Physiologically active composition, substituted 1-oxo-1,2-dihydro[2,7]naphthyridines, method for their preparing, using and set

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a new physiologically active composition effecting on nicotine receptors and prepared in the form of tablets, granules, capsules, suspensions, solutions and injections. As an active component the composition comprises pharmaceutically effective amount of substituted 1-oxo-1,2-dihydro[2,7]-naphthyridine of the general formula (1)

or its salt, N-oxide or hydrate wherein R1 represents hydrogen atom, inert substitute, optionally substituted (C1-C5)-alkyl, optionally substituted amino-group; R2 and R3 represent independently of one another hydrogen atom, nitrile group, formyl group, inert substitute, optionally substituted (C1-C5)-alkyl, carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group; R4 at carbon atoms of pyridine moiety represents: hydrogen atom, halogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group, optionally substituted carbamoyl group; R4 at nitrogen atom of pyridine moiety forms pyridinium salt with pharmacologically acceptable anion and represents inert substitute. Also, invention relates to new substituted 1-oxo-1,2-dihydro[2,7]naphthyridines of the general formula (1) or their salts, N-oxides or hydrates wherein R1 and R4 have value given in cl. 1, and R2 and R3 represent independently of one another carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group. Also, invention relates to a method for their preparing and to a method for modulating activity of nicotine receptor and using compounds of the general formula (1) by cl. 1 for preparing physiologically active composition, and as ligands of nicotine receptors for aims of experimental investigations of physiological processes as "pharmacological tools". Also, invention relates to a set for preparing the composition.

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

7 cl, 2 sch, 2 tbl, 5 ex

 

This invention relates to physiologically active substances, medicinal and agrochemical candidates to physiologically active compositions, synthesis of new chemical substances, the search for new methods of their preparation and use.

More specifically, the present invention relates to new physiologically active compositions, the new substituted 1-oxo-1,2-dihydro[2,7]naphthirydines, methods for their preparation and use.

There are a large number of physiologically active compounds leaders and drugs, molecules which include naphthyridinone fragment. It is enough to refer to the "EnsembleR" by Prous Science www.prous.com), including more than 130,000 biologically active compounds, of which more than one thousand three hundred compounds represent various substituted naphthyridine system with a broad spectrum of biological activity.

Known also several dozen 1-oxo-1,2-dihydro[2,7]naphthirydines below the General formula 1 and in table 1.

in which: R1represents a hydrogen atom, an inert Deputy, optionally substituted C1-C5 alkyl, optionally substituted amino group;

R2and R3independently from each other represent a hydrogen atom, a nitrile group, a formyl group, inert Deputy, optional the nutrient substituted C 1-C5alkyl, carboxyl group, optionally substituted C1-6allyloxycarbonyl group or optionally substituted karbamoilnuyu group, excluding the compounds in which R2and R3at the same time represent a carboxyl group, optionally substituted C1-6allyloxycarbonyl group or optionally substituted karbamoilnuyu group;

R4located at the carbon atoms of the pyridine fragment represents: a hydrogen atom, a halogen atom, an inert Deputy, optionally substituted With hydroxy1-5alkyl, optionally substituted amino group, optionally substituted hydroxyl group, optionally substituted C1-6allyloxycarbonyl group, optionally substituted karbamoilnuyu group;

R4at the nitrogen atom of the pyridine fragment, form a pyridinium salt with a pharmacologically acceptable anion and is inert Deputy.

Known 1-oxo-1,2-dihydro[2,7]naphthirydines are different videological activity. In particular, naphthyridine 42 (table 1) possesses analgesic activity associated with the fact that he is an antagonist tachykinin NK receptors [Hosoki, R., Yanagisawa, M., Onishi, Y., Yoshioka, K., Otsuka, M. Pharmacological profiles of new orally active nonpeptide tachykinin NK1 receptor anatgonists. Eur. J. Pharmacol. 1998, 341(2-3): 235].

Compound 28 (PL. 1) effectively and selectively inhibits phosphodiesterase-5, it can be used to treat various diseases of the circulatory system, for example, erectile dysfunction [Tanabe Seiyaku Co., Ltd. JP 2001031679, 02.06.2001; WO 0012503 03.09.2000]. The naphthiridine 43 (table 1) is a highly effective antagonist of the substance P (substance P) and can potentially be used to treat autoimmune diseases [Takeda Chemical Industries, Ltd. JP 2002348289, 12.04.2002; WO 0274771, 09.26.2002].

It should be noted that were not known physiologically active composition, acting on nicotinic receptors, comprising as active substance substituted 1-oxo-1,2-dihydro-[2,7]naphthiridine General formula 1. Were not known also substituted 1-oxo-1,2-dihydro-[2,7]naphthiridine-3,4-dicarboxylic acids and their derivatives.

Given the high potential physiological activity of substituted 1-oxo-1,2-dihydro[2,7]naphthirydines relevant is the development of new physiologically active and pharmaceutical compositions comprising compounds of this type, new ligands of nicotinic receptors, Nova is substituted 1-oxo-1,2-dihydro[2,7] naphthirydines, methods of their preparation and use.

As a result of research aimed at finding new physiologically active compositions, physiologically active substances, compounds leaders, inventors received new physiologically active composition comprising 1-oxo-1,2-dihydro[2,7]naphthirydines, including previously unknown substituted 1-oxo-1,2-dihydro[2,7]naphthirydines, has developed methods for their preparation and use.

The present invention relates to new physiologically active compositions comprising substituted 1-oxo-1,2-dihydro[2,7]naphthirydines, the new substituted 1-oxo-1,2-dihydro[2,7]naphthiridine-3,4-dicarboxylic acids and their derivatives, 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 connection-leader, as well as to optimize the physiological activity of hit or leader, 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 evement, special organized with the aim to increase 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) pathologies or diseases.

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

"Deputy" means a chemical moiety that is attached to scaffold or semi-synthesis in the process of their synthesis.

"Inert Deputy" (or "not interfering", "Non-interfering substituent"means low or directionspanel radical, including, but not limited1-C7alkyl, C2-C7alkenyl,2-C7quinil,1-C7alkoxy, C7-C12aralkyl, Sames the config aralkyl, With7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C2-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,1-C7alkoxy, 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 a group, the radical or scaffold, have a Deputy, including but not limited to inert Deputy, halogen atom, nitro group, cyano group, sulfo group, hydroxyl group, amino group, amoxicillina group, carboxyl group, carnemolla group. For example: substituted alkyl means alkyl with one or more substituents, for example, hydroxyalkyl or methoxycarbonylethyl, amino-methoxycarbonyl-methyl, dimethylaminoethyl, 2-hydroxy-2-methoxycarbonyl-ethyl and others; substituted amino group means an amino group which has one or two substituent, for example, acylamino group, N,N-dialkylamino group, N-acyl-N-aryl-amino group, acetyl-methoxycarbonylmethyl-amino group and others; substituted phenyl means phenyl, which has one or more substituents, for example, 2-ethoxycarbonylphenyl, 4-amino-3-ethoxycarbonylphenyl, 3,4-diaminophenyl and other

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

"Aryl" means one or more aromatic cycles, each of which includes 5 or 6 carbon atoms. "Aryl" may be kondensirovannykh political, for example, 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, unsaturated or aromatic cycles with 5, 6 or 7 atoms, at least one of which is a heteroatom. Preferred heteroatoms are nitrogen, sulfur and oxygen. "Heterocycle" may be condensed politicla, for example, benzimidazole, quinoline, benzothiazole, benzoxazole, or unfused, for example, as bipyridyl.

The aim of the present invention is to provide a new physiologically active compositions in the form of tablets, granules, capsules, suspensions, solutions, injections, biologically active compounds or their mixtures, placed in a suitable package, for use in medicine and agriculture.

This goal is achieved by a new physiologically active composition, acting on nicotinic receptors, in the form of tablets, granules, capsules, suspensions, solutions, injections, biologically active compounds, is placed in a suitable package, containing as active substance pharmaceutically effective amount of substituted 1-oxo-1,2-dihydro[2,7]naphthiridine General formula 1 or its salt, N-hydroxy is and or hydrate:

in which: R1and R4have the above value, a R2and R3independently from each other represent a hydrogen atom, a nitrile group, a formyl group, inert Deputy, optionally substituted C1-C5alkyl, carboxyl group, optionally substituted C1-6allyloxycarbonyl group or optionally substituted karbamoilnuyu group.

The aim of the present invention is also a method of obtaining a new physiologically active composition, acting on nicotinic receptors.

This goal is achieved by mixing a physiologically effective amount of the active substance, with inertie in relation to substance fillers and/or diluents, followed by pelletizing, granulating, kapsulirovaniem, suspendirovanie, dissolution or dilution and placing them in suitable packaging, the distinctive feature of which consists in using as the active substance substituted 1-oxo-1,2-dihydro[2,7]naphthiridine General formula 1, or its salt, N-oxide or hydrate, in which R1and R4have the above significance, and R2and R3independently from each other represent a hydrogen atom, a nitrile group, a formyl group, inert Deputy, optional what about the substituted C 1-C5alkyl, carboxyl group, optionally substituted C1-6allyloxycarbonyl group or optionally substituted karbamoilnuyu group.

The aim of the present invention is also a method of treating and preventing various diseases of warm-blooded animals and humans.

This goal is achieved by the application of new physiologically active compositions containing substituted 1-oxo-1,2-dihydro[2,7]naphthiridine General formula 1 or its salt, N-oxide or hydrate, in which R1and R4have the above significance, and R2and R3independently from each other represent a hydrogen atom, a nitrile group, a formyl group, inert Deputy, optionally substituted C1-C5alkyl, carboxyl group, optionally substituted C1-6allyloxycarbonyl group or optionally substituted karbamoilnuyu group.

The aim of the present invention is also the use of physiologically active substances to obtain physiologically active composition, as well as ligands of nicotinic receptors for experimental studies of physiological processes as pharmacological tools.

This goal is achieved by the application of physiologically active 1-oxo-1,2-dihydro[2,7]naphthirydines General form is s 1 or their salts, N-oxides or hydrates, in which R1and R4have the above significance, and R2and R3independently from each other represent a hydrogen atom, a nitrile group, a formyl group, inert Deputy, optionally substituted C1-C5alkyl, carboxyl group, optionally substituted C1-6allyloxycarbonyl group or optionally substituted karbamoilnuyu group, to obtain physiologically active composition, as well as ligands of nicotinic receptors for experimental studies of physiological processes as pharmacological tools.

The aim of the present invention are also new substituted 1-oxo-1,2-dihydro [2,7] naphthirydines.

This goal is achieved substituted 1-oxo-1,dihydro[2,7]naphthirydines General formula 1 in which R1and R4have the above significance, and R2and R3independently from each other represent a carboxyl group, optionally substituted C1-6allyloxycarbonyl group or optionally substituted karbamoilnuyu group.

The purpose of the present invention is also a method of obtaining substituted 1-oxo-1,2-dihydro[2,7]naphthirydines General formula 1 in which R1and R4have the above significance, and R2and R3independently from others who ha represent a carboxyl group, optionally substituted C1-6allyloxycarbonyl group or optionally substituted karbamoilnuyu group.

This goal is achieved by oxidation of 1,2-dihydro[2,7]naphthirydines General formula 2 according to the scheme:

where: R1and R4have the above significance, and R2and R3independently from each other represent a carboxyl group, optionally substituted C1-6allyloxycarbonyl group or optionally substituted karbamoilnuyu group.

Source 1,2-dihydro[2,7]naphthirydines General formula 2 receives, for example, by the reaction of 3-aminomethylpyridine 3 acetylene 4 [Ivashchenko A.V., Vvedensky V.Y. Ivanov, YU.V., grip A.V., Tkachenko S.E., Perch IM Application for patent of Russia, 2003, 2003127780(029855)].

Below the invention is described using examples, which illustrate but do not limit the invention.

All solvents and reagents were obtained from commercial sources, such as ACROS (Acros) (Belgium), Sigma-Aldrich (Sigma-Aldrich) (United States), Lancaster (Lancaster) (England) and Chemdiv (ChemDiv) (USA).1H and13The NMR spectra were obtained on a spectrometer firm Varian (Varian) Gemini-300 (300 MHz) in CDCl3chemical shifts are carried out in the scale δ (ppm). Internal standard tetramethylsilane.

The content of the main prophetic the tion was controlled by HPLC on the device Shimadzu (Shimadzu) 10-AV (column Luna C18, Phenomenex, 25 cm×4.6 mm, UV detection at 215 and 254 nm) and LC-MS instrument Applied Biosystems (Shimadzu 10-AV LC, Gilson 215 of the automatic submission of the sample, the mass spectrometer API 150EX, detectors UV (215 and 254 nm) and ELS, column Luna C18, Phenomenex, 5 cm×2 mm).

Analytical TLC was performed on silica gel on aluminum plates Silufol UV254(5 cm×15 cm) (Kavalier, Czech Republic) or on glass slides with a 0.25-mm layer of silica gel 60 F254(Merck, Germany). Visualization was accomplished with UV light at a wavelength of 254 nm. For chromatographic purification of used silica gel 5-40 μm (Chemapol, Czech Republic) and 63 μm (EM Science, USA). In accordance with these LC/MS all the synthesized compounds had a basic substance content above 95%.

The biological activity of the synthesized compounds and the possibility of their use as ligands of nicotinic receptors for experimental studies of physiological processes as pharmacological tools were determined in rhabdomyosarcoma cells and pheochromocytoma in which nicotinic receptor controls the sodium permeability and, as a result, the cellular transmembrane electrical potential. The latter was measured using a pair of anionic fluorescent probes (DiBAC4(5) and DiBAC4(3)by changing FRET during cellular depolarization, as described in [Okun, I., Okun, A., Kaler, G. Pat. US 6287758, 2001]. And what the intention of FRET was performed using fluorescent parallel reader VICTOR 2V (PerkinElmer, USA) by excitation of the fluorescent donor (DiBAC4(3)) light with a wavelength of 485 nm and measuring the fluorescence intensity of the acceptor (DiBAC4(5)) at a wavelength of 615 nm. When depolarization of the cell membrane as a result of activation of nicotinic receptor, the effectiveness of FRET increases, resulting in increase of the fluorescence intensity of the acceptor.

Example 1. A common way to obtain 1-oxo-1,2-dihydro[2,7]naftiridinov General formula 1. To a suspension of 300 mg KMnO4in 20 ml of CH2Cl2added 3-4 drops of 10% solution of 18-crown-6 in CH2Cl2and a solution of 0.2 mmol of 1,2-dihydro[2,7]naphthiridine 2 in 3 ml of CH2Cl2. The mixture was stirred for 2 h, filtered through Selita, filtered, evaporated filtrat on a rotary evaporator, the residue was subjected to flash chromatography (ethyl acetate). Received 1-oxo-1,2-dihydro[2,7]naftalina 1 output (85-95%), including diethyl 2-(3-forebesi)-1-oxo-1,2-dihydro[2,7]naphthiridine-3,4, in primary forms 1(1): yield 89%, LC-MS m/z 399 (M+H); NMR1H (CDCl3TMS): s 9.67 (1H, d 8.86 (1H, d 8.18 (1H, m, 7.26-7.32 (1H, m, 6.92-7.04 (3H, s 5.37 (2H), q 4.40 (2H), q 4.22 (2H, t 1.41 (3H, t, 1.14 (3H), 2-(3-forebesi)-1-oxo-1,2-dihydro[2,7]naphthiridine-3,4, in primary forms 1(2): yield 92%: LC-MS m/z 399 (M+H); NMR1H (CDCl3TMS): s 9.68 (1H, d 8.86 (1H, d 8.18 (1H, m, 7.22-7.30 (1H, m, 7.02-7.12 (3H, s 5.45 (2H), q 4.39 (2H), q 4.23 (2H), 11.39 (3H), t1.14 (3H).

Example 2. A common way to obtain 1-oxo-1,dihydro[2,7]naftiridinov General formula 1. To a solution of 0.5 mmol of 1,2-dihydro[2,7] naftalina General formula 2 in 4 ml of anhydrous ethanol 2 g of silica gel and dried on a rotary evaporator. The obtained granular mass was distributed in a thin layer in a Petri dish, was irradiated with a UV lamp within 12-36 h in contact with the oxygen of the air, was introduced in the starting area filled with silica gel chromatographic column and suirable a mixture of CHCl3/Meon/Et3N=100:6:1. After removal of the solvent from additionally separated by received 1-oxo-1,2-dihydro[2,7]naftalina 1 with a yield of 60-80%, including: diethyl 2-benzyl-1-oxo-1,2-dihydro[2,7]naftalin-3,4-in primary forms 1(3), yield 62%, yellow crystals,1H NMR, δ, ppm (CHCl3): 9.67(s, 1H), 8.84(d, J=5.8 Hz, 1H), 8.17(d, J=5.8 Hz, 1H), 7.27-7.35(m, 3H), 7.19-7.24(m, 2H), 5.4 (s, 2H), 4.39(q, J=7.1 Hz, 2H), 4.16 (q, J=7.1 Hz, 2H), 1.39(t, J=7.1 Hz, 3H), 1.08(t, J=7.1 Hz, 3H);13With NMR, δ, ppm (CHCl3): 164.1, 162.3, 161.0, 152.1, 151.8, 139.0, 135.4, 129.2, 128.6, 127.9, 127.2, 119.7, 118.4, 106.7, 63.0, 62.1, 48.8, 14.1, 13.3; LC-MS retention time 3.87 min, m/z 381(M+1); 2-(4-terbisil)-1,2-dihydro[2,7]naphthiridine-3,4, in primary forms 1(4), yield 61%, yellow crystals,1H NMR, δ, ppm (CDCl3): 9.64(s, 1H), 8.82(d, J=5.6 Hz, 1H), 8.15(d, J=5.6 Hz, 1H), 7.20-7.25(m, 2H), 6.95-7.00(m, 2H), 5.32 (s, 2H), 4.37(q, J=7.0 Hz, 2H), 4.22(q, J=7.1 Hz, 2H), 1.39(t, J=7.1 Hz, 3H), 1.15(t, J=7.1 Hz, 3H);13With NMR, δ, ppm (CDCl3): 164.1, 163.6, 162.4, 161.1, 161.0, 152.2, 151.8, 144.2, 139.0, 131.2, 131.1, 129.4, 129.3, 119.7, 118.4, 115.7, 115.5, 106.8, 63.1, 62.2, 48.4, 14.1, 13.4; LC-MS retention time 4.00 min, m/z 399(M+1).

Analogously to example 1 get the other the s 1-oxo-1,2-dihydro[2,7] naftiridinov General formula 1:

1-oxo-1,2-dihydro[2,7]naphthiridine-3,4, in primary forms,

2-methyl-1-oxo-1,2-dihydro[2,7]naphthiridine-3,4, in primary forms,

6-trifluoromethyl-1-oxo-1,2-dihydro[2,7]naphthiridine-3,4, in primary forms,

2-(2-cyanoethyl)-1-oxo-1,2-dihydro[2,7]naphthiridine-3,4, in primary forms,

2-(4-carboxy-cyclohexylmethyl)-1-oxo-1,2-dihydro[2,7]naphthiridine-3,4, in primary forms,

2-(3-pyridyl)-1-oxo-1,2-dihydro[2,7]naphthiridine-3,4, in primary forms,

2-(3-furyl)-1-oxo-1,2-dihydro[2,7]naphthiridine-3,4, in primary forms.

Example 3. The biological activity of 1-oxo-1,2-dihydro[2,7] naftiridinov General formula 1 and their use as ligands of nicotinic receptors for experimental studies of physiological processes as pharmacological tools. Fokusirovannyi library comprised of 35 compounds, including 1-oxo-1,2-dihydro[2,7]naftalina General formula 1, was tested for the ability to activate nicotinic receptor on the cell rhabdomyosarcoma and pheochromocytoma. As the standard used gramicidin. The rhabdomyosarcoma cells were grown in the environment of Dulbecco at 37°C in a humid atmosphere with CO25% to about 100% of confluently in the wells of 96-hole plates. The medium was removed from the wells and replaced with fresh medium (250 μL)containing a mixture of dyes in a ratio of 1:1 at a final concentration of 1 μm for each is racialy. Cells were incubated for 30 minutes in order that the concentration of the dyes was balanced between intra - and extracellular environments in accordance with the cellular transmembrane potential. After a 30-minute equilibration of the dye was made the first measurement of the fluorescence of the cells in a quiescent state (Iabout), after which the studied compounds of General formula (1) or (2), dissolved in dimethyl sulfoxide, was added to each well. The concentration was brought to 30 μM and measured fluorescence at zero time (°Ii). The cells were maintained for 10 minutes together with compounds of General formula (1) or (2), after which he made repeated measurement of fluorescence (10Ii). Increase intensity (ΔIi=10Ii-0Ii) characterized the depolarization of the cells, which were expressed relative to the depolarization induced by gramicidin D (ΔIGID=10IGID-0IGID):ΔIi/ΔIGIDX100%. The effect of each compound was measured in four repetitions and the validity effect was assessed by coefficient t-test with a confidence interval of 95%. Below are the results of screening of some 1-oxo-1,2-dihydro[2,7]naftiridinov General formula 1 on Biologicheskie activity on nicotinic cocktail recipes. is.

As seen in the results table, compounds 1(1) 1(4) (table 2) significantly change the intensity of fluorescence probes that are sensitive to membranome potential that clearly indicates the modulation of their activity nicotinic receptor.

Example 3. An example illustrating the preparation of tablets containing 50 mg of active ingredient. Mix 800 mg of starch, 800 mg of powdered lactose, 200 mg of talc and 500 mg of compound 1(4) and pressed 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 into tablets suitable form weighing 280 mg each.

Example 4. Capsules containing 200 mg of diethyl compound 1(4), according to the invention can be obtained by thorough mixing of compounds 1(4) with lactose powder in a 2:1 ratio. Received poroshkoobraznuju mix pack 300 mg in gelatin capsules of suitable size.

Example 5. Injectable compositions for intramuscular, intraperitoneal or subcutaneous injection can be prepared by mixing 500 mg of the active ingredient with suitable solubility, for example, hydrochloride of compound 1(4) with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injectable water. The resulting solution is filtered and placed on 1 im capsules, which are sealed and sterilized in an autoclave.

1. Physiologically active composition, acting on nicotinic receptors, in the form of tablets, granules, capsules, suspensions, solutions, injections, containing as active substance pharmaceutically effective amount of substituted 1-oxo-1,2-dihydro[2,7]naphthiridine General formula 1 or its salt, N-oxide or hydrate:

in which

R1represents a hydrogen atom, an inert Deputy, optionally substituted C1-C5alkyl, optionally substituted by an amino group;

R2and R3independently from each other represent a hydrogen atom, a nitrile group, a formyl group, inert Deputy, optionally substituted C1-C5alkyl, carboxyl group, optionally substituted

C1-6allyloxycarbonyl group or optionally substituted karbamoilnuyu group;

R4located at the carbon atoms of the pyridine fragment represents a hydrogen atom, a halogen atom, an inert Deputy, optionally substituted hydroxy-C1-5alkyl, optionally substituted by an amino group, optionally substituted hydroxyl group, optionally substituted C1-6allyloxycarbonyl group, optionally substituted carb is mailnow group;

R4at the nitrogen atom of the pyridine fragment, form a pyridinium salt with a pharmacologically acceptable anion and is inert Deputy.

2. The method of modulating the activity of nicotinic receptor by introducing a warm-blooded animal or human physiologically active composition according to claim 1.

3. The application of physiologically active substances of General formula 1 according to claim 1, having the properties acting on nicotinic receptors, to obtain physiologically active composition, as well as ligands of nicotinic receptors for experimental studies of physiological processes as pharmacological tools.

4. Substituted 1-oxo-1,2-dihydro[2,7]naphthirydines General formula 1 or their salts, N-oxides or hydrates,

in which R1and R4have the meanings specified in claim 1, a R2and R3independently from each other represent a carboxyl group, optionally substituted C1-6allyloxycarbonyl group or optionally substituted karbamoilnuyu group.

5. The method of obtaining compounds of General formula 1 according to claim 4, in which the effect of the oxidant on 1,2-dihydro[2,7]naphthiridine General formula 2

in which

R1and R4/sup> have the meanings specified in claim 1, a R2and R3independently from each other represent a carboxyl group, optionally substituted C1-6allyloxycarbonyl group or optionally substituted karbamoilnuyu group.

6. Set to obtain physiologically active composition, acting on nicotinic receptors containing the individual substituted 1-oxo-1,2-dihydro[2,7]naphthiridine General formula 1 or its salt, N-oxide or hydrate according to claim 1 or a mixture thereof, and an acceptable package, which is placed in the specified individual compound or a mixture.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes a compound of the general formula (I) or (II) wherein R1 represents hydrogen atom; R2 is taken among the group consisting of aryl and heteroaryl; R3 is taken among the group consisting of halogen atom, nitro-, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, trifluoromethyl, trifluoromethoxy-group, -NH2, -NH-(C1-C6)-alkyl and -N-(C1-C6)-alkyl)2; b is a whole number from 0 to 4; R4 is taken independently among the group consisting of halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkoxycarbonyl, phenyl (wherein phenyl group can be substituted optionally with one-three substitutes taken independently among RD), phenylsulfonyl, heteroaryl (wherein heteroaryl can be substituted optionally with one-three substitutes taken independently among RD), heterocycloalkyl, -NH2, -NHRA, -N-(RA)2,

wherein each RD is taken independently among halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C4)-alkyl, (C1-C4)-alkylthio, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylcarbonyl, trifluoromethyl, trifluoromethoxy-group, -NH2. -NHRA, -N-(RA)2, -C(O)N(RA)2, -SO2N(RA)2, acetylamino-, nitro-, cyano-group, formyl, (C1-C6)-alkylsulfonyl, carboxy-(C1-C6)-alkyl and aralkyl; c = 0; a means a whole number from 0 to 1; Y is taken among the group consisting of a residue -(C1-C)-alkyl, -C(O)-, -(C2-C6)-alkenyl)-carbonyl, -carbonyl-(C1-C6)-alkyl)-, -C(S)-, -C(O)NH-(C1-C6)_alkyl), -C(O)-(C3-C7)-cycloalkyl)- and (C3-C7)-cycloalkyl)-C(O)-; represents phenyl;

is taken among the group consisting of phenyl, heteroaryl and cycloalkyl under condition that when R1 represents hydrogen atom, R3 represents hydrogen atom, b = 0, c = 1, Y represents -CH2-, represents phenyl and represents phenyl then R2 is not trimethoxyphenyl, and its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition designated for inhibition of activity of phosphodiesterase comprising a pharmaceutically acceptable vehicle and compound by cl. 1, method for preparing pharmaceutical composition, methods for treatment of sexual dysfunction by using compound by cl. 1 or pharmaceutical composition, method for increasing the concentration of cGMP in penis tissue and method for treatment of state when inhibition of activity of phosphodiesterase shows the favorable effect. Invention provides preparing novel compounds possessing useful biological properties.

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

17 cl, 7 tbl, 98 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new urea-substituted imidazoquinolines of the formula (1):

wherein R, R1, R2 and n have values given in the description, and to pharmaceutical preparations based on these compounds. Proposed compounds possess effect of immunomodulators initiating biosynthesis of different cytokines. Also, invention relates to methods for treatment of different states, among them viral diseases and neoplastic pathologies.

EFFECT: improved method for induction, valuable properties of compounds.

47 cl, 11 tbl, 142 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, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

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

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

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

33 cl, 7 tbl, 42 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacology.

SUBSTANCE: invention relates to gyrase inhibitors that reduce amount of microorganisms in biological sample by contacting the indicated sample with compound of the formula (I): , to a method for treatment of bacterial infection by using compounds of the formula (I), compounds of the formula (I) and a pharmaceutical composition comprising compounds of the formula (I). Invention provides the enhanced effectiveness of treatment.

EFFECT: valuable medicinal properties of gyrase.

54 cl, 5 tbl, 13 ex

FIELD: organic chemistry, medicinal biochemistry, pharmacy.

SUBSTANCE: invention relates to substituted benzimidazoles of the formula (I): and/or their stereoisomeric forms, and/or their physiologically acceptable salts wherein one of substitutes R1, R2, R3 and R4 means a residue of the formula (II): wherein D means -C(O)-; R8 means hydrogen atom or (C1-C4)-alkyl; R9 means: 1. (C1-C6)-alkyl wherein alkyl is linear or branched and can be free of substituted by one-, bi- or tri-fold; Z means: 1. a residue of 5-14-membered aromatic system that comprises from 1 to 4 heteroatoms as members of the cycle that represent nitrogen and oxygen atoms wherein aromatic system is free or substituted; 1.1 a heterocycle taken among the group of oxadiazole or oxadiazolone that can be unsubstituted or substituted; 2. (C1-C6)-alkyl wherein alkyl is a linear or branched and monosubstituted with phenyl or group -OH; or 3. -C(O)-R10 wherein R10 means -O-R11, -N(R11)2 or morpholinyl; or R8 and R9 in common with nitrogen atom and carbon atom with that they are bound, respectively, form heterocycle of the formula (IIa): wherein D, Z and R10 have values given in the formula (II); A means a residue -CH2-; B means a residue -CH-; Y is absent or means a residue -CH2-; or X and Y in common form phenyl. The cyclic system formed by N, A, X, Y, B and carbon atom is unsubstituted or monosubstituted with (C1-C8)-alkyl wherein alkyl is monosubstituted with phenyl, and other substitutes R1, R2, R3 and R4 mean independently of one another hydrogen atom, respectively; R5 means hydrogen atom; R6 means the heteroaromatic cyclic system with 5-14 members in cycle that comprises 1 or 2 nitrogen atoms and can be unsubstituted or substituted. Also, invention relates to a medicinal agent for inhibition of activity of IkB kinase based on these compounds and to a method for preparing the indicated agent. Invention provides preparing new compounds and medicinal agents based on thereof for aims for prophylaxis and treatment of diseases associated with the enhanced activity of NFkB.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 7 tbl, 224 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives if azaindole of the formula (I)

or its pharmaceutically acceptable salts wherein the formula is taken among the group consisting of , , and and wherein each among R1, R2, R3 and R4 is taken independently among the group consisting of hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, halogen atom, cyano-group (CN), phenyl, nitro-group, -OC(O)R15, -C(O)R15, -C(O)OR16, -OR19, -SR20 and NR21R22 wherein R15 is taken independently among the group including hydrogen atom (H),(C1-C6)-alkyl and (C2-C6)-alkenyl; each among R16, R19 and R0 is taken independently among the group including hydrogen atom (H), (C1-C6)-alkyl or (C1-C6)-alkyl substituted with from 1 to 3 halogen atoms; each among R21 and R22 is taken among the group including hydrogen atom(H), hydroxy-group (OH), (C1-C6)-alkyl; R5 represents the group (O)m wherein m = 0 or 1; n = 1 or 2; R6 is taken among the group including hydrogen atom (H), (C1-C6)-alkyl, -C(O)R24 and -C(O)OR5 under condition that carbon atoms comprising carbon-carbon double bond of indicated (C3-C6)-alkenyl are not the addition point to nitrogen atom to which R6 is joined; R24 is taken among the group consisting of hydrogen atom (H), and (C1-C6)-alkyl; R25 represents (C1-C6)-alkyl; each among R7, R8, R9, R10, R11, R12, R13 and R14 is taken independently among the group including hydrogen atom (H) and (C1-C6)-alkyl; Ar is taken among the group including:

, and . Compounds of the formula (I) inhibit HIV-1 that allows proposing their applying in medicine.

EFFECT: valuable medicinal and antiviral properties of compounds.

22 cl, 13 sch, 2 tbl

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, herbicides, agriculture.

SUBSTANCE: invention elates to novel derivatives of uracil of the formula [I] possessing herbicide activity, a herbicide composition based on thereof and to a method for control of weeds. In derivatives of uracil of the formula [I] the group Q-R3 represents a substituted group taken among:

wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

The invention relates to a derivative of acrylic acid, useful in agriculture (especially as fungicides but also as plant growth regulators, insecticides and nematicides), to the processes of their production, agricultural (especially fungi) compositions containing them and to methods of using them to combat fungi, especially fungal infections of plants, for regulating the growth of plants and to destroy or suppress insect and nematode pests

FIELD: organic chemistry, fungicides, agriculture.

SUBSTANCE: invention describes 1-pyridinyl-2-azolyl-1-(4-fluorophenyl)ethanols of the general formula (I)

wherein X means nitrogen atom (N) or -CH, and their using as fungicides. Proposed compounds possess high fungicide activity and can be used as agricultural, industrial, medicinal and veterinary fungicides.

EFFECT: valuable properties of compounds.

3 cl, 1 tbl, 4 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved methods for preparing compounds of the formulae (I) and (II) or their salts wherein X represents halogen atom; Y represents halogen atom, halogenalkyl, alkoxycarbonyl or alkylsulfonyl; n = 0-3. Method for preparing compound of the formula (I) involves catalytic hydrogenation of compound of the formula (II) in the presence of a catalyst, such as palladium in solvent medium at temperature from 0°C to 60°C. Method provides preparing the end compounds with high yields (95-97%) and high purity degree due to minimization of by-side dehalogenation reaction of the parent reagents. Method for preparing compound of the formula (II) involves treatment of the corresponding derivative of 2-fluoro-derivative with the cyanide source in the presence of a catalyst, such as tetraalkyl ammonium salt in an aqueous solvent or without solvent at temperature from 10°C to 60°C. Method provides preparing the end compounds with high yields (80-90%), high purity (98%) at moderate temperatures.

EFFECT: improved preparing methods.

23 cl, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved methods for preparing compounds of the formulae (I) and (II) or their salts wherein X represents halogen atom; Y represents halogen atom, halogenalkyl, alkoxycarbonyl or alkylsulfonyl; n = 0-3. Method for preparing compound of the formula (I) involves catalytic hydrogenation of compound of the formula (II) in the presence of a catalyst, such as palladium in solvent medium at temperature from 0°C to 60°C. Method provides preparing the end compounds with high yields (95-97%) and high purity degree due to minimization of by-side dehalogenation reaction of the parent reagents. Method for preparing compound of the formula (II) involves treatment of the corresponding derivative of 2-fluoro-derivative with the cyanide source in the presence of a catalyst, such as tetraalkyl ammonium salt in an aqueous solvent or without solvent at temperature from 10°C to 60°C. Method provides preparing the end compounds with high yields (80-90%), high purity (98%) at moderate temperatures.

EFFECT: improved preparing methods.

23 cl, 3 ex

FIELD: organic chemistry, agriculture, insecticides.

SUBSTANCE: invention relates to a substituted anilide derivative of the formula (I): wherein R1 represents hydrogen atom, (C1-C6)-alkyl group; R2 represents hydrogen atom, halogen atom or halogen-(C1-C6)-alkyl group; R3 represents hydrogen atom, halogen atom, (C1-C6)-alkyl group, hydroxyl group or (C1-C6)-alkoxy-group; t = 1; m = 0; each among X that can be similar or different represents (C2-C8)-alkyl group, hydroxy-(C1-C6)-alkyl group or (C3-C6)-cycloalkyl-(C1-C6)-alkyl group; n = 1 or 2; Z represents oxygen atom; Q means a substitute represented by any of the following formulae: Q1-Q3, Q6, Q8-Q12, Q14-Q19, Q21 and Q23 (wherein each among Y1 that can be similar or different represents halogen atom, (C1-C6)-alkyl group, and so on); Y2 represents (C1-C6)-alkyl group or halogen-(C1-C6)-alkyl group; Y3 represents (C1-C6)-alkyl group, halogen-(C1-C6)-alkyl group or substituted phenyl group; p represents a whole number from 1 to 2; q represents a whole number from 0 or 2; r represents a whole number from 0 to 2. Also, invention proposes a chemical for control of pests of agricultural and fruit crops. The chemical comprises substituted anilide derivative of the formula (I) as an active component and represents insecticide, fungicide or acaricide. Also, invention proposes a method for addition of the chemical for control of pests of agricultural and fruits crops. Also, invention proposes aniline derivative represented by the general formula (II): wherein R1 represents hydrogen atom, (C1-C6)-alkyl group; R2 represents hydrogen atom, halogen atom or halogen-(C1-C6)-alkyl group; R3 represents hydrogen atom, halogen atom, (C1-C6)-alkyl group, hydroxyl group or (C1-C6)-alkoxy-group; t = 1; m = 0; each among X that can be similar or different represents (C2-C8)-alkyl group, hydroxy-(C1-C6)-alkyl group or (C3-C6)-cycloalkyl-(C1-C6)-alkyl group; n = 1 or 2. Invention provides the development of anilide derivative as insecticide, fungicide and acaricide against pests of agricultural and fruit crops.

EFFECT: valuable properties of compound.

5 cl, 6 tbl, 27 ex

FIELD: organic chemistry, agriculture, insecticides.

SUBSTANCE: invention relates to a substituted anilide derivative of the formula (I): wherein R1 represents hydrogen atom, (C1-C6)-alkyl group; R2 represents hydrogen atom, halogen atom or halogen-(C1-C6)-alkyl group; R3 represents hydrogen atom, halogen atom, (C1-C6)-alkyl group, hydroxyl group or (C1-C6)-alkoxy-group; t = 1; m = 0; each among X that can be similar or different represents (C2-C8)-alkyl group, hydroxy-(C1-C6)-alkyl group or (C3-C6)-cycloalkyl-(C1-C6)-alkyl group; n = 1 or 2; Z represents oxygen atom; Q means a substitute represented by any of the following formulae: Q1-Q3, Q6, Q8-Q12, Q14-Q19, Q21 and Q23 (wherein each among Y1 that can be similar or different represents halogen atom, (C1-C6)-alkyl group, and so on); Y2 represents (C1-C6)-alkyl group or halogen-(C1-C6)-alkyl group; Y3 represents (C1-C6)-alkyl group, halogen-(C1-C6)-alkyl group or substituted phenyl group; p represents a whole number from 1 to 2; q represents a whole number from 0 or 2; r represents a whole number from 0 to 2. Also, invention proposes a chemical for control of pests of agricultural and fruit crops. The chemical comprises substituted anilide derivative of the formula (I) as an active component and represents insecticide, fungicide or acaricide. Also, invention proposes a method for addition of the chemical for control of pests of agricultural and fruits crops. Also, invention proposes aniline derivative represented by the general formula (II): wherein R1 represents hydrogen atom, (C1-C6)-alkyl group; R2 represents hydrogen atom, halogen atom or halogen-(C1-C6)-alkyl group; R3 represents hydrogen atom, halogen atom, (C1-C6)-alkyl group, hydroxyl group or (C1-C6)-alkoxy-group; t = 1; m = 0; each among X that can be similar or different represents (C2-C8)-alkyl group, hydroxy-(C1-C6)-alkyl group or (C3-C6)-cycloalkyl-(C1-C6)-alkyl group; n = 1 or 2. Invention provides the development of anilide derivative as insecticide, fungicide and acaricide against pests of agricultural and fruit crops.

EFFECT: valuable properties of compound.

5 cl, 6 tbl, 27 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of 4-phenylpyridine N-oxides of the general formula (I) and their pharmaceutically acceptable acid-additive salts wherein R means hydrogen atom, lower alkyl or halogen atom; R1 means hydrogen atom; R2 and R2' mean independently of one another hydrogen, halogen atom, trifluoromethyl group, (lower)-alkoxy-group; or R2 and R2' can mean in common the group -CH=CH-CH=CH- optionally substituted with one or two substitutes taken among lower alkyl or (lower)-alkoxy-group; R3 and R3' mean independently of one another hydrogen atom, lower alkyl; R4 and R4' mean independently of one another -(CH2)mOR6 or lower alkyl; or R4 and R4' form in common with N-atom to which they are bound substituted R5-cyclic tertiary amine representing pyrrolidine-1-yl, piperidine-1-yl, piperazine-1-yl, morpholine-4-yl or 1,1-dioxomorpholine-4-yl; R5 means hydrogen atom, hydroxyl, -COOR3, -N(R3)CO-lower alkyl or -C(O)R3; R6 means hydrogen atom, lower alkyl; X means -C(O)N(R6)-, -N(R6)C(O)-; n = 0, 1, 2, 3 or 4; m = 1, 2 or 3. Also, invention describes a medicinal agent comprising these compounds. Compounds can be used as drugs in treatment or prophylaxis of diseases associated with antagonists of NK-1 receptor.

EFFECT: valuable medicinal properties of agent.

6 cl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of 4-phenylpyridine N-oxides of the general formula (I) and their pharmaceutically acceptable acid-additive salts wherein R means hydrogen atom, lower alkyl or halogen atom; R1 means hydrogen atom; R2 and R2' mean independently of one another hydrogen, halogen atom, trifluoromethyl group, (lower)-alkoxy-group; or R2 and R2' can mean in common the group -CH=CH-CH=CH- optionally substituted with one or two substitutes taken among lower alkyl or (lower)-alkoxy-group; R3 and R3' mean independently of one another hydrogen atom, lower alkyl; R4 and R4' mean independently of one another -(CH2)mOR6 or lower alkyl; or R4 and R4' form in common with N-atom to which they are bound substituted R5-cyclic tertiary amine representing pyrrolidine-1-yl, piperidine-1-yl, piperazine-1-yl, morpholine-4-yl or 1,1-dioxomorpholine-4-yl; R5 means hydrogen atom, hydroxyl, -COOR3, -N(R3)CO-lower alkyl or -C(O)R3; R6 means hydrogen atom, lower alkyl; X means -C(O)N(R6)-, -N(R6)C(O)-; n = 0, 1, 2, 3 or 4; m = 1, 2 or 3. Also, invention describes a medicinal agent comprising these compounds. Compounds can be used as drugs in treatment or prophylaxis of diseases associated with antagonists of NK-1 receptor.

EFFECT: valuable medicinal properties of agent.

6 cl, 32 ex

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