Anellated carbamoyl azaheterocycles, methods for their preparing (variants), pharmaceutical composition, focused library

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new anellated carbamoyl azaheterocycles of the general formula (1)

or (2) possessing the inhibitory effect on protein kinase activity, a focused library comprising these compounds, and pharmaceutical composition based on thereof. In the general formula (1) or (2) R1 represents hydrogen atom or optionally substituted (C1-C6)-alkyl; R2 and R3 represent independently of one another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; R4 represents optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; A and B in common with carbon and nitrogen atoms joined to the form an optionally substituted and optionally condensed azaheterocycle; D and F in common with carbon atoms joined form an optionally substituted and optionally condensed phenyl or aryl, optionally substituted and optionally condensed azaheterocycle. K and L in common with carbon and nitrogen atoms joined to them form an optionally substituted azaheterocycle. Also, invention related to methods for preparing compounds of the general formulae (1) or (2).

EFFECT: improved preparing methods.

10 cl, 2 sch, 25 tbl, 7 ex

 

This invention relates to the synthesis of new chemicals, the search for new physiologically active substances, compounds leaders and drug candidates that can be derived from the combinatorial or screening of focused libraries of compounds, and to pharmaceutical compositions, methods for their preparation and use.

More specifically, the present invention relates to new analyoung carbamoylaspartate of interest as a potential physiologically active substances (agonists, antagonists and modulators of receptors, enzyme inhibitors, oncolytic, antibacterial and antiparasitic agents and so on), to the focused library, including annelirovaniya carbamoylaspartate, pharmaceutical compositions containing as active substance annelirovaniya carbamoylaspartate, to methods for their preparation and use.

There are a large number of natural and synthetic physiologically active compounds whose molecules are annelirovaniya azaheterocycle. Among the natural it should be noted antineoplastics and antibacterial alkaloids languid, languid In and facilitative isolated from marine sponges Agelus genus, Homaxinella sp. and Phakellia mauritiana [Cafieri, F., et. al. J.Nat.Prod. 1998, 61: 122. Umeyama, A., et. al. J.Nat.Prod. 1998. 61: 1433. Poullennec K., Romo D. SoC. 2003, 25: 6344]

Synthetic annelirovaniya carbamoylaspartate exhibit an exceptionally wide range of physiological activity. For example, 4-methyl-2-(3-triptoreline)-hexahydropyrazino[1,2-a]pyrazin-3-he manifests the properties of anxiolytic and antidepressant [Silvestrini, B., Baiocchi, L. ACRAF SpA. WO 8705022, 1987], 3 - [1-oxo-2- [2-(piperidine-1-yl)ethyl] -1,2,3,4-tetrahydro-pyrrolo [1,2-a]pyrazin-7-ylcarbonyl]propionic acid is an antagonist fibrinogenesis gpIIb/IIIa receptor and thus effectively inhibit platelet aggregation [Askew, B.C. et al. J.Med.Chem. 1997, 40(12): 1779], and [6S-[6a[R*(TRANS),8Aα]]-N-[1-(4-aminocyclohexane)-2-(2-benzothiazolyl)-2-oxoethyl]-1,4-dioxo-2-(3-phenylpropyl)-perhydro-pyrrolo[1,2-a]pyrazin-6-carboxamide is angelaphantom by inhibiting serine protease thrombin and factor XA [Wiggum, K.A.; Doherty, A.M.; Edmunds< J.J.; Siddiqui, M.A. Pfizer Inc. WO 9748706, 1997].

Antibacterial properties shows 3-isopropylideneglycerol[1,2-a]pyrazin-1,4-dione [Kwon O. et.al. J.Antibiot. 2001, 54(2): 179], and N-[4-(3-oxo-3,5-dihydro-1,4,8b-createanimation-4-yl)butyl]triftormetilfullerenov is an inhibitor of PDGF receptor kinase and consequently a potential tool for the treatment of renal failure, hyperlipidemia, and hypertension [Ikemoto, T. et al. Tetrahedron 2000, 56(40): 7915]. High Antiprotozoal actinotherapy 3,4,7,8-tetrahydro-2H-pyrazino[1,2-a]indol-1,6,9-Trion [Tapia, R. et.al. Eur.J.Org.Chem. 2002, 23: 4005], and 2-{4-[4-(3-triptoreline)piperazine-1-yl]butyl}hexahydropyrazino[1,2-a]pyrazin-1,4-dione is a highly efficient ligand serotonin 5-NT and receptor [Lopez-Rodriguez, M. et.al. J.Med.Chem. 2001, 44(2): 186].

Given the high potential and a wide range of physiological activity analyoung of azaheterocycles, it is important to develop new compounds of this type, focused libraries and pharmaceutical compositions comprising these compounds and methods for their preparation and use.

As a result of research aimed at finding new physiologically active substances, compounds leaders, inventors received previously unknown annelirovaniya carbamoylaspartate, which possess physiological activity, focused library and pharmaceutical composition comprising these compounds, have developed methods for their preparation and use.

Below are definitions of terms used in the description.

"Combinatorial library" means a collection of compounds obtained by parallel synthesis, designed to search for connections-hit or leader, as well as to optimize the physiological activity of hit or leader, and each connection the library has in common with afforda 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).

"Connection-hit" ("hit") means a compound expressed during primary screening desired physiological activity.

"Connection-leader" ("leader") means the connection is outstanding (maximum) physiological activity associated with a specific biomechani relating to a particular (or several) of pathology or disease.

"Parallel synthesis" means a method of doing combinatorial chemical synthesis library.

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

"Nucleophilic" means electron-excess reagent.

"Electrophilic" means electron-deficient reagent.

"Deputy" means imicheskij radical, which joins scaffold or semi-synthesis in the process of their synthesis, such as nucleophilic Deputy", "electrophilic Deputy", "NH-protective Deputy" or "inert Deputy".

"Optionally substituted radical" means a radical without substituents or with one or more substituents, including nucleophilic Deputy", "electrophilic Deputy", "NH-protective Deputy" and/or "inert Deputy".

"Nucleophilic Deputy" means a chemical moiety that is attached to scaffold in the reaction with the 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-C7alkylhalogenide, optionally substituted aryls1-C7alkylhalogenide, optionally substituted heterocyclyl1-C7alkylhalogenide, optionally substituted aryl halides, optionally substituted heterocyclisation), organic acids or their derivatives (anhydrides, imidazolides, halides), e is IRow organic sulfonic acids or organic sulfochlorides, organic halogenfree, organic isocyanates and organic isothiocyanatobenzene.

"NH-Protective Deputy" means a chemical moiety that is attached to scaffold or semi-synthesis for the temporary protection of amino groups in multifunctional compounds including, but not limited to amide Deputy, such as formyl, optionally substituted acetyl (such as trichloroacetyl, TRIFLUOROACETYL, 3-phenylpropionyl and others), optionally substituted benzoyl and others; urethane Deputy such as optionally substituted C1-C7allyloxycarbonyl, such as methyloxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc), and others; optionally substituted C1-C7alkyl substituent, such as tert-butyl, benzyl, 2,4-dimethoxybenzyl, 9-phenylfluorene and others; sulfanilic Deputy, for example benzazolyl, p-toluensulfonyl and other More "NH-Protective substituents" described in the book: Protective groups in organic synthesis, Third Edition, Greene, T.W. and Wuts, P.G.M. 1999, p. 494-653. Publisher John Wiley & Sons, Inc., New York, Chichester, Weinheim, Brisbane, Toronto, Singapore.

"Inert Deputy" (or "not interfering", "Non-interfering substituent"means low or directionspanel radical including, but not limited to C1-C7alkyl, C2-C7alkenyl, C2-C7alkyne is l, With1-C7alkoxy, C7-C12aralkyl substituted with inert substituents, aralkyl,7-C12geterotsiklicheskikh substituted with inert substituents, geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl,2-C12alkoxyalkyl,2- C10alkylsulfonyl,2-C10alkylsulfonyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted with inert substituents aryl, substituted with inert substituents, alkoxy, foralkyl, aryloxyalkyl, heterocyclyl substituted with inert substituents 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 substituted with inert substituents C1-C7alkyl, phenyl, substituted by inert substituents phenyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl), aryl, substituted with inert substituents aryl, heterocycle is l and substituted with inert substituents heterocyclyl.

"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 substituents.

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

"Heterocycle" means one or more saturated, unsaturated 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 piperidine, morpholine, pyrrole, benzimidazole, benzoxazole. benzthiazole, quinoline.

"Substituted heterocycle" means a heterocycle having one or more substituents.

"Substituted azaheterocycle" means azaheterocycle with one or more substituents.

The aim of the present invention are new annelirovaniya carbamoylaspartate.

This goal is achieved annelirovannymi carbamoylaspartate General formula 1 and 2

or their pharmaceutically acceptable salts, N-oxides or hydrates, in which

R1represents a hydrogen atom or optionally substituted C1-C6alkyl;

R2and R3represent independently each other a hydrogen atom, an inert Deputy, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl;

R4are optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl;

A and b together with the attached carbon atoms and nitrogen form an optionally substituted and optionally condensed azaheterocycle;

D and E together with the attached carbon atoms form optionally substituted and optionally condensed phenyl or aryl, optionally substituted and optionally condensed azaheterocycle;

K and L together with the attached carbon atoms and nitrogen form an optionally substituted azaheterocycle;

According to the invention the most preferred annelirovannymi carbamoylaspartate the AMI are:

substituted 1-oxo-1,2,3,4,6,8A-hexahydro-pyrrolo[1,2-a]pyrazin-3-carboxamide General formula 1.1 or their pharmaceutically acceptable salts, N-oxides or hydrates

in which R1, R2, R3and R4have the above meaning, R5, R6and R7independently from each other represent a hydrogen atom, an inert Deputy, acetyl, or1-C6alkoxycarbonyl1-C4-alkyl, or R5and R6together with the carbon atoms to which they are attached, or R6and R7together with the carbon atoms to which they are attached to form optionally substituted benzene, cycloalkane or a heterocycle, such as azaheterocycle, thiophene, furan, 2,3-dihydrofuran, 3,6-dihydro-2H-peranovic or 3,6-dihydro-2H-Tierney;

substituted 8-oxo-5,6,7,6-tetrahydro-imidazo[1,2-a]pyrazin-6-carboxamide General formula 1.2 or their pharmaceutically acceptable salts, N-oxides or hydrates

in which R1, R2, R3and R4have the above meaning, R8and R9together with the carbon atoms to which they are attached, form an optionally substituted benzene;

substituted 2-substituted 4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-6-carboxamide General formula 1.3, or their pharmaceutically p is ielemia salt, N-oxides or hydrates

in which R1, R2, R3, R4, R8and R9have the above significance, or R8and R9together with the carbon atoms to which they are attached, form an optionally substituted benzene or azaheterocycle;

substituted 1-oxo-1,4-diaza-bicycloalkyl-3-carboxamide General formula 1.7

in which R1, R2, R3and R4have the above value, a R10and R11together with the carbon atoms and the nitrogen to which they are attached, form an optionally substituted and optionally condensed hydrogenated azaheterocycle;

annelirovaniya 3-oxo-2,3-dihydro-1H-pyrrolo[ 1,2-a]diazepin-1-carboxamide General formula 2.1

or their pharmaceutically acceptable salts, N-oxides or hydrates, in which R2, R3, R4, E and D have the above significance, and R12and R13independently from each other represent a hydrogen atom, a halogen atom, an inert Deputy.

The purpose of the present invention is a method of obtaining new analyoung of carbamoylaspartate General formula 1.

This goal is achieved by a method of obtaining a new condensed compounds, including 3-carbarnoyl-1-oxo-1,2,3,4-then it is carbonated the ro-pyrazinoic fragment of General formula 1, which is a three-component condensation of 1-(2-oxo-ethyl)-1H-azaheterocyclic)-2-carboxylic acids of General formula 2, the corresponding primary amine of General formula 3 and the corresponding isonitrile General formula 4 as shown in the diagram:

in which R1, R2, R3, R4, A and b have the above meaning.

The aim of the present invention is a method of obtaining new analyoung of carbamoylaspartate General formula 2.

This goal is achieved by a method of obtaining new analyoung of carbamoylaspartate General formula 2, which is the condensation of three components: the corresponding connection 5, the corresponding primary amine of General formula 3 and the corresponding isonitrile General formula 4 in the diagram below,

in which R2, R3, R4, D, E, K and L have the abovementioned meaning.

The aim of the present invention are focused library to search for biologically active compounds leaders.

This goal is achieved by the focused library that includes at least one analyoung carbamoylaspartate General formula 1 or 2 or their pharmaceutically acceptable salt, N-oxide or hydrate.

The aim of the present invention is the tsya new pharmaceutical composition in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing.

This goal is achieved by a pharmaceutical composition comprising at least one analyoung carbamoylaspartate General formula 1 or 2 or their pharmaceutically acceptable salt, N-oxide or hydrate.

Below the invention is described using the examples of the preparation of specific compounds and focused libraries and test its biological activity. The structure of the obtained compounds was confirmed by chromatographic and spectral data analysis. The following examples illustrate but do not limit the invention.

Example 1. A common way to obtain condensed compounds, including 3-carbarnoyl-1-oxo-1,2,3,4-tetrahydro-pyrazinoic fragment of General formula 1.

Was stirred at room temperature for 48-56 hours a mixture of 1-(2-oxo-ethyl)-1H-azaheterocyclic)-2-carboxylic acids of General formula 2 (3.1 mmol), primary amine 3 (3 mmol), isocyanide 4 (3 mmol) in dry methanol (5 ml), the precipitate was filtered. Received connection 1, which, if necessary, recrystallized from a suitable solvent or subjected to chromatographic purification on preparative chromatograph. Received, with the release of 40-95%, condensed compounds, including 3-carbarnoyl-1-oxo-1,2,3,4-tet is Agilera-pyrazinoic fragment of General formula 1 (see table 01-23).

Table 01. 1-Oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-3-carboxamide General formula 1.1.

Table 02. 1-Oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-3 - carboxamide General formula 1.1.

Table 03. 10-Acetylamino-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-3-carboxamide General formula 1.1.

Table 04. 1-Oxo-10-pyrrol-1-yl-1,2,3,4-tetrahydropyrazino[ 1,2-a]indol-3-carboxamide General formula 1.1.

Table 05. 5-Methyl-7-oxo-4,5,6,7-tetrahydro-1-oxa-3b,6-diaza-cyclopent[a]inden-5-carboxamide General formula 1.1.

Table 06. 5-Methyl-7-oxo-2-phenyl-4,5,6,7-tetrahydro-1-oxa-3b,6-diaza-cyclopent[a]inden-5 - carboxamide General formula 1.1.

Table 07. 5-Methyl-7-oxo-2-(R-methyl)-4,5,6,7-tetrahydro-1-oxa-3b,6-diaza-cyclopent[a]inden-5 - carboxamide General formula 1.1.

Table 08. 5-Methyl-7-oxo-2-(2-R-ethyl)-4,5,6,7-tetrahydro-1-oxa-3b,6-diaza-cyclopent[a]inden-5-carboxamide General formula 1.1.

Table 09. 5-Methyl-7-oxo-2-(3-R-propyl)-4,5,6,7-tetrahydro-1-oxa-3b,6-diaza-cyclopent[a]inden-5-carboxamide General formula 1.1.

Table 10. 7-Oxo-5-phenyl-4,5,6,7-tetrahydro-1-oxa-3b,6-diaza-cyclopent[a]inden-5-carboxamide General formula 1.1.

Table 11. 5-Methyl-7-oxo-4,5,6,7-tetrahydro-1-thia-3b,6-diaza-cyclopent[a]inden-5-carboxamide General formula 1.1.

Table 12. 5-Methyl-7-oxo-2-phenyl-4,5,6,7-tetrahydro-1-thia-3b,6-diaza-cyclopent[a]inden-5 - carboxamide General formula 1.1.

<> Table 13. 5-Methyl-7-oxo-2-(R-methyl)-4,5,6,7-tetrahydro-1-thia-3b,6-diaza-cyclopent[a]inden-5-carboxamide General formula 1.1.

Table 14. 5-Methyl-7-oxo-4,5,6,7-tetrahydro-2-(2-R-ethyl)-1-thia-3b,6-diaza-cyclopent[a]inden-5 - carboxamide General formula 1.1.

Table 15. 5-Methyl-7-oxo-2-(3-R-propyl)4,5,6,7-tetrahydro-1-thia-3b,6-diaza-cyclopent[a]inden-5 - carboxamide General formula 1.1.

Table 16. 7-Oxo-5-phenyl-4,5,6,7-tetrahydro-1-thia-3b,6-diaza-cyclopent[a]inden-5-carboxamide General formula 1.1.

Table 17. 1-XO-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-3-carboxamide General formula 1.2.

Table 18. 2-Alkyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-6-carboxamide General formula 1.

Table 19. 2-Alkyl-5-benzyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-6-carboxamide General formula 1.3.

Table 20. 2-Aryl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-6-carboxamide General formula 1.3.

Table 21. 2-Hetaryl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-6-carboxamide General formula 1.3.

Table 22. 2-Ethoxycarbonyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-6-carboxamide General formula 1.3.

Table 23. 1-Oxo-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline-3-carboxamide General formula 1.7.

Example 2. Equimolar mixture of dicarbonyl compounds 5, amine 3 and isonitrile 4 in a small amount of methanol was stirred at a temperature of 40-50°1-72 hours, controlling the course of the reaction by TLC (Silufol, methanol-chloroform 1:19). The formed precipitation was filtered and washed with ether. The homogeneous reaction mixture was poured into ice water, extracted the product with chloroform, and was chromatographically on a short column of silica gel. The eluate was evaporated and the residue was recrystallized from a mixture of hexane-ethyl acetate 10:1. Received, with the release of 45-90%, annelirovaniya 7-oxo-2,3,4,7-tetrahydro-1 H-[1,4]diazepin-2-urea of General formula 2, are presented in Table 24.

Example 3. Was focused library comprising compounds of General formula 1 and 2, are presented in Tables 01-24, and tested its ability to inhibit the activity of protein kinase, which was 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, was maintained in the wells of 96-hole plates with optically transparent bottom during the night. During this time, the polypeptide firmly sorbirovtsa on the surface of the hole. Adsorbed polypeptide served as substrate for the kinase, which was fosfaurilirovania tyrosine in this polypeptide.

Added 100 microliters 1U kinase (Calbiochem, USA, 1U is defined as the concentration of this enzyme is able to attach to the substrate picomole phosphate for 1 minute) in wells with adsorbed the first polypeptide without the test compounds (control activity) or in the presence of different concentrations of these compounds. After 30 minutes of incubation, the solutions were removed by shaking from the wells and the wells were washed twice with saline. The wells were filled with 100 microlitres solution anti-phosphotyrosine monoclonal IGg antibodies conjugated with horseradish peroxidase from horseradish (Sigma, USA). The amount of bound peroxidase antibodies was determined by the activity of peroxidase, which in turn was determined by conversion speed peroxidase substrate (OPD, phenolenediamine dihydrochloride, Sigma) into a colored product. The concentration of the product formed in 30 minutes the reaction was 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 reaction solution containing all components except kinase and 2) the reaction solution together with the kinase. The optical density measured in control wells (1) was taken as 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), was expressed as a percentage of the maximum activity. The percentage inhibition of kinase activity was calculated on the trail of the soup formula:

The magnitude of inhibition of ABL-kinase obtained from testing focused libraries vary in the range (30-100%) and confirm the biological activity of the compounds of General formula 1 and 2.

Example 4. Test the biological activity of the compounds of General formula 1. Was focused library comprising compounds of General formula 1.1 and tried it on anticancerous activity. Anticamara activity of the compounds was determined by their ability to kill concerne cells in tissue culture. For this purpose, we chose three cell lines representing three types of cancer: DLD-1 (adenocarcinoma of the rectum), DU-145 (carcinoma of the brain) and T-47D (a tumor of the breast). All cell cultures were obtained from the American collection of tissue cultures (ATSS).

Evaluation of the effectiveness of the compounds was carried out by measuring the amount of dead cells after treatment of the studied substances within 48 hours. Cells were sowed at a concentration of 5*103cells/well of a standard 96-well card and was left overnight to attach the cells to the bottom of the hole. After that, the cells were added to the substance at a final concentration of 30 μM and cards were left for 48 hours in the incubator at 37°supporting 5%CO2/95% air at 100% humidity. In the context of the e experiment environment with connections was aspirated from all wells and the wells were washed twice with saline. To each well was added 50 μM solution of Alamar Blue was measured by fluorescence (λex=531 nm, λem=589 nm) immediately after it is added and after 2 hours. The rate of increase in fluorescence is proportional to the number of cells remaining alive after their incubation with the target substances [John O'brien, lan Wilson, Terry Orton and Francois Pognan, Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity. Eur. J. Biochem. 2000,6 267, 5421-5426]. The percentage of suppression of cell growth was determined by the following equation:

% Growth inhibition=((Δfk-Δfi)/Δfk)*100%,

where Δf represents an increase of fluorescence for two hours after addition of Alamar Blue solution; subscripts K and i denote respectively the control (grown without chemicals) and experienced (grown in the presence of the tested substances) cells. Data for some of the tested substances is given in table 25. From the data presented in table 25, it can be seen that the tested substances showed good activity in suppressing the growth of tumor cells. While such substances as 1.3 (20-143), 1.3 (20-49), 1.1 (2-147) and 1.1 (12-28), equally well inhibit the growth of cells of all three cancers, while others have varying degrees of selectivity against different tumors.

Example 5. A method of obtaining a pharmaceutical composition in tablet form. Mix 800 mg krahm the La, 800 mg powdered lactose, 200 mg of talc and 500 mg cyclohexylamine 6-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-2-(4-ethylphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-6-carboxylic acid 1.1 (20-143) and spracovavat in the bar. The resulting block is crushed into granules and sieved through a sieve, collecting the granules with a size 14-16 mesh. The obtained granules tabletirujut in a suitable form tablets weighing 280 mg each. Similarly receive pharmaceutical composition in the form of tablets containing as active ingredient other 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]quinoline of General formula 1.

Example 6. A method of obtaining a pharmaceutical composition in capsule form. Thoroughly mix connection 1.1 (20-49) with lactose powder in a 2:1 ratio. Received poroshkoobraznuju mix pack 300 mg in gelatin capsules of suitable size.

Example 7. A method of obtaining a pharmaceutical composition in the form of injection for intramuscular, intraperitoneal or subcutaneous injection. Mix 500 mg of hydrochloride of compound 1.1 (20-49)with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injectable water. The resulting solution is filtered and placed in 1 ml ampoules which are sealed and sterilized in an autoclave.

1. Annelirovaniya carbamoylaspartate General formula 1 or 2

or their pharmaceutically acceptable salts or hydrates, in which

R1presented yet a hydrogen atom or optionally substituted C 1-C6alkyl;

R2and R3represent independently each other a hydrogen atom, an inert Deputy, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl;

R4are optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl;

A and b together with the attached carbon atoms and nitrogen form an optionally substituted and optionally condensed azaheterocycle;

D and E together with the attached carbon atoms form optionally substituted and optionally condensed phenyl or aryl, optionally substituted and optionally condensed azaheterocycle;

K and L together with the attached carbon atoms and nitrogen form an optionally substituted azaheterocycle.

2. Compounds according to claim 1, which represents a substituted 1-oxo-1,2,3,4,6,8A-hexahydropyrazino[1,2-a]pyrazin-3-carboxamide General formula 1.1

or their pharmaceutically acceptable salts or guy who rata in which

R1, R2, R3and R4have the above value, a R5, R6and R7independently from each other represent a hydrogen atom, an inert Deputy, acetyl, or C1-C6alkoxycarbonyl-C1-C4-alkyl, or R5and R6together with the carbon atoms to which they are attached, or R6and R7together with the carbon atoms to which they are attached, form an optionally substituted benzene, cycloalkane or heterocycle.

3. Compounds according to claim 1, which represents a substituted 8-oxo-5,6,7,6-tetrahydroimidazo[1,2-a]pyrazin-6-carboxamide General formula 1.2

or their pharmaceutically acceptable salts or hydrates, in which

R1, R2, R3and R4have the above meaning, R8and R9together with the carbon atoms to which they are attached, form an optionally substituted benzene cycle.

4. Compounds according to claim 1, which represents a substituted 2-substituted 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-6-carboxamide General formula 1.3

or their pharmaceutically acceptable salts or hydrates, in which

R1, R2, R3, R4, R8and R9have the above significance, or R8and R 9together with the carbon atoms to which they are attached, form an optionally substituted benzene or azaheterocycle.

5. Compounds according to claim 1, which represents a substituted 1-oxo-1,4-diazabicyclo-3-carboxamide General formula 1.7

or their pharmaceutically acceptable salts or hydrates, in which

R1, R2, R3and R4have the above significance, and R10and R11together with the carbon atoms and the nitrogen to which they are attached, form an optionally substituted and optionally condensed hydrogenated azaheterocycle.

6. Compounds according to claim 1, which represents annelirovaniya 3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]diazepin-1-carboxamide General formula 2.1

or their pharmaceutically acceptable salts or hydrates, in which

R2, R3, R4, E and D have the above significance, and R12and R13independently from each other represent a hydrogen atom, a halogen atom, an inert Deputy.

7. The method of obtaining compounds of General formula 1 according to claim 1, the condensation of three components: the corresponding 1-(2-oxoethyl)-1H-azaheterocyclic)-2-carboxylic acid of General formula 2, the corresponding primary amine of General formula 3 and the corresponding isonitrile General forms of the crystals 4

in which R1, R2, R3, R4, A and b have the above meaning.

8. The method of obtaining compounds of General formula 2 according to claim 1, the condensation of three components: the corresponding compounds of General formula 5, the corresponding primary amine of General formula 3 and the corresponding isonitrile General formula 4

9. Focused library to identify compounds leaders, including at least one compound of General formula 1 according to claim 1 or 2.

10. Pharmaceutical composition having inhibitory action on the activity of a protein kinase, comprising at least one compound of General formula 1 according to claim 1 or 2.



 

Same patents:

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of pyridothienodiazepine. Invention describes derivatives of pyridothienodiazepine of the general formula (I):

as a racemate or in form of enantiomers or diastereomers, or their mixture wherein R1 represents hydrogen atom or radical of the formula: R'1-NH-C(Y)- wherein R' represents phenyl radical optionally substituted with one or more similar or different substitutes taken among lower alkyl, lower alkoxy-group, lower alkylthio-group, lower alkoxycarbonyl, lower alkylsulfonyl, halogen atom, trifluoromethyl, trifluoromethyloxy-group, hydroxy-, nitro-, cyano-group, phenyl, phenoxy-group, cycloalkyl or heterocycloalkyl; R2 represents lower alkyl, trifluoromethyl or phenyl radical optionally substituted with one or more similar or different substitutes taken among hydroxy-group, halogen atom, lower alkyl or lower alkoxy-group; X and Y represent independently oxygen (O) or sulfur (S) atom; R3a represents hydrogen atom, lower alkyl, hydroxy-group or radical of the formula -OC(O)R'3a wherein R'3a represents alkyl radical comprising from 1 to 10 carbon atoms optionally substituted with radical of the formula: NR''3aR'''3a wherein NR''3a and R'''3a represent independently hydrogen atom, lower alkyl, phenyl, lower phenylalkyl, alkylcarbonyl or alkoxycarbonyl; R3b represents hydrogen atom or lower alkyl radical; R4 represents radical of the formula: -(CH2)n-CHR'4R''4 wherein n represents a whole number 0, 1, 2, 3, 4, 5 or 6; R'4 and R''4 represent independently hydrogen atom, lower alkyl, cycloalkyl, lower cycloalkylalkyl, phenyl, pyridyl, phenylcarbonyl or adamantyl wherein indicated radicals are substituted optionally with one or more similar or different substitutes taken among hydroxy-group, halogen atom, trifluoromethyl, lower alkyl or lower alkoxy-group; A----B represents -C=N- or -C-N(R5)- wherein R5 represents hydrogen atom, amino-radical, lower alkylamino-group, di-(lower alkyl)-amino-group, cycloalkyl, heterocycloalkyl, guanidyl optionally substituted with nitro- or cyano-group, phenyl optionally substituted with one or more similar or different substitutes taken among alkyl or alkoxyalkyl wherein indicated alkyl or alkoxyalkyl are substituted optionally with oxy- or amino-group; indolyl or radical of the formula: -NH-C(O)-(CH2)c-NH-C(O)(CH2)d-NH2; p represents a whole number 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; c and d represent independently a whole number 0, 1, 2 or 3; or salts of these compounds. Also, invention describes methods for preparing compounds of the general formula (I), pharmaceutical composition based on compounds of the general formula (I) eliciting activity to inhibit binding somatostatin-14 and an intermediate compound of the formula (2) given in the invention description. Invention provides preparing new compounds eliciting useful biological properties.

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

17 cl, 70 ex

The invention relates to new 3-substituted derivatives 3,4,5,6,7,8-hexahydropyrazino[4', 3': 4,5] -thieno[2,3-d] pyrimidine of the General formula I and their physiologically acceptable salts with selective action of antagonists 5HT1Band 5HT1Aand has inhibiting effect of reuse of serotonin

The invention relates to new biologically active chemical substance, namely 6-methyl-8-methoxymethyl-3-phenylisoxazole[3', 4': 4,5]thieno[2,3-b]pyridine of formula 1, showing the growth regulating and anti-stress activity

The invention relates to novel condensed pyrrolo (2,3-C)carbazole-6-Onam represented by the General formulas (I) and (II)

The invention relates to novel condensed isoindoline formula I

< / BR>
where ring b and F are independently from each other represent a 6-membered carbocyclic ring; R1means H, C1-C4alkyl; AND1and2pairs are selected from the group including =O, N, -OR", where R" denotes N;1and2pairwise mean =O; X in all positions independently from each other selected from the group: a) unsubstituted WITH1-C3alkylen, b) -S-; R3, R4, R5, R6independently from each other selected from the group comprising H1-C4alkyl; compounds 1 can be used for inhibiting protein kinase C (PKC) and inhibit the activity of tyrosine kinase (trk)

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The invention relates to bellrowan-carbolines, formula I, where R3denotes-CO-R1or group (a); R1- C1-C6alkoxy; R2- N2C1-C4alkyl, C1-C4alkoxy - C1-C2alkyl; And -- 5-6-membered unsaturated cycle, in which 1-2 carbon atoms may be replaced by N, O and/or S, which may be substituted with one R5or R6; R5and R6identical or different, denote H, C1-C6alkyl, NR7R8C1-C6alkyl which may be substituted by hydroxyl or C1-C4alkoxyl, phenyl, 5-6-membered heteroaryl residue, which contains one or two atoms of N, O or S, and phenyl and heteroaryl residue may be substituted C1-C4the alkyl, C1-C4alkoxyl, halogen, or R5and R6together,- CH2)nwhere n = 4; R7and R8- H, C1-C4alkyl, acyl, as well as their isomers, tautomers and salts

The invention relates to new derivatives of imidazo/1,2-a/ thieno /2,3-d/azepino having antiallergic activity

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to a heteroarylamino-substituted derivative of dihydropyrimido[4,5-d]pyrimidinone taken among of compounds order corresponding to the formula (I): wherein a subscript symbol n mans a whole number 1; R1 means (C1-C6)-alkyl (substituted with one or two substitutes taken among group involving hydroxy group, (C1-C6)-alkoxy group and others), piperidinyl-(C0-C4)-alkyl [wherein piperidinyl fragment is monosubstituted optionally with benzyl, carbamoyl, (C1-C4)-alkane sulfonyl, (C1-C6)-alkyl and so on], morpholinyl-(C0-C4)-alkyl, tetrahydropyranyl-(C0-C4)-alkyl, 2-oxoimidazolidinyl-(C0-C4)-alkyl, 2-oxopyrrolidinyl-(C0-C4)-alkyl or 1,1-dioxotetrahydrothienyl-(C0-C4)-alkyl, (C3-C6)-cycloalkyl (monosubstituted with monohydroxy group, (C1-C6)-alkoxy group and so on), 1,4-dioxaspiro[4,5]decane-8-yl, 2,4-dione-1,3-diazaspiro[4,5]decane-8-yl or (3-hydroxymethyl-3-methyl)-1,5-dioxaspiro[5,5]undecane-9-yl; R2 means (C1-C4)-alkyl, halogen atom; R3 means hydrogen atom, (C1-C6)-alkyl (optionally substituted with one or two substitutes taken among group involving (C1-C4)-alkoxy group, pyrrolidinyl, di-(C1-C4-alkyl)-amino-group and so on), phenyl, benzyl or piperidinyl (N-substituted optionally with (C1-C4)-alkyl); R4 means hydrogen atom, and also its individual isomers, racemic and nonracemic mixtures of isomers, prodrugs and its pharmaceutically acceptable salts. Also, invention proposes a pharmaceutical composition possessing inhibitory activity with respect to activity of p38 MAP kinase. The composition comprises a heteroalkylamino-derivative of dihydropyrimido[4,5-d]pyrimidinone of the formula (I), isomer, racemic or nonracemic mixture of isomers or its pharmaceutically acceptable salt in mixture with at least one pharmaceutically acceptable vehicle. Invention provides representing a heteroalkylamino-substituted derivative of dihydropyrimido[4,5-d]pyrimidinone possessing inhibitory activity with respect to activity of p38 MAP kinase.

EFFECT: valuable biochemical properties of compounds and composition.

14 cl, 4 tbl, 90 ex

FIELD: organic chemistry of heterocyclic compounds, biochemistry, pharmacy.

SUBSTANCE: invention describes alkylamino-substituted bicyclic nitrogen-containing heterocycles of the general formula (I):

wherein n = 1; R1 means (C1-C6)-alkyl; R2 means halogen atom; R3 means (C1-C6)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkylsulfonyl-(C1-C6)-alkyl, hydroxy-(C1-C6)-alkyl, dihydroxy-(C1-C6)-alkyl, N-heterocyclyl-(C1-C6)-alkyl or (C1-C6-alkylene)-C(O)R31 wherein R31 means hydroxy- or (C1-C6)-alkoxy-group, and its pharmaceutically acceptable salts. New compounds are inhibitors of protein kinase p38 and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

8 cl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted 2-aryl-3-(heteroaryl)imidazo[1,2-a]-pyrimidines of the formula (I):

or to their pharmaceutically acceptable salts wherein: (a) R1 is taken among the group consisting of -NH2, C1-5-alkylamino-, di-C1-5-alkylamino-, phenylmethylamino-group; (b) Y is taken among the group consisting of hydrogen atom (H), halogen atom, piperidine, OR4, SR4, -SO2CH3, NHR4 and NR4R5 wherein R4 and R5 are taken independently among hydrogen atom (H), α-alkylphenyl-C1-5-alkyl, linear or branched alkyl substituted optionally with C3-5-carbocycle, phenyl or substituted phenyl wherein indicated phenyl can be substituted with one or some substituted taken among C1-5-alkoxy-group; (c) R2 represents from one to five members taken independently among the group including hydrogen atom (H), halogen atom, trifluoromethyl; (d) R3 represents hydrogen atom (H), or radicals R3 taken in common form aromatic ring; (e) X represents nitrogen atom (N) or -CH. Also, invention relates to methods for preparing indicated compounds and to a method for treatment based on these compounds. Invention provides preparing novel compounds that can be used in relief states by reducing the level of inflammatory cytokines, for example, the indicated state represents proliferative (rheumatic) arthritis.

EFFECT: valuable medicinal properties of compounds and compositions.

40 cl, 1 tbl, 4 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes derivatives of imidazo-3-ylamine of the general formula (I):

wherein X and Y mean CH or nitrogen atom (N) under condition that X and Y don't mean nitrogen atom (N) simultaneously; R1 means tert.-butyl, (CH2)nCN wherein n means 4, 5 or 6, phenyl substituted optionally with (C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C4-C8)-cycloalkyl, 1,1,3,3-tetramethylbutyl or CH2Ra wherein Ra represents hydrogen atom, branched or linear (C1-C8)-alkyl, phenyl substituted optionally with halogen atom, (C1-C4)-alkoxy-group, CO(OR') wherein R' means linear (C1-C4)-alkyl or branched (C3-C5)-alkyl, PO(OR')2 wherein R' means linear (C1-C4)-alkyl or branched (C3-C5)-alkyl; R2 means hydrogen atom, CORb wherein Rb represents branched or linear (C1-C4)-alkyl; R3 means methyl, ethyl, tert.-butyl, (C3-C8)-cycloalkyl, phenyl monosubstituted optionally at position 3, 5 or 6 or optionally multisubstituted at position 4 and additionally at position 2 and/or 3, and/or 5, and/or 6 with halogen atom, hydroxyl group (OH), (C1-C4)-alkyl or (C1-C4)-alkoxy-group, naphthyl, optionally substituted (C1-C4)-alkoxy-group, di-(C1-C4)-alkylamino-group, pyrrole substituted optionally with (C1-C4)-alkyl, benzylsulfonyl, COOCH3, pyridyl substituted optionally with (C1-C4)-alkyl, OH, hydroxy-(C1-C4)-alkyl, furan substituted optionally with (C1-C4)-alkyl, nitro-group (-NO2), halogen-substituted phenyl, CH2COOCH3, COOH, thiophene substituted optionally with halogen atom, (C1-C4)-alkyl, (C1-C4)alkylsulfanyl, -NO2, phenoxy-group, thiophene, alkynylphenyl, unsubstituted anthracene or quinoline substituted optionally with halogen atom under condition that R3 doesn't means cyclohexyl-unsubstituted phenyl or phenyl monosubstituted with carboxylic acid amide at position 3 if R1 means tert.-butyl, n-propyl, n-butyl, 1,1,3,3-tetramethylbutyl, cyclohexyl, monosubstituted phenyl, 2,6-dimethylphenyl or benzyl, and R2 means simultaneously hydrogen atom or -CO-(methyl) and under condition that R2 doesn't mean hydrogen atom if R1 means benzyl simultaneously and R3 means methyl or R1 means simultaneously CH2C(O)-tert.-butyl and R3 means unsubstituted phenyl, in forms of bases or pharmaceutically acceptable salts, and a method for their preparing and a medicinal agent based on thereof. Described compounds possess analgesic activity and can be used in medicine.

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

7 cl, 2 tbl, 33 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to new derivatives of pyrrolopyrimidine of the formula (1) and their pharmaceutically acceptable salts possessing properties of selective inhibitor of specific cyclic guanosine 3',5'-monophosphate phosphodiesterase (specific cGMP PDE) (PDE V). In the formula (1) R1 represents hydrogen atom (H), (C1-C3)-alkyl substituted optionally with one or some fluorine atoms; R2 represents H, halogen atom, (C1-C6)-alkyl substituted optionally with hydroxyl group (-OH), (C1-C3)-alkoxy-group, (C3-C6)-cycloalkyl or one or some fluorine atoms, (C3-C6)-cycloalkyl; R3 represents (C1-C6)-alkyl substituted optionally with (C3-C6)-cycloalkyl or one or some fluorine atoms; R4 represents (C1-C6)-alkyl substituted optionally with one or some fluorine atoms; R5 represents -SO2NR6R, -NHSO2R8 or heterocyclyl such as tetrazolyl; each R6 and R7 represents independently H or (C1-C6)-alkyl substituted optionally with -CO2H or one or some fluorine atoms; or in common with nitrogen atom to which they are bound form monocylic ring, such as imidazole, pyrrolidine, piperidine, morpholine, piperazine and homopiperazine wherein indicated group is replaced optionally with R9 wherein R9 represents (C1-C6)-alkyl substituted optionally with one or some halogen atoms, hydroxyl group (OH), (C1-C3)-alkoxy-group that is replaced optionally with one or some fluorine atoms, -NR11R12, -C=NR13(NR14R15) or tetrazolyl group, 6-membered nitrogen-containing heteroaryl group; each R11 and R12 represents independently H or (C1-C4)-alkyl; R13represents H; each R14 and R15 represents independently H. Also, invention relates to intermediate compounds, methods for preparing compounds and pharmaceutical compositions. Proposed compounds can be used in treatment of impotency, sexual dysfunction in females, stable, nonstable and variant (Prinzmental) stenocardia and other diseases also.

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

15 cl, 1 tbl, 250 ex

FIELD: organic chemistry, medicine, hormones.

SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.

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

10 cl, 6 tbl, 337 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

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

26 cl, 1 tbl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

FIELD: medicine, oncology.

SUBSTANCE: invention relates to method for malignant tumor treatment (including cancer, sarcoma, melanocytoma) in human by ectasceine ET743 intravenous infusion in dose of 500-1650 mug/m2 of surface are; to similar treatment by combination of ET743 with antiemetic agent; as well as to relative composite preparation. Method of present invention provides clinical amelioration in subject suffering from progressive or metastasing cancer and improves treatment effectiveness of diseases being progressed after known chemotherapy.

EFFECT: new effective method for cancer treatment; drug with good acceptability.

31 cl, 3 ex, 1 tbl

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