Heterocyclic nitrogen-containing or oxygen-containing insecticidal compounds formed from dialdehydes, and production and use thereof

FIELD: chemistry.

SUBSTANCE: invention relates to novel heterocyclic nitrogen- and oxygen-containing compounds having insecticidal activity. In formulae (A) (B) (C) (D) R1 is a 5- or 6-member heterocyclic ring containing a nitrogen, oxygen and/ or sulphur atom, a halogen-substituted 5- or 6-member heterocyclic ring containing a nitrogen, oxygen and/or sulphur atom, a substituted or unsubstituted phenyl, where the substitutes are one or more groups selected from a group consisting of halogen atoms, C1-4 halogen alkyl or C1-4 chloroalkoxyl; R5, R6, R7, R8 and R9 are H, saturated or unsaturated C1-4 alkyl, halogen atom, saturated or unsaturated C1-4 alkoxyl, saturated C1-4 halogenalkoxyl, C1-4 alkylcarbonyl, C1-8 alkyl ester, C1-4 alkylsulphonyl, phenyl, benzyl or trifluoromethane sulphonyl ether group; Y is nitro, cyano, trifluoromethyl, trifluoroacetyl or trifluoromethylsuphonyl. Values of radicals R, R2-R4 are given in the claim.

EFFECT: invention also relates to an agrochemical composition containing said compounds, use of the agrochemical composition in pest control and a method of producing said compounds.

12 cl, 7 tbl, 36 ex

 

The technical field

This invention relates to new derivatives of neonicotinoid, to a method for their production and to their applications.

Prior art

Submitted by Imidacloprid, neonicotinoid insecticide was the triggering factor in the opening of pesticides to the property of high insecticidal activity, a wide insecticidal spectrum, low toxicity to mammals and aquatic animals, a good system properties suitable field stability and favourable for the environment. After Imidacloprid was developed series neonicotinoid insecticides, such as thiacloprid, clothianidin, thiamethoxam, acetamiprid, nitenpyram and dinotefuran (EP 247477, 296453, 685477, 235725, 235725, 315826, 192060, 244777, 0386565, 580553, 1031566, JP 62292765, 8259568, 8291171 and 7242633).

However, the application and development of these compounds is limited due to resistance caused by too frequent use of Imidacloprid, and cross-resistance among neonicotinoids insecticides caused structural similarity. However, neonicotinoid insecticides, mainly exhibit high activity against pests Homoptera and Coleoptera, and narrow insecticidal spectrum limits their wide application in pest control.

Thus, in this technical field, it is imperative to develop a connection with effektivnye activities from high-level nitromethylene compounds, to solve the problem of sustainability, to enhance insecticidal spectrum and apply them in insecticidal compositions.

Brief description of the invention

In this invention the proposed new and effective insecticides, which allow to solve the problem of resistance to neonicotinoid insecticides to enhance insecticidal spectrum and to solve the problems existing in this field of technology.

One aim of the invention is the development of derivatives for effective pest control, and receipt of them.

Another aim of the invention is to develop a growing and protection of collected plants and prevent their infestation by insects.

In accordance with the first aspect of the invention proposed compound of formula (A), (B), (C) or (D), its optical isomer, CIS-TRANS-isomer or its agrokhimichesky acceptable salt

where R1represents 5 - or 6-membered heterocycle containing nitrogen atom, oxygen and/or sulfur, substituted with halogen 5 - or 6-membered heterocycle containing nitrogen atom, oxygen and/or sulfur, substituted or unsubstituted phenyl, where the substituents are one or more than one group selected from the group consisting of halogen atoms, C1-4halogenoalkane the C 1-4haloalkoxy;

R2represents H, C1-8saturated or unsaturated alkyl, substituted with halogen, C1-8saturated or unsaturated alkyl, -CH2CH2OCH2CH3, -CH2CH2OCH3C1-8saturated or unsaturated alkoxyl, phenyl, benzyl, C1-4alkylsulphonyl or1-4alkylsulfonyl;

R3and R4independently selected from H, C1-6of alkyl, allyl, benzyl, C1-4alkoxy-C1-4of alkyl, C1-4alkoxycarbonyl, phenoxycarbonyl,2-6alkynylaryl, C2-3alkenylboronic,3-6cycloalkylcarbonyl, unsubstituted bentilee group or benzoline group, substituted by one or more than one group selected from the group consisting of halogen atoms, C1-4of alkyl, C1-4halogenoalkane,1-4alkoxyl or C1-4alkylcarboxylic, furancarboxylic or N,N-dimethylcarbamyl; or R3and R4together form-CH2-CH2-, -CH2-CH2-CH2- or-CH2-XR-CH2-where X represents N, O, S, or another heteroatom; R represents a Deputy on X and is selected from H, C1-6of alkyl, allyl, benzyl, phenyl, C1-4alkoxy-C1-4of alkyl, C1-4alkoxycarbonyl, phenoxycarbonyl, C2-6alkynylaryl,2-3alkenylboronic,3-61-4halogenoalkane, C1-8saturated or unsaturated alkyl or alkoxyl or1-4alkylcarboxylic, furancarboxylic or N,N-dimethylcarbamyl.

R5, R6, R7, R8and R9represents H, saturated or unsaturated With1-4alkyl, halogen atom, saturated or unsaturated C1-8alkoxy, saturated or unsaturated With1-4halogenoalkanes, C1-4alkylsulphonyl, C1-8alkyl ester With1-4alkylsulfonyl, phenyl or benzyl;

Y represents nitro, cyano, trifluoromethyl, TRIFLUOROACETYL or trifloromethyl.

In one preferred embodiment R1selected from pyridyl, thiazolyl, pyrimidinyl, tetrahydrofuryl, oxazolyl or their halogenated groups.

In one preferred embodiment R1is halogenerator, halogenoacetyl, halogenopyrimidines, halogenerator or halogenoacetyl. Preferred halogenated groups are chlorides.

In another embodiment R1represents,or.

In another embodiment R2pre is is a N, saturated or unsaturated With1-4alkyl, saturated or unsaturated With1-4halogenoalkane,1-4alkylsulphonyl, unsubstituted benzyl or benzyl substituted by one or more than one group selected from the group consisting of a halogen atom, a C1-4halogenoalkane or1-4haloalkoxy.

In one embodiment R2represents N or C1-3alkyl. More preferably R2represents H or methyl.

In another embodiment R3and R4represent H, C1-6alkyl, or R3and R4together form-CH2-CH2- or-CH2-CH2-CH2-.

In one embodiment R3and R4represent a hydrogen atom or a C1-3alkyl, preferably H, methyl or ethyl. Alternative R3and R4together form-CH2-CH2- or-CH2-CH2-CH2-.

In another embodiment R5, R6, R7, R8and R9represents H, saturated or unsaturated With1-2alkyl, halogen atom, saturated or unsaturated With1-4alkoxy, saturated or unsaturated C1-2halogenoalkanes,1-4alkylamino group (RCOO -),1-2alkylsulfonyl or triftormetilfosfinov group.

In one embodiment R5, R6, R7, R8and R9pose is a N, methyl, chlorine atom, bromine atom, methoxy or atoxyl and preferably represent H, methyl and methoxy.

In another embodiment Y represents a nitro-group or cyano.

In one embodiment Y represents a nitro-group.

In accordance with the second aspect of the invention proposed agrochemical composition containing:

(a) 0.001 to 99.99 wt.% the aforementioned compound, its optical isomer, CIS-TRANS-isomer, it agrokhimichesky acceptable salts or combinations thereof; and

(b) agrokhimichesky acceptable carrier or excipient.

In one embodiment, the concentration of component (a) is from 0.01 to 99.9 wt.%, and preferably 0.05 to 90 wt.%.

In one embodiment of the agrochemical composition is used for the destruction or control of insects selected from the group consisting of Coleoptera, Lepidoptera, Hemiptera, Orthoptera, Isoptera and dipteran insects.

In one embodiment, the pests have mouthparts piercing-sucking type or biting type.

In another embodiment pests include this aphid, brown rice Cicada, whiteflies, cinadco, thrips, well cotton, caterpillar, followed by cabbage, cabbage moth, well litura or caterpillar grass plants.

In another embodiment of the agrochemical composition further comprises other active compounds, selected from the group consisting of the of insecticide, cobalt, a bactericidal agent, acaricide, nematicide, fungicides and growth regulators.

In accordance with a third aspect of the invention the application of the agrochemical composition for destruction or combating agricultural pests, hygiene pests and pests harmful to health of animals; or agrochemical composition is used as an insecticidal composition for the destruction or control agricultural pests, hygiene pests and pests that are harmful to animal health.

In accordance with the fourth aspect of the invention, a method for destroying or controlling crop pests, sanitary pests and pests that are harmful to animal health, including the application of the above agrochemical or insecticidal composition on plants, their surrounding soil or the environment, which is under attack or be attacked by insects.

In accordance with the fifth aspect of the invention it is proposed to use the connection, its optical isomer or CIS-TRANS isomer, it agrokhimichesky acceptable salts or combinations thereof upon receipt of insecticidal compositions.

In accordance with the sixth aspect of the invention, a method for obtaining compounds, its optical isomer or CIS-TRANS isomer, it agrohimicheskih salts, includes the following stages:

In the presence of catalytic acid and 0-60°With the interaction of the compounds of formula (a) with compound (b), (C) or (d), resulting in a compound (A), (B), (C) or (D), where R2represents H,

where R1, R3, R4, R5, R6, R7, R8, R9and Y are as defined above, and n is 0 or 1.

In one embodiment the reaction temperature of 15-45°C., and preferably 20-30°C.

In another embodiment the solvent is selected from acetonitrile or ethanol, and preferably acetonitrile.

In another embodiment of the catalytic acid selected from concentrated hydrochloric acid, concentrated sulfuric acid or benzoic acid, preferably concentrated hydrochloric acid.

In one embodiment the method includes:

in the presence of catalytic acid, the following reaction is carried out at 20-30°C in acetonitrile for 2-24 hours, resulting in a compound (A), where R2is a N:

in the presence of catalytic acid, the following reaction is carried out at 20-30°C in acetonitrile for 2-24 hours, resulting in brasaetsa connection (In):

in the presence of catalytic acid, the following reaction is carried out at 10-50°C. in acetonitrile for 2-24 hours, resulting in a connection (S):

in the presence of catalytic acid, the following reaction is carried out at 10-50°C. in acetonitrile for 2-24 hours, resulting in a compound (D):

Detailed description of the invention

After a long and deep research of the inventors synthesized a new class neonicotinoid derivatives, which are obtained by the interaction nitromethylene connection with the dialdehyde based on nitromethylene group modern nitromethylene neonicotinoids insecticides. These new derivatives are significantly high activity and enhanced insecticidal spectrum. The inventors have completed the present invention based on the above.

The definition of the substituents

The term "C1-6alkyl" refers to pravarasena or branched alkyl with 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, emop-butyl, mpem-butyl or some similar group.

The term "C1-6alkoxyl" refers to pravarasena or branched alkoxy with 1-6 carbon atoms is kind, such as methoxyl, ethoxyl, propoxy, isopropoxy, butoxy, isobutoxy, second-butoxyl, tert-butoxy or some similar group.

The term "halogen" refers to fluorine atom, chlorine, bromine or iodine. The term "halogenated" refers to one or more than one substitution of the same or different atom of halogen as mentioned above, such cancriformis, pentafluoroethyl or similar group.

The term "5 - or 6-membered heterocyclic alkyl" refers to 5 - or 6-membered ring cyclic alkyl containing one or more than one heteroatom selected from a nitrogen atom, oxygen or sulfur, such as pyridyl, ciazil, pyrimidinyl, tetrahydrofuryl, oxazolyl etc.

Obtaining the compounds according to the invention

Compounds according to the invention can be synthesized as described above. The compound (a) can be obtained in accordance with the technical references in the art, such as WO 2006056108 A1, WO 2007101369 A1 and PCT/CN 2008/071115.

In one embodiment the compound of formula (A) can be synthesized according to the following method, where R2represents N;

In one embodiment the compound of formula (I) can be synthesized according to the following method:

In one embodiment the compound of formula (C) can sintezirovat is, according to the following method:

In one embodiment the compound of formula (D) can be synthesized according to the following method:

In one embodiment the compound of formula (A) can be synthesized according to the following method:

(1) a Solution of 2-chloro-5-(chloromethyl)pyridine in acetonitrile is added dropwise to a solution of 5-10 mol of diamine. The reaction is carried out at 0-50°C. for 5-10 hours. After the mixture is distilled under reduced pressure to remove diamine, dissolved in ethyl acetate and evaporated to obtain N-((6-chloropyridin-3-yl)methyl)diamine.

(2) a Mixture of N-((6-chloropyridin-3-yl)methyl)diamine and 1,1-dimethyldi-2-nitroethene dissolved in ethanol and refluxed for 4-8 hours with obtaining nitromethylene connection.

(3) In the presence of an acid catalyst such as hydrochloric acid, sulfuric acid, heteroalicyclic etc., nitromethylene compound interacts with octaldehyde (glyoxal) to obtain the compounds of formula (A).

In another embodiment the compound of formula (I) can be synthesized according to the following method:

(1) To aqueous solution of ethylamine add the appropriate amount of acetonitrile. Then 2-chloro-5-(chloromethyl)pyridine in acetonitrile is added dropwise in an ice b is not. The reaction monitoring is carried out using TLC (thin layer chromatography). After the mixture was added a large amount of water, extracted with DHM (dichloromethane), dried, filtered and evaporated to obtain N-((6-chloropyridin-3-yl)methyl)ethanamine in the form of oil.

(2) a Mixture of N-((6-chloropyridin-3-yl)methyl)ethanamine and 1,1-dimethyldi-2-nitroethene dissolved in ethanol and refluxed for 4-8 hours. After the mixture was concentrated and purified column chromatography to obtain N-((6-chloropyridin-3-yl)methyl)-N-ethyl-1-(methylthio)-2-nitroenamine.

(3) a Mixture of an alcohol solution of methylamine and N-((6-chloropyridin-3-yl)methyl)-N-ethyl-1-(methylthio)-2-nitroenamine dissolved in ethanol and subjected to interaction within 4-8 hours in an ice bath. After the mixture was concentrated and purified column chromatography to obtain N-((6-chloropyridin-3-yl)methyl)-N-ethyl-N'-methyl-2-nitroethene-1,1-diamine.

(4) In the presence of an acid catalyst such as hydrochloric acid, sulfuric acid, heteroalicyclic etc., N-((6-chloropyridin-3-yl)methyl)-N-ethyl-N'-methyl-2-nitroethene-1,1-diamine interacts with malonic aldehyde with obtaining the compounds of formula (In).

In another embodiment the compound of formula (C) can be synthesized according to the following method:

(1) a Solution of 2-chloro-5-(chloromethyl)pyridine in which aconitine added dropwise to a solution of 5-10 mol of diamine. The reaction is carried out at 0-50°C. for 5-10 hours. After the mixture is distilled under reduced pressure to remove diamine, dissolved in ethyl acetate and evaporated to obtain N-((6-chloropyridin-3-yl)methyl)diamine.

(2) a Mixture of N-((6-chloropyridin-3-yl)methyl)diamine and 1,1-dimethyldi-2-nitroethene dissolved in ethanol and refluxed for 4-8 hours with obtaining nitromethylene connection.

(3) In the presence of an acid catalyst such as hydrochloric acid, sulfuric acid, heteroalicyclic etc., nitromethylene connection communicates with succinic aldehyde with obtaining the compounds of formula (C).

In another embodiment the compound of formula (D) can be synthesized according to the following method:

(1) a Solution of 2-chloro-5-(chloromethyl)pyridine in acetonitrile is added dropwise to a solution of 5-10 mol of diamine. The reaction is carried out at 0-50°C. for 5-10 hours. After the mixture is distilled under reduced pressure to remove diamine, dissolved in ethyl acetate and evaporated to obtain N-((6-chloropyridin-3-yl)methyl)diamine.

(2) a Mixture of N-((6-chloropyridin-3-yl)methyl)diamine and 1,1-dimethyldi-2-nitroethene dissolved in ethanol and refluxed for 4-8 hours with obtaining nitromethylene connection.

(3) In the presence of an acid catalyst such as hydrochloric sour is a, sulfuric acid, heteroalicyclic etc., nitromethylene compound interacts with glutaraldehyde to obtain the compounds of formula (D).

Insecticidal activity of the active compounds according to the invention

The terms "active ingredient according to the invention" or "active compound according to the invention are a compound according to the invention, its optical isomer or CIS-TRANS isomer, or its agrokhimichesky acceptable salt. "Active compound according to the invention show significantly increased activity and enhanced insecticidal spectrum.

The term "agrokhimichesky acceptable salt" means a salt anion is known or acceptable in the formation insecticide acceptable salt. Preferably the salt is soluble in water. Salts formed by the compounds of the formula (A), (B), (C) and (D)include salts formed with inorganic acid (for example, hydrochlorate, phosphate, sulfate and nitrate), and salts formed with organic acids (such as acetate and benzoate).

The active compound according to this invention may be applied to the struggle and destruction of the normal insect pests of agricultural crops and plants, insect pests of grain, insects, harmful to health, and insects that are harmful to animal health. In this invention, the term "insecticide" the present is the focus of any connection which prevents or fights with any of the above insects. Approximate insects include, but are not limited to;

Coleoptera: Sitophilus zeamai, Tribolium castaneum, Henosepilachna vigintioctomaculata, Henosepilachna spars, Agriotes fuscicollis, Anomala cupripes, Popillia quadriguttata, Monolepta hieroglyphica, Monochamus alternatus, Echinocnemus squameus, Basiprionota bisignata, Anoplophora chinensis, Apripona gennari, Scolytus schevy, Agriotes fuscicollis.

Lepidoptera: Lymantria dispar, Malacosoma neustria testacea, Diaphania perspectalis, Clania variegate, Cnidocampa flauescens, Dendrolimus punctatus, Orgyia gonostigma, Paranthrene tabaniformis, Spodoptera litura, Chilo suppressalis, Ostrinia nubilalis, Ephestia cautella, Adoxophyes orana, Laspyresia splendana, Agrotis fucosa, Galleria mellonella, Plutella xylostella, Phyllocnistis citrella, or Mythimna separate.

Homoptera: Nephotettix cincticeps, Nilaparvata lugens, Pseudococcus comstocki, Unaspis yanonensis, Myzus persicae, Aphis gossydii, Lipaphis erysimi pseudobrassicae, Stephanitis nashi, or Bemisia tabaci.

Orthoptera: Blattella germanica, Periplaneta americana, Gryllotalpa africana, or Locusta migratoria.

Isoptera: Solenopsis invicta, Coptotermes formosanus.

Diptera: Musca domestica, Aedes aegypti, Delia platura, Culex sp., Anopheles sinensis.

Insects that are harmful to human health: Boophilus microplus, Haemaphysalis longicornis, Hyalomma anatolicum, Hypoderma spp., Fasciola hepatica, Moniezia Blanchard, Ostertagia spp., Trypanosoma enansi, Babesia bigemina, etc.

Compounds according to the invention have specific effects on nasekomykh pests of agricultural crops and plants that have piercing-sucking or biting mouthparts, such as aphids, Cicada, brown rice Cicada, thrips, whiteflies, etc.

Insecticidal composition comprising a compound according to the invention

Active the compounds according to the invention can usually be included in the insecticidal composition. The active compounds according to the invention can be included in conventional preparations such as solutions, emulsions, suspensions, powders, foams, pastes, granules, aerosols, natural and synthetic materials impregnated with active compounds, microcapsules in polymers, covering complex for seeds, products used with the combustion chamber (such as flue-cylinder, smoke box and flue plate) and preparations of cold spray and warm aerosol ULV.

These drugs can be obtained in a known manner, for example by mixing the active compounds with extenders, that is liquid or in the form of liquefied gas, solid diluents or carriers, optionally with the use of surface-active agents, that is emulsifying agents and/or dispersing agents and/or foaming agents. In the case of using water as a filler of organic solvents can also be used as auxiliary solvents.

Usually properly use liquid solvents as a diluent or carrier, for example, aromatic hydrocarbons such as xylene, toluene and alkylnaphthalenes; chlorinated aromatic or chlorinated aliphatic hydrocarbons, such as chlorobenzene, chloroethylene and methylene chloride; aliphatic hydrocarbons is childbirth, such as cyclohexane or paraffins, for example petroleum fractions; alcohols, such as ethanol or glycol and also their ethers and esters; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone; or uncommon polar solvents, such as dimethylformamide and dimethyl sulfoxide, and water. Under liquefied gaseous diluents or carriers are meant liquids which are gaseous at normal temperature and under normal pressure, for example aerosol propellants, such as halogenated hydrocarbons as well as butane, propane, nitrogen and carbon dioxide.

The solid carrier includes crushed natural minerals such as kaolins, clays, only, quartz, attapulgite, montmorillonite or diatomaceous earth; of ground synthetic minerals such as highly disperse silicic acid, alumina and silicate. Solid media used for particles, is a crushed and fractionated natural rocks such as calcite, marble, pumice, thick and dolomite, and also synthetic granules of inorganic or organic large powder and granules of organic material such as sawdust, coconut shell, corn cobs and stalks of tobacco, and the like.

As amongyou is their and/or foaming agents can be used non-ionic and anionic emulsifiers, such as esters of polyoxyethylene and fatty acids, ethers of polyoxyethylene and fatty alcohols, for example, alkyldiphenylamine ethers, alkyl sulphonates, alkyl sulphates, arylsulfonate, as well as the products of hydrolysis of albumin. Dispersing agents include, for example, lignin, spent sulfite liquors and methylcellulose.

Adhesives such as carboxymethylcellulose and natural and synthetic polymers (such as Arabian gum, polyvinyl alcohol and polyvinyl acetate) in the form of powders, granules or emulsions can be used in the preparations. It is possible to use colorants such as inorganic pigments, e.g. iron oxide, cobalt oxide and Prussian blue, and organic dyes, such as dyes, which are diazocompounds, or coloring matter, representing phthalocyanines metals and micronutrients, such as iron salts, manganese, boron, copper, cobalt, aluminum and zinc.

The active compound according to the invention can be presented in the form of a mixture with other active compounds in the commercial preparation or in the form of application, obtained from the commercial product. Other compounds can be an insecticide, a bactericide agent, acaricide, nematocide, fungicide, growth regulator and tomopterna. The insecticides include, for example, phosphates, carbamates, pyrethroids, chlorinated hydrocarbons, benzoylacetone, nereistoxin and the substance produced by microorganisms, such as ivermectin.

In addition, the active compound according to the invention can be presented in the form of a mixture with synergists in the commercial preparation or in the form of application, obtained from the commercial product. The synergist is used to enhance the action of the active connection, if the connection is active, do not have to use a synergist.

Generally, the preparations contain 0.001 to 99.99 wt.%, preferably from 0.01 to 99.9 wt.% and more preferably 0.05 to 90 wt.% the active compounds according to the invention. The concentration of the active compounds in the form of an application received from a commercial product, can vary over a wide range. The concentration of the active compound in the preparation for use is, for example, 0,0000001-100% (wt./about.) and preferably of 0.0001-1%.

Examples

Further, the invention is illustrated below by examples. It should be clear that these examples are intended only to illustrate the invention and do not limit the scope of the invention. With regard to experimental methods in the examples below, they are in normal conditions or in accordance with the manufacturer's instructions, unless otherwise specified Percentage and the share calculated by weight. The term "K.T." represents room temperature.

Example 1

Synthesis of 4-(1-((6-chloropyridin-3-yl)methyl)-4,5-dihydro-1H-imidazol-2-yl)-1-(1-((6-chloropyridin-3-yl)methyl)imidazolidin-2-ilidene)-1,4-dinitroso-3-EN-2-ol (compound 13)

In accordance with the method described in WO 2006056108 A1 and WO 2007101369 A1, 2-chloro-5-((2-(nitromethylene)imidazolidine-1-yl)methyl)pyridine was obtained from 2-chloro-5-(chloromethyl)pyridine (0.03 mol) at exit 56%. Rf=0,46 (petroleum ether: EtOAc=1:1); TPL=156,9°C To 161.8°C.; LC-MS (m/s): 220 (25), 126 (100), 90 (9).

Synthesis of 4-(1-((6-chloropyridin-3-yl)methyl)-4,5-dihydro-1H-imidazol-2-yl)-1-(1-((6-chloropyridin-3-yl)methyl)imidazolidin-2-ilidene)-1,4-dinitroso-3-EN-2-ol

In a 50 ml round bottom flask was added 1.27 g (0,005 mol) of 2-chloro-5-((2-(nitromethylene)imidazolidine-1-yl)methyl)pyridine, 30 ml of acetonitrile and 3 ml of 30% aqueous solution of Hexaldehyde. After stirring for 0.5 hours was added to the catalyst - concentrated HCl. Then the reaction mixture was stirred and monitored by TLC until completion. After that, the mixture was filtered to obtain a white powder, which was led with the receipt of 1.05 g of pure final product as a white powdery solid. Output: approximately 76%.

TPL=164,6-165,3°C;1H NMR (400 MHz, DMSO-d6): δ 9,01 (s, 1H), to 8.41 (d, J=2.0 Hz, 1H), scored 8.38 (d, J=2.0 Hz, 1H), 7,80-7,86 (m, 2H), 7,51-rate of 7.54 (m, 2H), 6,50 (d, J=7.2 Hz, 1H), of 5.34 (d, J=15.2 Hz, 1H), 5,18 (d, J=15.2 Hz, 1H), 4,84 (dd, J1=2.4 Hz, J2=7.2 Hz, 1H), 4,77 (d, J=16,8 Hz, 1H), 4,67 (d, J=16,8 Hz, 1H), 3,98 (d, J=2.4 Hz, 1H), 3,86-3,95 (m, 2H), 3,61-of 3.80 (m, 5H), 3,40-3,47 (m, 1H) million-1;13With NMR (100 MHz, DMSO-d6): δ 162,7, 158,7, 148,3, 148,2, 148,0, 147,7, 138,1, 137,7, 130,9, 130,2, 123,1, 123,0, 102,5, 101,4, 81,4, 53,8, 52,6, 49,4, 48,8, 46,4, 41,2, 41,0 million-1; MVR (mass spectrometry high resolution) (ES+) calculated for C22H23N8O535Cl2(M+N)+549,1168; found 549,1178. calculated for C22H23N8O535Cl37Cl (M+H)+551,1139; found 551,1152. calculated for C22H23N8O537Cl2(M+N)+553,1109; found 553,1108.

Example 2

Synthesis of 2-chloro-5-((4-(1-((6-chloropyridin-3-yl)methyl)imidazolidin-2-ilidene)-2-methoxy-1,4-dinitroso-3-enyl)-4,5-dihydroimidazole-1-yl)methyl) pyridine (compound 14)

In a 50 ml round bottom flask was added 0,549 g (0.001 mol) of the compound 13, 10 ml of methanol, 50 ml of dichloromethane and a catalytic amount of concentrated HCl. The reaction mixture is boiled under reflux and monitored by TLC. After the mixture is evaporated to remove solvent and purified column chromatography to obtain the final product as a yellow powder (yield 62%).

TPL=USD 151.6-153,1°C;1H NMR (400 MHz, DMSO-d6): δ 9,03 (s, 1H), scored 8.38 (d, J=2.0 Hz, 1H), at 8.36 (d, J=2.0 Hz, 1H), ,81-7,85 (m, 2H), 7,49-7,51 (m, 2H), 6,50 (d, J=7.2 Hz, 1H), 5,35 (d, J=15.2 Hz, 1H), 5,19 (d, J=15.2 Hz, 1H), 4,80 (d, J1=7.2 Hz, 1H), 4,77 (d, J=16,8 Hz, 1H), 4,69 (d, J=16,8 Hz, 1H), 3,68 (s, 3H), 3,88-3,95 (m, 2H), 3,61-of 3.85 (m, 5H), 3,38-to 3.41 (m, 1H) million-1;13C NMR (100 MHz, DMSO-d6): δ 162,6, 158,7, 148,9, 148,3, 148,1, 147,6, 138,1, 137,8, 130,9, 129,9, 122,8, 123,1, 102,2, 101,6, 81,6, 58,7, 53,8, 52,6, 49,6, 48,9, 46,4, 41,3, 41,0 million-1; MCBP (ES+) calculated for C23H25N8O535Cl2(M+N)+563,1325; found 563,1311. calculated for C23H25N8O535Cl37Cl (M+H)+565,1295.

Example 3

Synthesis of N1N7bis((6-chloropyridin-3-yl)methyl)-N1N7-diethyl-N1N7-dimethyl-2,6-dinitrate-2,5-Vendimia (Compound 37)

(1): Synthesis of N-((6-chloropyridin-3-yl)methyl)ethanamine

65-70% solution of ethylamine (70 g, 1 mol), acetonitrile, 50 ml, was added into the three-neck round bottom flask equipped with addition funnel with pressure compensation and a thermometer. The solution was stirred in an ice bath for 15 min with controlled temperature of about 0°C. Then was added 2-chloro-5-(chloromethyl)pyridine (16,10 g, 0.10 mol) in 25 ml of acetonitrile using a dropping funnel with pressure compensation for 3.5 h with a speed of 3 drops/min After added water, and the reaction mixture was extracted with DHM. The organic phase was collected with obtaining, thus, 14 g of N-((6-chloropyridin-3-the l)methyl)ethanamine in the form of oil at the exit of 70%. LC-MS: m/z (%)=170 ([M]+, 20), 155 (80), 126 (100), 114 (10), 90 (12).

(2): Synthesis of N-((6-chloropyridin-3-yl)methyl)-N-ethyl-1-(methylthio)-2-nitroenamine

In a 100 ml three-neck round bottom flask was added N-((6-chloropyridin-3-yl)methyl)ethanamine (17.0 g, 0.1 mol), (2-nitroethene-1,1-diyl)bis(methylsulfanyl) (15.0 g, 0.09 mol), dry ethanol (50 ml). The mixture is boiled under reflux. After completion, the reaction mixture was cooled to K.T. and concentrated under reduced pressure to get crude product in the form of oil, which was purified column chromatography to obtain 5.3 g of N-((6-chloropyridin-3-yl)methyl)-M-ethyl-1-(methylthio)-2-nitroenamine when the output of 18.5%.

LC-MS: m/z (%)=242 ([M]+-46, 53), 227 (15), 213 (100), 169 (45), 155 (28), 141 (29), 126 (91), 90 (12).

(3): Synthesis of N-((6-chloropyridin-3-yl)methyl)-N-ethyl-N'-methyl-2-nitroethene-1,1-diamine

In a 100 ml round bottom flask was added N-((6-chloropyridin-3-yl)methyl)-N-ethyl-1-(methylthio)-2-nitroethene (5 g, of 0.017 mol), alcoholic solution of methylamine (1.8 g, is 0.017 mol), dry ethanol (30 ml). The mixture was stirred in the bath with ice to reduce the temperature to 0°C and continuously stirred to complete the reaction. The reaction mixture is evaporated under reduced pressure to remove solvent and then concentrated to obtain a syrup, which was dissolved in a certain amount DHM and was purified column chromatography, ISOE is isua DHM/Meon=25:1 as the eluent and silica gel as a filler. Received 0.9 g of N-((6-chloropyridin-3-yl)methyl)-N-ethyl-N-methyl-2-nitroethene-1,1-diamine when the output of 19.1%. Rf=0,23 (DHM/acetone=5:1,); TPL=78-80°C (lit. [67] 79-81°C); LC-MS: m/z (%)=236 ([M]+-34, 32), 207 (49), 169 (52), 126 (49), 110 (20), 90 (16), 67 (100). 16,65.

(4): Synthesis of N1N7bis((6-chloropyridin-3-yl)methyl)-N1N7-diethyl-N1'N7'-dimethyl-2,6-dinitrate-2,5-thienamycin (compound 37)

In a 50 ml round bottom flask was added 1.35 g (0,005 mol) of N-((6-chloropyridin-3-yl)methyl)-N-ethyl-N-methyl-2-nitroethene-1,1-diamine, 30 ml of dry acetonitrile, 0,72 g (0.01 mol) of malonic aldehyde and a catalytic amount of concentrated HCl. The reaction mixture was stirred at K.T. and monitored by TLC. After the mixture is evaporated to remove solvent and purified column chromatography to obtain the final product in the form of a pale yellow powder with a yield of 56%.

TPL=117,3-118,7°C;1H NMR (400 MHz, DMSO-d6): δ at 8.36 (d, J=2.4 Hz, 2H), 7,88 (dd, J1=2.4 Hz, J2=8,4 Hz, 2H), 7,51 (d, J=8,4 Hz, 2H), equal to 4.97 (t, J=2,8 Hz, 2H), a 4.86 (d, J=15.2 Hz, 2H), 4,49 (d, J=15.2 Hz, 2H), 3.95 to 3,99 (m, 4H), 3,66-of 3.78 (m, 6H), 3,12-is 3.21 (m, 2H), 1,91-of 1.93 (m, 6H) million-1;13With NMR (100 MHz, DMSO-d6): δ 156,3, 148,5, 148,1, 137,3, 131,9, 122,5, 104,8, 49,2, 48,9, 48,0, 48,5, 28,1, 20,2 million1; MVR (EI+) calculated for C25H30N8O435Cl2(M+) 576,1767; found 576,1751.

Example 4

Synthesis of 2-chloro-5-((5-(1((6-chloropyridin-3-yl)methyl)-4,5-dihydro-1H-imidazol-2-yl)-1,5-dinitrophenol-1,4-dienyl)-4,5-dihydroimidazole-1-yl)methyl)pyridine (compound 39)

In a 50 ml round bottom flask was added 1.27 g (0,005 mol) of 2-chloro-5-((2-(nitromethylene)imidazolidine-1-yl)methyl)pyridine, 30 ml of dry acetonitrile, determined as 0.720 g (0.01 mol) of malonic aldehyde and a catalytic amount of HCl. The reaction mixture was stirred at K.T. and monitored by TLC. After the mixture is evaporated to remove solvent and purified column chromatography to obtain the final product in the form of a pale yellow powder with a yield of 52%.

TPL=136,5-137,8°C;1H NMR (400 MHz, DMSO-d6): δ 8.34 per (d, J=2.4 Hz, 2H), 7,82 (dd, J1=2.4 Hz, J2=8,4 Hz, 2H), 7,47 (d, J=8,4 Hz, 2H), 4,96 (t, J=2,8 Hz, 2H), to 4.81 (d, J=15,8 Hz, 2H), of 4.44 (d, J=15,8 Hz, 2H), 3,92-of 3.97 (m, 4H), 3,65-and 3.72 (m, 2H), 3.49 points of 3.56 (m, 2H), 1,92-of 1.93 (m, 2H) million-1;13With NMR (100 MHz, DMSO-d6): δ 155,3, 147,9, 147,8, 138,0, 130,9, 122,7, 104,8, 50,2, 48,9, 48,5, 48,5, 28,1 million-1; MVR (ES+) calculated for C23H23N8O435Cl2(M+N)+545,1219; found 545,1201. Calculated for C23H23N8O435Cl37Cl (M+H)+547,1190; found 547,1178. Calculated for C23H23N8O437Cl2(M+N)+549,1160; found 549,1181.

Example 5

Synthesis of 1-((2-chlorothiazole-5-yl)methyl)-5-(1-((2-chlorothiazole-5-yl)methyl)-4,5-dihydro-1H-imidazol-2-yl)-1,5-dinitrophenol-1,4-dienyl)-4,5-dihydro-1H-imidazole (compound 41)

Following the method described in Examples is e 1, 0.03 mol of 2-chloro-5-(chloromethyl)thiazole was used instead of 2-chloro-5-(chloromethyl)pyridine as starting substances and obtained 1-((2-chlorothiazole-5-yl)methyl)-2-(nitromethylene)imidazolidine at exit 56%. LC-MS (m/s) 226 (24), 132 (100), 77 (9).

Synthesis of 1-((2-chlorothiazole-5-yl)methyl)-5-(1-((2-chlorothiazole-5-yl)methyl)-4,5-dihydro-1H-imidazol-2-yl)-1,5-dinitrophenol-1,4-dienyl)-4,5-dihydro-1H-imidazole

In a 50 ml round bottom flask was added to 1.30 g (0,005 mol) 1-((2-chlorothiazole-5-yl)methyl)-2-(nitromethylene)imidazolidine, 30 ml of dry acetonitrile, determined as 0.720 g (0.01 mol) of malonic aldehyde and a catalytic amount of concentrated HCl. The reaction mixture was stirred at K.T. and monitored no TCX. After the mixture is evaporated to remove solvent and purified column chromatography to obtain the final product in the form of a pale yellow powder in a yield of 44%.

TPL=138,6-139,9°C;1H NMR (400 MHz, DMSO-d6): δ 7,63 (s, 1H), to 4.98 (t, J=2,8 Hz, 2H), around 4.85 (d, J=15,8 Hz, 2H), 4,43 (d, J=15,8 Hz, 2H), 3.96 points-to 3.99 (m, 4H), 3,67-3,71 (m, 2H), 3,51 of 3.56 (m, 2H), 1,95-of 1.97 (m, 2H) million-1;13With NMR (100 MHz, DMSO-d6): δ 157,6, 149,3, 138,3, 105,8, 50,6, 48,9, 48,4, 48,1, 29,1 million-1; MCBP (ES+) calculated for C19H19N8O4S235Cl2(M+N)+557,0348; found 557,0363 calculated for C19H19N8O4S235Cl37Cl (M+N)+559,0318; detecting the network 559,0620.

Example 6

Synthesis of 1-((6-chloropyridin-3-yl)methyl)-5-(1-((6-chloropyridin-3-yl)methyl)-1,4,5,6-tetrahydropyrimidin-2-yl)-1,5-dinitrophenol-1,4-dienyl)-1,4,5,6-tetrahydropyrimidine (compound 43)

In accordance with the method described in WO 2006056108 A1 and WO 2007101369 A1, 1-((6-chloropyridin-3-yl)methyl)-2-(nitromethylene)-hexahydropirimidine series were obtained from 2,42 g (0.015 mmol) of 2-chloro-5-(chloromethyl)pyridine at exit 56%; Rf=0,19 (EtOH: DHM=1:1); TPL=175,7°C-182,6°C.; LC-MS (m/s): 225 (100), 196 (9), 154 (10), 139 (11), 126 (31), 113 (10), 90 (31).

Synthesis of 1-((6-chloropyridin-3-yl)methyl)-5-(1-((6-chloropyridin-3-yl)methyl)-1,4,5,6-tetrahydropyrimidin-2-yl)-1,5-dinitrophenol-1,4-dienyl)-1,4,5,6-tetrahydropyrimidine

In a 50 ml round bottom flask was added 1,34 g (0,005 mol) 1-((6-chloropyridin-3-yl)methyl)-2-(nitromethylene)-hexahydropirimidine series, 30 ml of dry acetonitrile and determined as 0.720 g (0.01 mol) of malonic aldehyde and a catalytic amount of concentrated HCl. The reaction mixture was stirred at K.T. and monitored by TLC. After the mixture is evaporated to remove solvent and purified column chromatography to obtain the final product in the form of a pale yellow powder with a yield of 55%.

TPL=133,7-134,9°C;1H NMR (400 MHz, DMSO-d6): δ 8,32 (d, J=2.4 Hz, 2H), 7,81 (dd, J1=2.4 Hz, J2=8,4 Hz, 2H), 7,49 (d, J=8,4 Hz, 2H), is 4.93 (t, J=2,8 Hz, 2H), 4,78 (d, J=15,8 Hz, 2H), and 4.40 (d, J=15,8 Hz, 2H), 3,91-of 3.96 (m, 4H), 3,63-3,71 (m, 2H), 3,49-of 3.53 (m, 2H, 2,32-is 2.37 (m, 2H), 1,92-of 1.93 (m, 2H) million-1;13With NMR (100 MHz, DMSO-d6): δ 155,6, 148,3, 147,9, 138,0, 130,7, 122,7, 105,1, 50,2, 48,8, 48,5, 48,1, 36,2, 28,0 million-1; MVR (ES+) calculated for C25H27N8O435Cl2(M+H)+572,1454; found 572,1468; calculated for C25H27N8O435Cl37Cl (M+H)+574,1425; found 574,1416.

Example 7

Synthesis of N-((6-chloropyridin-3-yl)methyl)-N-ethyl-2-methyl-4-nitro-8-oxa-2-Aza-bicyclo[3.2.1]Oct-3-EN-3-amine (compound 46)

In a 50 ml round bottom flask was added 1.35 g (0,005 mol) of N-((6-chloropyridin-3-yl)methyl)-N-ethyl-N'-methyl-2-nitroethene-1,1-diamine, 30 ml of dry acetonitrile, 0,860 g (0.01 mol) of succinic aldehyde and a catalytic amount of concentrated HCl. The reaction mixture was stirred at K.T. and monitored by TLC. After the mixture is evaporated to remove solvent and purified column chromatography to obtain the final product in the form of a pale yellow powder with a yield of 40%.

TPL=125,3-125,7°C;1H NMR (400 MHz, DMSO-d6): δ 8,72 (s, 1H), 8,27 (d, J=2.4 Hz, 1H), of 7.75 (dd, J1=2.4 Hz, J2=8,4 Hz, 1H), 7,58 (d, J=8,4 Hz, 1H), 5.25-in, and 5.30 (s, 2H), to 4.41-4,50 (m, 2H), 2,96-3,26 (m, 2H), 2,86 (s, 3H), 2,36-to 2.41 (m, 2H), 1,81-1,5 (m, 4H), 1,16-of 1.26 (m, 3H) million-1;13With NMR (100 MHz, DMSO-d6): δ 158,5, 154,4, 151,6, 150,8, 148,1, 139,3, 137,1, 107,8, 89,5, 65,8, 49,8, 46,9, 40,6, 21,9, 20,3 million-1; MVR (EI+) calculated for C15H 21N4O335Cl (M+) 339,1224; found 339,1257. calculated for C15H21N4O337Cl (M+) 341,1194; found 341,1213.

Example 8

Synthesis of 1-((6-chloropyridin-3-yl)methyl)-9-nitro-2,3,5,6,7,8-hexahydro-1H-5,8-epoxidase[1,2-a]azepine (compound 52)

In a 50 ml round bottom flask was added 1.27 g (0,005 mol) of 2-chloro-5-((2-(nitromethylene)imidazolidine-1-yl)methyl)pyridine, 30 ml of dry acetonitrile, 0,860 g (0.01 mol) of succinic aldehyde and a catalytic amount of concentrated HCl. The reaction mixture was stirred at K.T. and monitored by TLC. After the mixture is evaporated to remove solvent and purified column chromatography to obtain the final product in the form of a pale yellow powder with a yield of 71%.

TPL=of 149.0-150,0°C;1H NMR (400 MHz, DMSO-d6): δ 8,35 (d, J=2.4 Hz, 1H), 7,81 (dd, J1=2.4 Hz, J2=8,4 Hz, 1H), 7,51 (d, J=8,4 Hz, 1H), are 5.36 of 5.39 (s, 2H), 5,00 (d, J=15.6 Hz, 1H), and 4.68 (d, J=15.6 Hz, 1H), 3,57-to 3.73 (m, 4H), 1,94-2,04 (m, 4H) ppm;13C NMR (100 MHz, DMSO-d6): δ 155,6, 149,7, 149,6, 139,7, 132,6, 124,5, 109,6, 87,0, 75,1, 51,2, 50,3, 46,6, 31,9, 31,7 million-1; MVR (ES+) calculated for C14H16N4O335Cl (M+N)+323,0911; found 323,0912; calculated for C14H16N4O337Cl (M+N)+325.0811; found 325,0895; calculated for C14H15N4O335 ClNa (M+Na)+345,0730; found 345,0722; calculated for C14H15N4O337ClNa (M+Na)+347,0701; found 347,0692.

Example 9

Synthesis of 1-((2-chlorothiazole-5-yl)methyl)-9-nitro-2,3,5,6,7,8-hexahydro-1H-5,8-epoxidase[1,2-a]azepine (compound 53)

In a 50 ml round bottom flask was added to 1.30 g (0,005 mol) 1-((2-chlorothiazole-5-yl)methyl)-2-(nitromethylene)imidazolidine, 30 ml of dry acetonitrile, 0,860 g (0.01 mol) of succinic aldehyde and a catalytic amount of concentrated HCl. The reaction mixture was stirred at RT and monitored by TLC. After the mixture is evaporated to remove solvent and purified column chromatography to obtain the final product in the form of a pale yellow powder with a yield of 63%.

TPL=151,7-152,1°C;1H NMR (400 MHz, DMSO-d6): δ 7.65 (s, 1H), 5.33-5.37 (s, 2H), 5.01 (d, J=15.6 Hz, 1H), 4.69 (d, J=15.6 Hz, 1H), 3.52-3.70 (m, 4H), 1.90-2.01 (m, 4H) million-1;13With NMR (100 MHz, DMSO-d6): δ 155.2, 149.6, 139.1, 124.5, 110.6, 87.1, 75.6, 51.3, 50.6, 46.9, 31.9, 31.2 million-1; MVR (ES+) calculated for C12H15N4O3S35Cl (M+H)+329,0475; found 329,0412; calculated for C12H15N4O3S37Cl (M+N)+331,0446; found 331,0423.

Example 10

Synthesis of 1-((6-chloropyridin-3-yl)methyl)-10-nitro-1,2,3,4,6,7,8,9-octahydro-6,9-epoxidized[1,2-a]azepine (compound 61)

In a 50 ml round bottom flask was added 1,34 g (0,005 mol) of (E)-1-((6-chloropyridin-3-yl)methyl)-2-(nitromethylene)-hexahydropirimidine series, 30 ml of dry acetonitrile and 0,860 g (0.01 mol) of succinic aldehyde and a catalytic amount of concentrated HCl. The reaction mixture was stirred at K.T. and monitored by TLC. After the mixture is evaporated to remove solvent and purified column chromatography to obtain the final product in the form of a pale yellow powder with a yield of 38%.

TPL=143,2 is 144.9°C;1H NMR (400 MHz, DMSO-d6): δ with 8.33 (d, J=2.4 Hz, 1H), 7,80 (dd, J1=2.4 Hz, J2=8,4 Hz, 1H), 7,49 (d, J=8,4 Hz, 1H), 5,32 to 5.35 (s, 2H), 5,00 (d, J=15.6 Hz, 1H), 4,66 (d, J=15.6 Hz, 1H), 3,51-3,68 (m, 4H), 2,33-to 2.41 (m, 2H), 1,89 is 2.00 (m, 4H) million-1;13With NMR (100 MHz, DMSO-d6): δ 155,5, 149,6, 149,3, 139,7, 132,6, 124,1, 109,3, 86,6, 75,1, 51,2, 50,7, 46,6, 32,1, 31,7, 26,9 million-1; MVR (ES+) calculated for C15H19N4O335Cl (M+H)+337,1067; found 337,1015; calculated for C15H19N4O337Cl (M+H)+339,1038; found 339,0995.

Example 11

Synthesis of 1-((6-chloropyridin-3-yl)methyl)-2,3,5,6,7,8-hexahydro-1H-5,8-epoxidase[1,2-a]azepin-9-carbonitrile (compound 64)

In a 50 ml round bottom flask was added 1,17 g (0,005 mol) of 2-(1-((6-chloropyridin-3-yl)methyl)imidazolidin-2-ilidene)acetonitrile, 30 ml of dry acetonitrile and 0,860 g (0.01 mol) of succinic and is of elegida and a catalytic amount of concentrated HCl. The reaction mixture was stirred at K.T. and monitored by TLC. After the mixture is evaporated to remove solvent and purified column chromatography to obtain the final product in the form of a pale yellow powder with a yield of 66%.

TPL=125,1-to 126.8°C;1H NMR (400 MHz, DMSO-d6): δ 8.34 per (d, J=2.4 Hz, 1H), 7,82 (dd, J1=2.4 Hz, J2=8,4 Hz, 1H), 7,55 (d, J=8,4 Hz, 1H), 5,33 (s, 1H), 5.25 in (s, 1H), 5,00 (d, J=15.6 Hz, 1H), 4,78 (d, J=15.6 Hz, 1H), 3,56-of 3.78 (m, 4H), 1.91 a is 2.00 (m, 4H) million-1;13With NMR (100 MHz, DMSO-d6): δ 153,6, 149,0, 148,6, 139,7, 132,3, 121,5, 99,6, 87,3, 75,7, 51,3, 50,2, 46,6, 31,5, 29,7 million-1; MVR (ES+) calculated for C15H16N4O35Cl (M+N)+303,1013; found 303,0992; calculated for C15H16N4O37Cl (M+H)+305,0983; found 305,0957.

Example 12

Synthesis of 1-((6-chloropyridin-3-yl)methyl)-10-nitro-1,2,3,5,6,7,8,9-octahydro-5,9-epoxidase[1,2-a]azocine (compound 77)

In a 50 ml round bottom flask was added 1.27 g (0,005 mol) of 2-chloro-5-((2-(nitromethylene)imidazolidine-1-yl)methyl)pyridine, 30 ml of acetonitrile, 3 ml of 25% aqueous glutaraldehyde (0,0075 mole of glutaraldehyde) and a catalytic amount of concentrated HCl. The reaction mixture was stirred at RT and monitored by TLC. After the mixture is evaporated to remove solvent and purified column chromatography to obtain of course what about the product as a pale yellow powder with a yield of 86%.

TPL=174,7-175,4°C;1H NMR (400 MHz, DMSO-d6): δ scored 8.38 (dd, J1=0.6 Hz, J2=2.4 Hz, 1H), to 7.84 (dd, J1=2.4 Hz, J2=8,4 Hz, 1H), 7,52 (dd, J1=0.6 Hz, J2=8,4 Hz, 1H), 5,12 (s, 1H), 5,04-of 5.05 (m, 1H), equal to 4.97 (d, J=15.6 Hz, 1H), 4,71 (d, J=15.6 Hz, 1H), 3,62-3,74 (m, 4H), 1,66-of 1.81 (m, 4H), 1,51-of 1.55 (m, 1H), 1.32 to the 1.44 (m, 1H) million-1;13With NMR (100 MHz, DMSO-d6): δ 156,6, 149,7, 149,6, 139,7, 132,9, 124,5, 105,8, 81,7, 68,9, 51,7, 50,0, 46,3, 28,8, 27,2, 14,8 million-1; MVR (EI+) calculated for C15H17N4O335Cl (M+) 336,0989; found 336,0988; calculated for C15H17N4O337Cl (M+) 338,0960; found 338,0968.

Example 13

Synthesis of 10-nitro-1-((tetrahydrofuran-3-yl)methyl)-1,2,3,5,6,7,8,9-octahydro-5,9-epoxidase[1,2-a]azocine (compound 80)

Following the method described in Example 1, 0.2 mol of 3-(chloromethyl)tetrahydrofuran (THF) was used instead of 2-chloro-5-(chloromethyl)pyridine as starting substances. Received 2-(nitromethylene)-1-((tetrahydrofuran-3-yl)methyl)imidazolidin at exit 51%. LC-MS (m/s) 177 (29), 99 (100), 56 (9).

Synthesis of 10-nitro-1-((tetrahydrofuran-3-yl)methyl)-1,2,3,5,6,7,8,9-octahydro-5,9-epoxidase[1,2-a]azocine

In a 50 ml round bottom flask was added 1,065 g (0,005 mol) of 2-(nitromethylene)-1-((tetrahydrofuran-3-yl)methyl)imidazolidine, 30 ml of acetonitrile, 3 ml of 25% aqueous glutaraldehyde (0,0075 mole of glutaraldehyde) and a catalytic amount to zentrierung HCl. The reaction mixture was stirred at K.T. and monitored by TLC. After the mixture is evaporated to remove solvent and purified column chromatography to obtain the final product in the form of a pale yellow powder with a yield of 36%.

TPL=115,3-116,9°C;1H NMR (400 MHz, DMSO-d6): δ 5,11 (s, 1H), 5,00-to 5.03 (m, 1H), 4,18 (d, J=3.2 Hz, 2H), 4,05-of 4.25 (m, 2H), 3,85-of 3.96 (m, 4H), of 2.25 (m, 1H), 1,66-of 1.81 (m, 4H), 1,63 -1,64 (m, 2H), 1,57-to 1.59 (m, 2H), 1,51-of 1.55 (m, 1H), 1.32 to the 1.44 (m, 1H) million-1;13With NMR (100 MHz, DMSO-d6): 6 81,7, 80,6, 78,5, 68,9, 50,0, 49,7, 46,9, 44,6, 36,8, 33,9, 28,8, 27,2, 17,8, 14,8 million-1; MVR (EI+) calculated for C14H21N3O4(M+) 295,1532; found 295,1598.

Example 14

Test for insecticidal activity of the compounds according to the invention

(1) the Test for activity against alfalfa aphid (Aphis craccivoral)

Aphids, which belong to Homoptera and have piercing-sucking mouthparts, are common insects for agricultural plants. Aphis craccivoral tested by immersion.

Test method: accurately weighed various samples independently added to N,N-dimethylformamide to obtain 10 g/l stock solution. The mixture was diluted with 0.2 ml/l aqueous solution of Triton X-100 to a concentration of 500 ppm stable After sucking on seedlings of beans adults of aphids without wings together with the bean sprouts were immersed into the breeding of 500 ppm, was removed after 5 with the Kund, and excessive breeding was aspirated blotting paper, and adults of aphids without wings incubated in a clean vessel at a constant temperature of 23°C. Each concentration was repeated 3 times, and the control group contained 0.2 ml/l aqueous solution of Triton X-100. The number of dead aphids were counted after 24 hours to calculate the mortality rate according to the following formula:

mortality (%) = (number of control live aphids - the number of processed live aphids)/control number of living aphids × 100%.

The results are shown below in tables 1-4.

(2) Test for activity against brown rice cicadas {Nilaparvata lugens)

Brown rice cicadas, which belong to Homoptera and have piercing-sucking mouthparts, are common insects for agricultural plants. Nilaparvata lugens tested by spraying.

Test method; test the connection, just prepared in acetone solution to a final concentration of 500, 250, 100, 50, 25, 12,5, 6,25, 3,13, 1,57 and 0.79 ppm Aqueous solution of acetone was used as control. Each process was repeated 3 vessels (3 times). 2 ml of the solution is uniformly sprayed on each Cup using a handheld mini-sprayer. 10 Nilaparvata lugens were introduced in each bath for 6 hours before spraying. Conducted three series of experiments. The death toll Nilaparvata lugens were counted after 24 hours to calculate SMARTNET is using the above formula. The results are presented below in tables 1-4.

(3) Test for activity against caterpillars, affecting crop plants (Pseudaletia separate Walker)

Larvae that infect crop plants, was tested by feeding submerged leaves. Test the connection, just prepared in acetone solution to a final concentration of 500, 250, 100, 50, 25, 12,5, 6,25, 3,13, 1,57 and 0.79 ppm Aqueous solution of acetone was used as control. Fresh corn leaves were immersed into the solution for 3 seconds and dried at room temperature and used for feeding the test insects. Each process was repeated 3 times, and each experiment was tested 10 caterpillars. The number of dead larvae were counted after 24 hours to calculate mortality using the above formula. The results are presented below in tables 1-4.

(4) Test for activity against Diamondback moth (Plutella xylostella)

Diamondback moth was tested by feeding submerged leaves. Fresh cabbage leaves were immersed in the above solution for 3 seconds and dried at room temperature and used for feeding the test insects. Each process was repeated 3 times, and each experiment was tested 10 cabbage moths. The death toll cabbage moths were counted after 24 hours to calculate mortality using seumanutafa formula. The results are presented below in tables 1-4.

R3and R4together form-CH2-CH2
Table 1
Insecticidal activity of the compounds of formula (A)
Conn. No.R1R2R3R4YInsecticidal activity
Aphid alfalfaBrown rice CicadaCaterpillar cerealThe cabbage moth
Mortality (100%) 500 ppmMortality (100%) 500 ppmMortality (100%) 500 ppmMortality (100%) 500 ppm
1HC2H5CH3NO2 8091100100
2CH3C2H5CH3NO2100100100100
3C2H5C2H5CH3NO2100100100100
4With3H7C2H5CH3NO2100100100100
5 i-C3H7With2H5CH3NO2100100100100
6benzilC2H5CH3NO2100100100100
7HNCH3NO224353521
8CH3NCH3NO245 446756
9C2H5NCH3NO28987100100
10With3H7NCH3NO245368790
11i-C3H7NCH3NO2769095100
12benzil NCH3NO2679297100
13NR3and R4together form-CH2-CH2NO2NO285100100
14CH3R3and R4together form-CH2-CH2NO2100100100100
15C2H5R3and R4together form-CH2-CH2NO2100100100 100
16With3H7R3and R4together form-CH2-CH2NO2100100100100
17i-C3H7R3and R4together form-CH2-CH2NO2100100100100
18benzilR3and R4together form-CH2-CH2NO2100100100100
19NR 3and R4together form-CH2-CH2CN90100100100
20NR3and R4together form-CH2-CH2CN98100100100
21NR3and R4together form-CH2-CN100100100100
CH2-
22HCN7310092100
23HR3and R4together form-CH2-CH2CN568787100
24HR3and R4together form-CH2-CH2CN658390100
25HR3and R4together form-CH2-CH2NO28987100100
26HR3and R4together form-CH2-CH2NO2100100100100
27HR3and R4together form-CH2-CH2NO2100100100100
28HR3and R4together form-CH2-CH2NO2100100100100
29HR3and R4together form-CH2-CH2 NO2100100100100
30HR3and R4together form-CH2-CH2-CH2-NO2100100100100
31HR3and R4together form-CH2-CH2-CH2-NO246777783
32HR3and R4together form-CH2-CH2-CH2-NO265618792
33 HR3and R4together form-CH2-CH2-CH2-NO232505852
34HR3and R4together form-CH2-CH2-CH2-NO276889086
35HR3and R4together form-CH2-CH2-CH2-NO276906877
36HR3and R4together form-CH2-CH2-CH2- NO28797100100

Table 2
Insecticidal activity of the compounds of formula (In)
Conn. No.R1R3R4YInsecticidal activity
Aphid alfalfaAphid alfalfaAphid alfalfaAphid alfalfa
Mortality (100%) 500 ppmMortality (100%) 500 ppmMortality (100%) 500 ppmMortality (100%) 500 ppm
37C2H5CH3NO2100 100100100
38HCH3NO2100100100100
39R3and R4together form-CH2-CH2NO2NO2100100100
40R3and R4together form-CH2-CH2CN568787100
41R3and R4together form-CH2-CH2NO2100 100100100
42R3and R4together form-CH2-CH2NO2100100100100
43R3and R4together form-CH2-CH2-CH2-NO2788710096

Table 4
Insecticidal activity of the compounds of formula (D)
Conn. No.R1R3R4R7 , R8, R9YInsecticidal activity
Aphid alfalfaAphid alfalfaAphid alfalfaAphid alfalfa
Mortality (100%) 500 ppmMortality (100%) 500 ppmMortality (100%) 500 ppmMortality (100%) 500 ppm
75C2H5CH3HNO2100100100100
76HCH3HNO2100100100100
77 R3and R4together form-CH2-CH2HNO2100100100100
78R3and R4together form-CH2-CH2HCN568787100
79R3and R4together form-CH2-CH2HNO2100100100100
80R3and R4together form-CH2-CH2HNO2100100100 100
81R3and R4together form-CH2-CH2-CH2-HNO2788710096

Example 15

Getting insecticidal compositions containing the active compound according to the invention

a) Oil suspension

Prepared from the following ingredients: 25 wt.% any compounds selected from compounds 1-73; 5 wt.% polyoxyethylenesorbitan of hexalate and 70 wt.% higher aliphatic hydrocarbon oils. All components was ground in a sand mill until such time as solid granules was reduced to less than about 5 micrometers. The resulting viscous slurry can be used directly or used after emulsification in water.

b) suspension in Water

Was prepared following components: 25 wt.% any compounds selected from compounds 1-73; 3 wt.% hydrate of attapulgite; 10 wt.% calcium lignosulfonate; 0.5 wt.% sodium dihydrophosphate and 61.5 wt.% water. All components were crushed in a ball mill until such time as solid granules was reduced to the size of the RA less than about 10 micrometers. The aqueous suspension can be used directly.

C) Preparation of bait

Prepared from the following ingredients: 0.1 to 10 wt.% any compounds selected from compounds 1-73; 80 wt.% wheat flour and 19.9-10 wt.% the molasses. All the ingredients are sufficiently mixed, and if necessary formed. Food bait can be swallowed, or it can be distributed in a domestic or industrial areas, such as kitchen, hospital, store, and outdoors in the area affected by insects that are harmful to the health of the population.

All documents cited in this application are included in the invention by reference, as if each was incorporated individually. In addition, it should be clear that in light of the above provisions, the invention is a specialist in the art can make various changes or modifications of the invention, and these equivalents will, however, be within the scope of the invention defined below by the claims.

Additional example 1:

Stage 1. Synthesis of N-benzyl-1,2-academia

Benzylchloride (1.26 g, 10 mmol) was dissolved in anhydrous ethanol (40 ml), the mixture was stirred in an ice bath was added anhydrous amandemen (50 mmol). The solution became yellow. After adding a mixture of peremeci the Ali at room temperature for 24 hours and monitored by TLC. After completion the mixture was filtered, and the filtrate was evaporated to remove ethanol. To the residue was added water and was extracted with the mixture using CH2Cl2(30 ml × 10). The organic phases were combined, dried over Na2SO4and concentrated to obtain the final product as a yellow oil (0,627, Output: 41,8%).

Stage 2. Synthesis of ((2-(nitromethylene)imidazolin-1-yl)methyl)benzene

N-benzyl-1,2-amandemen (10 mmol) was dissolved in anhydrous ethanol (10 ml) was added (2-nitroethylene-1,1-diyl)bis(methylsulfanyl) (1,61 g, 10 mmol). The mixture was boiled under reflux and monitored by TLC. After the mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate three times and dried to obtain the target product (1,012, Yield: 46%).

Stage 3. Synthesis of 1-benzyl-9-nitro-2,3,5,6,7,8-hexahydro-1H-5,8-epoxidase[1,2-a]azepine

The target compound was obtained by the method according to Example 8 except that 2-chloro-5-((2-(nitromethylene)imidazolidine-1-yl)methyl)pyridine was replaced by ((2-(nitromethylene)imidazolidine-1-yl)methyl)benzene. The yield was 30%.

MP. of 124.7-125,6°C,

1H NMR (400 MHz, DMSO-d6) δ 8,54 (d, J=2.2 Hz, 1 H), 8,51 (dd, J=4,8, 1.7 Hz, 1H), 7,74 (dt, J=7,8, 2.0 Hz, 2H), 7,39 (dd, J=7,8, a 4.7 Hz, 1H), 5,39 (d, J=4.5 Hz, 2H), to 5.03 (d,J=to 15.4 Hz, 1H), amounts to 4.76 (d, aJ=to 15.4 Hz, 1H),3,76-3,59 (m, 4H), 2,07-of 1.92 (m,4H).13With NMR (100 MHz, DMSO) δ 155,60; 149,44; 149,15; 135,95; 135,95; 132,81; 124,00; 109,66; 87,00; 75,19; 51,75; 50,23; 46,67; 31,84; 31,65. (ES+) calculated for C14H16N4O3(M+N)+, 288,1270; found 288,1301.

Additional example 2:

1. Synthesis of N-((pyridin-3-yl)methyl)-1,2-academia

Specified in the title compound was obtained according to Stage 1 of Additional example 1, except that benzylchloride substituted 3-chloromethyl-pyridine hydrochloride. The output was 41.8%.

2. 3-((2-(trifluoromethyl)Sulfuryl-vinyl)imidazolidin-1-yl)methyl)pyridine

The connection specified in the header, obtained according to Stage 2 Extra example 1, except that used other source materials, as indicated in the reaction scheme. The yield was 48%.

3. Synthesis of 1-(pyridin-3-yl)methyl)-9-(trifluoromethyl)Sulfuryl-2,3,5,6,7,8-hexahydro-1H-5,8-epoxidase[1,2-a]azepine

The connection specified in the header, obtained according to Stage 3 Additional example 1, except that used other source materials, as indicated in the reaction scheme. The yield was 36%.

1H NMR (400 MHz, DMSO-d6) δ charged 8.52 (d, J=2.2 Hz, 1 H), to 8.45 (dd, J=4,8, 1.7 Hz, 1H), 7,86 (dt, J=7,8, 2.0 Hz, 1H), 7,38 (dd, J=7,8, a 4.7 Hz, 1H), 4,88 (d, J=4.5 Hz, 2H), 4,43 (d, J=to 15.4 Hz, 1H), 4.26 deaths (d, J=to 15.4 Hz, 1H), was 2.76 at 2.59 (m, 4H, 2,05-of 1.73 (m, 4H).13With NMR (100 MHz, DMSO) δ 157,80; 154,70; 148,55; 147,35; 135,51; 135,60; 123,06; 107,90; 88,71; 66,51; 58,30; 53,76; 51,49; 35,51; 27,52.

Additional example 3:

1. Synthesis of N-((2-chloro-pyridin-5-yl)methyl)-1,2-academia

The connection specified in the header, obtained according to Stage 1 of Additional example 1, except that used other source materials, as indicated in the reaction scheme. The output amounted to 47.2%.

2. Synthesis of 2-chloro-5-((2-(trifluoromethyl-vinyl)imidazolidin-1-yl)methyl)pyridine

The connection specified in the header, obtained according to Stage 2 Extra example 1, except that used other source materials, as indicated in the reaction scheme. The yield was 57%.

3. Synthesis of 1-(2-chloro-pyridin-5-yl)methyl)-9-trifluoromethyl-2,3,5,6,7,8-hexahydro-1H-5,8-epoxidase[1,2-a]azepine

The connection specified in the header, obtained according to Stage 3 Additional example 1, except that used other source materials, as indicated in the reaction scheme. The yield was 61%.

1H NMR (400 MHz, DMSO-d6) δ charged 8.52 (d, J=2.2 Hz, 1 H), 7,86 (dt, J=7,8, 2.0 Hz, 1H), 7,38 (dd, J=7,8, a 4.7 Hz, 1H), 4,82 (d, J=4.5 Hz, 2H), 4,34 (d, J=to 15.4 Hz, 1 H), 4.26 deaths (d,J=to 15.4 Hz, 1H), 2,67 at 2.59 (m, 4H), 2,15-of 1.73 (m, 4H).

13With NMR (100 MHz, DMSO) δ 155,00; 148,50; 147,53; 135,51; 135,60; 123,06; 113,73; 108,29; 86,01; 58,57 58,31; 53,96; 52,24; 35,45; 28,62.

Additional example 4:

1. Synthesis of N-((5-chlorothiazole-2-yl)methyl)-1,2-academia

The connection specified in the header, obtained according to Stage 1 of Additional example 1, except that used other source materials, as indicated in the reaction scheme. The output amounted to 39.1%.

2. Synthesis of 5-chloro-2-((2-(triptoreline-vinyl)imidazolidin-1-yl)methyl)thiazole

The connection specified in the header, obtained according to Stage 2 Extra example 1, except that used other source materials, as indicated in the reaction scheme. The yield was 44%.

3. Synthesis of 1-(5-chlorothiazole-2-yl)methyl)-9-three formatosi-2,3,5,6,7,8-escogido-1H-5,8-Apostolides[1,2-a]azepine

The connection specified in the header, obtained according to Stage 3 Additional example 1, except that used other source materials, as indicated in the reaction scheme. The yield was 48%.

1H NMR (400 MHz, DMSO-d6) δ 7,49 (s, 1H), 4,88 (d, J=4.5 Hz, 2H), 4,43 (d, J=to 15.4 Hz, 1H), 4.26 deaths (d, J=to 15.4 Hz, 1H), 2,67 at 2.59 (m, 4H), 2,15-of 1.73 (m, 4H).

13With NMR (100 MHz, DMSO) δ 168,60; 138,53; 121,30; 123,05; 115,70; 108,29; 106,04; 79,11; 58,35; 53,96; 52,24; 35,45; 25,26.

Additional example 5:

Insecticidal activity of the compounds obtained according to Additional examples, what am 1-4 were tested in the same way, as in Example 14.

The test results showed that the mortality of the aphid alfalfa, brown rice cicadas, caterpillars, affecting crop plants, and cabbage moth was 90~100% at 500 million-1.

Insecticidal activity
ConnectionR1Yaphid alfalfaBrown rice CicadaCaterpillar cerealDiamondback moth
Mortality (100%) 500 million-1Mortality (100%) 500 million-1Mortality (100%) 500 million-1Mortality (100%) 500 million-1
Additional example 1-NO2951009090
Additional example 2 100100100100
Additional example 3100100100100
Additional example 3100100100100

Additional example 6: Synthesis of compound I-1

Compound 13 (0.01 mol) was subjected to a reaction with benzyl bromide (0.01 mol) in the presence of triethanolamine (TEA) (0.01 mol) in MeCN (30 ml) at room temperature. Monitored the reaction by TLC. After the mixture was evaporated to remove solvent, and the resulting mixture was purified column chromatography to obtain the final compounds. Yield: 85%.

TPL=168,1-168,9°C;

1H NMR (400 MHz; DMSO-d6): δ 8,42 (d; J=2.0 Hz; 1H); 8,39 (d; J=2.0 Hz; 1H); 7,81-7,86 (m; 2H); to 7.64 (d, J=8.0 Hz; 2H); 7,49-7,53 (m; 2H);7,47 (t; J=8.0 Hz; 1H); 7,41 (d; J=8.0 Hz; 2H); 6,51(d; J=7.2 Hz; 1H); from 6.22 (s; 2H); 5,34 (d; J=15.2 Hz; 1H); 5,18 (d; J=15.2 Hz; 1H); 4,84 (dd; J1=2.4 Hz; J2=7.2 Hz; 1H); 4.75 V (d; J=16,8 Hz; 1H); 4.63 to (d; J=16,8 Hz; 1H); 3.96 points (d; J=2,4 Hz; 1H); 3,84-3,92 (m; 2H); 3,63-3,81 (m; 5H); 3,35 is-3.45 (m; 1H) ppm;13C NMR (100 MHz; DMSO-d6): δ 154,9; 151,3; 150,0; 149,3; 137,1; 136,0; 128,3; 128,2; 125,2; 104,3; 84,6; 71,1; 54,6; 52,6; 44,5 ppm;

Mass spectrometry high resolution (ES+) calculated for C29H2935Cl2N8O5(M+H)+639,1560; found 639,1566. Calculated for C29H2937Cl2N8O5(M+H)+643,1560; found 643,1560.

Additional example 7: Synthesis of compound I-2

Compound I-2 was obtained according to example 5, except that used other source materials, as shown in the reaction scheme. Yield: 83%.

TPL=169, 5mm of 171.2°C;

1H NMR (400 MHz, DMSO-d6): δ to 8.41 (d, J=2.0 Hz; 1H); to 8.34 (d, J=2.0 Hz; 1H); 7,80-a 7.85 (m; 2H); 7,63 (d; J=8.0 Hz; 2H); 7,47-7,52 (m; 2H); 7,40 (d; J=8.0 Hz; 2H); 6,50 (d; J=7.2 Hz; 1H); 6,21 (s; 2H); 5,62 (s; 2H); 5,34 (d; J=15.2 Hz; 1H); 5,15 (d; J=15.2 Hz; 1H); 4.80 to (dd; J1=2.4 Hz; J2=7.2 Hz; 1H); to 4.81 (d; J=16,8 Hz; 1H); 4,62 (d; J=16,8 Hz; 1H); to 3.92 (d, J=2,4 Hz; 1H); 3,82-3,92 (m; 2H); 3,62-3,81 (m; 5H); 3,32-3,39 (m; 1H) ppm;13C NMR (100 MHz; DMSO-d6): δ 154,9; 151,4; 151,3; 150,0; 149,3; 136,0; 135,4; 130,4; 129,7; 128,7; 125,2; 104,3; 84,5; 71,1; 54,6; 52,8; 47,1; 44,5 ppm;

Mass spectrometry high resolution (ES+)calculated for C30H30N8O535Cl3(M+H)+687,1326; obnarujeno 687,1320. Calculated for C30H30N8O537Cl3(M+H)+689,1326; found 689,1320.

Additional example 8: Synthesis of compound I-3

Compound I-3 was obtained according to example 5 except that used other source materials, as shown in the reaction scheme. Yield: 73%.

TPL=202,2-203,1°C;

1H NMR (400 MHz; DMSO-d6): δ 8,43 (d; J=2.0 Hz; 1H); of 8.37 (d, J=2.0 Hz; 1H); 7,82-a 7.85 (m; 2H); the 7.65 (d, J=8.0 Hz; 2H); 7,44-7,50 (m; 2H); of 7.48 (t, J=8.0 Hz; 1H); 7,40 (d; J=8.0 Hz; 2H); is 6.61 (d, J=7,2 Hz; 1H); 5,35 (d; J=15,2 Hz; 1H); 5,18 (d; J=15.2 Hz; 1H); 4,82 (dd; J1=2.4 Hz; J2=7.2 Hz; 1H); 4.72 in (d; J=16,8 Hz; 1H); with 4.64 (d; J=16,8 Hz; 1H); 3,93 (d; J=2,4 Hz; 1H); 3,84-3,92 (m; 2H); 3,67-3,81 (m; 5H); of 3.25 to 3.35 (m; 1H) ppm;13C NMR (100 MHz; DMSO-d6): δ 151,4; 150,0; 149,3; 146,9; 136,0; 133,0; 130,0; 129,1; 128,7; 125,2; 102,7; 97,3; 54,6; 52,7; 44,5 ppm;

Mass spectrometry high resolution (ES+)calculated for C28H27N8O735Cl2S (M+N)+689,1022; found 689,1008. Calculated for C28H27N8O737Cl2S (M+H)+691,1022; found 691,1008.

Additional example 9: Synthesis of compound I-4

Compound I-4 was obtained according to Example 8, except that used other source materials, as shown in the reaction scheme. Yield: 62%.

TPL=128,2-129,8°C;

1H NMR (400 MHz; DMSO-d6): δ 8,35 (d; J=2,4 Hz; 1H); 781 (dd; L=2,4 Hz; J2=8,4 Hz; 1H); 7,51 (d; J=8,4 Hz; 1H); 7,47 (d; J=8.0 Hz; 1H); to 7.32 (t, J=8.0 Hz; 2H); 7,28 (d; J=8.0 Hz; 2H); are 5.36 (s; 2H); 5,18 (s; 2H); 5,00 (d; J=15.6 Hz; 1H); and 4.68 (d, J=15.6 Hz; 1H); 1,94-2,04 (m; 4H) ppm; 13C NMR (100 MHz; DMSO-d6): δ 155,6:149,7; 149,6; 139,7; 132,6; 124,5; 109,6; 87,0; 75,1; 51,2; 50,3; 46,6; 31,9; 31,7 ppm;13With NMR (100 MHz; DMSO-d6): δ 152,2; 150,0; 149,3; 144,7; 129,8; 125,2; 118,7; 84,4; 74,6; 56,9; 55,78; 31,6; 29,4; 14,2 ppm;

Mass spectrometry high resolution (ES+)calculated for C19H20N4O335Cl (M+H)+ 387,1146; found 387,1139. Calculated for C19H20N4O337Cl (M+H)+389,1146; found 389,1139.

Additional example 10: Synthesis of compound I-5

Compound I-5 was obtained according to Example 8, except that used other source materials, as shown in the reaction scheme. Yield: 68%.

TPL=130,2-130, 8mm°C;

1H NMR (400 MHz; DMSO-d6): δ 8,35 (d; J=2,4 Hz; 1H); 7,81 (dd; J1=2.4 Hz; J2=8,4 Hz; 1H);7,51 (d; J=8,4 Hz; 1H); are 5.36 (s; 2H); 5,18 (s; 2H); 5,00 (d; J=15.6 Hz; 1H); and 4.68 (d, J=15.6 Hz; 1H); 3,35 (s; ZN); 2,85 (s; 2H);1,94-2,04 (m; 4H) ppm;13C NMR (100 MHz; DMSO-d6): δ 156,1; 149,2; 135,4; 132,3; 124,7; 88,4; 81,4; 74,6; 56,6; 48,8; 30,8; 27,9 ppm;

Mass spectrometry high resolution (ES+)calculated for C14H18N4O435Cl (M+H)+341,0938; found 341,0933. Calculated for C14H18N4O437Cl (M+H)+343,0938; found 343,0933.

Additional example 11: Synthesis of connection is through the I-6

Compound I-6 was obtained according to Example 8, except that used other source materials, as shown in the reaction scheme. Yield: 71%.

TPL=144,2-145,8°C;

1H NMR (400 MHz; DMSO-d6): δ 8,32 (d; J=2,4 Hz; 1H); to 7.84 (dd; L=2,4 Hz; J2=8,4 Hz; 1H); EUR 7.57 (d, J=8,4 Hz; 1H); from 5.29 (s; 2H); 5,15(s; 2H); 5,10 (d; J=15.6 Hz; 1H); 4,78 (d; J=15.6 Hz; 1H); 3,37 (s; 3H); 1,94-2,00 (m; 4H) ppm;13C NMR (100 MHz; DMSO-d6): δ 162,4; 156,5; 149,2; 135,4; 124,7; 88,1; 74,6; 53,5; 48,8; 31,3; 27,9 ppm;

Mass spectrometry high resolution (ES+)calculated for C14H16N4O535Cl (M+N)+355,0731; found 355,0723. Calculated for C14H16N4O537Cl (M+N)+357,0731; found 357,0723.

Additional example 12: Synthesis of compound I-7

Compound I-7 was obtained according to Example 8, except that used other source materials, as shown in the reaction scheme. Yield: 72%.

TPL=158,2-159,8°C;

1H NMR (400 MHz; DMSO-d6): δ 8,32 (d; J=2,4 Hz; 1H); 7,80 (dd; J1=2.4 Hz; J2=8,4 Hz; 1H); 7,54 (d; J=8,4 Hz; 1H); 7,42 (d; J=8.0 Hz; 1H); 7,22 (d; J=8.0 Hz; 2H); 5,34 (s; 2H); 5,11 (s; 2H); 5,02 (d; J=15.6 Hz; 1H); 4,67 (d; J=the 15.6 Hz; 1H); 1,92 is 2.01 (m; 4H) ppm;13C NMR (100 MHz; DMSO-d6): δ 155,6; 149,7; 149,6; 139,7; 132,6; 124,5; 109,6; 87,0; 75,1; 51,2; 50,3; 46,6; 31,9; 31,7 ppm;13With NMR (100 MHz; DMSO-d6): δ 170,3; 151,0; 150,2; 148,6; 143,5; 135,8; 134,9; 129,8; 129,0; 127,7; 124,8; 84,4; 74,6; 47,9; 31,6; 30,8; 29,4 ppm;

Wt is spectrometry high resolution (ES+), calculated for C20H19N4O4Br35Cl (M+H)+493,0200; found 493,0191. Calculated for C20H19N4O4Br37Cl (M+H)+495,0200; found 495,0191.

Additional example 13: Synthesis of compound I-8

Compound I-8 was obtained according to Example 8, except that used other source materials, as shown in the reaction scheme.

Yield: 66%.

TPL=138,2-139,7°C;

1H NMR (400 MHz; DMSO-d6): δ 8,32 (d; J=2,4 Hz; 1H); 7,81 (dd; J1=2.4 Hz; J2=8,4 Hz; 1H); at 7.55 (d, J=8,4 Hz; 1H); 5,70 (s; 2H); 5,57 (s; 2H); 5,32 (s; 2H); 5,04 (d; J=15.6 Hz; 1H); br4.61 (d; J=15.6 Hz; 1H); 1,92-2,04 (m; 4H) ppm; 13C NMR (100 MHz; DMSO-d6): δ 155,6; 149,7; 149,6; 139,7; 132,6; 124,5; 109,6; 87,0; 75,1; 51,2; 50,3; 46,6; 31,9; 31,7 ppm; 13C NMR (100 MHz; DMSO-d6): δ 155,8; 150,0; 149,3; 136,0; 130,4; 125,2; 77,3; 70,9; 63,3; 53,9; 24,7 ppm;

Mass spectrometry high resolution (ES+)calculated for C14H16N4O435Cl (M+H)+339,0784; found 3390789. Calculated for C14H16N4O437Cl (M+H)+, 341,0784; found 341,0789.

Additional example 14: Synthesis of compound I-9

Compound I-9 was obtained according to Example 8, except that used other source materials, as shown in the reaction scheme. Yield: 63%,

TPL=168,2-169,4°C;

1H NMR (400 MHz; DMSO-d6): δ 8,31 (d; J=2,4 Hz; 1H); to 7.84 (dd; J1=2 Hz; J2=8,4 Hz; 1H); 7,52 (d, J=8,4 Hz; 1H); 5,71 (s; 2H); 5,57 (s; 2H); 5,31 (s; 2H); of 5.05 (d, J=15.6 Hz; 1H); br4.61 (d; J=15.6 Hz; 1H); 1.93 and-2,07 (m; 4H) ppm; 13C NMR (100 MHz; DMSO-d6): δ 155,6; 149,7; 149,6; 139,7; 132,6; 124,5; 109,6; 87,0; 75,1; 51,2; 50,3; 46,6; 31,9; 31,7 ppm;13With NMR (100 MHz; DMSO-d6): δ 178,2; 150,0; 149,3; 136,0; 130,4; 125,2; 89,2; 73,9; 57,5; 53,9; 51,5; 30,9; 27,9 ppm;

Mass spectrometry high resolution (ES+)calculated for C14H16N4O3S35Cl (M+N)+355,0553; found 355,0559. Calculated for C14H16N4O3S37Cl (M+H)+357,0553; found 357,0559.

Additional example 15: Synthesis of compound I-10

Compound I-10 was obtained according to Example 8, except that used other source materials, as shown in the reaction scheme. Yield: 68%.

TPL=155, 2mm-156,7°C;

1H NMR (400 MHz; DMSO-d6): δ 8,32 (d; J=2,4 Hz; 1H); of 7.82 (dd; J1=2.4 Hz; J2=8,4 Hz; 1H); 7,54 (d; J=8,4 Hz; 1H); 5,72 (s; 2H); 5,57 (s; 2H); 5,35 (s; 2H); 5,02 (d; J=15.6 Hz; 1H); with 4.64 (d, J=15.6 Hz; 1H); 1,94-2,07 (m; 4H); 1,15 (s; 3H) ppm;13C NMR (100 MHz; DMSO-d6): 6 162,1; 150,0; 149,3; 136,0; 130,4; 125,2; 89,5; 73,9; 67,2; 56,4; 42,9; 30,9; 27,9 ppm;

Mass spectrometry high resolution (ES+)calculated for C15H19N6O335Cl (M+N)+352,1098; found 352,1092. Calculated for C15H19N5O337Cl (M+N)+354,1092; found 354,1098.

Additional example 16: Synthesis of compound I-11

Compound I-11 was obtained according to Example 8, except that used other source materials, as shown in the reaction scheme. Yield: 71%.

TPL=142,2-143,8°C;

1H NMR (400 MHz; DMSO-d6): δ 8,35 (d; J=2,4 Hz; 1H); of 7.82 (dd; J1=2.4 Hz; J2=8,4 Hz; 1H); 7,52 (d, J=8,4 Hz; 1H); 7,43 (d; J=8,4 Hz; 2H); to 7.32 (t, J=8,4 Hz; 1H); 7,29 (d; J=8,4 Hz; 2H); 5,72 (s; 2H); 5,54 (s; 2H); 5,32 (s; 2H); of 5.05 (d, J=15.6 Hz; 1H); to 4.62 (d, J=15.6 Hz; 1H); 1,95-2,07 (m; 4H) ppm;13With NMR (100 MHz; DMSO-d6): δ 162,1; 150,0; 149,3; 146,9; 136,0; 130,4; 130,3; 125,2; 122,5; 117,7; 89,5; 73,9; 62,2; 60,5; 56,4; 30,9; 27,8 ppm;

Mass spectrometry high resolution (ES+)calculated for C20H21N5O335Cl (M+N)+414,1255; found 414,1263. Calculated for C20H21N5O337Cl (M+N)+416,1255; found 416,1263.

Additional example 17: Synthesis of compound I-12

Compound I-12 was obtained according to Example 8, except that used other source materials, as shown in the reaction scheme. Yield: 58%.

TPL=151,2-152,9°C;

1H NMR (400 MHz; DMSO-d6): δ 8,32 (d; J=2,4 Hz; 1H); to 7.84 (dd; J1=2.4 Hz; J2=8,4 Hz; 1H); 7,53 (d; J=8,4 Hz; 1H); 5,32 (s; 2H); to 5.03 (d, J=15.6 Hz; 1H); with 4.64 (d, J=15.6 Hz; 1H); 3,52-to 3.73 (m; 4H); 2,32 (s; 2H); 3,17 (s; 2H); 1,95-2,04 (m; 2H) ppm;13C NMR (100 MHz; DMSO-d6): δ 155,6; 149,7; 149,6; 139,7; 132,6; 124,5; 109,6; 87,0; 75,1; 51,2; 50,3; 46,6; 31,9; 31,7 ppm; 13C NMR (100 MHz; DMSO-d6): δ 171,7; 171,5; 150,0; 149,3; 136,0; 130,4; 125,2; 89,0; 71,6; 54,9; 52,2; 51,5; 50,6; 49,0 46,9 ppm;

Mass spectrometry high resolution (ES+)calculated for C18H19N4O35Cl (M+H)+ 439.0942; found 439,0933. Calculated for C18H19N4O35Cl (M+H)+, 441,0942; found 441,0933.

Additional example 18: Synthesis of compound I-13

Compound I-13 was obtained according to Example 8, except that used other source materials, as shown in the reaction scheme. Yield: 69%.

TPL=145, 2mm-146,8°C;

1H NMR (400 MHz; DMSO-d6): δ 8,33 (d; J=2,4 Hz; 1H); 7,81 (dd; J1=2.4 Hz; J2=8,4 Hz; 1H); 7,51 (d; J=8,4 Hz; 1H); 7,43 (t; J=8,4 Hz; 1H); 7,25-7,38 (m; 8H); 7,14 (t; J=8,4 Hz; 1H); 6,57 (s; 2H); 6,51 (s; 2H); 5,33 (s; 2H); of 5.05 (d; J=15.6 Hz; 1H); 4,67 (d; J=15.6 Hz; 1H); 3,54-to 3.73 (m; 2H); 2,32 (s; 2H); 3,21 (s; 2H); 1,98-2,04 (m; 2H) ppm; 13C NMR (100 MHz; DMSO-d6): δ 150,0; 149,3; 136,0; 130,4; 129,1; 128,7; 127,0; 125,2; 90,5; 76,8; 58,2; 50,6; 48,1; 46,9; 34,9; 33,2 ppm;

Mass spectrometry high resolution (ES+)calculated for C28H28N4O335Cl (M+N)+503,1772; found 503,1763. Calculated for C28H28N4O337Cl (M+N)+, 505,1772; found 505,1763.

Additional example 19: Synthesis of compound I-14

Compound I-14 was obtained according to Example 8, except that used other source materials, as shown in the reaction scheme. Yield: 64%.

TPL=188,2-189,8°C;

1H NMR (400 MHz; DMSO-d6): δ 8,35 (dd;J1=0.6 Hz; J2=2.4 Hz; 1H); of 7.82 (dd; J1=2.4 Hz; J2=8,4 Hz; 1H); 7,53 (dd; J1=0.6 Hz; J2=8,4 Hz; 1H); 5,12 (s; 1H); 5,04-of 5.06 (m; 1H); 4.92 in (d; J=15.6 Hz; 1H); 4.72 in (d; J=15.6 Hz; 1H); 3,64-3,74 (m; 4H); 3,55 (s; 3H); 1,71-of 1.84 (m; 3H); 1,51-of 1.56 (m; 1H); 1,31-1,40 (m; 1H) ppm; 13C NMR (100 MHz; DMSO-d6): δ 157,6; 150,0; 149,3; 136,0; 130,4; 125,2; 75,6; 66,3; 54,9; 50,6; 47,7; 39,2; 32,5; 26,8 ppm;

Mass spectrometry high resolution (ES+)calculated for C16H20N4O5S35Cl (M+H)+ 415,0765; found 415,0760. Calculated for C16H20N4O5S37Cl (M+N)+, 417,0765; found 417,0760.

Additional example 20: Synthesis of compound I-15

Compound I-15 was obtained according to Example 8, except that used other source materials, as shown in the reaction scheme. Yield: 63%.

TPL=148,2-149,8°C;

1H NMR (400 MHz; DMSO-d6): δ 8,33 (dd; J1=0.6 Hz; J2=2.4 Hz; 1H); to 7.84 (dd; J1=2.4 Hz; J2=8,4 Hz; 1H); 7,63 (d; J=8,4 Hz; 1H); 7,41 (t; J=8,4 Hz; 2H); 7,52 (dd; J1=0.6 Hz; J2=8,4 Hz; 1H); 7,29 (d; J=8,4 Hz; 2H); 5,15 (s; 1H); 5,04-5,06 (m; 1H); to 4.98 (d, J=15.6 Hz; 1H); 4.72 in(d; J=15.6 Hz; 1H); 3,66-3,74 (m; 4H); 1,78-of 1.88 (m; 3H); of 1.52-1.55V (m; 1H); 1.32 to 1.41 for (m; 1H) ppm;13C NMR (100 MHz; DMSO-d6): δ 155,9; 150,4; 149,2; 142,8; 140,2; 137,4; 136,1; 130,4; 125,6; 75,8; 66,5; 54,4; 50,8; 47,1; 32,8; 26,8 ppm;

Mass spectrometry high resolution (ES+)calculated for C21H22N4O335Cl (M+H)+413,1302; found 413,1311. Calculated C21H22N4O337Cl (M+H)+415,1295; found 415,1304.

Augment the capacity example 21:

Insecticidal activity of the compounds obtained according to Examples 5 to 20 was determined by the same method as in Example 14 of the present application.

The test showed that all compounds I-1 to I-15 have very good insecticidal activity.

1. The compound of formula (A), (B), (C) or (D), or agrokhimichesky acceptable salt,


where R1represents 5 - or 6-membered heterocycle containing nitrogen atom, oxygen and/or sulfur, halogenosilanes 5 - or 6-membered heterocycle containing nitrogen atom, oxygen and/or sulfur, substituted or unsubstituted phenyl, where the substituents are one or more than one group selected from the group consisting of halogen atoms, C1-4halogenoalkane or1-4chlorococcal;
R2represents H, C1-8saturated or unsaturated alkyl, halogenosilanes C1-8saturated or unsaturated alkyl, -CH2CH2OCH2CH3, -CH2CH2Och3, phenyl, unsubstituted benzyl or benzyl substituted by one or more than one group selected from the group consisting of a halogen atom, a C1-4ha is genealogie or 1-4chlorococcal,1-4alkylsulphonyl or1-4alkylsulfonyl;
R3and R4independently selected from H, C1-6of alkyl, allyl, benzyl,1-4alkoxy-C1-4of alkyl, C1-4alkoxycarbonyl, unsubstituted bentilee group or benzoline group, substituted by one or more than one group selected from the group consisting of halogen atoms, C1-4of alkyl, C1-4halogenoalkane,1-4alkoxyl or C1-4alkylsulphonyl; or R3and R4together form-CH2-CH2-, -CH2-CH2-CH2- or-CH2-XR-CH2-where X is a heteroatom N, O and S; R is a Deputy on X and is selected from H, C1-6of alkyl, allyl, benzyl, phenyl, C1-4alkoxy-C1-4of alkyl, C1-4alkoxycarbonyl, unsubstituted bentilee group or benzoline group, substituted by one or more than one group selected from the group consisting of halogen atoms, C1-4halogenoalkane, C1-8saturated or unsaturated alkyl or alkoxyl or1-4alkylcarboxylic,
R5, R6, R7, R8and R9represents H, saturated or unsaturated C1-4alkyl, halogen atom, saturated or unsaturated With1-8alkoxy, saturated C1-4halogenoalkanes,1-4alkylsulphonyl, sub> 1-8alkilany ester, C1-4alkylsulfonyl, phenyl, benzyl or trifloromethyl ester group;
Y represents nitro, cyano, trifluoromethyl, TRIFLUOROACETYL or trifloromethyl.

2. Connection or agrokhimichesky acceptable salt according to claim 1, where R1selected from pyridyl, thiazolyl, tetrahydrofuryl, oxazolyl or their halogenated groups.

3. Connection or agrokhimichesky acceptable salt according to claim 1, where R2represents H, saturated or unsaturated With1-4alkyl, saturated or unsaturated With1-4halogenoalkane,1-4alkylsulphonyl, unsubstituted benzyl or benzyl substituted by one or more than one group selected from the group consisting of a halogen atom, a C1-4halogenoalkane or1-4chlorococcal.

4. Connection or agrokhimichesky acceptable salt according to claim 1, wherein R3and R4represent H, C1-6alkyl group, or R3and R4together form-CH2-CH2- or-CH2-CH2-CH2-.

5. Connection or agrokhimichesky acceptable salt according to claim 1, where R5, R6, R7, R8and R9represent H, saturated With1-2alkyl, halogen atom, saturated or unsaturated With1-4alkoxyl saturated With1-2halogenoalkanes,1-2alkyls hanil or trifloromethyl ester group.

6. Connection or agrokhimichesky acceptable salt according to claim 1, where Y is a nitro-group or cyano.

7. Agrochemical composition having insecticidal activity, containing:
(a) 0.001 to 99.99 wt.% connection or agrokhimichesky acceptable salts according to any one of claims 1 to 6, or combinations thereof; and
(b) agrokhimichesky acceptable carrier or excipient.

8. The application of the agrochemical composition according to claim 7 for the destruction or control agricultural pests, hygiene pests and pests that are harmful to animal health.

9. The method of obtaining the compound or its agrokhimichesky acceptable salts according to any one of claims 1 to 6, comprising the following stages:
in the presence of catalytic acid and 0-60°With the interaction of the compounds of formula (a) with compound (b) by means of which one obtains the compound (A) or (B), where R2represents H,

where R1, R3, R4, R5, R6, R7, R8, R9and Y are as defined in claim 1, and n is 0 or 1.

10. The method according to claim 9, including:
in the presence of catalytic acid carry out the following reaction at 20-30°C in acetonitrile for 2-24 h, through which they receive a connection (A), where R2is a N:

in the presence of catalytic acid, conduct the following reaction at 20-30°C in acetonitrile for 2-24 h, whereby get connection ():
.

11. The method of obtaining the compound or its agrokhimichesky acceptable salts according to any one of claims 1 to 6, comprising the following stages:
in the presence of catalytic acid and 0-60°With the interaction of the compounds of formula (a) with compound (C) or (d), through which they receive a connection (C) or (D)

where R1, R3, R4, R5, R6, R7, R8, R9and Y are as defined in claim 1, and n is 0 or 1.

12. The method according to claim 11, including:
in the presence of catalytic acid carry out the following reaction at 10-50°C. in acetonitrile for 2-24 h, whereby get connection ():
;
in the presence of catalytic acid carry out the following reaction at 10-50°C. in acetonitrile for 2-24 h, through which they receive a connection (D):
.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described macrocyclic phenylcarbamates of formula (I), wherein A represents -C(=O)OR1 or -C(=O)-NH-SO2-R2, wherein R1 represents hydrogen or C1-C6alkyl; R2 represetns C3-7cycloalkyl, phenyl, thiazolyl or pyridyl each of which is optionally substituted by one or more substituted specified in C1-6alkyl, C1-6alkoxy, trifluoromethyl and halogen; X represents N or CH; E represents NR5; R5 represents hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl or C3-7cycloalkyl; n is equal to 4 or 5; wherein a dash line -----, adjoining the fragment -(CH2)n-, represents a double bond; and wherein the dash line in a five-merous cycle including X, represents a single bond, and R7 represents hydrogen; R8 is such as specified in the patent claim, or N-oxide thereof, a pharmaceutically acceptable additive salt or a pharmaceutically acceptable solvate possessing antiviral activity, and used as HCV inhibitors; as well as pharmaceutical compositions containing the above compounds as an active ingredient.

EFFECT: preparing the pharmaceutically acceptable additive salt or pharmaceutically acceptable solvate possessing antiviral activity.

10 cl, 23 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazo[4,5-b]pyrazine derivatives of general formula or to its pharmaceutically acceptable salt wherein: R1 represents either aryl unsubstituted or substituted by one of the groups: halogen, hydoxyl, C1-6alkyl, C1-6alkoxyl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, NHC1-6alkylC1-6alkoxy, C1-6alkylhydroxy, -C(O)NH2, -C(O)OC1-6alkyl, -C(O)NH C1-6alkyl, cyano, carboxy, heteroaryl and heterocycloalkyl; or heteroaryl unsubstituted or substituted by one of the groups: C1-6alkoxy, hydroxy, -C1-6alkyl, NH2 and NHC1-6alkyl; heterocycloalkyl unsubstituted or substituted by one group =O; and R2 represents H; unsubstituted C3-4alkyl; C1-4alkyl substituted by C5-6cycloalkyl unsubstituted or substituted by one group specified in amino, hydroxyl, C1-6alkoxy, or heterocycloalkyl unsubstituted or substituted by 1-2 groups specified in =O, C1-6alkyl; or C5-6cycloalkyl substituted by one group specified in hydroxyl, C1-6alkoxyl, C1-6alkylC1-6alkoxy, C1-6alkylhydroxy, CONH2; or substituted ir unsubstituted heterocycloalkyl; wherein aryl represents an aromatic structure consisting of 6-10 carbon atoms containing one ring or two condensed rings; wherein heteroaryl represents a 5-10-member aryl ring system containing 1-2 heteroatoms specified in nitrogen, oxygen and sulphur; wherein heterocycloalkyl represents a 5-9-member nonaromatic cycloalkyl wherein 1-2 heteroatoms specified in nitrogen and oxygen; provided the compound does not represent 1,3-dihydro-5-phenyl-2H-imidazo[4,5-b]pyrazin-2-one. Also, the invention refers to the specific imidazo[4,5-b]pyrazine derivatives, to a based pharmaceutical composition, to a method of treating or preventing cancer, inflammatory conditions, immunological diseases, metabolic conditions, and to a method of kinase inhibition in a cell expressing said kinase.

EFFECT: there are produced new imidazo[4,5-b]pyrazine derivatives showing effective biological properties.

17 cl, 2 tbl, 210 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 2-substituted-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-ones and 2-substituted-2,3,5,6-tetrahydrooxazolo[3,2-a]pyrimidin-7-ones of formula (I): where p, n, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are described in the description. These compounds are modulators of metabotropic glutamate receptors (mGluR), particularly the mGluR2 receptor. Compounds in the present invention are therefore suitable for use as pharmaceutical agents, especially in treating and(or) preventing various disorders of the central nervous system (CNS), including, among others, acute and chronic neurodegenerative disorders, psychosis, convulsions, anxiety, depression, migraine, pain, sleep disorder and emesis.

EFFECT: improved method.

14 cl, 148 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a novel intermediate epoxy compound of general formula (2), where R1 represents hydrogen or a lower alkyl group; and R2 represents a piperidinyl group of general formula (A1), where R3 represents a phenoxy group, having a halogen-substituted lower alkoxy group, substituted with a phenyl group, and other similar groups; and n is an integer from 1 to 6, to obtain 2,3-dihydroimidazo[2,1-b]oxazole. The invention also relates to specific epoxy compounds, a method of producing epoxy compounds of formula (2) and a method of producing 2,3-dihydroimidazo[2,1-b]-oxazole using a novel intermediate epoxy compound.

EFFECT: obtaining 2,3-dihydroimidazo[2,1-b]oxazole with high output and high purity.

4 cl, 30 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , and pharmaceutically acceptable salts thereof, where L denotes O, S, or CH2; Y denotes N or CH; Z denotes CR3; G denotes CH; R1 denotes a heteroaryl ring of formula , where D1 denotes S, O; D2 denotes N or CR12; D3 denotes CR12; R2 denotes (C6-C10)-aryl; 5-9-member mono- or bicyclic heteroaryl with 1 or 2 heteroatoms independently selected from N or S; a saturated or partially saturated (C3-C7)-cycloalkyl; or a saturated 5-6-member heteocyclyl with 1 heteroatom selected from N, where said aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with one or two groups independently selected from (C1-C6)-alkyl, F, Cl, Br, CF3, CN, NO2, OR6, C(-O)R6, C(=O)OR6, C(=O)NR6R7, saturated 6-member heterocyclyl with 2 heteroatoms independently selected from N or O, and S(O)2R6, and where said alkyl is optionally substituted with one -OR8 group; R3 denotes H; (C1-C6)-alkyl; (C2-C6)-alkenyl; Cl; Br; OR6; SR6; phenyl; or a 6-member heteroaryl with 1 heteroatom selected from N, where said alkyl and alkenyl are optionally substituted with one group selected from C(=O)OR8, -OR8, -NR8R9; or a saturated 6-member heterocyclyl with 1 heteroatom selected from N or O.

EFFECT: disclosed compounds are used in treating and preventing diseases mediated by insufficient level of glucokinase activity, such as sugar diabetes.

16 cl, 479 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula 1, or their pharmaceutically acceptable salts showing the properties of incretin secretagogues, preferentially the properties of a bile acid receptor TGR5 agonist. The compounds are applicable for treating metabolic diseases associated with glucose metabolism, such as diabetes, obesity, metabolic syndrome, etc. In formula 1 R1, R2 and R3 independently represent a cyclic system substitute specified in: hydrogen, C1-C3alkyl, halogen, a trifluoromethyl group, C1-C3alkoxy, a cyano group, a trifluoromethoxy group; an amino group substituted by C1-C3alkyl; or two radicals R3, found at carbon neighbours in a benzene ring, together with the benzene ring bound therewith form 3,4-methylene dioxyphenyl; R4 represents hydrogen, C1-C5alkyl, a carboxyl group, C1-C3alkoxycarbonyl or an amide group CONHR5; R5 is an optionally substituted by C1-C3alkyl, C5-C6cycloalkyl optionally substituted by phenyl, benzyl, pyridyl; X and Y represent two hydrogen atoms or an oxygen atom, provided Y=O, then X=2H, provided Y=2H, then X=O or X=Y=2H; the sign (N) shows the possibility of bioisosteric substitution of the benzene ring by the pyridine, pyrimidine, pyridazine, triazine or pyrazine ones.

EFFECT: preparing the pharmaceutical composition and the combined drugs with the use of the compounds of formula 1 or the based pharmaceutical composition and a protein kinase DPP-IV inhibitor specified in Vildagliptin or Sitagliptin, and/or an endogenous bile acid or mied bile acid secretagogues.

53 cl, 7 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: described are novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side with considerable absorption in the region up to 410-420 nm, having general formulae (a)-(k) (structural formula and values of radicals are given in the description), composition which is stabilised with respect to UV radiation and containing novel UV-absorbers, and use of the novel compounds as UV light stabilisers for organic materials.

EFFECT: obtaining novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side.

13 cl, 23 ex, 2 tbl

Polycyclic compound // 2451685

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a new polycyclic compound with general formula (I-1) and (1-3) or a pharmaceutically acceptable salt thereof where X1- -CR1 =CR2 - where R1 and R2 independently stand for hydrogen or C1-6 alkyl while Het stands for a radical of the following formulae: that may be substituted 1-3 times additionally described is a pharmaceutical composition containing such compound and intended for prevention or treatment of diseases caused by β-amyloid.

EFFECT: production of a pharmaceutical composition prevention or treatment of diseases caused by β-amyloid.

7 cl, 392 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (R)-N-(3-amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-4-methyl-benzamide substantially free from (S)-N-(3-amino-propyl)-N[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methypropyl]-4-methyl-benzamide, or its pharmaceutically acceptable salt which shows the properties of Eg5 inhibitor.

EFFECT: invention also refers to a pharmaceutical composition containing said compound and its pharmaceutically acceptable salt.

4 cl, 27 ex

Azole compounds // 2493154

FIELD: chemistry.

SUBSTANCE: invention relates to compounds which are pyridin-3-yl 4-(3-phenyl-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-[3-(4-fluoromethyl)-1H-1,2,4-triazol-5-yl]piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-[5-(4-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate, 2,6-dimethylpyridin-3-yl 4-[5-(3,4-difluorophenyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxylate, 2-methylpyridin-3-yl 4-[3-(2-fluorophenyl)-1H-1,2,4-triazol-5-yl]piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-(3-phenyl-1H-pyrazol-1-yl)piperidine-1-carboxylate, 2-methylpyridin-3-yl 4-[5-(3-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate and 6-methylpyridin-3-yl 4-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate or to a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds, having inhibiting effect on fatty acid amide hydrolase (FAAH).

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine for treating neuropathic pain.

13 cl, 38 tbl, 159 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound, which is N3-1H-indol-5-yl-5-pyridin-4-ylpyrazine-2,3-diamine, or a pharmaceutically acceptable salt thereof, which can act as inhibitors of protein kinase, especially FLT3 tyrosine kinase. The invention also relates to a pharmaceutical composition which contains said compound in combination with another molecularly directed (target) agent, which is a traditional cytotoxic agent or a compound used after chemotherapy, supporting therapy targeted on stem cells and in case of MLL rearrangement acute lymphoblastic leukaemia in children.

EFFECT: obtaining a novel compound which can be used in medicine for preventing or treating haematological malignant growths such as AML, MLL, T-ALL, B-ALL and CMML, myeloproliferative diseases, autoimmune diseases and skin diseases, such as psoriasis and atopic dermatitis.

16 cl, 2 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to antibacterial compounds of formula (I) , where one or two of U, V, W and X represent N, the remaining ones represent CH or, in case X, can also represent CRa, where Ra represents fluorine; R1 represents alcoxygroup, halogen or cyanogroup; R2 represents H, CH2OH, CH2N3, CH2NH2, alkylcarbonylaminomethyl or triazol-1-ylmethyl; R3 represents H or, when n=1, R3 can also represent OH, NH2, NHCOR6 or triazol-1-yl; A represents CR4; K represents O, NH, OCH2, NHCO, NHCH2; CH2NH5 CH2CH2, CH=CH, CHOHCHOH or CHR5; R3 represents H or together with R5 forms bond, or R4 can also represent OH, when K is not O, NH, OCH2 or NHCO; R5 represents OH or together with R4 forms bond; R6 represents alkyl; m=0 or 1 and n=0 or 1; and G is specified in i.1 of the formula; and to salt of such compound.

EFFECT: obtaining antibacterial compounds.

19 cl, 1 tbl, 44 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel pyridine derivatives pyridine1-A-pyridine2 of formula (1), where pyridine1 represents

, , or , ,

where asterisks stand for bond, which contains pyridine1 ring with A; R1 represents C1-5alkyl, C1-4alkoxygroup, C3-6-cycloalkyl, hydroxymethyl or NR1aR1b, R1a represents C1-4alkyl; R1b represents hydrogen or C1-3alkyl; or R1a and R1b, together with nitrogen atom, which is bound to pyridine, form pyrrolidine ring; R2 represents hydrogen or C1-4alkyl, or in case, when R1 represents C1-5alkyl or C3-6-cycloalkyl, R2 can additionally represent methoxygroup; R3 represents C1-4alkyl, C1-4alkoxygroup, C3-6-cycloalkyl or NR3aR3b; R3a represents C1-4alkyl; R3b represents hydrogen or C1-3alkyl; R4 represents C1-4alkyl or hydrogen; R5 represents C1-5alkyl, methoxygroup or NR5aR5b; and R6 represents C1-2alkyl; R5a represents C1-4alkyl; R5 represents hydrogen or C1-3alkyl; or R5 represents C1-2alkyl or methoxygroup; and R6 represents C1-5alkyl or NR6aR6b; R6a represents C1-4alkyl; R6b represents hydrogen or C1-3alkyl; R7 represents C1-5alkyl; R8 represents C1-2alkyl or methoxygroup; R9 represents C1-5alkyl; R10 represents C1-2alkyl; A represents

, , or ,

where asterisks stand for bond, binding pyridine1 ring with A; pyridine2 represents

, , or , ,

where asterisks stand for bond, which binds pyridine ring with A; R11 represents C1-4alkyl; C1-3alkyloxy group, hydroxymethyl or NR11aR11b; R,1a represents C1-3alkyl; R11b represents hydrogen or C1-2alkyl; R12 represents hydrogen or C1-4alkyl; R13 represents C1-4alkyl or NR13aR13b; R13a represents C1-4alkyl; R13b represents hydrogen or C1-2alkyl; R14 represents C1-2alkyl; R15 represents C1-4alkyl or NR15aR15b; and R16 represents C1-2alkyl; R15a represents C1-3alkyl; R15b represents hydrogen or C1-3alkyl; or R15 represents C1-2alkyl; and R16 represents C1-4alkyl or NR16aR16b; R16a represents C1-3alkyl; R16b represents hydrogen or C1-2alkyl; R17 represents C1-4alkyl; R18 represents C1-2alkyl or methoxygroup; R19 represents C1-4alkyl; and R20 represents C1-2alkyl; with exception of 3-(2-ethyl-4-pyridyl)-5-(2-ethyl-4-pyridyl)-1,2,4-oxadiazole; or pharmaceutically acceptable salt of such compound.

EFFECT: obtaining pyridine derivatives, which possess agonistic activity with respect to S1P1/EDG1.

15 cl, 2 tbl, 131 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel aminitriazole derivatives of formula (I), where A is phenyl, heterocyclyl or propan-1,3-diyl; E is *-C1-4alkyl-O-, -CH=CH- or , where asterisks stand for bond, through which binding with R1; Q- O or S occurs; R3 is hydrogen, C1-4alkyl, cyclopropyl, C1-4alkoxy-C1-4alkyl, benzyl or -CH2CH2C(O)O-tert-Bu; R1 is pyridyl or phenyl, possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, C1-4fluoroalkyl, C1-4fluoroalkoxy, di-( C1-3alkyl)amino or C1-4alkoxy-C1-2alkyl; and R2 is -CO-C1-3alkyl,-CF2-C1-3alkyl or -SO2-C1-3alkyl; or their pharmaceutically acceptable salts, pharmaceutical composition, which contains them.

EFFECT: obtaining novel compounds for treatment of inflammatory disease or Alzheimer's disease.

20 cl, 105 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula 1:

or pharmaceutically acceptable salts thereof, where values of Cy1; Cy2; L1; L2, R; R1; Rx and Ry and R2 are given in claim 1.

EFFECT: compounds are suitable for use as Raf protein kinase inhibitors.

36 cl, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to polymorphous form of compound

,

which is characterised by picture of X-ray diffraction, including discriminatory peaks approximately 7.269, 9.120, 11.038, 13.704, 14.481, 15.483, 15.870, 16.718, 17.087, 17.473, 18.224, 19.248, 19.441, 19.940, 20.441, 21.469, 21.750, 22.111, 23.319, 23.763, 24.120, 24.681, 25.754, 26.777, 28.975, 29.609, 30.073 degree 2Θ. Invention also relates to method of obtaining polymorphous form of compound (IX), which includes processing of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-ylthiazol-2-ylamino)phenyl]benzamide with methanesulfonic acid at temperature from 20 to 80°C in solvent, selected from group, which includes methanol, ethanol, acetone, diethyl ether, dioxane and their mixtures.

EFFECT: obtaining polymorphous form of compound (IX), which remains dry at 80% relative humidity and thermodynamically stable at temperatures lower than 200°C.

7 cl, 3 dwg, 4 ex

Organic compounds // 2491285

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein V is specified in -O- or a single bond; W is specified in -N(R5)C(O)-, -S(O)t- and -C(O)O-; X is specified in C(H) or N; Y is specified in S, N(H) or N(CH3); p means 0 or 2; t means 1 or 2; R1 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by 1 or 2 halogroups, C3-7cycloalkylC1-6alkyl, 2,3-dihydro-1H-indenyl, C6arC1-6alkyl optionally substituted by one or two halogroups and heteroarylC1-6alkyl, wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen optionally oxidated, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9-member bicyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen, oxygen and sulphur, wherein monocyclic heteroaryl of the heteroarylalkyl group may be optionally substituted by one or two substitutes independently specified in a group consisting a halogroup, a cyanogroup, C1-6alkyl, haloC1-6alkyl and C1-6alkyl-O-C(O)-; R2 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by phenoxy, hydroxy C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, phenyl optionally substituted by a halogroup, haloC1-6alkyl, C6arC1-6alkyl (optionally substituted by a halogroup, haloC1-6alkyl or haloC1-6alkoxygroup), 2-oxo-imidazolidinyl, heterocyclylC1-6alkyl and heteroarylC1-6alkyl, wherein heterocyclyl of heterocyclylalkyl means 5- or 6-member monocycle containing oxygen, and wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocycle containing 1-3 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9- or 10-member bicycle containing 1 to 2 heteroatoms specified in a group consisting of nitrogen and sulphur, wherein monocyclic heteroaryl of the heteroaryl alkyl group may be optionally substituted by 1 or 2 substitutes independently specified in a group consisting of a halogroup, C1-6alkyl, haloC1-6alkyl and phenyl optionally substituted by a halogroup; R3 is specified in a group consisting of hydrogen and alkyl; two adjacent R4 groups together with carbon atoms whereto attached can form phenyl; R5 means hydrogen; or a pharmaceutically acceptable salt thereof.

EFFECT: preparing the heterocyclic derivatives which modulate activity of stearoyl CoA desaturase, methods of using the above derivatives for modulating activity of stearoyl CoA desaturase and pharmaceutical compositions containing the above derivatives.

26 cl, 1 tbl, 153 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a 2H-chromen compound or a derivative thereof having action of a S1P1 agonist. The above may be used for preventing and/or treating a disease caused by undesired lymphocyte filtration, or a disease caused by abnormal cell proliferation or accumulation.

EFFECT: preparing the compounds for preventing and/or treating the disease caused by undesired lymphocyte filtration, or the disease caused by abnormal cell proliferation or accumulation.

8 cl, 131 tbl, 156 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to derivatives of aminopyrazol with the formula of , where A, E, R1 and R2 have values specified in the invention claims, and to their pharmaceutically acceptable salts. Compounds of the formula (I) are agonists of the ALX receptor. Besides, the invention relates to a pharmaceutical composition on the basis of the compound of the formula (I) or its pharmaceutically acceptable salt and to application of these compounds for production of a medicinal agent for prevention or treatment of a disease selected from inflammatory diseases, wheezing diseases, allergic states, HIV-mediated retrovirus infections, cardiovascular diseases, neuroinflammations, neurological disorders, pain, prion-mediated diseases and amiloid-mediated diseases; and for modulation of immune responses.

EFFECT: higher efficiency of compound application.

23 cl, 1 tbl, 466 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel of 2,4-pyrimidine diamine compounds of formula I, which inhibit degranulation of immune cells and can be used in treating cell reactions mediated by FcεRI or FcγRl receptors. In formula (I) each R2 and R4 is independently phenyl substituted with one or more R8 groups or a heteroaryl selected from a group consisting of , where the heteroaryl is optionally substituted with one or more R8 groups and at least one of R2 and R4 is a heteroaryl; R5 is selected from a group consisting of (C1-C6)alkyl, optionally substituted with one or more identical or different R8 groups, -ORd, -SRd, fluorine, (C1-C3)halogenalkyloxy, (C1-C3)perhalogenalkyloxy, -NRcRc, (C1-C3)halogenalkyl, -CN, -NO2, -C(O)Rd, -C(O)ORd, -C(O)NRcRc, -C(NH)NRcRc, -OC(O)Rd, -OC(O)ORd, -OC(O)NRcRc; -OC(NH)NRcRc, - [NHC(O)]nORd, R35 is hydrogen or R8; each Y is independently selected from a group consisting of O, S and NH; each Y1 is independently selected from a group consisting of O, S and NH; each Y2 is independently selected from a group consisting of CH, CH2, S, N, NH and NR37. Other values of radicals are given in the claim.

EFFECT: improved efficiency.

19 cl, 6 tbl.

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