organic solvent, preferably alcohol, such as ethanol. The reaction temperature may be, for example, from 30 to 60°usually from 40 to 50°C.

Option (B) of the method can be carried out using known methods, for example by interaction associated with the substrate compound with a free acid in known conditions of peptide combinations, for example, in the presence of tertiary amine and the above binding peptide agent. The reaction can be performed in an inert organic solvent such as dimethylformamide (DMF). Acceptable reaction temperature is 0 to 40°With, for example, 15-25°C. the Product can be split from the substrate by a known method, for example by treatment triperoxonane acid in the case where the N atom is associated with SN2benzyl groups in Z.

The compounds of formula III either go on sale or you can get them known methods. The compounds of formula III-A can be obtained by the interaction of the acid of formula III with 2,2'-dibenzothiazepine in the presence of triphenylphosphine and a tertiary base, such as N-methylmorpholine, for example according to the methods described in the examples.

The compounds of formula II can be obtained by the coupling of compounds of formula

with the compound of the formula

where Ar1, R1and n have the above meanings, with the proviso that when R1contains a reactive functional group such as a hydroxy-group, the reactive group may be present in protected form, for example the hydroxy-group is protected as tert-butoxypropyl, R7denotes hydrogen or aminosidine group, for example tert-butoxycarbonyl group, and X denotes a halogen, and where R7denotes a protective group by replacing R1in the product hydrogen, and when R1the product contains a protected functional group by replacement of the protective groups by hydrogen. If R7denotes hydrogen, the reaction between the compound of formula V and the salt of the compounds of formula VI can be carried out according to the processes described in patent US 4559349. If R denotes a protective group, the reaction between the compounds of formulae V and VI can be performed with known methods, for example, in the presence of a tertiary organic base such as triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), usually in an inert solvent, for example, in a polar solvent such as dimethylformamide, the reaction is usually carried out at 0-40°C, preferably at ambient temperature. Replacement of the protective group R7hydrogen can be carried out is ü using known methods; for example, if R7denotes tert-butoxycarbonyl, processing carboxylic acid, such as triperoxonane acid. Replacement of the protective group in R1can be done using known methods, for example, when R1contains a hydroxy-group-protected simple ether group, such as tert-butoxypropan, treatment with HBr in carboxylic acid, such as acetic acid; when R7represents a protective group, such treatment also leads to the replacement of R7the hydrogen. Compounds of formulas V and VI are known or can be obtained by the known methods.

If the description has a link to a protected functional group or a protective group, it is assumed that the protective group can be chosen depending on the nature of the functional group, for example, as described in "Protective Groups in Organic Synthesis", T.W.Greene and P.G.M.Wuts, John Wiley & Sons Inc, 2nd ed., 1991, which describes the methods used for replacement of the protective groups by hydrogen.

The compounds of formula II can also be obtained by reacting the compounds of formula V with the compound of the formula

where R1, R7and n have the above values, and a reducing agent, such as lambrogini sodium or triacetoxyborohydride sodium, for example, using known processes recovery is about amination, typically, in an inert organic solvent, for example a simple ether, such as tetrahydrofuran (THF), the reaction temperature usually ranges from 0 to 40°S, and if R7denotes a protective group by the replacement of its hydrogen. The compounds of formula VII are known or can be obtained using known processes.

The compounds of formula II in which R1represents hydroxymethyl, can also be obtained by reacting the compounds of formula V with tert-butyl ether (R)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid of the formula

and a reducing agent, such as triacetoxyborohydride sodium, for example, in the conditions described above for the interaction of the compounds of formulas V and VII, and the interaction of the product with a reagent, which can split oxazolidinone ring, and replacement associated with nitrogen ester group by hydrogen, for example hydrogen chloride in ethanol or dioxane, as described below in the examples, in this case, the receive connection of the formula II in the form of hydrochloride. The reaction product of the compounds of formulas V and VIIa, for example, to improve, if necessary, the enantiomeric purity can before splitting oxazolidinone ring handle optically active acid, such as di-O-benzoyl-L-tartaric acid. The compound of formula VIIa can receive the diamonds according to the method described in A.D.Campbell etc., Synthesis 1707-1709 (1998) or G.Ageno and others, Tetrahedron 51, 8121-8134 (1995).

The compounds of formula II in which R denotes a1-C8alkoxymethyl or acyloxymethyl, can be obtained using a suitable esterification or acylation of compounds of formula II in which R1represents hydroxymethyl.

The compounds of formula IV can be obtained by the coupling of compounds of formula V with the compound of the formula

where R1, Z and n have the above values, for example, using known processes, such as interaction in an inert organic solvent such as DMF, in the presence of a tertiary amine, usually at a temperature of from 40 to 60°C. the compounds of formula VIII can be obtained by the coupling of compounds of formula

where R1, Z and n have the above values, with iodine, for example, using known processes, such as interaction in an inert organic solvent such as a mixture of THF and acetonitrile, in the presence of triarylphosphine and imidazole, as a rule, at temperatures from 10 to 40°C. the compounds of formula IX can be obtained by the coupling of compounds of formula

where R1and n have the above meanings, with a solid-phase substrate Z, which carries the group is at, such as the aldehyde group reacts with the amino group. Such solid-phase substrates, including modified resin primarily modified polystyrene resins are available commercially. The compounds of formula X are known or can be obtained by the known methods.

The compounds of formula I in free form conventional methods can be converted into a salt, and Vice versa, the compounds in free form or in salt form can be obtained in the form of a hydrate or of a solvate containing solvent used for crystallization. The compounds of formula I can be isolated from reaction mixtures and clean conventional methods. Isomers, such as enantiomers, you can get a conventional method, for example, using fractionated crystallization or asymmetric synthesis of the starting materials, which are correspondingly asymmetrically substituted, for example, optically active materials.

The compounds of formula I in free form or in the form of a pharmaceutically acceptable salt, denoted hereinafter as the agents according to the invention can be used as pharmaceutical agents. Thus, the invention also relates to the compound of formula I in free form or in the form of a pharmaceutically acceptable salt intended for use as a pharmacist is economic agent. The agents according to the invention act as antagonists of CCR-3 receptor, thereby inhibiting inflammation and the infiltration and activation of inflammatory cells, especially eosinophils, and inhibiting an allergic reaction. Inhibitory activity of the agents according to the invention can be demonstrated using the following analysis:

The analysis of binding CCR-3

Using this analysis assessing the impact of the agents according to the invention on the binding of human eotaxin with human CCR-3. Recombinant cells expressing human CCR-3, immobilized using covered agglutinins from wheat germ (PAP) polyvinyltoluene manufacturer (OEM) SPA-granules (firm Amersham) by specific binding between the PAP and carbohydrate residues of glycoproteins on the cell surface. Labeled with [125I] human eotaxin (firm Amersham) associated with specific CCR-3 receptor, leading human [125I]-eotaxin in close contact with SPA-granules. Emitted by human [125I]-eotaxin alpha particles excite because of their close location of the fluorophore in the granules and cause light emission. Free human [125I]-eotaxin in solution does not have close contact with the scintillator and therefore does not cause light emission. Therefore, the number of flashes is m is Roy, the extent to which the test compound inhibits the binding eotaxin with CCR-3.

Preparation of buffer for analysis: 5,96 g HEPES and 7.0 g of sodium chloride dissolved in distilled water and added 1 M aqueous solution of CaCl3(1 ml) and 1 M aqueous solution of MgCl2(5 ml). The pH value was adjusted to 7.6 with NaOH and the final volume of the solution is brought to 1 l with distilled water. Then in the solution dissolve 5 g of bovine serum albumin and 0.1 g of sodium azide and the resulting buffer is stored at 4°C. on the day of use in 50 ml buffer add a tablet containing a mixture of protease inhibitors, type Complete™ (Boehringer).

Preparation of buffer for homogenization: Tris-base (2,42 g) dissolved in distilled water, the pH value of the solution was adjusted to 7.6 with hydrochloric acid and the solution was diluted with distilled water to a final volume of 1 L. the resulting buffer is stored at 4°C. on the day of use in 50 ml buffer add a tablet containing a mixture of protease inhibitors type Complete™.

Obtaining membranes: confluent cells, rat basophilic leukemia (RBL-2H3), stably expressing CCR-3, isolated from the flasks for tissue culture using does not contain the enzyme buffer for dissociation of cells, and resuspended in phosphate buffered saline solution. Cells are centrifuged (800×g, 5 min), deb is the IP resuspended in chilled on ice buffer for homogenization, using 1 ml of buffer for homogenization of 1 g of cells, and incubated on ice for 30 minutes, the Cells are homogenized on ice by 10 strokes in a glass mortar with a pestle. The homogenate was centrifuged (800 g, 5 min, 4° (C), the supernatant again centrifuged (48000×g, 30 min, 4° (C) and debris re-dissolved in buffer for homogenization, containing about 10. % glycerol. The protein in the preparation of the membranes evaluated by the method of Bradford (Anal. Biochem., 72:248 (1976)) and aliquots, quickly frozen and stored at - 80°C.

The analysis is carried out in a final volume of 250 μl per well of the tablet type Optiplate (firm Canberra Packard). In certain wells Optiplate add 50 μl of solutions of the test compound in the buffer for analysis, containing 5% DMSO (0.01 nm to 10 μm). For the determination of total binding in certain other wells add 50 ál of buffer for analysis, containing 5% DMSO. To determine nonspecific binding to other selected wells add 50 ál of 100 nm human eotaxin (firm R&D Systems) in the buffer for analysis, containing 5% DMSO. To all wells add 50 ál of human [125I]-eotaxin (firm Amersham) in buffer for analysis, containing 5% DMSO at a concentration of 250 PM (with final concentration of 50 PM per well), 50 μl of PARP-HTP SPA granules in the buffer for analysis (with the final concentration of 10 mg of granules per well) and 100 μl of the preparation of the membranes at a concentration of 100 µg protein in buffer for analysis (with the final concentration of 10 µg protein per well). The tablet then incubated for 4 h at room temperature. The tablet is sealed with TopSeal-S (firm Canberra Packard) according to the manufacturer's instructions. Received the flash count with the help of the device Canberra Packard TopCount, accounting for each of the wells is carried out for 1 min. From the graphs of the dependence of inhibition on the concentration in the normal way to calculate the concentration of test compound at which the binding is inhibited by 50% (IC50).

For compounds of the following examples using the above analysis, it was established that the values of the IC50is less than 1 μm. For example, compounds of examples 1, 2, 4, 7, 9, 13, 20, 23, 25, 28, 30, 38, 40, 43 and 44 values IC50(nm) are 125, 68, 13, 15, 5, 26, 8, 10, 11, 2, 13, 14, 6, 22 and 25, respectively.

For most of the compounds from examples found selective effect in relation to inhibition of binding to CCR-3 compared with inhibition of binding to alpha-1 adrenergic receptor. The inhibitory activity of the agents according to the invention in relation to binding to alpha-1 adrenergic receptor can be demonstrated by the following analysis:

The cerebral cortex of male rats Sprague-Dawley (175-200 g) cut and homogenized in 10 volumes of chilled on ice of 0.32 M sucrose solution containing 1 mm dehydrate MgCl2and 1 mm To2NRA4in the article the glass/Teflon homogenizer. Membranes are centrifuged at 1000×g for 15 min, debris on the floor and repeat the centrifugation. Supernatant combined and centrifuged at 18000×g for 15 min Debris is subjected to an osmotic shock in 10 volumes of water and incubated on ice for 30 minutes, the Suspension is centrifuged at 39000×g for 20 min, resuspended buffered Krebs-Henseleit, pH 7.4 (1,17 mm MgSO4(anhydrous) 4,69 mm KCl, 0.7 mm To2HPO4(anhydrous), of 0.11 M NaCl, 11 mm D-glucose and 25 mm NaHCO3)containing 20 mm Tris and incubated for 2 days at - 20°C. Then the membrane is subjected to defrosting 20-23°C, washed three times with Krebs buffer-Henseleit by centrifugation at 18000×g for 15 min, incubated over night at 4°and again washed three times. Final debris resuspending in the same buffer using a glass/Teflon homogenizer at the rate of 125 ml/100 membranes. A sample is taken to determine the concentration of protein (using analysis of Bradford using gamma globulin as standard) and the remaining aliquots stored at - 80°C.

The resulting membranes analyze binding radioligand. The analysis carried out in triplicate using 96-well plates containing [125I]-NEAT (firm Amersham) (40 PM, Kd:58,9+18,7 PM), unlabeled test the connection, and is embrane (57,1 µg/ml). receiving the final volume of 250 μl of buffer (buffer for analysis containing 50 mm Tris-base and 0.9% (wt/V) NaCl, pH 7.4). Tablets incubated at 37°C for 60 min, followed by rapid vacuum filtration using 96-well filtration tablets Whatman GF/C Then each tablet three times washed with 10 ml of chilled on ice buffer for analysis using a cell harvester company Brandel (Gaithersburg, Maryland). After drying of the tablets for 3 h at 50°in each well add 40 ál scintillation fluid Microscint 20, tablets incubated at room temperature for another 20 min and evaluate quantitatively retained radioactivity using a scintillation counter type Packard Topcount NXT.

Royal solutions of test compounds are first dissolved in 100% DMSO and diluted with buffer for analysis to the required concentrations, bringing the concentration of DMSO to 1%vol.

From the graphs of the dependence of inhibition on the concentration in the normal way to calculate the concentration of test compound at which there is 50%inhibition (IC50).

Using this analysis found that the compounds of examples 1, 2, 4, 7, 9, 13, 20, 23, 25, 28, 30, 38, 40, 43 and 44 values IC50(nm) are 210, 221, 94, 48, 58, 53, 89, 131, 387, 72, 121, 1519, 215, 356 331.

With regard to their ability to inhibit binding of the s with CCR-3 agents according to the invention can be used to treat conditions, mediated by CCR-3, especially inflammatory or allergic conditions. According to the invention, the treatment may be symptomatic or preventive.

Thus, the agents according to the invention can be applied for the treatment of inflammatory or obstructive diseases of the respiratory tract, which leads, for example, in reduction of tissue damage, bronchial hyperresponsiveness, remodeling or reduction of disease development. Inflammatory or obstructive diseases of the respiratory tract, which can be treated according to the present invention include asthma, regardless of its type or Genesis, including hereditary (non-allergic) asthma and acquired (allergic) asthma, mild asthma, asthma moderate, severe asthma, bronchial asthma caused by exercise asthma, occupational asthma and asthma caused by bacterial or viral infection. The term "asthma" refers also to the treatment of patients under the age of 4 or 5 years of age who have symptoms of stridor and in respect of which diagnosed or may be diagnosed as suffering from stridor child", i.e. patients related to having great medical value patients, which currently often referred to as asthmatics with initial or early the stage of asthma. (For simplicity, this specific asthmatic condition called "syndrome suffering from stridor child").

The effectiveness of preventive treatment of asthma can be identified to reduce the frequency or severity of symptomatic episodes, such as acute asthma attacks or attacks bronchostenosis, improve lung function or reduce the increased reactivity of the Airways. In addition, it can be estimated by reducing the frequency of use of other funds symptomatic treatment, i.e. treatment intended to limit or eliminate symptomatic seizures if they occur, such as the frequency of use of anti-inflammatory drugs (such as corticosteroids or bronchodilators. Prophylactic efficacy in asthma is most evident for patients who are prone to the so-called "morning dipping". "Morning dipping" is an asthmatic syndrome that affects a certain percentage of asthmatics, characterized by asthma attack, for example, approximately between 4 and 6 a.m., i.e. in the interval of time sufficiently distant from the time when a previously produced any symptomatic treatment of asthma.

Other inflammatory or obstructive disease or condition of the respiratory tract for the treatment of co is that you can use the present invention, include acute lesions of the lung (PSV), respiratory distress syndrome of adults (rdsw), chronic obstructive pulmonary disease or respiratory (COPD or HSDP), including chronic bronchitis or associated shortness of breath, emphysema, and increased hyperresponsiveness of the Airways as a result of treatment with other medicines, in particular treatment with other medicines, administered by inhalation. The invention can also be used for treatment of bronchitis of any type or Genesis, for example acute, arachidonic, catarrhal, lobar, or chronic purulent tuberculous bronchitis. Other inflammatory or obstructive Airways disease, for which treatment it is possible to apply the present invention include pneumoconiosis (an inflammatory, usually an occupational disease of the lungs, frequently accompanied by airway obstruction, which may be chronic or acute and is linked to the constant inhalation of dust) of any type or Genesis, including, for example, aluminas, antraks, asbestosis, helicos, Philos, sideros, silicosis, tabacos and bissines.

With regard to their anti-inflammatory activity, especially with regard to inhibition of activation of eosinophils, the agents according to the invention can also be applied to the ecene associated with eosinophils diseases, e.g. eosinophilia, in particular mediated by eosinophils of respiratory diseases, such as pathological infiltration of eosinophils in pulmonary tissues)including hypereosinophilia as they affect the respiratory tract and/or lungs, as well as, for example, for treatment associated with eosinophils disorders diseases of the respiratory tract, which are due or which accompany the syndrome Leffler, eosinophilic pneumonia, parasitic (in particular caused by representatives of the Metazoa) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, Nowotny polyarteritis (including syndrome Jurga-Strauss), eosinophilic granuloma and associated with eosinophils diseases affecting sensitive to the effects of drugs to the respiratory tract.

The agents according to the invention can also be used for the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, exudative erythema, hepatitis herpetiformis, scleroderma, vitiligo, hypersensitive of angiitis, urticaria, bullous of pemphigoid, systemic lupus erythematosus, puzyrchatki, congenital bullous of bullosa and other inflammatory or allergic conditions of the skin.

The agents according to the invention can be applied is also for other diseases or conditions, first of all diseases or conditions that have an inflammatory component, for example to treat diseases and conditions of the eye such as conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases of the nose including allergic renit, such as atrophic chronic or seasonal rhinitis, inflammatory diseases of the gastrointestinal tract, such as inflammatory bowel disease such as ulcerative colitis and Crohn's disease, diseases of bone and joints, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and systemic sclerosis, and other diseases, such as atherosclerosis, multiple sclerosis, diabetes (type I), heavy psevdomatematicheskoe male, Hyper-IgE syndrome and acute and chronic allograft rejection, for example, after transplantation of heart, kidney, liver, lung or bone marrow.

The ability of the agents according to the invention to inhibit inflammatory condition, such as inflammatory diseases of the respiratory tract, can be demonstrated in the simulation on animals such as mice or rats, inflammation of the Airways or other inflammatory conditions, for example according to the methods described by Szarka and others, J.Immunol. Methods 202: 49-57 (1997); Renzi and others, Am. Rev. Respir. Dis., 148: 932-939 (1993); Tsuyuki and others, J.Clin. Invest., 96:2924-2931 (1995); and other Cernadas Am. J.Respir. CellMol. Biol. 20: 1-8(1999).

The agents according to the invention can also be used as an auxiliary therapeutic agents in combination with anti-inflammatory, bronchodilatory or antihistamine drugs primarily for the treatment of the above obstructive or inflammatory diseases of the respiratory tract, for example, as a potential means to enhance therapeutic activity of such drugs or as a means to reduce the required doses or possible side effects of such medicines. The agent according to the invention can be mixed with other medicinal product to receive a fixed pharmaceutical composition or it can be entered individually before, concurrently or after administration of another drug. Such anti-inflammatory drugs include steroids, especially corticosteroids, such as budesonide, beclamethasone, fluticasone, ciclesonide or mometazon, LTB4 antagonists (leukotriene B4), for example, described in patent US 5451700 antagonists LTD, such as montelukast and zafirlukast, receptor agonists of dopamine, such as cabergoline, parlodel, ropinirole and 4-hydroxy-7-[2-[[2-[[3-(2-phenylethane)propyl]sulfonyl]ethyl]amino]ethyl]-2(3H)-benzothiazolone and its pharmaceutically acceptable salt (EmOC is emer, hydrochloride, sold under the trademark Viozan®firm AstraZeneca), and PDE4 inhibitors such as Ariflo® (company GlaxoSmith Kline), roflumilast (company Byk Gulden), V-11294A (firm Napp), BAY19-8004 (Bayer), SCH-351591 (firm Schering-Plough) and PD189659 (company Parke-Davis). Such bronchodilatory drugs include anticholinergic or antimuskarinovoe act occurs agents, in particular ipratropium bromide, bromide oxytrope and Tiotropium bromide, and agonists beta-2-adrenoreceptor, such as salbutamol, terbutaline, salmeterol, and above all, formoterol, and their pharmaceutically acceptable salts, and the compounds of formula I, in free form or in salt form or MES), described in international patent application PCT WO 00/75114, which is incorporated into this description by reference, preferably compounds of the following in the application examples, the first compound of the formula

and its pharmaceutically acceptable salts. Antihistamine medications that can be used for joint treatment include hydrochloride, cetirizine, acetaminophen, fumarate of clemastine, promethazine, loratidine, desloratidine, diphenhydramine hydrochloride and Fexofenadine. Combinations of agents according to the invention and steroids, beta agonists-2, PDE4 inhibitors or LTD4 antagonists can be used, for example, for the treatment of COPD or pre is de only, asthma. Combinations of agents according to the invention and anticholinergic antimuskarinovoe act occurs or agents, PDE4 inhibitors or agonists of the receptor dopamine can be applied, for example, for the treatment of asthma or primarily COPD.

Other valuable combination of agents according to the invention with anti-inflammatory drugs are a combination with other antagonists of receptors chemokines, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR-10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly antagonists of CCR-5, such as antagonists of the firm Schering-Plough SC-351125, SCH-55700 and SCH-D, antagonists company Takeda, such as chloride, N-[[4-[[[6,7-dihydro-2-(4-were)-5H-benzocycloheptene-8-yl]carbonyl]amino]phenyl]methyl]tetrahydro-N,N-dimethyl-2H-Piran-4-ammonium (TAK-770), and antagonists of CCR-5, described in the patent US 6166037 (in particular, in paragraphs 18 and 19 of the claims), in WO 00/66558 (in particular, in paragraph 8 of the claims and in WO 00/66559 (in particular, paragraph 9 of the claims).

According to the above, in the invention, a method of treatment of a condition mediated by CCR-3, for example an inflammatory or allergic condition, in particular an obstructive or inflammatory Airways disease that involves the introduction of a patient, especially a human in need of such treatment, an effective amount described in the above compounds of formula I in free form or in the form of its pharmaceutically acceptable salts. Another object of the invention is the use of the above compounds of formula I in free form or in the form of pharmaceutically acceptable salts for preparing a medicinal product intended for the treatment mediated by CCR-3 States, for example, for treatment of inflammatory or allergic conditions, first of all, obstructive or inflammatory Airways disease.

The agents according to the invention can be entered by any suitable route, for example orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; by inhalation, especially in the treatment of obstructive or inflammatory diseases of the respiratory tract; intranasally, for example, in the treatment of allergic rhinitis; topically to the skin, for example, in the treatment of atopic dermatitis, or rectocele, for example, in the treatment of inflammatory bowel disease.

Another object of the invention is a pharmaceutical composition comprising a compound of formula I in free form or in the form of its pharmaceutically acceptable salts, optionally in combination with a pharmaceutically acceptable diluent or carrier. The composition may contain additional therapeutic agent, such as described above protivovospalitelnoe or bronchodilator drug. Such comp the positions can be prigotovlivajut using conventional diluents or excipients and methods known in the field of preparation of galenic forms. So, forms for oral administration may be tablets and capsules. Compositions for topical application may include creams, ointments, gels and transdermal delivery systems, such as plaques. Compositions for inhalation may be an aerosol or other spray composition or composition based on the dry powder.

Thus, the object of the invention is (A) the agent according to the invention, which can be administered by inhalation, for example in the form of an aerosol or other spray composition or suitable for inhalation of particles, for example, in micronized form; (B) intended for inhalation drug, comprising the agent according to the invention in a form suitable for inhalation; (C) a pharmaceutical product comprising the agent according to the invention in a form suitable for inhalation, in combination with a device for inhalation; and (G) a device for inhalation containing the agent according to the invention in the form of suitable for inhalation.

Doses of the agents according to the invention, used in the practical implementation of the invention, must naturally vary depending on, for example, on the particular condition to be treated, the expected action and route of administration. Typically, a suitable daily dose in the introduction put the m inhalation of approximately 0.01 to 30 mg/kg, a suitable daily dose for oral administration comprise from about 0.01 to 100 mg/kg

Below the invention is illustrated in the examples.

Examples 1-47

The compounds of formula I, which are also represented by the formula

and methods for their preparation are given in the following table, and the methods themselves are described below. Ra' represents H, all of the examples except example 12, where it designates F. the table shows the data of mass spectrometry ([MN]+and, if in the example described obtaining salt, indicated salt-forming acid

Example No.RaRbRcRdReRfRgM/CForm saltsMethod
1FNHCNHHH406,1CF3CO3NIn
2FHCNHHH496,8-B
3FH CNHHH448,5-B
4FOch2CH3HHBrH593,3-B
5FHHCNOch3HH436,2CF3CO3NIn
6FHOch3HHOch3H441,3CF3CO3NIn
7FHOch3HHBrH491,2CF3CO3NIn
8FHCNHHH497.4 mCF3CO3NAnd
9FOch3HHBr H580,2-And
10FNOHNNClN431,7CF3CO2NIn
11FNOch3NNFN429,0CF3CO2NIn
12FNOch3NNBrNto 508.6CF3CO2NIn
13ClNOch3NNBrN506,7CF3CO2NIn
14FNOch3NNCNNkm 436.0CF3CO2NIn
15FNOch3NNClN445,2CF3CO2NIn
16F NOch2CH3NNClN459,3CF3CO2NIn
17FNO(CH2)2CH3NNClN473,3CF3CO2NIn
18FNNNClN473,3CF3CO2NIn
19FNO(CH2)2CH3NNBrN519,2CF3CO2NIn
20FNNNBrN519,2CF3CO2NIn
21FNOch3NNCH3N425,3CF3CO2NIn
22F NNNCH3N453,3CF3CO2NIn
23FHNNCNN486,4-And
24FOch3NNOch3N521,4-And
25FOch3NNBrN521,2-B
26FNNNCNN503,4-And
27FOch3NNOch3N624,4-G, And
28F Och3NNCNN516,5-And
29FOch3NNBrN571,1-And
30FOch3NnCNN516,6-B
31FOch3NnCNN516,5-And
32FNNNCH3Nn395,4CF3CO2NIn
33FNFFFFF471,3CF3CO2NIn
34F NNCF3NCF3N517,4CF3CO2NIn
35FNNNO2NNN426,3CF3CO2NIn
36FNnSOON3Och3NOch3499,9CF3CO2NIn
37FOch3NNCNN466,1-E
38C1Och3NNCNNRUB 482.2-D
39FNNNCNN420,5-B
40 ClOch3NNClN491,1CF3CO2NB
41ClNOch3NNCNN452,0CF3CO2NB
42FOch3NNBrN533,3-
43ClOch3NNBrN537,0-D
44FOch3NNCNN527,6-And
45FOch3NNCNN480,5-E
46ClOch3NNCNN482W
47ClOch3NNCNN482-W

Method And

Obtain tert-butyl ester ((R)-2-hydroxy-1-pyridin-3-iletiler)carbamino acid.

To a solution of (R)-2-tert-butoxycarbonylamino-3-pyridin-3-ylpropionic acid (0.9 g, 3,37 mmole) in dimethoxyethane (18 ml) is added N-methylmorpholine (of 0.44 ml, Android 4.04 mmole) and isobutylparaben (of 0.48 ml, 3,71 mmole). The reaction mixture was stirred at ambient temperature for 20 min and then filtered. The filtrate is treated with an aqueous solution of sodium borohydride (25 ml, 10,11 mmole) and the reaction mixture was immediately diluted with water (200 ml). Stirring is continued for 1 h at ambient temperature. The reaction mixture is distributed between ethyl acetate and water. The organic phase is separated, dried over magnesium sulfate and evaporated. The crude product is purified rapid chromatography on silica gel (elution EtOAc)to give tert-butions ester ((R)-2-hydroxy-1-pyridin-3-iletiler)carbamino key is lots. [MN]+253,5.

Obtain tert-butyl ester ((R)-2-bromo-1-pyridin-3-iletiler)carbamino acid.

To a solution of tert-butyl ester ((R)-2-hydroxy-1-pyridin-3-iletiler)carbamino acid (0,43 g of 1.70 mmole) in dichloromethane (10 ml) add chetyrehhloristy carbon (0.33 g, 2,04 mmole) and triphenylphosphine (0,23 g of 1.70 mmole). The reaction mixture was stirred at ambient temperature for 2 h, filtered and the filtrate is distributed between ethyl acetate and hydrochloric acid (1 M). The aqueous phase is separated, neutralized with saturated sodium bicarbonate solution and extracted with dichloromethane. The dichloromethane layer is dried on magnesium sulfate and evaporated, obtaining tert-butyl ester ((R)-2-bromo-1-pyridin-3-iletiler)carbamino acid1H-NMR (400 MHz, CDCl3) (1,29 (s, N), was 3.05 (dd, J 14,3, 9,8, 1H), 3,18 (dd, J 14,3 of 4.9, 1H), 3,51 (d, J 4,9, 2H), 4,07-4,16 (m, 1H), to 7.84 (dd, J of 7.9 and 5.9, 1H), 8,35 (d, J 7,9, 1H), 8,65 (d, J 5,4, 1H), 8,86 (s, 1H).

Obtain tert-butyl ester {(R)-2-[4-(4-perbenzoic)piperidine-1-yl]-1-pyridin-3-immediatel}carbamino acid

(4-Forfinal)piperidine-4-ylmethanol (0.15 g, 0.73 mmole) are added to a solution containing tert-butyl ester ((R)-2-bromo-1-pyridin-3-iletiler)carbamino acid (0.21 g, of 0.66 mmole) and 1,8 diazabicyclo[5.4.0]undec-7-ene (0,12 ml of 0.79 mmole) in dimethylformamide (3 ml). The reaction mixture was stirred at ambient temperature for 24 h is before distribution between ethyl acetate and water. An ethyl acetate layer is dried over magnesium sulfate and evaporated. The crude product is dried with rapid chromatography on silica gel (elution with a mixture of 97:3, dichloromethane: methanol)to give tert-butyl ester {(R)-2-[4-(4-perbenzoic)piperidine-1-yl]-1-pyridin-3-immediatel}carbamino acid.1H-NMR (400 MHz, CDCl3) δ1,36 ('s. N), 1,68-of 1.85 (br m, 4H), 2.00 in of 2.38 (br m, 4H), 2,78-only 2.91 (m, 4H), 3,05-3,19 (m, 1H), 3,81-3,93 (m, 1H), 7,05 (t, J 8,8, 2H), 7,12-to 7.18 (m, 1H), of 7.48 (d, J 7,9, 1H), 7,85-to 7.93 (dd, J 8,8 5,4, 2H), at 8.36 (d, J 1,5, 1H), to 8.40 (dd,J 4,9 1,5, 1H).

Obtain [1-((R)-2-amino-3-pyridine-3-ylpropyl)piperidine-4-yl]-(4-forfinal)methanone

To a solution of tert-butyl ester {(R)-2-[4-(4-perbenzoic)piperidine-1-yl]-1-pyridin-3-immediatel}carbamino acid (0,149 g 0,34 mmole) in dichloromethane (2 ml) is added triperoxonane acid (0.5 ml) and the reaction mixture stirred at ambient temperature for 1 h, the Reaction mixture was evaporated and the residue is dissolved in hydrochloric acid (1M), the solution is alkalinized with sodium hydroxide solution (4M) and the precipitate is extracted with dichloromethane. The dichloromethane layer is dried over magnesium sulfate and evaporated, receiving [1-((R)-2-amino-3-pyridine-3-ylpropyl)piperidine-4-yl]-(4-forfinal)methanon. H-NMR (400 MHz, CDCl3) δ1,63-of 1.85 (m, 4H), 1,88 is 2.00 (m, 1H), 2,08 of-2.32 (m, 5H), 2,50 (dd, J 13,5, 7,9, 1H), to 2.67 (dd, J 13,5, 4,9, 1H), 2,78 are 2.98 (m, 2H), 3.04 from-3,20 (m, 2H),? 7.04 baby mortality (t, J 8,8, 2H), 7,17 (dd, J 6,9, 4,9, 1H), of 7.48 (d, J of 7.9, 1H), 7,88 (dd, J 8,8, 5,4, 2H), 8,33-to 8.45 (m, 2H).

Receipt is (E)-3-(3-tianfeng)-N-{(R)-2-[4-(4-perbenzoic)piperidine-1-yl]-1-pyridin-3-immediatel}acrylamide.

To a solution of (E)-3-(4-tianfeng)acrylic acid (0,022 g, 0,126 mmole) in dichloromethane (1 ml), add triethylamine (0,016 ml, 0,126 mmole) and hexaflurophosphate (benzotriazol-1 yloxy)triprolidine (0.06 g, 0,116 mmole). The reaction mixture was stirred at ambient temperature for 5 min and then add a solution of 1-((R)-2-amino-3-pyridine-3-ylpropyl)piperidine-4-yl]-(4-forfinal)methanone (0.036 g, 0,105 mmole) in dichloromethane (1 ml). Stirring is continued for another 1.5 h, then the reaction mixture is filtered. The filtrate is evaporated and the crude product purified rapid chromatography on silica gel (dichloromethane: methanol: acetic acid, 10:0,5:0,05), obtaining (E)-3-(3-tianfeng)-N-{(R)-2-[4-(4-perbenzoic)piperidine-1-yl]-1-pyridin-3-immediatel}acrylamide [MN]+497.4 m.

Method B

Obtain tert-butyl ester {(R)-1-benzyl-2-[4-(4-perbenzoic)piperidine-1-yl]ethyl}carbamino acid

A solution containing tert-butyl ester ((R)-1-benzyl-2-oxoethyl)carbamino acid (0.5 g, 2.0 mmole), (4-forfinal)piperidine-4-ylmethanol (0,414 g, 2.0 mmole) and triacetoxyborohydride sodium (0,638 g, 3.0 mmole) in tetrahydrofuran (20 ml), stirred at ambient temperature for 24 hours the Solvent is evaporated and the residue re-dissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The dichloromethane layer is dried over sulfate m is fester and evaporated. The crude product is purified rapid chromatography on silica gel (elution with a mixture of ethyl acetate:hexane, 3:1)to give tert-butyl ester [(R)-1-benzyl-2-[4-(4-perbenzoic)piperidine-1-yl]ethyl}carbamino acid [MN]+441,3.

Obtain [1-((R)-2-amino-3-phenylpropyl)piperidine-4-yl](4-forfinal)methanone.

A solution of tert-butovogo ester {(R)-1-benzyl-2-[4-(4-perbenzoic)piperidine-1-yl]ethyl}carbamino acid (1.12 g, of 2.54 mmole) and triperoxonane acid (3 ml) in dichloromethane (6 ml) was stirred at ambient temperature for 3 hours the Solvent is evaporated and the residue is dissolved in hydrochloric acid (2M), washed with ethyl acetate and alkalinized with sodium hydroxide solution (4M) to pH 8-9. The suspension is extracted with dichloromethane, the dichloromethane layer is dried over magnesium sulfate and the solvent is evaporated, receiving [1-((R)-2-amino-3-phenylpropyl)piperidine-4-yl](4-forfinal)methanon. [MN]+341,7.

Obtaining (E)-N-{(R)-1-benzyl-2-[4-(4-perbenzoic)piperidine-1-yl] ethyl} -3-(3-tianfeng)acrylamide

To a solution of (E)-3-(4-tianfeng)acrylic acid (0,042 g, 0,242 mmole) in dichloromethane (1 ml), add triethylamine (0,046 ml, 0,331 mmole) and hexaflurophosphate (benzotriazol-1 yloxy)triprolidine (0.126 g, 0,242 mmole). The reaction mixture was stirred at ambient temperature for 5 min and then add a solution of [1-((R)-2-amino-3-phenylprop the l)piperidine-4-yl](4-forfinal)methanone (0.075 g, 0,220 mmole) in dichloromethane (1 ml). Stirring is continued for a further 3 h, then the reaction mixture was diluted with dichloromethane (25 ml) and washed with saturated sodium bicarbonate solution and saturated salt solution. The dichloromethane layer is dried over magnesium sulfate and the solvent is evaporated. The crude product is purified rapid chromatography on silica gel (elution with a mixture of ethyl acetate: hexane, 5:1)to give (E)-N-{(R)-1-benzyl-2-[4-(4-perbenzoic)piperidine-1-yl]ethyl}-3-(3-tianfeng)acrylamide [MH]+496,8.

Method In

Obtaining (E)-3-(5-bromo-2-methoxyphenyl)-N-{2-[4-(4-chlorobenzoyl)piperidine-1-yl]ethyl}acrylamide.

To a suspension containing 2-(formyl-3-methoxyphenoxy)adiponitrile (AMEV) resin, Novabiochem) (6.85 g, 3.33 mmole) in a mixture of methanol/dichloromethane (60 ml, 1:1 V/V), add 2-aminoethanol and triacetoxyborohydride sodium (4,00 g, 18,85 mmole) and the mixture shaken for 16 h at 20°C, then filtered. The resin is washed with methanol, DMF and dichloromethane, then dried under vacuum. To the dried resin add a mixture of THF/acetonitrile (50 ml, 1:1 V/V)and then iodine (4,80 g, 18,85 mmole), imidazole (1.28 g, 18,85 mmole) and triphenylphosphine (4,90 g, 18,85 mmole). The resulting suspension is shaken for 18 h at 20°C, then filtered. The resin was washed with THF and dried under vacuum. To the freshly prepared resin (0.50 g, 0.35 mmole) is added dissolve the hydrochloride (4-chlorophenyl)piperidine-4-ylmethanone (0.18 g, 0,70 mmole)dissolved in DMF (2 ml) and diisopropylethylamine (0.36 g, 2.8 mmole). The mixture was kept at 50°C for 16 h and then filtered. The resin was washed with DMF. To the washed resin type (E)-3-(5-bromo-2-methoxyphenyl)acrylic acid (0.27 g, 1.05 mmole), tetrafluoroborate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (0.34 g, 1.05 mmole), diisopropylethylamine (0,29 g, 1.05 mmole) and DMF (4 ml) and the mixture shaken at 20°C for 16 h, then washed with DMF and methanol, and then to separate the product from the resin is treated with a mixture triperoxonane acid/dichloromethane (6 ml, 1:1 V/V) at 20°C for 1 h the Resulting mixture is filtered and the filtrate evaporated under vacuum, obtaining the desired product, [MH]+506,7.

Method G

Obtain tert-butyl ester {(R)-1-(4-aminobenzyl)-2-[4-(4-perbenzoic)piperidine-1-yl]ethyl} carbamino acid

To a solution of tert-butyl ester [(R)-2-[4-(4-perbenzoic)piperidine-1-yl]-1-(4-nitrobenzyl)ethyl]carbamino acid (1,41 g, 2,90 mmole) in acetic acid (11 ml), cooled to 0°add an aqueous solution of calcium chloride (4 ml, 0,47M) and powdered zinc (3,9 g, 59,6 mmole). The reaction mixture was stirred at 0°C for 35 min and then filtered through a plug of celite. The filtrate is evaporated and the residue is dissolved in water and extracted with dichloromethane. The dichloromethane layer is evaporated and osteoclastoma in water and alkalinized with an aqueous solution of sodium bicarbonate and extracted with dichloromethane. The dichloromethane layer is dried over magnesium sulfate and evaporated, obtaining tert-butyl ester {(R)-1-(4-aminobenzyl)-2-[4-(4-perbenzoic)piperidine-1-yl]ethyl}carbamino acid, [MN]+456,5.

Obtain tert-butyl ester [(R)-2-[4-(4-perbenzoic)piperidine-1-yl]-1-(4-methanesulfonylaminoethyl)ethyl]carbamino acid

To a solution of tert-butyl ester {(R)-1-(4-aminobenzyl)-2-[4-(4-perbenzoic)piperidine-1-yl]ethyl}carbamino acid (1.19 g, 2,61 mmole) in dichloromethane (15 ml), cooled to 0°With, add triethylamine (0.37 sq ml, approximately 2.65 mmole) and methanesulfonamide (0,192 ml, 2,49 mmole). The reaction mixture is allowed to warm to ambient temperature, stirring for 1 h, then washed with water and saturated saline solution, dried over magnesium sulfate and evaporated. The crude product is purified rapid chromatography on silica gel (elution gradient of ethyl acetate:hexane 6:4 to 1:0)to give tert-butyl ester [(R)-2-[4-(4-perbenzoic)piperidin-yl]-1-(4-methanesulfonylaminoethyl)ethyl]carbamino acid, [MN]+534,7.

Method D

Obtain tert-butyl ether (S)-4-[4-(4-chlorobenzoyl)piperidine-1-ylmethyl]-2,2-dimethyloxazolidine-3-carboxylic acid

To a solution of tert-butyl methyl ether (R)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid (0.5 g, 2.18 mmole) in tetrahydrofuran (15 ml) is added (4-chlorophenyl)piperidine-4-and mechanon (0,49 g, 2.18 mmole) and triacetoxyborohydride sodium (0,69 g of 3.27 mmole) and the reaction mixture was stirred for 3.5 h at ambient temperature. The solvent is evaporated and the residue distributed between ethyl acetate (50 ml) and saturated sodium bicarbonate solution (50 ml). An ethyl acetate layer is dried over magnesium sulfate and evaporated. The crude product is purified rapid chromatography on silica gel (elution with ethyl acetate:hexane, 1:1)to give tert-butilovyi ether (S)-4-[4-(4-chlorobenzoyl)piperidine-1-ylmethyl]-2,2-dimethyloxazolidine-3-carboxylic acid, [MN] 437,2.

Getting hydrochloride [1-((S)-2-amino-3-hydroxypropyl)piperidine-4-yl](4-chlorophenyl)methanone.

Treat-butyl ether (S)-4-[4-(4-chlorobenzoyl)piperidine-1-ylmethyl]-2,2-dimethyloxazolidine-3-carboxylic acid (0.68 g, of 1.55 mmole) are added to a solution of hydrogen chloride in ethanol (5 ml, 5.5 M). The reaction mixture was stirred at ambient temperature for 1 h, then evaporated to dryness receiving hydrochloride [1-((S)-2-amino-3-hydroxypropyl)piperidine-4-yl](4-chlorophenyl)methanone, [MN]+297,0.

Obtaining (E)-3-(5-cyan-2-methoxyphenyl)acrylic acid

To a suspension of palladium(II) acetate (0,77 g of 3.42 mmole) in N,N-dimethylacetamide (375 ml) under nitrogen atmosphere add chloride of tetraethylammonium (19,36 g, 114,5 mmole), dicyclohexylmethane (35,1 g of 174.5 mmole) and 3-bromo-4-methoxybenzonitrile (25,51 g, 18,0 mmole). The suspension is heated to 100-105°With, then slowly over 45 min add tert-butyl acrylate (14,82 g, 114,5 mmole). After stirring for a further 30-60 min at 100°the solution is cooled to room temperature and diluted with TBME (375 ml). The resulting two-phase mixture is intensively stirred for 10 min, the Upper phase (TBMA) washed successively with water (100 ml), 10%aqueous citric acid solution (100 ml) and 25%aqueous NaCl solution (100 ml). The combined aqueous phases are extracted with TBME (100 ml). After the addition of activated carbon (0.4 g) United TBMA-phase intensively stirred for 10 min and filtered. Add anhydrous Na2SO4(10 g) and the resulting suspension is stirred for another 10 min and filtered. The filtrate is concentrated to a volume of 50-70 ml under reduced pressure for 25-30 minutes, add at room temperature to anhydrous triperoxonane acid (150 ml). The resulting solution was stirred at room temperature for 60 min the precipitate is cooled to 0-5°C in an ice bath and diluted with ethyl acetate (410 ml). After intensive stirring at 0°C for another 60 min, the suspension is filtered. The residue is dried under vacuum at 45-50°receiving (E)-3-(5-cyan-2-methoxyphenyl)acrylic acid in the form of a crystalline solid, tPL252-23° C. MC (ES): [M-N]-202.

Obtaining (E)-N-{(S)-2-[4-(4-chlorobenzoyl)piperidine-1-yl]-1-hydroxymethylation}-3-(5-cyan-2-methoxyphenyl)acrylamide.

To a solution containing (E)-3-(5-cyan-2-methoxyphenyl)acrylic acid (0.31 g, of 1.55 mol), triethylamine (0.2 ml, of 1.55 mmole) and tetrafluoroborate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (0,49 g of 1.55 mmole) in dichloromethane (5 ml)add a solution of hydrochloride [1-((S)-2-amino-3-hydroxypropyl)piperidine-4-yl](4-chlorophenyl)methanone and triethylamine (0.4 ml, 3.1 mmole) in dichloromethane (5 ml) and the reaction mixture stirred at ambient temperature for 1 h, the Reaction mixture was diluted with dichloromethane (20 ml), sequentially washed with saturated sodium bicarbonate solution (25 ml) and saline (25 ml), then dried over magnesium sulfate. The solvent is evaporated and the crude residue purified rapid chromatography on silica gel (methanol:dichloromethane 5:95)to give (E)-N-{(S)-2-[4-(4-chlorobenzoyl)piperidine-1-yl]-1-hydroxymethylation}-3-(5-cyan-2-methoxyphenyl)acrylamide, [MN]+RUB 482.2.

Method E

Obtain tert-butyl ether (S)-4-[4-(4-perbenzoic)piperidine-1-ylmethyl]-2,2-dimethyloxazolidine-3-carboxylic acid

To a solution of (4-forfinal)piperidine-4-ylmethanone (3.5 g, 17 mmol) in anhydrous tetrahydrofuran (50 ml) is added tert-butyl ether (R)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid (3.9 g, 17 is moles) and triacetoxyborohydride sodium (5,4 g, 25 mmol) and the reaction mixture stirred for 18 h at ambient temperature. The reaction mixture is filtered and the solvent is evaporated, getting a solid white color. The solid is dissolved in dichloromethane (50 ml) and washed with saturated sodium bicarbonate solution (50 ml), water (2x 50 ml) and with brine (50 ml). The organic phase is dried over magnesium sulfate and evaporated, obtaining the desired product, [MN]+420,9.

Getting hydrochloride [1-((S)-2-amino-3-hydroxypropyl)piperidine-4-yl]-(4-forfinal)methanone.

To a suspension of tert-butyl methyl ether (S)-4-[4-(4-perbenzoic)piperidine-1-ylmethyl]-2,2-dimethyloxazolidine-3-carboxylic acid (4.9 g, an 11.7 mmole) in ethanol (25 ml) is added hydrogen chloride in dioxane (25 ml, 4 M). The resulting clear solution is stirred for 4 h at ambient temperature, forming a white precipitate. The reaction mixture was cooled to 0°and the precipitate is filtered, obtaining the desired product, [MH]+281,6.

Obtaining (E)-N-{(S)-2-[4-(4-perbenzoic)piperidine-1-yl]-1-hydroxymethylation}-3-(5-cyan-2-methoxyphenyl)acrylamide.

To a solution of hydrochloride [1-((S)-2-amino-3-hydroxypropyl)piperidine-4-yl]-(4-forfinal)methanone (1.8 g, 5.7 mmole) and diisopropylethylamine (2.0 ml, 11.4 mmole) in dichloromethane (45 ml) is added (E)-3-(5-cyan-2-methoxyphenyl)acrylic acid (1.1 g, 5.7 IMO is I), and then tetrafluoroborate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (1,83 g, 5.7 mmole). The reaction mixture was stirred at ambient temperature for 4.5 h, then filtered and the filtrate washed with water (50 ml), saturated sodium bicarbonate solution (50 ml), water (50 ml) and with brine (50 ml). The organic phase is dried over magnesium sulfate, the solvent is evaporated and the residue purified rapid chromatography on silica gel (elution gradient of dichloromethane: methanol 98:2 to 92:8)to give the desired product, [MN]+466,1.

Method W

Getting Dibenzoyl-L-tartrate tert-butyl ether (S)-4-[4-(4-chlorobenzoyl)piperidine-1-ylmethyl]-2,2-dimethyloxazolidine-3-carboxylic acid (dibasic).

To a cooled (0° (C) suspension of sodium borohydride (2,40 g, 63,55 mmole) in anhydrous toluene (50 ml) for 1 h add to the atmosphere of inert gas acetic acid (of 11.45 g, 189,9 mmole). Stirring is continued at ambient temperature for 5 h before the termination of the hydrogen (suspension 1). In another flask hydrochloride 4-(4-chlorobenzoyl)piperidine (obtained by the interaction of N-formyl-4-(4-chlorbenzoyl)of piperidine and acetylchloride) (5,51 g, 21,18 mmole) is suspended in anhydrous toluene (20 ml) at room temperature. Add triethylamine (2.57 m) g, 25,42 mmole) and added dropwise over 45 min with stirring, the toluene solution (55 ml) of tert-bouteloua ether (R)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid (5,59 g, 24,36 mmole). Stirring is continued for another 20 min, then slowly under stirring for 60 min add suspension 1. The resulting suspension stirred at ambient temperature until such time as according to the TLC does not stop the absorption of primary products (14 h), then slowly added to a solution of NaHCO3(25 g, 297,6 mmole) in water (120 ml). The resulting emulsion is stirred at 20°C for 60 min to separate the aqueous phase of the mixture and the organic phase is washed twice successively with 20 ml of 10%aqueous solution of NaHCO3and water. After adjusting the pH of the combined aqueous phases to 9.5 with solid Na2CO3the aqueous phase is extracted with toluene (2×25 ml). To the combined organic phases add celite (0.5 g), then filtered and evaporated to dryness, obtaining the free base which is then dissolved in isopropanol (35 ml) and incubated at the temperature of reflux distilled. Add dropwise a solution of di-O-benzoyl-L-tartaric acid (4.0 g, 10.6 mmole) in isopropanol (10 ml). After stirring at 79-81°C for 20 min the mixture is cooled, diluted with methyl tert-butyl ether (TBME) and the product is crystallized at 0°C, filtered, washed with cold (0° (C) a mixture of TBME: isopropanol, 1:2 (15 ml) and cooled (0° (C) TBME (3×5 ml) and dried under vacuum. After s the recrystallization of the dried product from isopropanol and drying under vacuum get listed in title product as a crystalline solid t PL174°C.

MS (ES+): [M}+437.

Getting dihydrochloride [1-((S)-2-amino-3-hydroxypropyl)piperidine-4-yl](4-chlorophenyl)methanone

Dibenzoyl-L-tartrate tert-bootlogo ether (S)-4-[4-(4-chlorobenzoyl)piperidine-1-ylmethyl]-2,2-dimethyloxazolidine-3-carboxylic acid (dibasic) (4.0 g, 3.2 mmole) is suspended in n-butyl acetate (40 ml). Add water (32%) hydrochloric acid (2,18 g, and 19.2 mmole) and the mixture was stirred at ambient temperature until such time as according to the TLC does not stop the absorption of primary products (2 hours). The suspension is stirred in an ice bath for a further 3 h and filtered. The solid product is washed with cold (0° (C) n-butyl acetate (2×5 ml) and dried under vacuum at 45-50°getting listed in title product as colorless crystals tPL232-237°C. MS (ES+): [MN]+297.

Getting S-benzothiazol-2-silt ether (E)-3-(5-cyan-2-methoxyphenyl)tigrillos acid

The suspension containing the disulfide 2,2'-dibenzothiazyl (4.0 g, 12.0 mmol) and triphenylphosphine (3.15 g, 12.0 mmol) in CH2Cl2(60 ml), intensively stirred at 25°C for 30 minutes After cooling to 0°C in an ice bath, add (E)-3-(5-cyan-2-methoxyphenyl)acrylic acid (obtained according to D) (2.24 g, 11.0 mmol)and then N-methylmorpholine (to 1.21 ml, 11.0 mmol). The suspension is intensively stirred heated and give the Xia to room temperature over night. After stirring for 24 h at room temperature the precipitate is filtered at 0°and washed With cold (0° (C) CH2Cl2(10 ml). After drying under vacuum at 35°get listed in title product in the form of crystalline powder, tPL183-185°C. MS(EI): [M]+352.

Receiving the floor-(L)-tartrate (E)-N-{(S)-1-[4-(4-chlorobenzoyl)piperidine-1-ylmethyl]-2-hydroxyethyl}-3-(5-cyan-2-methoxyphenyl)acrylamide

To a suspension dihydrochloride [1-((S)-2-amino-3-hydroxypropyl)piperidine-4-yl]-(4-chlorophenyl) methanone (9,24 g, 25.0 mmol) in ethanol (250 ml) is added N-methylmorpholine (2,53 g, 25.0 mmol). The suspension is stirred at 45°C for 30 min, then add S-benzothiazol-2-silt ether (E)-3-(5-cyan-2-methoxyphenyl)tigrillos acid (4,40 g, 12.5 mmole)and the suspension is diluted with ethanol (20 ml) and continue stirring at 45°C for 3 hours Add another portion of tiefer (2.64 g, 7.5 mmole) and the suspension is stirred for another 4 h at 45°C. Add the last portion of tiefer (1,76 g, 5.0 mmole) and after stirring for a further 3 hours, add another portion of N-methylmorpholine (1.26 g, 12,46 mmole) and stirring is continued overnight, then add the last bit N-methylmorpholine (1.26 g, 12,46 mmole). The suspension is immediately filtered and the filtrate evaporated to dryness under reduced pressure. The residue is dissolved VSN 2Cl2(250 ml) and washed successively 10%aqueous Na2CO3(2×100 ml) and 10%aqueous NaCl (4×100 ml). The organic phase is stirred with telicom (1 g), filtered and evaporated to dryness. The residue is dried under vacuum and dissolved in ethanol (130 ml). Add under stirring at 35°With a solution of L-tartaric acid (4.5 g, 30.0 mmol) in ethanol (100 ml) and the resulting suspension stirred at 50-55°C to obtain a clear solution. After the turbidity associated with the formation of crystals, the suspension is slowly cooled to 0°and stirred in an ice bath for 45 min, then the precipitate is filtered, washed with cold (0° (C) ethanol (20 ml) and recrystallized from ethanol, receiving specified in the header of the product, tPL90-120°C (decomposition). MS (ES+): [MN]+482.

Obtaining (E)-N-{(S)-1-[4-(4-chlorobenzoyl)piperidine-1-ylmethyl]-2-hydroxyethyl}-3-(5-cyan-2-methoxyphenyl)acrylamide

10%aqueous Na2CO3(100 ml) is added under stirring at room temperature to a suspension semi-(L)-tartrate (E)-N-{(S)-1-[4-(4-chlorobenzoyl)piperidine-1-ylmethyl]-2-hydroxyethyl}-3-(5-cyan-2-methoxyphenyl)acrylamide (6,32 g, 10.0 mmol) in CH2Cl2(150 ml) and water (50 ml). After stirring at ambient temperature for 30 minutes the phases are separated and the aqueous phase extracted with CH2Cl2(100 ml)Obyedinenie CH 2Cl2-phase is extracted with 10%aqueous NaCl (2×100 ml), stirred with telicom (500 mg) and filtered after evaporation under reduced pressure, obtaining a colorless foam. After adding butyl acetate (200 ml) formed a clear solution, which was heated to 80°and allow to slowly cool to room temperature. After dilution of TBME (150 ml), the suspension is cooled to 0°, saducees the crystals are filtered, washed with cold (0° (C) a mixture of butyl acetate/TBME, 1:1 (50 ml) and dried under vacuum at 45-50°receiving (E)-N-{(S)-1-[4-(4-chlorobenzoyl)piperidine-1-ylmethyl]-2-hydroxyethyl}-3-(5-cyan-2-methoxyphenyl)acrylamide, tPL162-163°C. MS (EI): [MN]+482.

1. Derivatives of piperidine derivatives of the formula

in free form or in salt form,

where Ar1denotes phenyl, substituted by one or more halogen atoms,

Ar2denotes phenyl or naphthyl, which is unsubstituted or substituted by one or more substituents selected from the series comprising halogen, cyano, hydroxy, nitro, C1-C8alkyl, C1-C8haloalkyl,1-C8alkoxy or1-C8alkoxycarbonyl,

R1denotes hydrogen or C1-C8alkyl, optionally substituted hydroxy, C1-C alkoxy-, alloctype, -N(R2R3, halogen, carboxypropyl,1-C8alkoxycarbonyl, -CON(R4R5or a monovalent cyclic organic group,

R2and R3each independently of one another denotes hydrogen or C1-C8alkyl, or R2denotes hydrogen and R3denotes acyl or-SO2R6or R2and R3together with the nitrogen atom to which they are attached, form a 5 - or 6-membered heterocyclic group,

R4and R5each independently of one another denotes hydrogen or C1-C8alkyl, or R4and R5together with the nitrogen atom to which they are attached, form a 5 - or 6-membered heterocyclic group,

R6stands With1-C8alkyl, C1-C8haloalkyl or phenyl, optionally substituted C1-C8the alkyl, and

n denotes 1, 2, 3,or 4

provided that when Ar1denotes parachlorophenyl and R1denotes hydrogen, then Ar2does not denote a phenyl or paranitrophenyl.

2. The compound according to claim 1, where Ar2denotes a monosubstituted phenyl, a Deputy of which is halogen, cyano-, nitro - or1-C4alkoxygroup; or disubstituted phenyl, the substituents of which are selected from a range that includes halo is Yong, cyano, hydroxy, nitro, C1-C4alkoxy, C1-C4alkyl and C1-C4haloalkyl; or tizamidine phenyl, the substituents of which are selected from the series comprising halogen, hydroxy, C1-C4alkoxy and C1-C4alkoxycarbonyl; or pentamidine phenyl, substituents which are halogen atoms.

3. The compound according to claim 1, where R1stands With1-C4alkyl, optionally substituted hydroxy, C1-C8alkoxy-, alloctype, halogen, carboxypropyl,1-C8alkoxycarbonyl, -CON(R4R5or a monovalent cyclic organic group.

4. The compound according to claim 1, where

Ar1denotes phenyl, substituted by fluorine or chlorine in paraprotein relative to the indicated carbonyl group and optionally additionally substituted by halogen in anthopology relative to the indicated carbonyl group,

Ar2denotes phenyl, monosubstituted Deputy, selected from the series comprising halogen, cyano, nitro and C1-C4alkoxy, phenyl, substituted by two substituents, which may be the same or different, selected from the series comprising halogen, cyano, hydroxy, C1-C4alkoxy, C1-C4alkyl, C1-C4haloalkyl and nitro, or phenyl, substituted three what zamestitelyami, which may be the same or different, selected from the series comprising halogen, hydroxy, C1-C4alkoxy and C1-C4alkoxycarbonyl,

R1denotes hydrogen, C1-C4alkyl or C1-C4alkyl, substituted hydroxy-group, With3-C8cycloalkyl, phenyl, phenyl substituted With1-C4alkylsulfonamides, or 5 - or 6-membered heterocyclic aromatic group bearing one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and

n denotes 1 or 2.

5. The compound according to claim 1, where

Ar1denotes phenyl, substituted by fluorine or chlorine in paraprotein relative to the indicated carbonyl group,

Ar2denotes phenyl, substituted in anthopology relative to the specified-CH=CH-group1-C4alkoxygroup and paraprotein relatively1-C4alkoxygroup by cyano, halogen or1-C4alkoxygroup,

R1stands With1-C4alkyl, substituted hydroxy-group, phenyl, phenyl substituted With1-C4alkylsulfonamides, or 5 - or 6-membered heterocyclic aromatic group bearing one or two ring heteroatoms selected from nitrogen, oxygen and sulfur, and

n the hereafter which includes 1.

6. The compound according to claim 1 of the formula

in free form or in salt form,

where Ra' denotes hydrogen and Ra, Rb, Rc, Rd, Re, Rg and Rf have the values listed in the following table,

CN
RaRbRcRdReRfRg
FNNCNHHH
FNCNHHH
FNCNHHH
FOch2CH3HHBrH
FNNCNOch3HH
FNOch3HHOch3H
FNOch3HHBrH
FCNHHH
FOch3HHBrH
FNHEHHClH
FNOch3HHFH
ClNOch3HHBrH
FNOch3HHCNH
FNOch3HHClH
FNOch2CH3HHClH
FNO(CH2)2CH3HHClH
FNHHClH
FNO(CH2)2CH3HHBrH
FNHHBrH
FNOch3HHCH3H
FNHHCH3H
FHNNCNN
FOch3NNOch3N
FOch3NNBrN
FHNNCNN
FOch3NNOch3N
FOch3NNCNN
FOch3 NNBrN
FOch3NNCNN
FOch3NNCNN
FHNNCH3NN
FHFFFFF
FHNCF3NCF3N
FHNNO2NNN
FHNSOON3Och3NOch3
FOch3NNCNN
ClOch3NNCNN
FNNNN
ClOch3NNClN
ClHOch3NNCNN
FOch3NNBrN
ClOch3NNBrN
FOch3NNCNN
FOch3NNCNN

or where Ra and Ra' denotes fluorine, Rb, Rd, Re and Rg denote hydrogen, Rc denotes methoxy, and Rf denotes bromine.

7. The method of obtaining compounds of formula I, including interaction of the compounds of formula

with the compound of the formula

or amide forming derivative,

where Ar1, Ar2, R1and n are specified in claim 1 value is,

with subsequent isolation of the target product in free form or in salt form.



 

Same patents:

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes new substituted derivatives of pyrazole of the general formula (I): wherein n = 0 or 1; group A represents independently hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms or phenyl group having substituting groups optionally; group D represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkoxy-group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms, halogen atom, alkoxycarbonyl group with 1-4 carbon atoms, alkylsulfonyl group with 1-4 carbon atoms or phenyl group; group E represents hydrogen atom, halogen atom or phenyl group; groups R1 and R2 both represent halogen atom; group R3 represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms or benzyl group; groups R4 and R5 are similar or different and each represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-8 carbon atoms that can be substituted with alkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms, cyanomethyl group or phenyl group; or each R4 and R5 group means benzyl group; or each R4 and R5 group represents α- or β-phenethyl group having substituting groups at benzyl ring optionally. Indicated substituting groups represent alkoxy-groups with 1-4 carbon atoms wherein indicated substituting groups substitute hydrogen atom at the arbitrary positions 0-2 of the benzyl ring; or groups R4 and R5 form in common 5-membered or 6-membered aliphatic ring wherein the indicated ring can be substituted with alkyl groups with 1-4 carbon atoms and indicated ring can comprise one or two heteroatoms chosen from nitrogen oxygen and sulfur atom, and a method for their preparing. Also, invention describes herbicide compositions based on compound of the formula (I). Invention provides preparing herbicide compositions showing the strong herbicide effect and broad herbicide spectrum of their effect.

EFFECT: improved preparing method, valuable properties of derivatives and compositions.

7 cl, 6 tbl, 3 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to a new biologically active compound of 4-oxoquinoline that is useful as an anti-HIV agent and to its pharmaceutically acceptable salt. Invention describes an anti-HIV agent comprising compound of 4-oxoquinoline represented by the following formula [I] or its pharmaceutically acceptable salt as an active component wherein ring Cy represents phenyl group, naphthyl group or pyridyl group and each this group is substituted optionally with 1-5 substituted chosen from the following group A wherein A represents the group consisting of cyano-group, phenyl group, nitro-group, halogen atom, (C1-C4)-alkyl group, halogen-(C1-C4)-alkyl group, halogen-(C1-C4)-alkoxy-group, -ORa1, -SRa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -NRa1CORa3, -SO2Ra3, -NRa1SO2Ra3 and -COORa1 wherein Ra1 and Ra2 are similar or different and each represents hydrogen atom, (C1-C4)-alkyl group or benzyl group, and Ra3 represents (C1-C4)-alkyl group; R1 represent a substitute chosen from the following group B, or (C1-C10)-alkyl group optionally substituted with 1-3 substitutes chosen from halogen atom and the following group B wherein the group B represents the group consisting of phenyl group optionally substituted with phenyl group or 1-5 halogen atoms; (C3-C6)-cycloalkyl group, imidazolyl group, benzothiophenyl group, thiazolyl group optionally substituted with 1-3 (C1-C6)-alkyl groups, morpholinyl group, pyridyl group, -ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4 and -NRa5COORa6 wherein Ra4 and Ra5 are similar or different and each represents hydrogen atom, (C1-C4)-alkyl group or phenyl group; Ra6 represents (C1-C4)-alkyl group; R2 represents hydrogen atom or (C1-C4)-alkyl group; R31 represents hydrogen atom, cyano-group, hydroxy-group, halogen atom or (C1-C4)-alkoxy-group; X represents -C-R32, and Y represents -C-R33 or nitrogen atom wherein R32 and R33 are similar or different and each represents hydrogen atom, cyano-group, halogen atom, pyrrolidinyl group, (C1-C10)-alkyl group optionally substituted with 1-3 halogen atoms, -ORa7, -SRa7, -NRa7Ra8, -NRa7CORa9, -COORa10 or -N=CH-NRa10Ra11 wherein Ra7 and Ra8 are similar or different and each represents hydrogen atom, phenyl group or (C1-C10)-alkyl group optionally substituted with (C3-C6)-cycloalkyl group or hydroxy-group; Ra9 represents (C1-C4)-alkyl group and Ra10 and Ra11 are similar or different and each represents hydrogen atom or (C1-C4)-alkyl group. Also, invention describes compound of the formula (III) given in the invention description, integrase inhibitor, antiviral agent, ant-HIV composition, anti-HIV agent, using compound of 4-oxoqionoline, method for inhibition of integrase activity, method for prophylaxis or treatment of viral infectious disease, pharmaceutical composition used for inhibition of integrase activity, antiviral composition and commercial package (variants). Invention provides the development of a pharmaceutical agent possessing inhibitory effect on activity of integrase.

EFFECT: valuable medicinal properties of compound, agent and composition.

40 cl, 7 tbl, 250 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing heterocyclic compounds describing by the general formula (I): . Invention describes a method for preparing compounds of the formula (I) wherein R1 represents hydrogen atom or alkyl group; A represents ethylene group that can be substituted with alkyl or trimethylene group that can be substituted with alkyl; D represents nitro- or cyano-group; X represents oxygen or sulfur atom, or the group of the formula: or wherein R3 represents hydrogen atom or alkyl group; Z represents 2-chloropyrid-5-yl. Method involves interaction of compound of the formula (II): wherein A, D and X abovementioned values with a base in the presence of diluting agent followed by interaction of the reaction mixture with a mixture consisting of 2-chloro-5-chloromethylpyridine/2-chloro-5-methylpyridine with corresponding hydrochlorides.

EFFECT: simplified technology, enhanced yield of end product.

4 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to water-soluble azole compounds that can be used in biology and medicine. Invention describes a water-soluble azole compound of the formula (I):

or its pharmaceutically acceptable salt wherein each R and R1 means independently hydrogen atom or (C1-C6)-alkyl; A means group of the formula:

wherein R3 represents phenyl group with one or more halide atoms as substitutes; R4 represents hydrogen atom or -CH3; R5 represents hydrogen atom or in common with R4 it can represent =CH2; R6 represents 5- or 6-membered nitrogen-containing cycle that can comprise if necessary as substituted one or more groups taken among halogen atom, =O group, phenyl substituted with one or more groups taken among -CN, -(C6H4)-OCH2-CF2-CHF2 and -CH=CH-(C6H4)-OCH2-CF2-CHF2 or phenyl substituted with one or more groups taken among halogen atom and methylpyrazolyl group. Also, invention describes a method for preparing a water-soluble azole compound. Invention provides preparing new compounds that can be useful in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing compound of the formula: . Method involves interaction of compound of the formula: with compound of the formula: wherein Q means chlorine or bromine atom in the presence of solvent or diluting agent, an interphase catalyst and a base wherein solvent or diluting agent represent carbonic acid esters, an interphase catalyst represents ammonium quaternary salt, and a base represents carbonate. Method provides inhibition of process in formation of undesirable isomers.

EFFECT: improved preparing method.

1 cl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to epothilones with modified thiazole substituent, methods for production thereof and pharmaceutical composition capable of cell growth inhibiting containing the same. Claimed compounds have general formula I , wherein P-Q represents double carbon bond or epoxy; R represents H, C1-C6-alkyl; G represents ; R1 represents and ; G1 and G2 represent hydrogen; G3 represents O, S, and NZ1; G4 represents H, optionally substituted C1-C6-alkyl, OZ2, Z2C=O and Z4SO2; G5 represents halogen, N3, CN, NC, heteroaryl containing nitrogen or oxygen, and heterocycle; G6 represents H, C1-C6-alkyl, or OZ5, wherein Z5 represents H, C1-C6-alkyl; G9 represents oxygen; Z1 represents H, optionally substituted C1-C6-alkyl, optionally substituted acyl; Z2 represents optionally substituted C1-C6-alkyl or aryl; Z4 represents optionally substituted aryl.

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to new type of compounds representing crown-containing styryl dyes with ammonium group at N-substitute of heterocyclic residue that can be used as photo- and thermosensitive compounds. Invention describes new crown-containing styryl dyes with ammonium group at N-substitute of a heterocyclic residue. Also, invention describes two variants of the method for their preparing. The first method is based on the interaction of a heterocyclic base quaternary salt with formyl derivative of the corresponding crown-compound, and the second method involves quaternization reaction of crown-containing heteroarylphenylethylene at heterocycle nitrogen atom. Proposed crown-containing styryl dyes are prepared from available raw with high yield and represent compounds of the new type able to stereospecific reactions [2 + 2], i. e. photocyclo-addition and possessing thermochromism properties.

EFFECT: improved preparing methods, valuable properties of dyes.

4 cl, 4 dwg, 16 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes new substituted derivatives of pyrazole of the general formula (I): wherein n = 0 or 1; group A represents independently hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms or phenyl group having substituting groups optionally; group D represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkoxy-group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms, halogen atom, alkoxycarbonyl group with 1-4 carbon atoms, alkylsulfonyl group with 1-4 carbon atoms or phenyl group; group E represents hydrogen atom, halogen atom or phenyl group; groups R1 and R2 both represent halogen atom; group R3 represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms or benzyl group; groups R4 and R5 are similar or different and each represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-8 carbon atoms that can be substituted with alkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms, cyanomethyl group or phenyl group; or each R4 and R5 group means benzyl group; or each R4 and R5 group represents α- or β-phenethyl group having substituting groups at benzyl ring optionally. Indicated substituting groups represent alkoxy-groups with 1-4 carbon atoms wherein indicated substituting groups substitute hydrogen atom at the arbitrary positions 0-2 of the benzyl ring; or groups R4 and R5 form in common 5-membered or 6-membered aliphatic ring wherein the indicated ring can be substituted with alkyl groups with 1-4 carbon atoms and indicated ring can comprise one or two heteroatoms chosen from nitrogen oxygen and sulfur atom, and a method for their preparing. Also, invention describes herbicide compositions based on compound of the formula (I). Invention provides preparing herbicide compositions showing the strong herbicide effect and broad herbicide spectrum of their effect.

EFFECT: improved preparing method, valuable properties of derivatives and compositions.

7 cl, 6 tbl, 3 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes derivative of 3,4-dihydroisoquinoline of the formula (I) or its nontoxic salt and a pharmaceutical agent comprising its as an active component (wherein all symbols have the same values as given in description). Compound of the formula (I) possesses agonistic effect on CB2-receptors and, therefore, it can be used for prophylaxis and/or treatment of different diseases, for example, asthma, nasal allergy, atopic dermatitis, autoimmune diseases, rheumatic arthritis, immune dysfunction, postoperative pain and carcinomatous pain.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 33 tbl, 561 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of sulfonylpyrrolidine of the formula (I): wherein R1 means aryl optionally substituted with halogen atom; R2 means aryl optionally substituted with halogen atom or (lower)-alkyl; R3 means -OR', cyano-group, halogen atom, N-hydroxyamidino-group, -C(O)-OR, -C(O)NR'R'', -N(R')-C(O)-R4, -N(R')-S(O)2-R, -N(R')-C(S)-NR'R, or 5- or 6-membered heteroaryl group comprising from 1 to 4 heteroatoms one of that represents oxygen atom and others represent nitrogen atom, or all heteroatoms represent nitrogen atom only and optionally substituted with (lower)-alkyl or (C3-C7)-cycloalkyl; R4 means (C3-C7)-cycloalkyl, phenyl or (lower)-alkyl that are optionally substituted with halogen atom; R means (lower)-alkyl; R' means hydrogen atom (H), (lower)-alkyl or (C3-C7)-cycloalkyl-(lower)-alkyl being independently of one another if above one R' presents; R'' means H, (lower)-alkyl; n means a whole number from 0 to 5, and to their pharmaceutically acceptable salts under condition that 1-[4-(methylphenyl)sulfonyl]-5-phenylpyrrolidinemethanol is excluded. Compounds of the formula (I) possess affinity to metabotropic glutamate receptors of group I that allows their using as a medicinal agent in treatment, prophylaxis of acute and/or chronic neurological disturbances and states that result to development of glutamate insufficiency taken among the following disorders: damage of spinal cord, head trauma, hypoxia caused by pregnancy, hypoglycemia, Alzheimer's disease, Huntington chorea, amyotrophic lateral sclerosis, disturbance in cognitive ability, memory disturbance and chronic and acute pain, schizophrenia, idiopathic parkinsonism and parkinsonism caused by medicinal agents, convulsions, anxiety (fear) and depressions.

EFFECT: valuable medicinal properties of compounds.

21 cl, 6 sch, 1 tbl, 153 ex

Muscarinic agonists // 2269523

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein Z1 represents -CR1 or nitrogen atom (N); Z2 represents -CR2; Z3 represents -CR3 or N; Z4 represents -CR4; W1 represents oxygen (O), sulfur (S) atom or -NR5; one of W2 and W3 represents N or -CR6 and another among W2 and W3 represents CG; W1 represents NG; W2 represents -CR5 or N; W3 represents -CR6 or N; or W1 and W3 represent N and W2 represents NG; G represents compound of the formula (II): wherein Y represents oxygen atom (O), -C(O)- or absent; p = 1, 2, 3, 4 or 5; Z is absent; each t = 2. Also, invention describes a method for enhancing activity of the muscarinic cholinergic receptor and a method for treatment of morbid states when modification of cholinergic and, especially, muscarinic receptors m1, m4 or both m1 and m4 offers the favorable effect.

EFFECT: valuable medicinal properties of agonists.

14 cl, 2 tbl, 101 ex

FIELD: organic chemistry, chemical technology, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of propene carboxylic acid amidooximes of the formula (I):

wherein R means phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R' means hydrogen atom (H); R4 and R5 mean independently of one another H, (C1-C5)-alkyl, phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; or R4 and R5 in common with adjacent nitrogen atom form 5- or 6-membered saturated or unsaturated heterocyclic group that can comprise additional nitrogen atom or oxygen atom as a heteroatom and it can be condensed with benzene ring, and heterocyclic group and/or benzene ring can comprise one or two substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R1 and R2 mean H; R3 means H, OH; or R1 in common with R2 forms carbonyl group wherein carbon atom is joined with oxygen atom adjacent with R1 and with nitrogen atom adjacent with R2; R3 means H, OH; or R2 means H; and R1 in common with R3 form a valence bond between oxygen atom adjacent with R1 and carbon atom adjacent with R3; and its geometric isomers and/or optical isomers, and/or its pharmaceutically acceptable acid-additive salts. Compounds of the formula (I) inhibit activity of poly(adenisone diphosphate ribose) polymerase and can be used in pharmaceutical composition in treatment of states based on inhibition of this enzyme activity, and in treatment of states associated with oxygen insufficiency of heart and brain. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

9 cl, 1 tbl, 41 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of aroylpiperazine of the formula (I):

wherein Y means lower alkylene; R1 means phenyl with 1 or 2 substitutes taken among group consisting of trihalogen-(lower)-alkyl, halogen atom, lower alkylamino-, di-(lower)-alkylamino- and nitro-group; R2 means phenyl or indolyl and each comprises 1 or 2 substitutes taken among group consisting of lower alkyl, trihalogen-(lower)-alkyl, lower alkylene dioxy-, hydroxy-group, hydroxy-(lower)-alkyl, lower alkoxy- lower alkylamino- and di-(lower)-alkylamino-group; R3 means hydrogen atom; R4 means morpholinyl-(lower)-alkyl comprising 1 or 2 substitutes taken among group consisting of ethyl, hydroxy-(lower)-alkyl, halogen-(lower)-alkyl and lower alkoxy-(lower)-alkyl, or morpholinyl-(lower)-alkynyl that can comprise 1 or 2 substitutes taken among group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo-(lower)-alkyl, lower alkoxy-(lower)-alkyl, hydroxy-(lower)-alkyl, carboxy-(lower)-alkyl, di-(lower)-alkyl-carbamoyl, lower alkoxycarbonyl and halogen-(lower)-alkyl. Also, invention relates to a method for preparing, pharmaceutical composition based on these compounds and a method for treatment of tachykinine-mediated diseases, such as respiratory diseases, ophthalmic, cutaneous, inflammatory diseases, and as analgetic agents. Describes compounds are antagonists of tachykinine.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 94 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula (I): wherein Y represents lower alkylene; R1 represents phenyl substituted with one or two similar or different substitutes taken among a group including lower alkoxy-group, mono- (or di-, or tri-)-halogen-lower)-alkyl, nitro-, amino-, lower alkylamino-, di-(lower)-alkylamino-, lower alkylthio-group,alkylsulfonyl, lower alkylaminosulfonyl, di-(lower)-alkylaminosulfonyl, and pyrrolyl; R2 means phenyl substituted with hydroxy-group at position 3 and with lower alkyl and halogen atom additionally; R3 means hydrogen atom; R4 represents (2,6-dimethylmorpholino)-(lower)-alkyl, (2-methoxymethylmorpholino)-(lower)-alkyl, (3-methoxymethylmorpholino)-(lower)-alkyl. Also, invention relates to their pharmaceutically acceptable salts, to method for their preparing, pharmaceutical composition and a method for vomiting inhibition. Proposed compounds are antagonists of tachykinin and can be used for vomiting inhibition.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

9 cl, 47 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to new type of compounds representing crown-containing styryl dyes with ammonium group at N-substitute of heterocyclic residue that can be used as photo- and thermosensitive compounds. Invention describes new crown-containing styryl dyes with ammonium group at N-substitute of a heterocyclic residue. Also, invention describes two variants of the method for their preparing. The first method is based on the interaction of a heterocyclic base quaternary salt with formyl derivative of the corresponding crown-compound, and the second method involves quaternization reaction of crown-containing heteroarylphenylethylene at heterocycle nitrogen atom. Proposed crown-containing styryl dyes are prepared from available raw with high yield and represent compounds of the new type able to stereospecific reactions [2 + 2], i. e. photocyclo-addition and possessing thermochromism properties.

EFFECT: improved preparing methods, valuable properties of dyes.

4 cl, 4 dwg, 16 ex

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