The method of obtaining nitrogen-containing heterocyclic compounds

 

(57) Abstract:

Usage: as preparations possessing antifungal activity. Somnote of the invention: a product of the General formula; , where Ar is phenyl, substituted by one or more Halogens, (C1-C3- haloalkyl or (C1-C4- haloalkoxy; K, X1, Z represent independently from each other O, B1and B2that magub be the same or different and represent linear or branched (C1-C6- alkylidene, Rh denotes a (C1-C6- haloalkyl containing from 1 to 9 halogen atoms, (C3-C8- haloalkoxy, where the halogen is fluorine or chlorine, And denotes a nitrogen heterocyclic group selected from imidazoles, substituted C1-C6- alkilani or pyridine. Reagent 1: compound of the formula: Ar-X1-B1-Y , where Ar, X1and B1have the above values, Y is a halogen. Reagent II: amine of the formula: NA2-B2, -ZH , where B2and Z have the above meanings. Environment - organic solvent, in the presence of a base at room temperature. Reagent III: Ar-X1-B1-NH-B2-ZH , where Ar, X1B1B2And Z have the above meanings. Rea is CH3in dipolar aprotic or alcoholic solvent, in the presence of a strong base at 5C. the Reagent V: carbonyl derivative of imidazole, substituted imidazole or pyridine, aromatic, or halogenated solvent at 80C. table 2.

The invention relates to heterocyclic nitrogen compounds endowed with high antifungal activity, processes for their preparation and their use in agriculture as fungicides.

The aim of the invention are compounds of General formula I

Ar-X1-B1--Z-Rh1where AG is phenyl; phenyl substituted by one or more Halogens,1-C3-alkilani,1-C3-haloalkyl,2-C4-alkenylamine,

WITH2-C4-haloalkenes,1-C3-alkoxy groups, WITH1-C4-haloalkoxy, pyridyl, pyridyl which may be substituted by one or more Halogens or WITH1-C3-haloalkyl; K,X,Z represent independently from each other 0 or S;1IN2that may be the same or different from each other, each represents C1-C6-alkyliden normal or ISO-structure, Rh1is1-Ca, WITH3-C8-haloalkoxy,3-C8-haloalkoxy, where the halogen is preferably represented by fluorine, And - represents a nitrogen heterocyclic group selected from the radicals of formulae

RR2R2< / BR>
R1where R1, R2, R3that may be the same or different, each represents H, C1-C6-alkyl, C1-C6-haloalkyl,2-C6alkenyl,2-C6-haloalkyl,2-C6alkenyl,2-C6-haloalkyl, G represents CH

or n

Other objectives of the invention include:

salts of compounds of General formula (I) formed of an inorganic acid, such as galoidovodorodov, for example, uudistoodetena acid, Hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid, tatiania acid and phosphoric acid or organic acid such as acetic acid, propionic acid, ataliba acid, preventiva acid, methanesulfonate acid, benzoic acid, 4-methylbenzenesulfonate acid, etc.

complexes with metals formed in the complexation derivative of the formula (I) with organic or neo is.

Examples of compounds of General formula (1) of the invention are given in table. 1.

Compounds of General formula (I) can be obtained by using multiple schemes syntheses, some of which are summarized below.

The scheme of synthesis A.

GD Y represents the outgoing group, such as, for example: halogen or an ester of sulfonic acid.

According to the scheme And the compound of formula (VII) is obtained by reaction of compounds of formula (V) with the compound of the formula (VI) in the presence of a base, such as, for example: sodium hydroxide, potassium hydroxide, sodium hydride, tert-piperonyl sodium or carbonate of an alkali metal, to which is added the catalyst transfer phases, priemlimom solvent, such as for example water or alcohol, such as methanol, ethanol, butanol, ethylene glycol or, if the reaction is carried out under the conditions of the transfer phase, an aprotic polar solvent, such as for example dimethylformamide, the go organic aromatic solvent such as toluene, or a halogenated solvent such as methylene chloride or dichloroethane.

The reaction temperature may be between 0aboutC to the boiling point of the solvent in accordance with the methodology described in the train used in the form of a salt with an alkaline metal or alkaline-earth metal.

Then the compound of formula (VII) enter into reaction with the amine (VIII) or an amine (IX) in the presence of organic or inorganic bases, such as, e.g.: the alkali metal hydroxide, carbonate or bicarbonate of an alkali metal, triethylamine or pyridine, or by using an excess of amine of formula (VIII) or (IX) as the acid binding means, in an organic solvent and under conditions similar to the conditions of the previous step.

Depending on the amine are respectively of the intermediate compound of formula (X) or formula (XI).

After this intermediate compound of formula (XI) enter into reaction with carbonyl derivatives of heterocyclic nitrogen compounds (A), for example, carbonyl diimidazol in aromatic or halogenated solvent at a temperature component of the interval 0aboutC to the boiling point of the solvent, and obtaining the compounds of formula (I).

In accordance with another by the synthesis of the compound of formula (XI) is treated with phosgene or thiophosgene in such an organic solvent as ethyl acetate and receive compound of formula (XII), on the basis of which in the subsequent reaction with nitrogen heterocycle (A)-ti is the Union of the formula (XI) enter into reaction with the acid chloride of nicotinic acid and obtain the connection formula (I).

The intermediate compound of formula (XI) can also be obtained by the reaction of joining the compounds of formula (X) with poliferation, such as a formula:

CF2= CX1X2where X1= CI, F, CF3, OCF3. X2= F, CF3in the presence of catalytic or stoichiometric amount of a strong base such as sodium hydride or tertbutoxide sodium and in such a dipolar aprotic solvent like dimethylsulfoxide or dimethylformamide, or an alcohol solvent, such as, for example tert-butanol in the temperature range from -20 to 100aboutC.

the reaction of alkali metal salts of the compounds of formula (X) with the compound of the formula Y-R1where Y represents an acceptable waste group, such as halogen or ether sulfonic acid.

Similarly, the amine of formula (IX) can be synthesized from compounds of formula (VIII) using the methods described above for obtaining the compounds of formula (XI).

Compounds having a group Rh1where at least one hydrogen atom and more than one halogen atom, using reaction dehydrohalogenating can be converted into the corresponding unsaturated sedimentary (XIV) is obtained by reaction of compounds of formula (XIII) with the compound of the formula (V) in the presence of an organic or inorganic base and in a solvent such as methanol, ethanol, ethylene glycol, polyethylene glycols, dimethylformamide or under the reaction conditions of the transfer phase.

Then the compound of formula (XIV) restore the connection formula X, for example, sociallyengaged in solvents of the type ethers, such as tetrahydrofuran, after which the intermediate compound of formula (X) into a compound of formula (I) one of the methods outlined in the diagram above, the synthesis A.

The scheme of synthesis OF

where m = 1-6.

In accordance with reaction scheme for the reaction of compounds of formula (XV) with compounds of the formula (V) receive the acetal of the formula (XVI), followed by unlocking which synthesize the aldehyde of formula (XVII), which is injected into the reaction with the amine of formula (VIII) in the presence of a reducing agent, for example, hydrogen and a catalyst such as PT or Pd in an organic solvent, such as, for example, methyl alcohol in neutral or acidic medium, for example, in the presence of sulfuric acid, to obtain the compounds of formula (X), from which the use of transformations, indicated in the reaction scheme And obtain the connection formula (I).

Alternatively, the aldehyde of formula (XVIII) is used in the reaction restorative alkalima technical literature, obtaining the compounds of formula (XI), which is then converted into a compound of formula (I) according to one of the above schemes of synthesis.

Compounds of General formula (I) are very potent inhibitors of the growth of certain types of pathogenic fungi that infect planting of cultivated plants.

These compounds exhibit both preventive and curative activity when applied to cultivated plants or on parts of such plants, such as leaves, resulting prove particularly effective for the prevention of diseases caused by common pathogenic fungi, such as, for example the genus Erysiphe and the genus Puccinia.

Examples of diseases treatable using compounds of the present invention include:

- Erysiphe graminis on cereals,

Sphaeroteca fuliginea on cucurbits (e.g., the cucumbers),

- Puccinia on grain

- Seploria on grain

- Helminthosporium on grain

- Rhynehosporium on grain

- Poolosphaera leucdricha on Apple trees

- Uncinula necator on grapes

- Venturia inaegualis on Apple trees

- Piricularia oryzae on rice

- Boheytis cinerea

- Fusarium on cereals and other diseases.

For practical application in rural Hoseini several compounds of formula (I).

Such compositions can be applied to any parts of the plant such as leaves, stems, branches and roots of plants or plant seeds before planting, or the soil in which the plant is grown.

Can be used in compositions in the form of dry powders, wettable powders, emulsifiable concentrates, pastes, granules, solutions, suspensions, etc. and the choice of the type of composition depends upon the particular application. Get composition by known methods, for example by diluting or dissolving the active substance in the environment of the solvent and/or a solid diluent, possibly in the presence of surfactants. As solid diluents or carriers can be used the following materials: silicon oxide, colic, bentonite, talc, infusoria earth, dolomite, calcium carbonate, magnesium oxide, gypsum, clays, synthetic silicates, attapulgite, sepilift. As liquid diluents in addition to water, of course, can be used in various types of solvents, for example: aromatic solvents (benzene, xylene or a mixture of alkyl benzenes), chloroaromatics solvents (chlorobenzene), paraffins (petroleum fractions), alcohols (methanol, propanol) butanol, amines, amiat).

As surface-active substances can be used sodium, calcium or triethanolamine salts of alkyl sulphates, alkyl sulphonates, alkylarylsulphonates, polyethoxysiloxane alkyl phenols condensed with ethylene oxide, fatty alcohols, polyethoxysiloxane fatty acids, ligninsulfonate. The composition may also include additives for special purposes, such binders, for example: gumarabic, polyvinyl alcohol and polyvinylpyrrolidone.

If desired, the composition of the invention can be introduced also other joint active substances such as fungicides, plant protection, plant growth regulators, herbicides, insecticides, fertilizers.

The concentration of active component in provided compositions may vary within wide limits depending on the active ingredient, plant, pathogen, environmental conditions and the type of composition. Typically, the concentration of the active substance is the range of 0.1 to 95 wt.%, preferably, 0.5 to 90 wt.%.

P R I m e R 1 Synthesis of N-2-1(1, 1,2,2-tetrafluoroethoxy)ethyl-N-(2-(3-trifluoromethyl-phenoxy)ethyl (-1-carboxymethylate (compound I). To a solution of 1.3 g of N-2-(1,1,2,2-tetrafluoroethoxy 8 h at 80aboutC in nitrogen atmosphere. After removal of the solvent by evaporation in vacuo the residue is transferred in methylene chloride and the resulting solution was washed with water, dried over sulfonate sodium and evaporated under reduced pressure. The resulting crude product was then purified by chromatography on silica using as eluent a mixture of CH2CL2-Meon/95:5 volume (volume (vol./about)).

Obtained 1.2 g of oil, the spectral characteristic which corresponds to connection 1.

1H-NMR (60 MHz) in l3: 3,39 (2H, t), of 3.96 (2H, t), 4,25 (4H, t), 6,13 (1H, triple t), 7-7,5 (6N, m), 8 (1H, s)

P R I m m e R 2 (B). Synthesis of N-2-(1,1,2,2-tetrafluoroethoxy)ethyl-N-/2-(3-triptoreline) ethyl/Amin.

To a solution of 2 g 2-/2-(3-triptoreline)ethylamino/-ethanol in 14 ml of dimethyl sulfoxide, cooled to 5aboutTo add 0.35 g of tert-butoxide potassium, after which the reaction vessel miss tetrafluoroethylene, during which there is a slight evolution of heat. The reaction mixture is left for a few hours in the atmosphere of the same gas, after which the solution is transferred into deionized water and extracted with methylene chloride. The organic phase is dried over sodium sulfate and evaporated. Obtain 1.3 g of oily residue.

To a solution of 14.1 g ethanolamine in 33 ml of ethanol are added dropwise to 17.7 g of 1-bromo-2-(triptoreline)ethane and the mixture is stirred for 40 h at room temperature. The solvent is then evaporated under reduced pressure, the residue is transferred into 5 N. NaOH (26 ml). The resulting solution was extracted with methylene chloride, the extract washed with water, dried over sodium sulfate and evaporated to dryness. The obtained white crystalline substance which is transferred into hexane, filtered and washed with the same solvent. Obtained 12.2 g of the product.

1H-NMR (60 MHz) in DCl3, : 2,95 (2H, t), and 3.2 (2H, t), 3,9 (2H, t), 4,35 (2H, t), 7-7,5 (4H, m).

P R I m e R 4. Synthesis of 1-bromo-2-(3-triptoreline)ethane.

To a solution of 2.5 g of 3-triptoreline and 1,2-dibromoethane (30 g) in deionized water (30 ml) added dropwise 33% solution of NaOH (17 ml), after which the mixture is boiled for 1 h Then the reaction mixture is cooled, the resulting oil is separated from the aqueous phase and dispersed at 15 mm. Select the fraction with a boiling point of 118-120aboutC, the yield of the desired product 26,

1H-NMR (60 MHz) in CDCl3: 2,95 (2H, t), and 3.2 (2H, t) 3,9 (2H, t) of 4.35 (2H, t), 7-7,5 (4H, m)

P R I m e R 5 (C). Synthesis of N-/2-(1,1,2,2-tetrafluoroethoxy)ethyl-N-/2-(2,4,6-trichlorophenoxy) ethyl/1-carbene N-/2-(1,1,2,2-tetrafluoroethoxy)ethyl/-N-/2-(2,4,6-trichlorophenoxy) ethyl/Amin.

1H-NMR (60 MHz) in DCl3: 3,9 (4H, m), 4.2V (4H, m), to 5.66 (1H, triple t), 7-7,44 (3H, s), and 7.9 (1H, s)

P R I m e R 6 (B). Synthesis of N-(2-(1,1,2,2-tetrafluoroethoxy)ethyl/-N-/2-(2,4,6-trichloro - noxy)ethylamine.

Reproduce the technique of example 2, using as starting compound 2-/2-(2,4,6-trichlorophenoxy) ethyl - amino)ethanol.

1H-NMR (60 MHz) in CDCl3: 2,95 (2H, t), of 3.05 (2H, t), 4,1 (4H, t), to 5.66 (1H, triple t), 7,33 (2N, C).

P R I m e R 7 (A). Synthesis of 2-/2-(2,4,6-trichlorophenoxy)ethylamino/ethanol.

Reproduce the method of example 3 using as starting compound 1-bromo-2(2,4,6-trichlorophenoxy) ethane.

1H-NMR (60 MHz) in CDCl3: 2,7 (2H, t), 2,87 (2H, t), the 3.65 (2H, t), 4,4 (2H, t), 7,72 (2N, C).

P R I m e R 8. Synthesis of 1-bromo-2-(2,4,6-trichlorophenoxy)ethane.

Reproduce the method of example 4 using as starting compound 2,4,6-trichlorophenol

1H-NMR (60 MHz) in DCl3: the 3.65 (2H, t) to 4.3 (2H, t), 7,31 (2N, C).

P R I m e R s 9-14. Using a technique similar to the technique of example 1, on the basis of appropriate amines, the following compounds.

Connection 3.

N-2-(1,1,2,2-tetrafluoroethoxy)ethyl-N-/2-4-chlorphenoxy) -ethyl/-1-carboxamidine

N-2-(1,1,2,2-tetrafluoroethoxy)ethyl-N-/2-(2,4,5-trichlorophenoxy) ethyl/-1-carboxamid - imidazol

1H-NMR (60 MHz) in CdCl3: 3,95 (4H, m), 4.2V (4H, m) 5,7 (1H, triple t), 6,95 and 7.5 (4H, m), 8 (1H, s)

Connection 5.

N-2-(1,1,2,2-tetrafluoroethoxy)ethyl-N-/2-(2,4-dichlorophenoxy) ethyl/-1-carboxamid-diimidazole

1H-NMR (60 MHz) in DCl3: of 4.05 (4H, m), 4,3 (4H, m)

5,7 (1H, triple t), the 6.9 to 7.5 (5H, m), 8 (1H, s).

Connection 6.

N-2-(1,1,2,2-tetrafluoroethoxy)propyl-N/2-(1,4,6-trichlorophenoxy) ethyl/-1-Carbo-samedaypayday

1H-NMR (60 MHz) in DCl3: to 1.35 (3H, d), 3,6-4,3 (7H, m)

5,7 (1H, triple t), and 7.5 (4H, m), 8 (1H, s)

Connection 7

N-3-(1,1,2,2-tetrafluoroethoxy)propyl-N-/2-(2,4,6-trichlorophenoxy) ethyl/-1-carbox-samedaypayday

1H-NMR (60 MHz) in DCl3: of 2.15 (2H, m), and 3.8 (4H, m)

the 4.1 (4H, m), the 5.65 (1H, triple t), 7-7,4 (4H, m), 7,95 (1H, s)

Connection 8.

N-2(1,1,2-Cryptor-2-triptoreline-toxi) ethyl-N-/2-(3-triptoreline)ethyl-1-carboxamidine

1H-NMR (60 MHz) in DCl3: 3,9 (4H, m), and 4.6 (4H, m)

the 5.65 (1H, DV. t), 6,9-7,6 (6N, m) 8 (1H, s).

P R I m e R 15. Synthesis of N-2 (1,1,2,2-tetrafluoroethoxy)ethyl-N-/2-(4-chlorophenoxy) ethyl/-3-carboxamidine

Connection 9.

To a solution of N-2 (1,1,2,2-tetrafluoroethoxy)achilleus the triethylamine (6.9 g) and then the mixture is stirred for a day at room temperature. Then the reaction mixture is treated with water, the organic phase is separated, dried and evaporated under reduced pressure.

The resulting mixture is distilled chromatographytandem on silica using as eluent a mixture of CH2CL2-Meon (95:5 V/V). Received 0.5 g of oil, the spectral characteristics of which correspond to the connection 9.

1H-NMR (60 MHz) in CDCl3: 3,9 (4H, m), 4.2V (4H, m), of 5.75 (1H, triple t), 6,6-8 (7H, m), 8,65 (1H, s).

Connection 10.

N-2-(1,1,2,2-tetrafluoroethoxy)ethyl-N-/2-/4-(1,1,2,2 -tetrafluoroethoxy) phenoxy/ethyl/-1-carboxamidine

1H-NMR (60 MHz) in CDCl3: 3,9 (4H, m), 4.2V (4H, m), the 5.65 (1H, triple t), by 5.87 (1H, triple t), the 6.7 to 7.3 (5H, m), of 7.97 (1H, s).

The connection 11.

N-2-(1,1,2,2-tetrafluoroethoxy)ethyl-N-/2-(3 - floratone)ethyl-1-carboxamidine

1H-NMR (60 MHz) in CDCl3: of 3.8 (4H, m), 4,25 (4H, m)

of 5.75 (1H, triple t), 6,5-of 7.55 (5H, m), with 8.05 (1H, s).

The connection 12.

N-2-(1,1,2,2-tetrafluoroethoxy)ethyl-N-/2-(2-pertenece) ethyl-1-carboxamidine-dasol

1H-NMR (60 MHz) in DCl3: of 3.85 (4H, m), is 4.15 (4H, m)

5,6 (1H, triple t), 6,8;-7,4 (5H, m), to 7.93 (1H, s).

The connection 13.

N-2-(1,1,2,2-tetrafluoroethoxy)ethyl-N-/2-(4-tert-booth, Rainey t) 6,75 was 7.45 (5H, m), 8 (1H, s)

The connection 14.

N-2-(1,1,2-Cryptor-2-chloroethoxy)ethyl-N-/2-(2,4,6-trichlorophenyl) ethyl/-1-carbox-samedaypayday

1H-NMR (60 MHz) in DCl3: 4 (8H, m), 6 (1H, DV. t) of 6.6 to 7.3 (6N, m), and 7.9 (1H, s).

P R I m e R 16.

Synthesis of N-2-(1,1,2,2-tetrafluoroethoxy) ethyl-N-/2-(2,4,6-trichlorophenoxy)ethyl/-5-ka - rocksmith-1-methylimidazole

The connection 15

A solution of 1-methyl-5-carboxyamide (1 g) in chloride tionale (30 mol), boiled for 2 h, excess chloride tiomila then evaporated under reduced pressure and the residue is transferred in pyridine (15 ml). The resulting solution was cooled to 0aboutWith and to it is slowly added dropwise a solution of N-2-(1,1,2,2-tetrafluoroethoxy)ethyl-N-/2-(2,4,6 - trichlorophenoxy)-ethyl/amine (2.5 g) in pyridine (5 ml). The mixture is stirred for 18 hours at room temperature, then transferred into water and extracted with methylene chloride. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. The resulting crude product is distilled chromatographytandem on silica using as eluent a mixture of CH2CL2-Meon (97:3 V/V). Received 0,85 g solids, spectral characteristics correspond to the connection 15.1H-NMR (60 MHz) in DCl3: 3.7 FMD wheat (Erysiphe Graminis D. C.)

Preventive activity.

Leaves of wheat varieties Irnerio, grown in pots in the greenhouse, are treated by spraying both surfaces of water-acetone solution of the test compound at a content of acetone 20% (V/V).

After curing in the greenhouse for 1 day at a relative humidity (RH) of 70% of both surfaces of the leaves are sprayed with an aqueous suspension of Erysiphe graminis (20000 cndy/ml).

After 24-hour incubation in an atmosphere of saturated humidity at the 21aboutWith plants left in the greenhouse for the incubation of the fungus.

By the end of the incubation period (12 days) visually determine the degree of contamination on the scale of 100) (healthy plant) to 0 (completely infected plant).

Therapeutic activity

Leaves of wheat varieties Irnerio, grown in pots in the greenhouse, should be treated by spraying both surfaces of all leaves with an aqueous suspension of Erysiphe graminis (200,000 condi/ml).

After 24-hour incubation in an atmosphere saturated with humidity at 21aboutWith both surfaces of all leaves of plants treated by spraying water acetone solution of the test compounds at concentrations of acetone 20% (V/V).

The results are shown in table. 2.

P R I m e R 18. Determination of the fungicidal activity against linear rust of wheat (Puccinia graminis Pers)

Preventive activity.

Leaves of wheat varieties Irnerio, grown in pots in the greenhouse, should be treated by spraying the test compound in odnoaremenno solution (20% V/V) of both surfaces of all leaves.

After 1 day in the greenhouse at 23aboutC and RH 70% of both surfaces of the leaves are sprayed with a mixture of spores Puccinia graminis with talc (100 mg of spores per 5 g of talc).

After 48 h in an atmosphere saturated with humidity at 21aboutWith plants left in the greenhouse for the incubation of the fungus.

At the end of the incubation period (14 days) to visually determine the degree of contamination on the scale from 100 (healthy plant) to 0 (completely infected plant)

Therapeutic activity

Both surfaces of all leaves of wheat varieties Irnerio grown in a greenhouse in pots, are treated by spraying with a mixture of spores Puccinia graminis with talc (100 mg of spores per 5 g of talc). After 48 hours was kept in an atmosphere saturated with humidity at 21aboutWith both surfaces of the leaves treated with the test compound in water-acetone Aut the degree of contamination on the scale from 100 (healthy plant) to 0 (completely infected plant).

The results are shown in table. 2.

The METHOD of OBTAINING NITROGEN-containing HETEROCYCLIC COMPOUNDS of General formula

Ar-X1-B1--Z-Rh

where Ar is phenyl, substituted by one or more halogen, C1- C3-haloalkyl or C1- C4-haloalkoxy groups;

K, X1And Z are independently of each other oxygen;

B1and B2- same or different, linear or branched C1- C6-alkylidene;

Rh - C1- C6-haloalkyl containing from 1 to 9 halogen atoms, C3- C8-haloalkoxy, where the halogen is fluorine or chlorine;

A nitrogen heterocyclic group selected from imidazoles, imidazoles, substituted C1- C6-alkilani, or pyridine,

characterized in that the compound of the formula

Ar - X1- B1- Y

where Ar, X1and B1have the specified values;

Y is halogen,

subjected to interaction with the amine of the formula

NH2- B2- ZH,

where B2and Z have the above values,

in an organic solvent in the presence of a base at room temperature and the compound obtained, having the formula

Ar - X1- B1- NH - B2- ZH,

the nom formula

CF2=CX1X2,

where X1Is Cl, F, CF3, OCF3;

X2-F, CH3,

in dipolar aprotic or alcohol solvent in the presence of a strong base at a temperature of 5oWith and thus obtained intermediate compound is subjected to interaction with the carbonyl derivative of imidazole, substituted imidazole or pyridine in an aromatic or halogenated solvent at a temperature of 80oC.

 

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5 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining 4-amino-5-fluoro-3-halogen-6-(substituted)picolinate of formula I , where W represents Cl, Br or I; R represents C1-C4 alkyl, cyclopropyl, C2-C4 alkenyl or phenyl, substituted with 1-4 substituents, independently selected from halogen, C1-C4 alkyl, C1-C4 halogenalkyl, C1-C4 alkoxy or C1-C4 halogenalkoxy; and R1 represents C1-C12 alkyl or non-substituted C7-C11 arylalkyl; which includes the following stages: fluorine exchange, amination, halogen exchange, halogenation and binding by means of transition metal.

EFFECT: method improvement.

7 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention refers to pharmaceutical chemistry and discloses two crystalline forms of hidamide, in particular, crystalline form A of hidamide and crystalline form B of hidamide, as well as a method of producing crystalline forms A and B of hidamide, use thereof and a pharmaceutical composition based thereon.

EFFECT: technical result is obtaining crystalline forms A and B of hidamide, which have low toxicity, stability during storage and processing, and also have the advantage in oral use and inhibiting the cell differentiation and proliferation.

7 cl, 8 dwg, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of imidazole of the formula (I):

or its pharmaceutically acceptable salts wherein X represents -CH2-(CH2)p-, -O-; R1 represents phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl wherein indicated phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl are substituted optionally with 1-3 substitutes taken independently among halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group and OH-(C1-C6)-alkyl; R2 represents hydrogen atom (H) or (C1-C6)-alkyl; R3 represents H or (C1-C6)-alkyl; R4 represents H or (C1-C6)-alkyl; R5 represents H, or R5 and R7 form in common a bond; each R6 represents independently halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group or OH-(C1-C6)-alkyl; R7 represents H, or R7 and R5 form in common a bond; each R8 represents independently -OH, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl or (C1-C6)-alkoxy group; m = 0, 1, 2 or 3; n = 0 or 1; p = 0 or 1; r = 0 or 1; t = 0. Also, invention relates to a method for preparing compounds of the formula (I) and to a pharmaceutical composition showing affinity to alpha-2-adrenoceptors based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof used in aims for treatment of neurological disturbances, psychiatric disorders or disturbances in cognitive ability, diabetes mellitus, lipolytic diseases, orthostatic hypotension or sexual dysfunction.

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

25 cl, 1 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of formula (I): and to its salts with acid, where: R1 and R2 represent hydrogen; Q represents (CH2)m-X-(CH2)n-A; A represents direct bond, O, SO2, NR5; X represents direct bond, O, SO2, C(O) or NR5; Z represents group selected from : m and n represent, each independently, 0, 1, 2, 3 or 4; p represents 1, 2, 3 or 4; q represents 0, 1 or 2; dotted line means that R8 and/or R9 can be situated in any position of benzothiophene ring; R3 and R8 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11 or NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10; when Q-Z represents n 0, 1 or 2 and p represents 1, one of R3 and R8 represents hydroxy, nitro, NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CONR10R11, and the other represents hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11 OSO2NR10R11, NR12SO2NR10R11, CO2R10; R4 and R9 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CHO; when p represents 2, 3 or 4, R9 can be similar or different; R6 and R7 represent hydrogen; each R5, R10, R11 and R12 represents hydrogen; when Z represents and p represents 1, then R8 and R9 can also together with phenyl ring form benzoxathiazine dioxide. Invention also relates to pharmaceutical composition and to application of derivatives by any of ii.1-25.

EFFECT: obtaining novel biologically active compounds which possess inhibiting activity with respect to aromatase and/or steroid-sulfatase and/or carboanhydrase.

36 cl, 67 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) in form of a separate stereoisomer, a mixture of stereoisomers or a racemic mixture of stereoisomers and their pharmaceutically acceptable salts. In formula (I) ring A, C or D is independently completely or partially saturated; each of C1, C4, C11, C12, C15 and C16 is independently substituted with two hydrogen atoms; each of C9 and C14 is independently substituted with a hydrogen atom; R1 represents -OR7 or -N(R7)2. Values of the rest of the radicals are given in the formula of invention. The invention also relates to a pharmaceutical composition with anti-inflammatory activity and contains an effective amount of the disclosed compound and to use of the said compounds to make a medicinal agent with anti-inflammatory activity.

EFFECT: disclosed compounds have anti-inflammatory activity.

23 cl, 47 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel cyclic N,N'-diarylthioureas or N,N'-diarylureas of general formula (1), their optic (R)- and (S)-isomers and their pharmaceutically acceptable salts - antagonists of androgenic receptors. In formula (1), where: X represents oxygen or sulfur atom; m=0 or 1, mR1 represents C1-C3alkyl; R2 and R3 represent hydrogen atom; or R2 and R3 together with carbon atom, to which they are bound, form group C=O; or represents group NH; R4 and R5 represent hydrogen atom; or R4 represents hydrogen atom, and R5 represents methyl; or R4 represents hydrogen atom, methyl, and R5 represents group Zn-Y-R6, in which n=1 or 2, Z represents CH2 or C=0 and Y- oxygen atom or N-CH3, or Y represents C=O, and Z represents CH2; R6 represents hydrogen atom, methyl, benzyl, hydroxygroup or R5 and R4 together with atoms, to which they are bound, form five or sic-member heterocycle, including, at least, oxygen or nitrogen atom, which can be substituted by methyl. Invention also relates to method of obtaining compounds.

EFFECT: invention relates to anti-cancer substance, pharmaceutical composition, medication and method of treating prostate cancer with application of invention compounds.

12 cl, 6 dwg, 16 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to a method of producing 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, also known as medetomidine, having structural formula I: , which involves alkylation of N-trimethylsilyl imidazole with 2,3-trimethylbenzyl chloride in the presence of titanium tetrachloride in the medium of chlorine-containing organic solvents with molar ratio with 2,3-trimethylbenzyl chloride: trimethylsilyl imidazole:TiCl4 equal to 1.0:4.0-5.0:3.6-4.5.

EFFECT: improved method of producing medetomidine, characterised by high output of the end product.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 4-(2,3-dimethylbenzyl)-1H-imidazole, also known as detomidine, having formula I: , which involves alkylation of trimethylsilyl imidazole with a compound of formula II: , where X: CI, Br, OH, in the presence of titanium tetrachloride in the medium of a chlorine-containing organic solvent, where molar ratio of titanium tetrachloride to N-trimethylsilyl imidazole must be maximum but must not be more than 0.95.

EFFECT: novel method of producing detomidine, characterised by high output of the end product.

1 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method for preparing 2-methylimidazole involving mixing 40% aqueous glyoxal, acetaldehyde and aqueous ammonia, further recovering an end product by distillation, differing by the fact using 25% ammonia, mixing acetaldehyde and ammonia at temperature 05C; adding glyoxal preliminary purified from impurities by electrodialysis at temperature no more than 60C; the agents taken in a ratio of ammonia : acetaldehyde : glyoxal = 2:1:1; the reaction conducted at temperature 90-95C for 3 hours; besides, the end product recovered by vacuum distillation at residual pressure 0.5-1.5 kPa and vapour temperature 120-140C preceded by water distillation.

EFFECT: what is developed is the new method for preparing 2-methylimidazole differing by high yield and end product quality, as well as simplified process of recovering and purifying.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to benzimidazole derivatives of general formula (I) and to their pharmaceutically acceptable salts, mixed stereoisomers and enantiomers, wherein R1 is L1C(O)OL2C(O)OT; R2 is unsubstituted C1-C10alkyl; L1 is a bond; L2 is unsubstituted C2-C10alkylene; T is C1-C10alkyl. Also, the invention refers to a pharmaceutical composition of the compound of formula (I) and a method of anaesthetising on the basis of using the compound of formula (I).

EFFECT: there are prepared new imidazole derivatives effective as an anaesthetising agent.

15 cl, 9 dwg, 15 ex

FIELD: pharmacology.

SUBSTANCE: compounds of the invention are intended for manufacture of a pharmaceutical composition, kit or drug. The invention also relates to a process for preparation of compounds of the invention (versions). Compounds of the invention are intended for use in the prevention or treatment of diseases caused by RNA-containing viruses belonging to enteroviruses, metapneumoviruses or pneumoviruses.

EFFECT: amide compounds for treatment or prevention of diseases caused by RNA-containing viruses.

26 cl, 8 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

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

14 cl, 36 ex

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