Substituted 7-sulfonyl-benzo[b][1,4]diazepines (variants), methods for their preparing (variants), focused library and pharmaceutical composition

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new substituted 7-sulfonyl-benzo[b][1,4]diazepines of the general formula (1) , their pharmaceutically acceptable salts, N-oxides or hydrates that elicit properties of a protein kinase inhibitor that can be used in pharmaceutical industry. In compounds of the general formula (1) R1 and R2 represent independently of one another hydrogen atom, inert substitute, optionally substituted carboxymethyl group, optionally substituted carbamoylmethyl group; R3 and R4 represent independently of one another hydrogen atom or inert substituted, or R3 and R4 in common with carbon atom to which they are bound form optionally substituted (C3-C7)-cycloalkyl, optionally substituted (C4-C7)-heterocyclyl or optionally substituted ethylene group; R5 represents optionally substituted amino-group or optionally substituted azaheterocyclyl. Also, invention relates to sulfochlorides of the general formula (2) that are used for preparing compound of the formula (1), and to methods for preparing compounds of general formulae (1) and (2). Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injection formulations placed into pharmaceutically acceptable package, and to the focused library for the search of biologically active compound-leaders.

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

7 cl, 2 sch, 1 tbl, 3 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 7-sulfonyl-benzo[b][1,4]benzodiazepines 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 7-sulfonyl-benzo[b][1,4]benzodiazepines and pharmaceutical compositions containing as active substance new 7-sulfonyl-benzo[b][1,4]benzodiazepines, to methods for their preparation and use.

There are a large number of synthetic physiologically active compounds, including benzo[1,4]diazepinone fragments. So, for example, 1-[1-cyclohexyl-2,4-dioxo-5-(2-oxo-2-pyrrolidin-1-retil)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-3-(4-forfinal)-urea as an inhibitor of DNA topoisomerase II (oncolytic) [Drag/Data Rep. 1998, VM-2419].(7-chloro-)-methyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-amide 1H-indole-2-carboxylic acid is CCL and SCA x is licitaciones antagonist (anorexigenic) [Aventis Pharma, 1988, U.S. Pat. EP 0376849, Pat. France 2641280, Pat. Japan 1990215774], and 3-cyclohexyl-N-(1,5-aminobutiramida 2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-propionamide - blocker of potassium channels (antiaritmikom) [Merck & Co, 1995, U.S. Pat. USA 5691331,PCT W0 9640655].

Given the wide range of physiological activity of benzo[b][1,4]benzodiazepines, it is important to develop new compounds of this type, focused libraries and pharmaceutical compositions comprising these compounds and methods of their preparation and use.

As a result of research aimed at finding new physiologically active substances, compounds leaders, inventors received previously unknown benzo[b][1,4]benzodiazepines, which possess physiological activity, focused library and pharmaceutical composition comprising these compounds, have developed methods for their preparation and use.

It should be noted that despite the huge amount of benzo[b][1,4]benzodiazepines, published in the patent and scientific literature, 7-sulfonylmethane benzo[b][1,4]benzodiazepines up to the present time were not known.

Below are definitions of terms used in the description:

"Combinatorial library" means a collection of compounds obtained by parallel synthesis of p is designated to search Lida or optimize the biological activity of the lead compounds, 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" means a compound 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 homoactive potassium channels" or "known gametip kinase inhibitors", etc. As a rule, the presence of common structural fragment of the connection is to changes in one of chemotype is a necessary and sufficient condition for the existence of common properties.

"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, alphagraph, a sulfa group, hydroxyl group, amino group, carboxialkilnuyu group, alkoxycarbonyl group, carnemolla group and others

"Inert Deputy" ("Non-interfering substituent"means low or directionspanel radical inert to further transformations and the environment, including, but not limited1-C7alkyl, C2-C7alkenyl,2-C7quinil,1-C7alkoxy, C7-C12aralkyl, substituted aralkyl,7-C12geterotsiklicheskikh, substituted 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 aryl, substituted alkoxy, foralkyl, aryloxyalkyl, heterocyclyl, substituted heterocyclyl and nitroalkyl, where m and n have a value from 1 to 7. Preferred inert substituents are1 -C7alkyl, C2-C7alkenyl,2-C7quinil,7-C12alkoxy, C7-C12aralkyl,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted aryl, heterocyclyl and substituted heterocyclyl.

"Substituted group, substituted radical or scaffold" means respectively the group, the radical or scaffold, have a Deputy, including but not limited to inert Deputy, a halogen atom, a nitro-group, cyano, alphagraph, hydroxyl group, amino group, carboxialkilnuyu group, carboxyl group, carnemolla group. For example: substituted alkyl means alkyl with one or more substituents, for example, hydroxyalkyl or methoxycarbonylethyl, aminoethoxyethanol, 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-killingray, acetylethylenediamine group and others: substituted phenyl means phenyl, which has one or more substituents, such as 2-metuximab ylphenyl, 4-amino-3-ethoxycarbonylphenyl, 3,4-diaminophenyl and other

"Optionally substituted group optionally substituted radical or scaffold" means respectively the 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-killingray, allocarbitraryblob and other

"Aryl" means one or more aromatic cycles, each of which includes 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 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 bobiri the mud.

"Azaheterocycle" means a heterocycle containing 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 are new benzo[b][1,4]benzodiazepines.

This goal is achieved substituted 7-sulfonyl-benzo[b][1,4]benzodiazepines of General formula 1

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

R1and R2independently from each other represent a hydrogen atom, an inert Deputy, optionally substituted carboxymethyl group, optionally substituted carbamoylmethyl group;

R3and R4independently from each other represent a hydrogen atom or an inert Deputy, or R3and R4together with the carbon atom to which they are attached, form an optionally substituted C3-C7cycloalkyl, optionally substituted C4-C7heterocyclyl or optionally substituted ethylene group;

R5is optionally substituted by an amino group or neobyazatel is substituted azaheterocyclic;

This goal is achieved substituted benzo[b][1,4] - benzodiazepines-7-sulfonyl chlorides of General formula 2

in which R1, R2, R3and R4have the above value.

The aim of the present invention is a method of obtaining new 2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-sulfonamides of General formula 1.

This goal is achieved by way of the obtain, which is in effect on sulfochloride 2 optional substituted amines or optionally substituted azaheterocycle General formula 4 in the diagram below,

in which R1, R2, R3, R4and R5have the above value.

The aim of the present invention is a method of obtaining new 2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-sulfonyl chlorides of General formula 2.

This goal is achieved by way of the obtain, which is the action of chlorosulfonic acid on 2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-2,4-diones of General formula 3 in the diagram below,

in which R1, R2, R3and R4have the above value.

The aim of the present invention is focused library to search for biologically active compounds is of eaders.

This goal is achieved by the focused library that includes at least one 7-sulfonyl-benzo[b][1,4]diazepin General formula 1 or its pharmaceutically acceptable salt, N-oxide or hydrate.

The aim of the present invention is a 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 7-sulfonyl-benzo[b][1,4]diazepin General formula 1 or its pharmaceutically acceptable salt, N-oxide or hydrate. Pharmaceutically acceptable salts of the compounds can be obtained in a traditional way, for example by the action of the compounds corresponding acid or base. N-oxides can be obtained by oxidation of the corresponding nitrogen-containing compounds. Hydrates of compounds can be obtained, for example, by recrystallization from aqueous solutions, or are formed spontaneously in the synthesis process.

The following examples illustrate but do not limit the invention.

Example 1. A common way to obtain 2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-sulfonyl chloride 2. Was added 1,5-dihydrobenzo[b][1,4]diazepin-2,4-dione 3 (0.2 mol) with stirring to 75 ml) cooled to 0-5°With chlorosulfonic acid, and then stirred reacts the traditional mass at room temperature for 1 hour, and then at 60°s to stop shedding HCl. The reaction mass was cooled to 0-5°and poured on crushed ice. The crystals formed were filtered and dried in vacuum. Got 2 with the release of 70-85%. For example, 2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-sulfonyl chloride 2(1) was obtained with a yield of 75% and with TPL 250-253°;1H NMR (δ): 10.18 (s, 2H, N-H), 7.45 (s, 1H, H6), 7.38 (d, 1H, H7, J8.2 Hz), 7.08 (d, 1H, H8, J8.2 Hz), 3.15 (s, 2H, CH2); Mass spectrum (m/z): M+274, 232. 206. 133, 105, 78, 69, 51, 36.

Example 2. A common way to obtain benzo[b][1,4]diazepin-7-sulfonamides 1, suitable for parallel synthesis of combinatorial libraries. To a suspension of amine 4 (1.1 mmol) and pyridine (0.16 ml) in dry DMF (3 ml) was added 2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-sulfonyl chlorides 2 (1.00 mmol). The reaction mass was stirred for 12 h at room temperature, was diluted with water, precipitation was filtered and recrystallized from a mixture of ethanol-DMF). Got a combinatorial library of compounds of General formula 1 with the release of 30-75%, are presented in Table 1

Example 3. Was focused library, including 264 compounds of General formula 1 (see table) and tested its ability to inhibit the activity of protein kinases, which were 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, is respectively, was maintained in the wells of 96 well 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 b, 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 1 picomole phosphate for 1 minute) in the wells with the adsorbed polypeptide without the test compounds (control activity) or in the presence of different concentrations of these compounds. After a 30 minute incubation the solutions were removed by shaking out from the wells, and the wells were washed twice with saline. The wells were filled with 100 microlitres solution antiphosphotyrosine 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, o-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 iasnoi 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 by the following formula:

The magnitude of inhibition of ABL-kinase (tyrosinemia kinase responsible for the development of leukemia Abelson - chronic myelogenous leukemia), obtained from testing focused library of compounds 1 at a concentration of 30 μm, are ranged in the interval from 1% to 25%, which confirms the biological activity of the compounds of General formula 1.

1. Substituted 7-sulfonyl-benzo[b][1,4]benzodiazepines of General formula 1

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

R1and R2independently from each other represent a hydrogen atom, an inert Deputy, optionally substituted carboxymethyl group, optionally substituted carbamoylmethyl group;

R3and R4

R3and R4together with the carbon atom to which they are attached, form an optionally substituted C3-C7cycloalkyl, optionally substituted C4-C7heterocyclyl or optionally substituted ethylene group;

R5is optionally substituted by an amino group or optionally substituted azaheterocyclic.

2. Substituted benzo[b][1,4]diazepin-7-sulphonylchloride General formula 2

2

in which R1, R2, R3and R4have the above value.

3. The method of obtaining compounds of General formula 1 according to claim 1, consisting in effect on sulfochloride General formula 2

in which R1, R2, R3and R4have the above meaning,

the corresponding optionally substituted amine or optionally substituted azaheterocycle.

4. The method of obtaining compounds of General formula 2 according to claim 2, consisting in the action of chlorosulfonic acid on 2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-2,4-diones of General formula 3

in which R1, R2, R3and R4have the above value.

5. Focused library to search for biologically active compounds-whether the development, including at least one 7-sulfonyl-benzo[b][1,4]diazepin General formula 1 or its pharmaceutically acceptable salt, N-oxide or hydrate.

6. Pharmaceutical composition having the properties of inhibitors of protein kinases, in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing comprising at least one 7-sulfonyl-benzo[b][1,4]diazepin General formula 1 or its pharmaceutically acceptable salt, N-oxide or hydrate.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

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

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 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, hormones, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that act as agonists of peptide hormone vasopressin. Invention describes the compound of the general formula (1) or its pharmaceutically acceptable salt wherein V represents a covalent bond or NH; X is taken among CH2, oxygen atom (O) and N-alkyl; Z represents sulfur atom (S) or -CH=CH-; R1 and R2 are taken independently among hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom and alkyl; R3 is taken among hydroxyl group (OH), O-alkyl and NR4R5 wherein each R4 and R5 represents independently hydrogen atom (H) or alkyl, or both represent -(CH2)q-; p = 0, 1, 2, 3 or 4; q = 4 or 5. Also, invention describes a pharmaceutical composition eliciting agonistic activity with respect to V2-receptors, a method for treatment of enuresis, nicturia and diabetes insipidus, method for control of enuresis and a method for treatment of enuresis and a method for treatment of diseases associated with damage in blood coagulability. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 31 ex

The invention relates to new derivatives of diazepinone having valuable properties, in particular derivatives of diazepinone General formula (I)

< / BR>
where B is one of the divalent residues and) g)

< / BR>
and

X, l, m, n and R1R7have the following meanings:

X Gruppen or, if B denotes the divalent residue (a), a nitrogen atom,

l integer 1, 2 or 3,

m is an integer 1 or 2,

n is an integer of 1 to 4,

R1a hydrogen atom or an unbranched or branched alkyl with 1 to 6 carbon atoms,

R2a hydrogen atom, an unbranched or branched alkyl with 1 to 8 carbon atoms, unbranched or branched alkenyl with 4 to 6 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, unsubstituted or substituted by alkyl with 1 to 3 carbon atoms, substituted, phenyl, unsubstituted or substituted by one or two methyl groups or methoxypropane or one halogen atom, or phenylalkyl with 1 to 3 carbon atoms in the alkyl part, unsubstituted or substituted at the fragrance stands or methoxy group or a halogen atom,

R3and R4the same or the difference is,

R5a hydrogen atom or a chlorine or methyl,

R6and R7the same or different and denote hydrogen atoms or alkali with 1 to 3 carbon atoms, and, in addition, R7may also indicate a halogen atom,

mixtures of their isomers or their individual isomers and their salts, mainly their physiologically tolerated acid additive salts, in particular with pharmacological action

FIELD: organic chemistry, vitamins, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the formula (I): wherein X means hydrogen atom or hydroxy group; R1 and R2 that can be similar or different mean hydrogen atom, (C1-C4)-alkyl; R3 means hydrogen atom, methyl group, fluorine or chlorine atom. Also, invention relates to its esters able to hydrolysis in vivo in combination with pharmaceutically acceptable acids. Also, invention relates to a pharmaceutical composition eliciting the inhibitory activity with respect to proliferation and promoting differentiation of cells and comprising the effective dose of compound of the formula (I) in common with pharmaceutically acceptable carriers and/or excipients. Also, invention relates to applying compound of the formula (I) for preparing a medicine used in treatment and prophylaxis of disease characterizing by abnormal differentiation of cells and/or proliferation of cells.

EFFECT: valuable medicinal properties of compounds.

13 cl, 3 sch, 3 tbl, 6 ex

FIELD: organic chemistry, vitamins, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the formula (I): wherein X means hydrogen atom or hydroxy group; R1 and R2 that can be similar or different mean hydrogen atom, (C1-C4)-alkyl; R3 means hydrogen atom, methyl group, fluorine or chlorine atom. Also, invention relates to its esters able to hydrolysis in vivo in combination with pharmaceutically acceptable acids. Also, invention relates to a pharmaceutical composition eliciting the inhibitory activity with respect to proliferation and promoting differentiation of cells and comprising the effective dose of compound of the formula (I) in common with pharmaceutically acceptable carriers and/or excipients. Also, invention relates to applying compound of the formula (I) for preparing a medicine used in treatment and prophylaxis of disease characterizing by abnormal differentiation of cells and/or proliferation of cells.

EFFECT: valuable medicinal properties of compounds.

13 cl, 3 sch, 3 tbl, 6 ex

FIELD: medicine, oncology.

SUBSTANCE: invention elates to treatment of tumors. Method involves administration of aplidine in the dose not exceeding the recommended dose and limiting by the toxicity of the preparation in patient and in the correspondence of one the following schedule: 24 h infusion, once time per a week for 3 weeks and with the following one resting week; 24 h infusion, once time per two weeks; 1 h infusion, once per a week for 3 weeks in each 4 weeks; 1 h infusion, once per a day for 5 days for 3 weeks; 3 h infusion by each the second week. Applying indicated regimens enhances the effectiveness of treatment of malignant tumors being among them with resistance to the conventional treatment and in combination with the absence of the therapy toxicity.

EFFECT: improved and enhanced effectiveness of treatment.

4 cl, 15 dwg, 18 ex

FIELD: medicine.

SUBSTANCE: invention proposes applying bis-phosphonic acids (bis-phosphonates) for the embolic treatment of angiogenesis and corresponding methods for prophylaxis or treatment of angiogenesis by embolization. Invention provides suppression of growth, invasion or metastasis of tumors, treatment of angiogenesis in myocardium ischemia, rheumatic arthritis, osteoarthritis by embolization of newly formed vessels in intra-arterial route of administration of bis-phosphonate (for example, pamidronic acid or zoledronate).

EFFECT: valuable medicinal properties of medicine agents.

10 cl, 3 dwg, 7 ex

FIELD: medicine, oncology, immunology, tumor biology.

SUBSTANCE: invention relates, in particular, to methods for enhancing cytotoxicity based on applying anti-CD38-immune toxins. Method involves carrying out the treatment of patient with pathophysiological state taken among the group including myelomas and leukosis and involves the following stages: a) administration to the indicated patient the pharmacologically effective dose of retinoid that enhances expression of antigen CD38; and b) administration to the indicated patient the pharmacologically effective dose of immune toxin acting against effectively expressing antigen CD38. Method provides enhancing the cytotoxicity with respect to above said diseases in their resistance to anti-tumor medicinal agents.

EFFECT: enhanced and valuable method for treatment.

6 cl, 1 tbl, 9 dwg, 10 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide of the formula: and to its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition inhibiting activity of protein-tyrosine kinases and comprising the indicated compound, a method for treatment of disorders associated with protein-tyrosine kinases, such as an immune disorder, and oncology disease, and a method for cancer treatment.

EFFECT: valuable biochemical and medicinal properties of compounds and composition.

5 cl, 2 tbl, 581 ex

FIELD: organic chemistry, microbiology.

SUBSTANCE: invention relates to new synthetic biologically active derivatives of pyrimidine, namely to 2,4-dioxo-5-(2-hydroxy-3,5-dichlorobenzylidene)imino-1,3-pyrimidine potassium, sodium or ammonium salt of the general formula: wherein X is taken among the group: Na+, K+, NH+4. The claimed substance shows expressed antibacterial activity directed mainly against different fungi, bacteria, protozoan and viruses.

EFFECT: valuable biological properties of compounds.

13 tbl, 13 ex

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating locally metastasing forms of bladder's cancer at T2b-4N0-1M0 stages. It deals with performing chemotherapy due to fractional introduction of total therapeutic dosage of cytostatic preparation into pubic bone - adriamycin at a single dosage being not more than 30 mg every other day per one course up to total dosage of 70 mg/m2. After each injection one should introduce per 2 ml 2%-lidocaine solution through the same needle. For patients with contra-indications for systemic chemotherapy total adriamycin dosage should be decreased twice to be distributed for three injections. The method increases adriamycin concentration in tumor at optimal way and mode of its injection by providing decreased number of toxic complications, in patients above 75 or with severe accompanied pathology, among them.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine, oncology.

SUBSTANCE: invention relates to a method for treatment of patients with disseminated forms of prostate cancer. Method involves administration of navelbine in the dose 30 mg/m2 on the background of anti-androgenic therapy. The course time in navelbine administration is 4 weeks and from 7-th day after the last injection of navelbine method involves administration of strontium-89 chloride in the dose 4 mKi (150 MBk), once time per 3 months, two injections. For patients with the amount of osseous metastases above 6 the dose of strontium-89 chloride is 8 mKi per one administration (300 MBk). In further courses of systemic therapy are repeated in 3 months, not early. Method shows the optimal regimen set in administration of preparations and provides the maximal effect of navelbine on osseous metastases followed by damaging effect of strontium-89 chloride on blood vessels of tumor and its cells and the absence of the potentiation toxicity on the hemopoiesis system.

EFFECT: improved and enhanced effectiveness of treatment.

3 dwg, 2 ex

FIELD: medicine, oncology.

SUBSTANCE: invention relates to a method for treatment of patients with disseminated forms of prostate cancer. Method involves administration of navelbine in the dose 30 mg/m2 on the background of anti-androgenic therapy. The course time in navelbine administration is 4 weeks and from 7-th day after the last injection of navelbine method involves administration of strontium-89 chloride in the dose 4 mKi (150 MBk), once time per 3 months, two injections. For patients with the amount of osseous metastases above 6 the dose of strontium-89 chloride is 8 mKi per one administration (300 MBk). In further courses of systemic therapy are repeated in 3 months, not early. Method shows the optimal regimen set in administration of preparations and provides the maximal effect of navelbine on osseous metastases followed by damaging effect of strontium-89 chloride on blood vessels of tumor and its cells and the absence of the potentiation toxicity on the hemopoiesis system.

EFFECT: improved and enhanced effectiveness of treatment.

3 dwg, 2 ex

FIELD: organic chemistry, microbiology.

SUBSTANCE: invention relates to new synthetic biologically active derivatives of pyrimidine, namely to 2,4-dioxo-5-(2-hydroxy-3,5-dichlorobenzylidene)imino-1,3-pyrimidine potassium, sodium or ammonium salt of the general formula: wherein X is taken among the group: Na+, K+, NH+4. The claimed substance shows expressed antibacterial activity directed mainly against different fungi, bacteria, protozoan and viruses.

EFFECT: valuable biological properties of compounds.

13 tbl, 13 ex

Up!