5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxamide synthesis method

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxamide and/or one of its physiologically acceptable salts, characterised by that a compound of formula (I),

, in which L is CI, Br, I, SO2F, SO2CF3, SO2C2F5, is reacted with 3-(4-piperazin-1-ylbutyl)indole-5-carbonitrile through transition metal catalysed combination through complex compounds of Pd and/or that the formed 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxamide is converted to one of its acid addition salt through treatment with an acid, and to a second method which is characterised by that a formula (II) compound, as a base or salt HX (where X=Cl, Br), is reacted with 3-(4-oxobutyl)-1H-indole-5-carbonitrile through reductive amination, and or that 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxamide is converted to one of its acid addition salt through treatment with an acid.

EFFECT: obtaining a compound which is a 5-HT1A receptor agonist.

4 cl, 2 ex

 

The invention relates to a method for producing 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinil)benzofuran-2-carboxamide and its physiologically acceptable salts using chemoselective catalyzed by metal combinations of precursor 3-(4-piperazine-1-libutil)indole-5-carbonitrile derivative galogenirovannami benzofuran-2-carboxamide.

In addition, the invention relates to a method for producing 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinil)benzofuran-2-carboxamide and its physiologically acceptable salts by reductive amination of 3-(4-oxobutyl)-1H-indol-5-carbonitrile using 5-piperazinylmethyl-2-carboxamide.

To date, the approach was based on the combination of activated 5-cyano-3-butional derivative 5-piperazinylmethyl, as it is known, for example, J. Med. Chem. (2004), 47(19), 4684-4692, Heinrich, T.; Böettcher, H.; Gericke, R.; Bartoszyk, G.D.; Anzali, S.; Seyfried, C.A.; Greiner, H.E.; van Amsterdam, C. and J. Med. Chem. 2004, 47, 4677-4683, Heinrich, T., Böettcher, H.Bartoszyk, G.D.Greiner, H.E.Seyfried, C.A., van Amsterdam, C. and cited in literature.

Unexpectedly studies, as part of the synthesis of drugs, for example described in EP 0648767 showed that 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinil)-benzofuran-2-carboxamide can be obtained with at least comparable or higher total yield compared with the previous prior art, in the which important advantages, what can be mentioned, are the simplicity of the reaction, including fewer stages of synthesis and, consequently, a more simple selection of the product. It is, therefore, also means lower costs of solvents and energy.

Thus, the invention relates to a method for producing 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinil)benzofuran-2-carboxamide and/or one of its physiologically acceptable salts in which the compound of the formula I

,

in which L represents Cl, Br, I, SO2F, SO2CF3, SO2C2F5enter into reaction with 3-(4-piperazine-1-libutil)indole-5-carbonitrile catalyzed by transition metal combinations through complex compounds of Pd,

and/or in which the resulting 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinil)benzofuran-2-carboxamide turn into one of its salts accession acid by treatment with acid (method a)).

Preferably used radical L represents bromine.

Thus, the above-mentioned method according to option a) based on catalyzed by metal combination of piperazine with the derived 5-galingale, preferably with the derived 5-bromoindole, in the presence of transition metal catalyst to obtain the above-mentioned final product. Compared to the pic is the means known from prior art, which could include up to 10 stages, this method is much shorter and therefore less expensive.

Applied catalysts of transition metals are preferably complexed Pd(0), such as Tris(dibenzylideneacetone)dipalladium or similar complex compounds in combination with phosphorus ligands, such as, for example, P(tert-Bu)3. However, derivative Pd2+such as, for example, PdCl2or Pd(OAc)2can also be used as the palladium source.

Methods of obtaining 5-(1-piperazinil)benzofuran-2-carboxamide known, for example, from WO 01/40219 (Merck Patent GmbH), using a transition metal catalyst. For catalyzed by metal combinations are used aprotic solvents, such as toluene, xylene, THF, or other ethers.

Suitable bases are alkoxides of alkali metals, preferably tert-piperonyl sodium, or carbonates of alkali metals.

Depending on the reaction conditions, the reaction time is from several minutes to 7 days, the reaction temperature is 0 to 150°C., preferably from 20° to 120°C.

The invention also relates to a method for obtaining 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinil)b is souran-2-carboxamide and/or one of its physiologically acceptable salts, in which the compound of formula II

as a base or salt HX (where X=Cl, Br, sulfate or organic counterions such as, for example, anion methanesulfonic acid (CH3SO3-)is injected into the reaction with 3-(4-oxobutyl)-1H-indol-5-carbonitrile by reductive amination, and/or in which the resulting 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinil)benzofuran-2-carboxamide turn into one of its salts accession acid by treatment with acid (method option b)).

Reductive amination (method variant b)) aldehydes is a widely used synthesis of amines (see Baxter, E.W.; Reitz, A.B. Organic Reactions 2002, 59, 1). In the present method, first get the aldehyde 3-(4-oxobutyl)-1H-indol-5-carbonitril of 3-(4-hydroxybutyl)-1H-indol-5-carbonitrile. At a later stage, the aldehyde is combined with the compound of the formula II with the addition of the reducing agent, to obtain 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinil)benzofuran-2-carboxamide in the form of a Foundation that can be selected using conventional laboratory methods, or an alternative base is converted into monohydrochloride (vilazodone) in solution or as solids after treatment with acids, such as, for example, hydrochloric acid. Thus, it becomes possible to replace the stage is alkilirovanija 3-(4-chlorobutyl)indole-5-carbonitrile reagent, as described in J. Med. Chem. (2004), 47 (19), 4684-4692, Heinrich, T.; Böettcher, H.; Gericke, R.; Bartoszyk, G.D.; Anzali, S.; Seyfried, C.A.; Greiner, H.E.; van Amsterdam, C. and cited in the literature, by reductive amination using (3-(4-oxobutyl)-1H-indol-5-carbonitrile).

Suitable solvents are alcohols, preferably methanol, and ethers, hydrocarbons or other solvents, which dissolve the starting materials to an adequate degree. Depending on the reaction conditions, the reaction time is from several minutes to 7 days, the reaction temperature is 0 to 150°C., preferably from 0 to 30°C.

In the following examples, "conventional laboratory processing" means the following procedure: if necessary, water is added, if necessary, establish a pH value of from 2 to 10, depending on the structure of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the product was then purified using chromatography on silica gel and/or crystallization.

The basis of 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinil)benzofuran-2-carboxamide can be converted into salt accession acid using acid, for example, by bringing in the reaction of equivalent amounts of base and acid in an inert Rast is oricale, such as ethanol, followed by evaporation. Suitable acids for this reaction are, in particular, are those that yield physiologically acceptable salts. Thus, it is possible to use mineral acids, for example sulfuric acid, nitric acid, halogen acids such as HCl or HBr, phosphoric acid such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic mono - or politonalnye carboxylic, sulfonic or sulfuric acids.

Catalyzed by metals amination (method a))

Example 1.

In a protective gas atmosphere of 80 mg of Tris(dibenzylideneacetone)diplodia and 65 mg of Tris-tert-butylphosphine introduced into 70 ml of dimethyl ether of diethylene glycol at 20°C with stirring. Next, add 1.5 g of 5-bromobenzophenone-2-carboxamide and 2.5 g of 3-(4-piperazine-1-libutil)indole-5-carbonitrile. When following the addition of 2.3 g of tert-butoxide sodium is formed yellow-gray suspension. The reaction mixture is heated at 120°C for 48 hours, then cooled to room temperature (about 23°C), treated with conventional laboratory methods and produce the target compound in the form of the base of vilazodone or monohydrochloride(vilazodone - 5-{4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinil}benzofuran-2-carboxamide hydrochloride) after treatment dissolved the Foundation of the aqueous solution of hydrochloric acid.

The identity of the target compounds was confirmed using chromatographic comparison with the sample material.

Reductive amination (method variant b))

Example 2.

The precursor 3-(4-oxobutyl)-1H-indol-5-carbonitril

18 g of 3-(4-hydroxybutyl)-1H-indol-5-carbonitrile and 34 ml of triethylamine are dissolved in 300 ml dichloromethane and cooled to about 0°C in ice/methanol bath. Then dosed introduce a solution of 39 g of complex compounds of sulfur trioxide / pyridine and 140 ml of dimethyl sulfoxide at a temperature of from 2 to 5°C. the Mixture is stirred at a temperature of from 2 to 3°C for about 20 min, then the reaction solution is heated to 22-23°C (room temperature) for 2 hours. The reaction mixture is diluted by adding 200 ml of dichloromethane and then extracted with water, 10%citric acid solution and 10%sodium chloride solution. The organic phase is concentrated to an oil residue in a vacuum, then chromatographic on silica gel using a mixture of dichloromethane and MTV broadcast.

Comparative H-NMR and MS confirmed the identity.

Obtain 5-{4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinil}benzofur is n-2-carboxamide hydrochloride

At 20°C 1.7 g of 5-(1-piperazinil)benzofuran-2-carboxamide and 1.1 g of cyanoborohydride sodium are dissolved in 200 ml of methanol under stirring. A solution of 2.4 g of 3-(4-oxobutyl)-1H-indol-5-carbonitrile and 50 ml of methanol is added dropwise within 15 min at the same temperature. The reaction mixture is stirred at 20°C for approximately 18 hours, then cooled to 10°C for 6 hours. The precipitated solid product was separated, washed with methanol and with water, dried in vacuum. The solid residue is dissolved in tetrahydrofuran at 20°C with stirring and filtered. Water 1 N. HCl is added to the filtrate. The reaction mixture is then stirred at 20°C, then the precipitated solid product is filtered off. The residue on the filter is washed using THF and water, and thermally dried in a vacuum.

According to chromatographic comparison with the sample material obtained target compound is vilazodone (5-{4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinil}benzofuran-2-carboxamide hydrochloride).

1. The way to obtain 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinil)-benzofuran-2-carboxamide and/or one of its physiologically acceptable salts, characterized in that the compound of the formula I
,
in which L represents Cl, Br, I, SO2F, SO2CF3, SO2C2F5enter into reaction with 3-(-piperazine-1-libutil)indole-5-carbonitrile catalyzed by transition metal combinations through complex compounds of Pd,
and/or the fact that the resulting 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinil)benzofuran-2-carboxamide turn into one of its salts accession acid by treatment with acid.

2. The method according to claim 1, wherein L in the compound of formula I represents bromine.

3. The method according to claim 1 and/or 2, characterized in that the catalyst transition metal is a Tris(dibenzylideneacetone)-dipalladium or similar complex compounds Pd (0).

4. The way to obtain 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinil)benzofuran-2-carboxamide and/or one of its physiologically acceptable salts, characterized in that the compound of formula II

as a base or salt HX (where X=Cl, Br),
enter into reaction with 3-(4-oxobutyl)-1H-indol-5-carbonitrile by reductive amination, and/or the fact that 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinil)benzofuran-2-carboxamide turn into one of its salts accession acid by treatment with acid.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new chroman derivatives of formula I: , or to their pharmaceutically acceptable salts where m has a value of 0; p has a value of 2; q has a value of 2; Ar represents phenyl optionally substituted with halogen atom; R2 represents ; X represents -NR9-; n has a value of 2 or 3; each R3, R4, R5 and R6 independently represents hydrogen or C1-12alkyl; each R7 and R8 independently represents either hydrogen, or C1-12-alkyl, or R7 and R8 together with nitrogen whereto attached, can form 4-6-members ring, or one of R7 and R8 and one of R5 and R6 together with atoms whereto attached can form 4-6-members ring; and R9 represents hydrogen or C1-12-alkyl, or when R7 represents hydrogen or methyl, R9 together with R8 and atoms whereto attached can form 6-members ring.

EFFECT: preparation of chroman new derivatives and the pharmaceutical composition containing compounds of formula (I).

22 cl, 1 tbl, 5 ex

Amide derivatives // 2396259

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compound of formula I where m equals 0 or 1; R1 represents halogeno, (C1-6)alkyl, (C1-6)alkoxy, amino-(C2-6)alkoxy, (C2-6)alkylamino-(C2-6)alkoxy, di-[(C1-6)alkyl]amino-(C2-6)alkoxy, (C1-6)alkoxy-(C2-6)alkoxy, carbamoyl-(C1-6)alkoxy, N-(C1-6)alkylcarbamoyl-(C1-6)alkoxy, amino-(C1-6)alkyl, (C1-6)alkylamino-(C1-6)alkyl, di(C1-6)alkyl]amino-(C1-6)alkyl, carbamoyl-(C1-6)alkyl, N-(C1-6)alkylcarbamoyl-(C1-6)alkyl, (C1-6)alkoxy-(C2-6)alkylamino, heteroaryloxy, heterocyclyl-(C1-6)alkyl, heterocyclyloxy or heterocyclyl-(C1-6)alkoxy, and where any heteroaryl or heterocyclyl group in substituent R1 probably can have 1 or 2 substituents, selected from hydroxy, halogeno, (C1-6)alkyl, (C1-6)alkoxy, (C2-6)alkanoyl, hydroxy-(C1-6)alkyl, (C1-6)alkoxy-(C1-6)alkyl, and where any of determined above R1 substituents, which contains CH2 group bound with 2 carbon atoms, or group CH3, bound with an atom of carbon or nitrogen, probably can have on each said CH2 or CH3 group one or more substituents, selected from halogeno, hydroxy, amino, oxo, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkinyl,. (C3-6)cycloalkyl, (C3-6)cycloalkoxy, (C1-6)alkoxy, (C1-6)alkoxy-(C1-6)alkyl, (C1-6)alkylsulphamoyl, heteroaryl, heteroaryl-(C1-6)alkyl and heterocyclyl, and where any heterocyclyl group in substituent R1 probably can have 1 or 2 oxo or tioxo substituents; R2 represents (C1-6)alkyl; R3 represents hydrogen; R4 represents (C3-6)cycloalkyl, (C1-6)alkyl or heteroaryl, and R4 probably can be substituted with one or more substituents, selected from halogeno, (C1-6)alkyl, (C1-6)alkoxy; and R5 represents hydrogen, halogeno or (C1-6)alkyl; or its pharmaceutically acceptable salt, to method of obtaining said compounds, to pharmaceutical composition for application in treatment of diseases mediated by based on them cytokines. Invention also relates to methods of inhibiting p38α-kinase enzymes, TNFα production and production of cytokines.

EFFECT: obtained and described are novel compounds, which can be applied in treatment of medical conditions mediated by cytokines.

14 cl, 31 ex, 9 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I') which have inhibitory effect on ALK kinase: , where n' is selected from 1 and 2; R'2 is selected from halogen; R'3 is selected from -S(O)2NR'5R'6, -S(O)2R'6 and -C(O)NR'5R'6, where R'5 is selected from hydrogen and C1-6alkyl, and R'1 is selected from C1-6alkyl; and R'1 is selected from phenyl which is substituted with 3 radicals independently selected from C2-6alkoxy group, C1-6alkyl, -X'R'4 and -OXR'4, where X' denotes a bond, and R'4 is selected from piperazinyl, piperidinyl, pyrrolidinyl, morpholino, where R'4 can be optionally substituted with 1-3 radicals independently selected from C1-6 alkyl, provided that the following compound is excluded .

EFFECT: design of a method of inhibiting and using compounds for making a medicinal agent for treating diseases which respond to ALK kinase inhibition.

7 cl, 61 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel triazole-substituted aminobenzophenone compounds of formula (Ia) or (Ib), (values of radicals are given in the formula of invention) and a pharmaceutical composition containing the said compounds.

EFFECT: obtaining novel compounds which can be used in treating inflammatory, ophthalmological diseases or cancerous growths.

20 cl, 67 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I) and pharmaceutically acceptable salts, where R1-R7 mean the same as provided in the invention description and claim. Compounds of the formula (I) are specific inhibitors of 11b-HSD1. They can be applied in treatment and/or prevention of diseases caused by dysfunctions related to 11b-HSD1 enzyme, particularly in treatment and/or prevention of metabolic diseases, obesity, dyslipidemia, hypertension and/or diabetes, especially diabetes type "П". Additionally subject matter includes pharmaceutical composition for treatment and/or prevention of the said diseases.

EFFECT: improved efficiency of derivatives.

21 cl, 1 tbl, 146 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I): , where R1 is C1-C8alkyl optionally substituted with one to three substitutes selected out of substitute group A; R2 is C1-C6alkyl or C1-C6alkoxyC1-C6alkyl; R3 is C1-C6alkyl or C1-C6alkoxy; or R2 and R3 together with adjoining carbon atoms form optionally substituted non-aromatic 5-10-member carbon ring; R4 is hydrogen; G is group represented by the formula: or the rest as provided in the invention claim; and to pharmaceutical composition, application of claimed compounds, and method of atopic dermatitis prevention or treatment.

EFFECT: novel compounds useful as atopic dermatitis treatment medication and antipruritic medicines.

24 cl, 75 ex, 290 tbl

FIELD: chemistry.

SUBSTANCE: in novel compounds of the formula (I) R is radical selected out of i) , ii) , iii) , iv) , where R7 is halogen, cyano, C1-4alkyl, C1-4alkoxy; p is integer within 0 to 3; R1 is hydrogen, C2-4alkenyl or C1-4alkyl; R2 is hydrogen or C1-4alkyl; R3 and R4 are independently hydrogen or C1-4alkyl; R5 is: phenyl substituted with 1-3 groups selected independently out of trifluoromethyl, C1-4alkyl, cyano or halogen; naphthyl substituted with 1-3 groups selected independently out of trifluoromethyl, C1-4alkyl, cyano or halogen; benzofurane substituted with 1-3 groups selected independently out of C1-4alkyl or halogen; R6 is hydrogen or (CH2)qR8; R8 is hydrogen; m is zero or 1; n is 1; q is an integer within 1 to 4; r is 1 or 2; provided that if R5 is phenyl substituted with 1-3 groups selected independently out of trifluoromethyl, C1-4alkyl, cyano or halogen, then R is not radical i) ; and pharmaceutically acceptable salts or solvates thereof. The invention also refers to method (A) of compound obtainment, to compound application, to pharmaceutical composition, as well as to mammal treatment method.

EFFECT: obtainment of novel bioactive compounds with tachykinin receptor antagonist activity.

16 cl, 116 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I

where A, B and D each denotes N or CR5, where one of A, B and D denotes N, R1 denotes OR6, R2 denotes halogen, C1-C4alkyl, halogen(C1-C4)alkyl or OR7, R3 denotes a heteroarylalkyl group in which the heteroaryl fragment contains 5-6 atoms in the ring, at least one of which is an N atom, and the alkyl fragment with a branched or straight chain contains 1-5 carbon atoms, R4 denotes C3-C10cyclalkyl, C6-C14aryl, unsubstituted or substituted with one or more substitutes selected from a group comprising halogen, alkoxy, terazol-5-yl, 2-(heterocyclyl)tetrazol-5-yl or a carboxy group; heteroaryl containing 5-6 atoms in the ring; heterocyclic group saturated or partially saturated, containing 5-6 atoms in the ring, at least one of which is an N atom, unsubstituted or substituted with one or more substitutes selected from a group comprising alkoxy, alkoxyalkoxy, oxo, alkoxycarbonyl, alkylsulfanyl, alkylsufonyl or phenylsulfonyl; R5 denotes H; R6 denotes H or C1-C4alkyl with a branched or straight chain, unsubstituted or substituted with one or more halogens, R7 denotes H or C1-C12alkyl with a branched or straight chain, unsubstituted or substituted with one or more substitutes selected from a group which includes halogen; C3-C10cyclalkyl; saturated heterocyclic group containing 5-6 atoms in the ring, at least one of which is an O atom, or a heterocylcylalkyl group in which the heterocyclic fragment is saturated, partially saturated or unsaturated and contains 5-10 atoms in the ring, at least one of which is an O atom; or to a pharmaceutically acceptable salt thereof, as well as to a pharmaceutical composition for inhibiting PDE4 enzyme activity and to use of the said compound to prepare a medicinal agent.

EFFECT: novel compounds which can be used in medicine are obtained and described.

65 cl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cycloalkene derivatives of formula (I) in which X and Y are a group, in which X and Y together with a carbon atom on ring B to which they are bonded form a ring A, X and Y together represent a ring B substitute, or each of X and Y is a hydrogen atom.

EFFECT: invention relates to a medicinal agent based on the said compounds, which has inhibitory effect on intracellular signal transduction or cell activation induced by an endotoxin.

21 cl, 3 tbl, 191 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 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 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, 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: 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, 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: 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, 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: 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, 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

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