Substituted 5-sulfo-2-oxo-1,2-dihydroquinoline 4-carboxylic acids and their derivatives (variants) and focused library

FIELD: organic chemistry, chemical technology, biochemistry.

SUBSTANCE: invention relates to new substituted 6-sulfo-2-oxo-1,2-dihydroquinoline 4-carboxylic acids and their derivatives of the general formula (1):

eliciting physiological activity, in particular, capacity to inhibit activity of protein kinase, and also to intermediate compounds for their preparing and to the focused library, for search compound-leaders and medicinal candidates obtaining on the basis of screening combinatory libraries. In compounds of the general formula (1) R1 represents hydrogen atom or electrophilic substitute; R2 represents hydrogen atom or inert substitute; R3 represents optionally substituted hydroxyl group, optionally substituted amino-group and optionally substituted azaheterocycle; R4 represents optionally substituted amino-group and optionally substituted azaheterocycle. Also, invention relates to compounds of the general formula (1.1):

wherein R1, R2 and R3 have above given values; R5 represents hydroxyl or chlorine atom, and to their applying for preparing compounds of the general formula (1.2):

and (1.3):

wherein R1, R2 and R4 have above given values.

EFFECT: valuable medicinal and biochemical properties of compounds.

6 cl, 4 tbl, 5 ex

 

This invention relates to new chemical substances and new physiologically active substances, compounds leaders and drug candidates (drug-candidates)that can be derived from the screening of combinatorial libraries, as well as to methods for novel compounds and combinatorial libraries.

More specifically, the present invention relates to new substituted 6-sulfo-2-oxo-1,2-dihydroquinoline-4-carboxylic acids and focused library of compounds in this series.

There are a large number of physiologically active substances of class, quinoline-4-carboxylic acids having antibacterial, anti-inflammatory, immunomodulatory and other properties, for Example, amides of the quinoline-4-carboxylic acids of the following structure:

are antagonists tachykinins (Tachykinin NK2 and/or NK3) receptors and possess a wide spectrum of physiological activity, which allows to consider them as potential analgesic, anti-inflammatory, anti-arthritis, immunomodulatory drugs (GlaxoSmithKline SpA; Laboratoire GlaxoSmithKline SAS. WO 0238547, 2002).

2-Oxo-1,2-dihydroquinoline-4-carboxylic acids and their derivatives have biological activity, for example, are 5-NT3, NMDA receptors and AT1 antagonists. For example, 1-alkyl-2-oxo-1,2-dihydroquinoline-4-carboxylates, one of the categories below are 5-NT3 antagonists (Kyowa Hakko Kogyo Co., Ltd. Jap. Pat. 1992226980,1992; Pat. EP 0458636).

Known to only a few representatives of substituted 6-sulfo-2-oxo-1,2-dihydroquinoline-4-carboxylic acids, including: 6-diethylcarbamoyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid [Database Chemcats of STN, (AN) 2003, 2884896, No. 438029-22-2, publ. 15.11.2001] and 6-(2-methoxyphenylacetyl)-2-oxo-1,2-dihydroquinoline-4-carboxylic acid [Database Chemcats of STN, (AN) 2002, 288889, No. 379730-31-1, publ. 15.11.2001]. In the patent DE 19613591 A1 (1997) among the proposed quinoline derivatives and the method of their derivation are mentioned and derivatives of 2-oxo-6-alufoil-1,2-dihydroquinoline-4-carboxylic acid, however, in the description, there is at least one example of a specific connection that match the specified General formula

In this regard, the design of the new 6-sulfamoylbenzoic-4-carboxylic acids and their derivatives, synthesis of new physiologically active substances in this series, the development of methods of their production and the creation of combinatorial libraries of these compounds is a promising approach to the discovery of new compounds leaders with high affinity to tachykinin receptors and deprived side of the property.

This invention relates to new substituted 6-is ULFO-2-oxo-1,2-dihydroquinoline-4-carboxylic acid and focused library of compounds in this series, possessing physiological activity, including specific physiological activity, allowing their use as inhibitors of serine proteases and kinases, as well as allowing their use as intermediates for the synthesis of substituted 6-sulfamoyl - and 6-oxycarbonyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acids and their derivatives. Below are definitions of terms used in the description.

"Combinatorial library" means a collection of compounds obtained by parallel synthesis and designed for search leader or optimize the biological activity of lead compounds, with each compound of the library meets the General scaffold and the library is a collection of related homologues or analogues.

"Focused library" means a combinatorial library, or a combination of several combinatorial library, or a set of libraries and substances, specially organized for the purpose of increasing the probability of finding hits and leaders, or to improve the efficiency of their optimization. The design of focused libraries, typically associated with directional search effectors (inhibitors, activators, agonists, antagonists, etc.) certain biological targets (enzymes, receptors, ion channels, and so on).

"Lead compound" who appoints connection with outstanding activity related to a particular disease.

"Scaffold" means the General structural formula or molecular skeleton or invariant connections area common to all compounds included in the combinatorial library.

"Gametip" means a series of compounds having a common structural formula, and with a certain common property, such as some form fiziologicheskii activity. We can say, for example, "new gametip activators of potassium channels", or "known gametip kinase inhibitors", etc. As a rule, the presence of common structural fragment of compounds within one chemotype is a necessary and sufficient condition for the existence of common properties.

"Nucleophilic" means elektronoizbytochnye reagent.

"Electrophilic" means electron reagent.

"Deputy" means a chemical moiety or group that is attached to another moiety or group to scaffold, including, but not limited to the halogen atom, the "inert Deputy", the nitrogroup, alphagroup, a sulfa group, hydroxyl group, amino group, carboxialkilnuyu group, alkoxycarbonyl group, karbamoilnuyu group and others

"Inert Deputy" ("Non-interfering substituent"means low or directionspanel radical inert to further transformations and to the rede including, but not limited to C1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl, substituted aralkyl,7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C2-C12alkoxyalkyl, C2-C10alkylsulfonyl, C2-C10alkylsulfonyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted aryl, substituted alkoxy, foralkyl, aryloxyalkyl, heterocyclyl, substituted heterocyclyl and nitroalkyl; where m and n have a value from 1 to 7. Preferred inert substituents are C1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)m, aryl, substituted aryl, heterocyclyl and substituted heterocyclyl.

"Nucleophilic Deputy" means a chemical moiety that is attached to scaffold as a result, reaction nucleophilic reagent, for example, selected from the group of primary or secondary amines, alcohols, phenols, mercaptans and thiophenols.

"Electrophilic Deputy" means a chemical moiety that is attached to scaffold as a result of reaction with an electrophilic reagent, for example, selected from the group of organic halides (optionally substituted C1-C7alkyl halides, optionally substituted aryls1-C7alkyl halides, optionally substituted heterocyclyl1-C7alkyl halides, optionally substituted aryl halides, optionally substituted heterocyclyl halides), organic acids or their derivatives (anhydrides, imidazolides, halides, esters of organic sulfonic acids or organic sulfochlorides, organic halogenfree, organic isocyanates and organic isothioscyanates.

"Substituted group, substituted radical or scaffold" means, respectively, group, radical or scaffold, have a Deputy, including but not limited to inert Deputy, a halogen atom, a nitro-group, a cyano, alphagroup, hydroxyl group, amino group, carboxialkilnuyu group, carboxyl group, karbamoilnuyu group. For example, substituted alkyl means alkyl with one or more substituents, e.g. the measures hydroxyalkyl or methoxycarbonylethyl, amino-methoxycarbonyl-methyl, dimethylaminoethyl, 2-hydroxy-2-methoxycarbonyl-ethyl and others; substituted amino group means an amino group which has one or two substituent, such as alluminare, N,N-dialkylamino, N-acyl-N-aryl-amino group, acetyl-methoxycarbonylmethyl-amino group and others; substituted phenyl means phenyl, which has one or more substituents, such as 2-ethoxycarbonylphenyl, 4-amino-3-ethoxycarbonylphenyl, 3,4-diaminophenyl and other

"Optionally substituted group optionally substituted radical or scaffold" means a group, the radical or scaffold, including groups, radicals or scaffold with deputies and without deputies. For example, the concept of optional substituted amino group includes an unsubstituted amino group and amino group containing any, not inconsistent with chemistry substituents, including, but not limited to alluminare, N,N-dialkylamino, N-acyl-N-aryl-amino, acyl-methoxycarbonylmethyl-amino group and others

"Aryl" means one or more aromatic cycles, each of which contains 5 or 6 carbon atoms. "Aryl" may be condensed political, such as naphthalene, or unfused, such as biphenyl.

"Substituted aryl" has one or more "not interfering" deputies.

"Halogen"means a fluorine atom, chlorine, bromine or iodine.

"Heterocycle" means one or more saturated or aromatic cycles with 5, 6 or 7 atoms, at least one of which is a heteroatom. Preferred heteroatoms are sulfur, oxygen and nitrogen. "Heterocycle" may be condensed political, such as benzimidazole, benzoxazole, benzthiazole, quinoline, or unfused, for example, as bipyridyl.

"Azaheterocycle" means a heterocycle comprising at least one nitrogen atom, such as benzimidazole, benzoxazole, benzthiazole, quinoline.

"Substituted heterocycle" means a heterocycle having one or more "not interfering" deputies.

"Parallel synthesis" means a method for chemical synthesis of combinatorial libraries of individual connections.

The aim of the present invention is a new substituted 6-sulfo-2-oxo-1,2-dihydroquinoline-4-carboxylic acid.

This goal is achieved substituted 6-sulfo-2-oxo-1,2-dihydroquinoline-4-carboxylic acids and their derivatives of the General formula (1):

in which:

R1represents: a hydrogen atom, an inert Deputy or electrophilic Deputy;

R2represents: a hydrogen atom or an inert Deputy;

R3is not necessarily Thames is nnow hydroxyl group, optionally substituted by an amino group or optionally substituted azaheterocycle;

R4is: optionally substituted by an amino group or optionally substituted azaheterocycle, excluding 6-diethylcarbamoyl-1-methyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, 6-(3-methoxybenzenesulfonyl)-1-methyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid and compounds of General formula 1 for which R4mean NH2.

This goal is achieved substituted 6-sulfo-2-oxo-1,2-dihydroquinoline-4-carboxylic acids and their derivatives of General formula (1.1)

which R1, R2and R3have the above significance, and R5is hydroxyl or chlorine atom.

According to the invention the preferred new compounds are substituted 6-chlorosulfonyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acids and their derivatives of General formula (1.1.1)

in which R1, R2and R3have the above value.

According to the invention the preferred new compounds are substituted 6-sulfamoyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid of General formula (1.2)

in which R1, R2and R4have the above value.

According to the invention p is impactfully new compounds are substituted 6-sulfo-2-oxo-1,2-dihydroquinoline-4-carboxylic acids and their derivatives of General formula (1.3)

which R1, R3and R4have the above value.

According to the invention compounds of General formula (1.1 and 1.1.1) is used as intermediates for the synthesis of substituted 6-sulfo-2-oxo-1,2-dihydroquinoline-4-carboxylic acids and their derivatives of General formula (1.2) and (1.3).

The aim of the present invention is also a new focused library of compounds to search for bioactive lead.

This goal is achieved by the focused library of compounds to search for bioactive lead comprising at least one compound of General formula (1)in which R1, R2, R3and R4have the above value.

Below the invention is described using specific examples of the preparation of specific compounds and combinatorial libraries. The structure of the obtained compounds was confirmed by the data of chemical, chromatographic and spectral analysis. Liquid-phase concurrent sites new compounds and combinatorial libraries was carried out using a special synths "CombiSyn-012-3000" [M. Baru, A. Ivashchenko, Patent of Russia 2180609, 2002; PCT WO 02/087740 A1, 2002] and equipment [Technology Platform. In Custom Chemistry; Chemical Diversity Labs, Inc.; San Diego, CA, 2002; p.5, http://www.chemdiv.com.]. The following examples illustrate but do not limit this image is giving.

General information. All solvents and reagents were obtained from commercial sources, such as ACROS (Belgium), Sigma-Aldrich (USA), Lancaster (England) and Chemdiv (USA). The melting point (TPL) were obtained on the instrument company Buchi (Switzerland) model-520.13The NMR spectra were obtained on a spectrometer of the company Bruker model AM-300 and model DRX-500 in dimethyl sulfoxide-d6chemical shifts are given in the scale δ (ppm). The internal standard tetramethylsilane was. Mass spectra were measured on a device Kratos Model MS-890.

Analytical TLC was performed on silica gel on aluminium plates Silufol UV254(5 cm × 15 cm) (Kavalier, Czech Republic) or on glass slides with a 0.25 - mm layer of silica gel 60 F254 (Merck, Germany). Visualization was accomplished with UV light at a wavelength of 254 nm. For chromatographic purification of used silica gel 5-40 μm (Chemapol, Czech Republic). In accordance with these LC/MS all the synthesized compounds had a basic substance content above 95%.

Examples 1. Ethyl 6-chlorosulfonyl-2-oxo-1,2-dihydro-4-quinoline-carboxylate (1.1: R1=R2=H, R3=OC2H5). Gradually add 54 g (0.25 mol) of ethyl 2-oxo-1,2-dihydro-4-chinainternational (obtained by the method: Org. Synthesis, 1947, 28, p.70) in 100 ml of chlorosulfonic acid. The reaction mass is stirred for 1 h at room temperature, and then 5 h at 50-60#x000B0; C. the Reaction mass is gradually poured into ice, the precipitate is filtered off, washed twice on the filter with ice water and dried in vacuum. The resulting product is recrystallized from glacial acetic acid and obtain ethyl 6-chlorosulfonyl-2-oxo-1,2-dihydro-4-chinainternational (1.1: R1=R2=H, R3=OC2H5) as white prisms.

Examples 2. Combinatorial library 6-sulfamoyl-2-oxo-1,2-dihydro-4-quinoline-carboxylic acid (1.2 {1-11}). Parallel synthesis of combinatorial libraries spend synthesizer "CombiSyn-012-3000". In each of the 11 reactors synthesizer load in 25 ml of water, 0.24 g of NaOH, 0,006 mol of the corresponding amine and 1.58 g (0,005 mol) 6-chlorosulfonyl-2-oxo-1,2-dihydro-4-chinainternational (1.1: R1=R2=H, R3=OS2H5). The reaction mass is stirred for 3 h at room temperature, after which add more to 0.48 g (0.012 mol) of NaOH and 25 ml of ethanol and boiled for 1 h the Reaction mixture evaporated in vacuum to dryness, and the residue is dissolved in 15 ml of water and with stirring, add 20% H2SO4to pH=5. The precipitation is filtered off, washed on the filter with water and dried in vacuum over P2About5. The obtained precipitation was washed with boiling ethyl acetate, filtered and dried. Get 6-sulfamoyl-2-oxo-1,2-dihydro-4-quinoline-carboxylic acid 1.2{1-11}, exit elm), 65-78%, are presented in Table 1.

Examples . Combinatorial library 6-sulfamoyl-2-oxo-1,2-dihydro-4-chinainternational 1.3 {1-480}. Dissolve 300 mol 6-sulfamoyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid 1.2 in 100 ml of DMF. To the resulting solution was gradually added of 49.4 g (305 mol) of carbonyldiimidazole, kept under stirring at room temperature for 10 min, and then incubated 3 h at 80-90°C. the resulting solution was diluted with dry DMF, 500 ml and loaded on a 5 ml 100 reaction tubes. In each reaction tube add 3.2 mol of the corresponding primary or secondary amine, dissolved in 3 ml of dry DMF. The reaction mixture incubated for 8 h under stirring at 75-80°C, then diluted with 50 ml of cold water. The precipitation is filtered off and recrystallized from a mixture of ethanol-DMF). Get 6-sulfamoyl-2-oxo-1,2-dihydro-4-chinainternational 1.3, with a yield of 60-80%are presented in Table 2.

Examples 4. Be focused library, including 538 6-sulfonylamino, including 491 synthesized 6-sulfanylhexan-4-carboxylic acids and their derivatives of General formula (1.2 and 1.3), and have it on antiprotease activity. Antiprotease activity determined by the serine protease (Caspase 3), which are involved in the regulation of programmed cell death (apoptosis). The activity of Caspase 3 is determined by the speed of the split is I peptide substrate, containing fluorescent molecule (methylcoumarin). Removal methylcoumarin from the peptide molecules in the proteolytic reaction of the enzyme is accompanied by increased fluorescence intensity measurements which are produced using fluorescent parallel reader VICTOR2V (PerkinElmer, USA) at a wavelength of excitation of 355 nm and the wavelength of emission of 460 nm. For carrying out reactions using optical 96-hole of the blade. In experiments using caspase 3 and the fluorescent substrate of the company Sigma (USA). The reaction conditions and the composition of the medium used in accordance with the recommendation of the manufacturer. The original solutions of the test compounds prepared by dissolution in DMSO (dimethyl sulfoxide) to a concentration of 10 mm. The original solutions of compounds are added to a solution of the enzyme in such an amount to obtain a final concentration of 10 μm. After 10-minute incubation of the enzyme with the test compound to the solution was added an enzyme substrate and measuring the fluorescence spend later, 1 hour after addition of the substrate (Fie). For the correction on its own fluorescence of the tested compounds fluorescence measurement (Fi0) carried out in a separate circuit boards that do not contain enzyme reagents (enzyme plus substrate). Full enzyme activity by measuring the t fluorescence in the reaction wells, containing all reaction components except the test compounds (F100), and zero activity is determined by the fluorescence of the wells containing the appropriate test connection and all the reaction reagents except the enzyme (F0).

Calculation of inhibition was produced by the following formula:

where Fi=Fie-Fi0, subscript corresponds to the test compound, in the presence of which is measured fluorescence, and the superscripts (e) and (0) means the presence or absence of enzymatic reagents, respectively.

Some examples of the tested compounds showed at the screening of focused libraries moderate or low activity, are shown in Table 3.

Examples 5. Be focused library, including 538 6-sulfonylamino, including 491 synthesized 6-sulfanylhexan-4-carboxylic acids and their derivatives of General formula (1.2) and (1.3), and test its ability to inhibit the activity of protein kinases, which is determined as follows. The solution of the polypeptide (Calbiochem, USA), consisting of a random sequence of glutamic acid and tyrosine in the proportion 4:1, respectively, incubated in the wells of 96-hole plates with optically transparent bottom of the night. During this time, the polypeptide is firmly adsorbed on the surface of the hole. Adsorbed polypeptide is a substrate for the kinase, which was fosfaurilirovania tyrosine in this polypeptide.

100 microlitres 1U kinase (Calbiochem, USA, 1U is defined as the concentration of this enzyme is able to attach to the substrate 1 picomole phosphate for 1 minute) add to the wells with the adsorbed polypeptide without the test compounds (control activity) or in the presence of different concentrations of these compounds. After 30-minute incubation, these solutions are removed by shaking from the wells and the wells washed twice with saline. In wells pour 100 microliter solution antiphosphotyrosine monoclonal IGg antibodies conjugated with horseradish peroxidase from horseradish (Sigma, USA). The amount of bound peroxidase antibodies is determined by the activity of peroxidase, which, in turn, determined by the rate of conversion peroxidase substrate (OPD, phenolenediamine dihydrochloride, Sigma) into a colored product. The concentration of the product formed in 30 minutes of reaction, determined by optical density at 490 nm, measured using a parallel 96-well reader VICTOR2V (PerkinElmer, USA).

To calculate the percentage inhibition of kinase activity each 96-well plate contained the following control wells: 1) the reactions the config solution, containing all components except kinase and 2) the reaction solution together with the kinase. The optical density measured in control wells (1)is taken as the zero activity (OD0), and the optical density measured in control wells (2) - 100% (OD100). The optical density measured in the presence of test compounds (ODi), expressed in percentage of the maximum activity, and the percentage of inhibition of kinase activity are calculated according to the following formula:

Table 2 shows the values of inhibition of the ABL kinase, confirming the biological activity of 6-sulfanylhexan-4-carboxylic acids and their derivatives.

Thomasenia 6-sulfanylhexan-4-carboxylic acids and their derivatives of the General formula (1)

in which R1represents a hydrogen atom or an electrophilic Deputy;

R2represents a hydrogen atom or an inert Deputy;

R3is optionally substituted hydroxyl group, optionally substituted by an amino group and optionally substituted azaheterocycle;

R4is optionally substituted by an amino group and optionally substituted azaheterocycle, excluding 6-diethylcarbamoyl-1-methyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, 6-(3-methoxybenzenesulfonyl)-1-methyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, and compounds of General formula (1), for which R4mean NH2.

2. Substituted 6-sulfo-2-oxo-1,2-dihydroquinoline-4-carboxylic acids and their derivatives of General formula (1.1)

(1.1)

in which R1, R2and R3have the above meaning,

R5is hydroxyl or chlorine atom./p>

3. Compounds according to claim 1, represents a substituted 6-sulfamoyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid of General formula (1.2)

in which R1, R2and R4have the above value.

4. Compounds according to any one of claims 1 and 3, representing the substituted 6-sulfo-2-oxo-1,2-dihydroquinoline-4-carboxylic acids and their derivatives of General formula (1.3)

(1.3)

in which R1, R2and R4have the above value.

5. The use of substituted 6-sulfo-2-oxo-1,2-dihydroquinoline-4-carboxylic acids and their derivatives of General formula (1.1) as intermediates for the synthesis of substituted 6-sulfo-2-oxo-1,2-dihydroquinoline-4-carboxylic acids and their derivatives of General formula (1.2) or (1.3) according to claim 3 or 4.

6. Focused library of compounds to search for biologically active compounds leaders, including at least one compound of General formula (1)in which R1, R2, R3and R4have the above value.



 

Same patents:

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

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

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new flavone, xanthone and coumarone derivatives of formula I

[R and R1 each are independently lower C1-C6-alkyl or together with nitrogen atom attached thereto form 4-8-membered heterocycle, optionally containing one or more heteroatoms, selected from group comprising N or O, wherein said heterocycle is optionally substituted with benzyl; Z has formula (A) , wherein R3 and R4 each are independently hydrogen, optionally substituted aromatic group containing in cyclic structure from 5 to 10 carbon atoms, wherein substituents are the same or different and represent lower C1-C4-alkyl, OR10 (OR10 is hydrogen, saturated or unsaturated lower C1-C6-alkyl or formula ) or linear or branched C1-C6-hydrocarbon; or R2 and R3 together with carbon atom attached thereto form 5-6-membered carbocycle; and R4 represents hydrogen or attaching site of group –OCH2-C≡CCH2NRR1; or formula (B) , wherein R5 is hydrogen, linear or branched lower C1-C6-hydrocarbon, with the proviso, that when Z represents R and R1 both are not methyl or R and R1 together with nitrogen atom attached thereto cannot form groups , or ]. Also disclosed are drug component with proliferative activity for prophylaxis or treatment of neoplasm and pharmaceutical composition with proliferative activity based on the same. Derivatives of present invention have antyproliferative properties and are useful as modulators of drug resistance in cancer chemotherapy; as well as in pharmaceuticals for prophylaxis or treatment of neoplasm, climacteric disorders or osteoporosis.

EFFECT: new compounds with value bioactive effect.

31 cl, 2 tbl, 32 ex

FIELD: bioactive compounds.

SUBSTANCE: invention relates to new 3-phenyl-1,2,4-benzotriazines and their derivatives of general formula 1

wherein R1 and R2 are independently fluorine or C1-C4-alkoxy, optionally substituted with halogen or tetrahydrofuryl. Compounds of present invention are useful in treatment and prophylaxis of diseases, induced by pathogenic for human and animals viruses including pathogenic for human orthopoxviruses, as well as postvaccinal sequelae.

EFFECT: compounds with improved antiviral activity.

1 cl, 12 ex, 7 tbl

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of borrelidin of the general formula (I)

wherein R represents the group of the general formulae -COOR1, -CONR2R3, -CONR4CONR2R5 or -CH2OR6 wherein R1 represents (C2-C6)-alkyl group, (C1-C6)-alkyl group substituted with hydroxyl group or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprise oxygen atom in addition to nitrogen atom) or 5-6-membered nitrogen-containing aromatic heterocyclic group or (C3-C6)-cycloalkyl group; R2 and R3 are similar or different and represent independently hydrogen atom or (C1-C6)-alkyl group that can be substituted optionally with hydroxyl, (C2-C5)-alkoxycarbonyl or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprises oxygen atom in addition to nitrogen atom) or 5-6-membered aromatic homocyclic group or aromatic heterocyclic group comprising oxygen and/or nitrogen atom, 5-6-membered cycloalkyl or heteroaryl group; R4 and R5 are similar or different and represent independently hydrogen atom or (C3-C6)-cycloalkyl group; R6 represents hydrogen atom; also, invention relates to tautomers, solvates of these compounds, their mixtures and acid-additive salts. Also, invention relates to pharmaceutical compositions comprising compounds of the general formula (I) as an active component. Angiogenesis inhibitors of the present invention inhibit formation of new vessels in tissues of live organisms and can be used for prophylaxis and inhibition of the angiogenesis process arising in the tumor proliferation, and for prophylaxis of formation of tumor metastasis. Invention provides preparing new derivatives of borrelidin eliciting the value physiological effect.

EFFECT: valuable medicinal properties of compounds.

8 cl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I):

as a free form or salt wherein Ar means group of the formula (II):

wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.

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

13 cl, 3 tbl, 35 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

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

26 cl, 4 tbl, 476 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 relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

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

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

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

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of aminomethylpyrrolidine of the formula (I) , their salts or hydrates wherein R1 represents aryl with from 6 to 10 carbon atoms or heteroaryl wherein heteroaryl is a five-membered ring or a six-membered ring and comprises from 1 to 2 heteroatoms taken among nitrogen, oxygen and sulfur atom; aryl and heteroaryl can comprise one or more substitutes taken among the group consisting of halogen atom or (C1-C6)-alkoxyl; each radical among R2, R3, R4, R5, R6, R7 and R8 represents hydrogen atom (H) independently; Q represents incomplete structure representing by the following formula: wherein R9 means (C3-C6)-cyclic alkyl that can be substituted with halogen atom; R10 means hydrogen atom (H); R11 means hydrogen atom (H), NH2; X1 means halogen atom; A1 represents incomplete structure representing by the formula (II): wherein X2 means hydrogen atom (H), halogen atom, halogenmethoxyl group, (C1-C6)-alkyl or (C1-C6)-alkoxyl group; X2 and above indicated R9 can be combined to form the ring structure and inclusion part of the main skeleton and such formed ring comprises oxygen, nitrogen or sulfur atom as a component atom of the ring and the ring can comprise (C1-C6)-alkyl as a substitute; Y means hydrogen atom (H). Compounds of the formula (I) elicit an antibacterial effect and can be used for preparing a therapeutic agent.

EFFECT: valuable medicinal properties of compounds.

2 tbl, 61 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: organic chemistry and pharmaceutical compositions.

SUBSTANCE: invention relates to new 3-(5)-heteroaryl-substituted pyrazoles of formula I , tautomers or pharmaceutically acceptable salt of compounds and tautomers. In formula R1 is hydride, piperidinyl substituted with methyl, lower alkyl optionally substituted with halogen, hydroxyl, lower alkylanimo or morpholino; R2 is hydride, lower alkyl, amino, aminocarbonylamino, lower alkylaminocarbonylamino, lower alkylsulfonylamino, aminosulfonylamino, lower alkylaminosulfonylamino; Ar1 is phenyl optionally substituted with one or more independently selected halogen; HetAr2 is pyridinyl with the proviso that R2 is not amino or n-propyl when HetAr2 is pyridinyl; and HetAr2 is not 2-pyriridinyl when R2 is hydrogen or lower alkyl. Compounds of formula I have kinase p38 inhibitor activity and are useful in pharmaceutical compositions for treatment of various diseases.

EFFECT: new effective kinase p38 inhibitors.

23 cl, 6 dwg, 1 tbl, 1 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds.

15 cl, 2 sch, 3 tbl, 162 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new inhibitors of farnesyltransferase of the formula (I):

wherein R1 means hydrogen atom (H), group of the formula R5C(O)- wherein R5 means phenyl, pyridyl or N-methylpiperidine; R2 means hydrogen atom (H), isopropyl, cyclopentyl or N-methyltetrahydropyridyl; R3 means hydrogen atom (H), halogen atom; R4 means hydrogen atom (H), halogen atom; L means -CH2-Z- wherein Z means NH; Y means sulfur atom (S), S(O) or S(O)2; or its salt. Compounds of the formula (I) inhibit activity of enzyme, farnesyl(protein)transferase, that allows their using in pharmaceutical composition in cancer treatment.

EFFECT: valuable medicinal properties of inhibitors.

18 cl, 3 tbl, 3 sch, 6 ex

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