Trifluoromethylpyrrole carboxamides

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to novel trifluoromethylpyrrole carboxamides of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C4)-alkyl; R2 means (C1-C4)-alkyl, (C1-C4)-halogenalkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, cyano-group or (C1-C6)-alkylcarbonyl; A means the group of the formula:

, or wherein R3 means (C1-C6)-alkyl, (C1-C6)-halogenalkyl, (C2-C6)-alkenyl, (C3-C7)-cycloalkyl, (C1-C4)-alkyl-(C3-C7)-cycloalkyl, (C4-C7)-cycloalkenyl, (C1-C4)-alkyl-(C4-C7)-cycloalkenyl, phenyl, naphthyl or phenoxy-group, or substituted phenyl, or substituted phenoxy-group wherein substituted represent 1-3 groups taken independently among an order comprising halogen atom, (C1-C4)_alkyl, (C1-C4)-alkoxy-, cyano-group, (C1-C4)-alkylcarbonyl, (C1-C4)-halogenalkyl, (C1-C4)-halogenalkoxy-, methylenedioxy-, difluoromethylenedioxy-group or phenyl; R4 means hydrogen, halogen atom or (C1-C4)-alkyl; each among R5, R6 and R7 means (C1-C6)-alkyl. Compounds of the formula (I) are used for control of phytopathogen organisms or for prophylaxis in damaging cultured plants by these organisms.

EFFECT: valuable properties of compounds.

10 cl, 3 tbl, 1 sch, 12 ex

 

The present invention relates to new triftormetilfullerenov having bactericidal activity, in particular fungicidal activity. The invention also relates to a method for producing these compounds, to agrochemical compositions containing as active ingredient at least one of the new compounds, the preparation of these compositions and to the use of active substances or compositions for combating phytopathogenic microorganisms, preferably fungi, or to prevent plant infection by these organisms in agriculture and horticulture.

Cryptomaterial of the present invention have a General formula I

where:

R1denotes hydrogen, halogen, C1-C4haloalkyl or1-C4alkyl,

R2stands With1-C4alkyl, C1-4haloalkyl,1-C4alkoxy-C1-C4alkyl, cyano, C1-C4alkylsulfonyl, phenylsulfonyl, di(C1-C4alkyl)aminosulfonyl,1-C6alkylsulphonyl, benzoyl or substituted phenylsulfonyl or benzoyl and

And refers to a group

or

where

R3stands With1 -C6alkyl, C1-C6haloalkyl,2-C6alkenyl,2-C6haloalkyl,2-C6quinil,1-C6alkoxy, C1-C6haloalkoxy,3-C6alkenylacyl,2-C6haloalkoxy,2-C6alkyloxy,3-C7cycloalkyl,1-C4alkyl-C3-C7cycloalkyl,4-C7cycloalkenyl,1-C4alkyl-C4-C7cycloalkenyl,3-C7cycloalkane,1-C4alkyl-C3-C7cycloalkane,5-C7cycloalkenyl,1-C4alkyl-C5-C7cycloalkenyl, phenyl, naphthyl, phenoxy, naphthyloxy or substituted phenyl or fenoxaprop, where the substituents are 1-3 groups independently of one another selected from the series comprising halogen, C1-C4alkyl, C1-C4alkoxy, C1-C4alkylthio, cyano, C1-C4alkoxycarbonyl,1-C4alkylsulphonyl,1-C4haloalkyl,1-C4haloalkoxy, methylenedioxy or diversitronics or phenyl;

R4denotes hydrogen, halogen, C1-C4alkyl, C1-C4haloalkyl,1-C4alkoxy or1-C4haloalkoxy; and

R5, R6and R7independently from the Ruga choose from a number, include1-C6alkyl, C3-C7cycloalkyl or3-C7cycloalkyl-C1-C4alkyl.

The amide of nicotinic acid with antifungal properties, which can be used in agricultural practice, described in EP-A-0545099. The described connections with their practical application is not always satisfy the needs of modern agriculture.

In the claimed invention unexpectedly found that the compounds of formula I have improved biological properties, which makes possible their use in the practice of agriculture and horticulture.

If in the compounds of formula I are asymmetric carbon atoms, these compounds can exist in optically active form. The invention relates to the pure isomers, such as enantiomers and diastereoisomers, as well as all possible mixtures of isomers, such as mixtures of diastereomers, racemates or mixtures of racemates.

In the context of the present description, the alkyl means methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl and neopentyl. Preferred is an unbranched alkyl. It should be noted that Akil, as part of other radicals, such as alkoxy, alkylthio, haloalkyl, alkylsilanes, alkylalkoxy, alkylborane is, alkylsulfonyl, alkylamino etc. has analogique values. Under the halogen is usually understood fluorine, chlorine, bromine or iodine. Preferred are fluorine, chlorine or bromine. It should be understood that the halogen, as part of other radicals, such as haloalkyl, haloalkoxy, haloalkyl, haloalkoxy or halophenol etc. has similar values. The number of substituents of substituted phenylsulfonyl and benzoyl can vary from 1 to 5, and preferably is chosen independently of one another from the series comprising halogen, C1-C4alkyl, C1-C4alkoxy, C1-C4alkylthio, cyano, C1-C4alkoxycarbonyl,1-C4alkylsulphonyl,1-C4haloalkyl,1-C4haloalkoxy, methylenedioxy or diversitronics or phenyl. If the phenyl group, as part of phenyl, phenylsulfonyl, phenoxy and bentolila substituted such radicals, they are 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-forfinal, 3-forfinal, 4-forfinal, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4-differenl, 3,4-differenl, 3,5-differenl, 2-triptoreline, 3-triptoreline, 4-triptoreline, 2-trifloromethyl, 3-trifloromethyl, 4-trifloromethyl, 4-were, 4-ethylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 3,4-dimetilfenil, 2,4,6-trimetilfenil, 3-chloro-4-FPO is phenyl, 4-chloro-3-forfinal, 4-biphenyl, 3-biphenyl, etc.

A subset of active substances represented by such compounds of the formula I, in which

R1denotes hydrogen or C1-C4alkyl,

R2stands With1-C4alkyl and

And means refers to a group

or

R3stands With1-C6alkyl, C1-C6haloalkyl,2-C6alkenyl,2-C6haloalkyl,2-C6quinil,1-C6alkoxy, C1-C6haloalkoxy,2-C6alkenylacyl,2-C6haloalkoxy,2-C6alkyloxy, C3-C7cycloalkyl,1-C4alkyl-C3-C7cycloalkyl,4-C7cycloalkenyl,1-C4alkyl-C4-C7cycloalkenyl,3-C7cycloalkane,1-C4alkyl-C3-C7cycloalkane,5-C7cycloalkenyl,1-C4alkyl-C5-C7cycloalkenyl, phenyl, naphthyl, phenyl, substituted with 1-3 groups independently of one another selected from the series comprising halogen, C1-C4alkyl, C1-C4alkoxy, C1-C4alkylthio, cyano, C1-C4alkoxycarbonyl,1-C 4alkylsulphonyl,1-C4haloalkyl,1-C4haloalkoxy, methylenedioxy or diversitronics or phenyl;

R4denotes hydrogen or C1-C4alkyl; and

R5, R6and R7independently from each other chosen from the series, including1-C6alkyl, C3-C7cycloalkyl or3-C7cycloalkyl-C1-C4alkyl.

In this group of compounds of formula I are preferred compounds in which

a) R1denotes hydrogen or methyl, or

b) R2denotes methyl, or

C) R3denotes phenyl or phenyl substituted by halogen.

Another preferred subgroup includes the compounds of formula I in which R1denotes hydrogen or methyl, R2denotes methyl and R3denotes phenyl or phenyl substituted by halogen.

Specific preferred compounds are:

N-(2-biphenylyl)-1-methyl-4-cryptomaterial-3-carboxamide,

N-(4'-chloro-2-biphenylyl)-4-cryptomaterial-3-carboxamide,

N-(4'-fluoro-2-biphenylyl)-4-cryptomaterial-3-carboxamide,

N-[2-(4-forfinal)-3-thienyl]-4-cryptomaterial-3-carboxamide,

N-[2-(4-chlorophenyl)-3-thienyl]-4-cryptomaterial-3-carboxamide,

N-(3',4'-debtor-2-biphenylyl)-4-cryptomaterial-3-carboxamide,

N-(3'-trifluoromethyl-2-biphenylyl)-4-tripto methylpyrrole-3-carboxamide and

N-(4'-chloro-3'-fluoro-2-biphenylyl)-4-cryptomaterial-3-carboxamide.

The compounds of formula I can be obtained according to the following reaction scheme 1.

Scheme 1:

where A, R1and R2have the meanings specified for formula I, X and Y represent leaving groups, alkyl denotes the fragment (ness.)the alkyl and aryl denotes phenyl or tolyl.

Leaving groups X and Y preferably represent halogen atoms, but can also denote fragments of mixed anhydrides, for example, -OCO-alkyl, -O-PO (alkyl)2, -O-C(=N-alkyl), triazolyl etc.

In another embodiment, introduction of the radicals R2and can be done in another way according to the scheme 2.

Scheme 2:

where A, R1, R2X and Y have the values listed for scheme 1.

In certain embodiments, the substitution may be preferable to apply the protective group at position 1 of the pyrrole rings in order to avoid adverse interactions during the amidation reaction at the carbonyl function in position 3. Acceptable protective groups are benzyl, etc. Also the introduction and removal of protective groups takes place during normal reactions benzylidene and hydrolysis.

New carboxamide formula I are preferably obtained by interaction of aktivirovani the th carboxylic acid of formula II with an aromatic amine. Depending on the leaving group Y the reaction is carried out in the presence of an acid binding agent. Preferably an inert solvent, but can also apply a mixture of water, solvent, corresponding to the reaction conditions of Schotten's-Bauman.

Activation of reach as a result of interaction terracarbon acid III with an activating agent such as a halide, e.g. thionyl chloride or oxalicacid, to obtain the corresponding acylchlorides (Y denotes chlorine), or using any other common activation method of binding known from the literature.

Carboxylic acids of formula III can be obtained from the corresponding esters by hydrolysis using standard hydrolysis conditions.

N-alkylation terracarbon esters of formula V to obtain the N-alkyl terracarbon esters of the formula IV can be carried out by the interaction terracarbon esters of formula V with an alkylating agent such as diallylsulfide, alkylhalogenide or alkylsulfonate, using standard conditions. Terracarbon esters of the formula V, as a rule, can be obtained according to the Protocol of van Leysin, i.e. the interaction of alkylacrylate with arylsulfonamides in the presence of a base. Typical bases which can be used according to scheme 1, include the guy who ride metals, the alcoholate of metals and metal hydroxides. May be any solvent that is inert in these reaction conditions. Representative solvents include ethers (diethyl ether, dimethoxyethane, THF and the like), polar aprotic solvents, such as DMSO, DMF, DMA, or proton solvents, such as alcohols. Can also be used mixtures of such solvents. In many cases, can be used reaction conditions, phase transition, which would naturally require a two-phase reaction system. Preferably the entire sequence of reactions is depicted in figure 1, conduct the reaction in a single vessel.

Unexpectedly, it was found that the new compounds of formula I have very valuable for practical purposes, the range of activities in relation to the protection of plants against diseases caused by fungi and bacteria and viruses.

The compounds of formula I as active substances have the ability to prevent infection and/or destroy plant pests and can be applied in the agricultural sector and other areas. New connections are not only distinguished by high activity even at low concentrations, but also well tolerated by plants and are safe for environment. They possess valuable therapeutic, preventive and systemic action, and romanatica to protect many species of cultivated plants. Using compounds of formula I can inhibit or destroy the pests which occur on plants or on parts (fruits, flowers, leaves, stems, tubers, roots) in different crops of useful plants, while protecting, for example, from phytopathogenic microorganisms also applies to those parts of plants, which are formed in the later period.

The compounds of formula I can also be used as agents for material processing for reproduction of plants, especially seeds (fruit, tubers, grains) and to protect cuttings of plants (e.g. rice) from damage by fungi and to protect against soil pathogenic fungi.

Saedinenie formula I are effective, for example, against the phytopathogenic fungi of the following classes: imperfect fungi Fungi deuteromycota (for example, Botrytis, Pycicularia, Helminthosporium, Fusarium, Septoria, Cercospora and Alternaria) and Basidiomycetes (for example, Rhizoctonia, Hemileia, Puccinia). In addition, they possess activity against fungi of the class Ascomycetes (for example Venturia and Erysiphe, Podosphaera, Monilinia, Uncinula) and class Oomycetes (for example, Phytophthora, Pythium, Plasmopara). Especially high activity was observed against the pathogen powdery mildew (Erysiphe spp.). In addition, the new compounds of formula I are effective against phytopathogenic bacteria and viruses (for example, against Xanthomonas spp., Pseudomons spp., Erwinia amylovora, and in the case of tobacco mosaic virus).

Subject to the protection of cultural plants falling under the scope of the present invention include, for example, the following species of plants: cereals (wheat, barley, rye, oats, rice, maize, sorghum and related crops); beet (sugar beet and fodder beet); pome fruit, stone fruit, fruit and small fruit crops (apples, pears, plums, peaches, almonds, cherries, strawberries, raspberries and blackberries); leguminous plants (beans, lentils, peas, soybeans); oil crops (rape, mustard, poppy, olive, sunflower, coconut, castor, cocoa beans, groundnuts); cucumber plants (pumpkins, cucumbers, melons); fibre plants (cotton, flax, hemp, jute); citrus crops (oranges, lemons, grapefruit, mandarins); vegetables (spinach, lettuce, asparagus, cabbage, carrots, onions, tomatoes, potatoes, peppers); Laurel crops (avocado, cinnamon tree, camphor tree); or plants such as tobacco, nuts, coffee, eggplants, sugar cane, tea, pepper, grapes, hops, bananas, natural rubber plants and ornamentals.

The compounds of formula I are used in unmodified form or preferably together with the adjuvants commonly used for the manufacture of preparative forms. For this purpose, they are mostly prepared in a known manner to receive the service for example, emulsion concentrates, covering pastes, ready-to-use solutions for spraying or dilutable solutions, diluted emulsions, wettable powders, soluble powders, Farrukh Dustov, granules, and also the encapsulation, for example in polymeric substances. Depending on the type of composition processing methods, such as spraying, spraying in the form of a mist, dusting, scattering, coating or watering, are chosen in accordance with the objectives and specific conditions. The connection can also contain additional adjuvants, such as stabilizers, defoamers, viscosity regulators, binders or adhesives, as well as fertilizers, micronutrient donors or other composition, contributing to the achievement of the desired effects.

Acceptable carriers and adjuvants can be solid or liquid and are substances that are commonly used for the manufacture of preparative forms, such as, for example, natural or regenerated mineral substances, solvents, dispersing agents, wetting agents, adhesives, thickeners, binders or fertilizers. Such carriers are described, for example, in WO 97/33890.

The compounds of formula I, generally used in the form of compositions and can be cultivated area or Podles is within the processing plant simultaneously or sequentially with other compounds. These additional compounds may represent, for example, fertilizers or micronutrient donors or other preparations that influence plant growth. They can also be selective herbicides as well as insecticides, fungicides, bactericides, nematicides, molluscicides or mixtures of several of these preparations, if necessary with further carriers, surfactants or intensifying penetration of adjuvants commonly used in the field of preparation preparative forms.

The compounds of formula I can be mixed with other fungicides, resulting in unexpectedly can be obtained a synergistic effect.

Preferred components of such mixtures are:

azoles, such as azaconazole, bitertanol, propiconazol, difenoconazol, diniconazole, cyproconazole, epoxiconazole, Fluconazol, flusilazol, flutriafol, hexaconazole, imazalil, kabekona, ipconazole, tebuconazole, tetraconazole, fenbuconazole, metconazole, myclobutanil, perforated, penconazole, bromuconazole, pirivenas, prochloraz, triadimefon, triadimenol, triflumizole, triticonazole;

pyrimidinylidene, such as ancymidol, fenarimol, nuarimol; 2-aminopyridines, such as bupirimate, dimethirimol, ethirimol; morpholines such as dodemont, fenpropidin, f is propior, spiroxamine, tridemorph;

anilinopyrimidines, such as cyprodinil, mepanipyrim, Pyrimethanil; pyrrole, such as fenpiclonil, fludyoksonil;

phenylamide, such as benalaxyl, parallaxis, metalaxyl, R-metalaxyl, operas, oxadixyl;

the benzimidazole, such as benomyl, carbendazim, dibakar, fuberidazole, thiabendazole;

dicarboximide, such as chlozolinate, diplozoon, iprodion, mickleton, procymidon, vinclozolin;

carboxamide, such as carboxin, fanforum, flutolanil, mepronil, oxycarboxin, leflunomid;

guanidine, such as guazatine, Dodin, iminoctadine;

strobilurin, such as AZOXYSTROBIN, kresoximmethyl, metamyosyn, SSF-129, methyl-2-[(2-trifluoromethyl)pyrid-6-intoximeter]-3-ethoxyacrylate or O-metoxi methyl ester 2-[α{[(α-methyl-3-trifloromethyl)imino]oxy]-ortho-tolyl] Glyoxylic acid (Trifloxystrobin);

dithiocarbamate, such as ferbam, MANCOZEB, MANEB, metiram, propineb, thiram, zineb, Tsira;

N-holomediterranean, such as captafol, Captan, dichlofluanid, pluromed, folpet, tolyfluanid;

copper-containing compounds such as Bordeaux liquid, copper hydroxide, copper oxychloride, copper sulphate, copper oxide(1), marcopper, oxen copper;

nitroaniline derivatives, such as dinocap, nitrates-isopropyl; organophosphorus derivatives, is how edifenphos, iprobenfos, isoprothiolane, forgiven, pyrazophos, tolios-methyl;

other compounds with different structures, such as acibenzolar-S-methyl, anilazine, blasticidin-S, chinomethionat, chloroneb, CHLOROTHALONIL, having cymoxanil, Dylan, dilamtin, dichloran, dietphenterm, dimethomorph, dithianon, etridiazole, famoxadone, fenamidone, fentin, verison, fluazinam, glucolipid, fenhexamid, fosetyl aluminum, hymexazol, kasugamycin, metasurfaces, pencycuron, phtalic, polyoxin, provenzal, propamocarb, pyroxylin, jenoxifen, hintzen, sulfur, triazoxide, tricyclazole, triforine, validamycin, (S)-5-methyl-2-methylthio-5-phenyl-3-phenylamino-3,5-dihydroimidazole-4-one (RPA 407213), 3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide (RH-7281), N-allyl-4,5-dimethyl-2-trimethylsilylmethyl-3-carboxamide (MON 65500), 4-chloro-4-cyan-N,N-dimethyl-5-para-tolylimidazo-1-sulfonamide (IKF-916), N-(1-cyan-1,2-dimethylpropyl)-2-(2,4-dichlorphenoxy)propionamide (AC 382042) or iprovalicarb (SZX 722).

The preferred method of applying the compounds of formula I or agricultural composition containing at least one of these compounds is the treatment of the leaves. The frequency of treatments and the consumption rate depends on the risk of defeat by the corresponding pathogen. However, the compounds of formula I can also penetrate the plant through the root system from the soil (systemic action) if us is not the same habitats of plants with a liquid composition or introduction of substances in solid form into the soil, for example, in the form of granules (soil application). In the case of crops paddy rice such granules may be made in certain quantities in flooded rice fields. The compounds of formula I can also be used for seed treatment (coating) either by immersing the grains or tubers in the liquid composition of the fungicide, or by coated with a dry composition.

Preparative form, i.e. the compositions containing the compound of the formula I and optionally a solid or liquid adjuvant, get a known method, for example by thorough mixing and/or grinding the compound with extenders, e.g. solvents, solid carriers and optionally with surfactants (detergents).

The agrochemical compositions usually contain 0.1 to 99 wt.%, preferably from 0.1 to 95 wt.% the compounds of formula I, from about 99.9 to 1 wt.%, preferably from 99,8 to 5 wt.% solid or liquid adjuvant and 0 to 25 wt.%, preferably from 0.1 to 25 wt.% surface-active substances.

The preferred consumption rates typically range from 5 g to 2 kg of active ingredient (A.I.) per hectare (ha), preferably from 10 g to 1 kg A.I/ha, most preferably from 20 g to 600 g A.I/ha When used for seed norms of consumption, preferably sostavlyayet 10 mg to 1 g of active substance per 1 kg of seeds.

At that time, as concentrated compositions are more preferred as marketed products, direct consumer typically uses dilute compositions.

The following examples are given to more detailed illustration of the invention and are not intended to limit its scope. Temperatures are given in degrees Celsius. Used the following abbreviations:

tPLthe melting temperature, tKip- boiling point; "NMR" refers to a range of nuclear magnetic resonance; "MS" refers to mass spectrum; "%" means%by weight, if concentrations are not given in other units.

Examples retrieve

Example P 1: N-(2-biphenylyl)-1-methyl-4-cryptomaterial-3-carboxamide

a) 1-Methyl-4-cryptomaterial-3-carboxylic acid

Sodium hydride (8.0 g 75%dispersion in oil) are suspended at +5°in a mixture of DMSO (300 ml) and diethyl ether (100 ml). Dropwise via addition funnel is added a solution of ethyl-4,4,4-trifurcation (20 g) and TOSMIC (23 g) in DMSO (100 ml) at such a rate that the temperature did not exceed 10°C. After stirring the reaction mixture for a further 1 h at room temperature while cooling add methyliodide (15.6 ml). After incubation for 2 h at room temperature, the reaction mixture is liveout on ice chips. After re-extraction of simple ether, washing of the combined organic phases with brine and evaporation of the solvent under reduced pressure get mixed product in the form of an oil with a light amber color. The crude mixed product is maintained at 60°in a mixture of ethanol (100 ml) and sodium hydroxide (50 ml of 30%aqueous solution). After washing solution is simple ether, acidification of the aqueous phase with concentrated hydrochloric acid, and filter gain 1-methyl-4-cryptomaterial-3-carboxylic acid in the form of a solid crystalline substance.

1H-NMR (CDCl3): from 7.24 (d, 1H), to 6.88 (d, 1H), 3,63 (s, 3H).

b) N-(2-biphenylyl)-1-methyl-4-cryptomaterial-3-carboxamide

A solution of 1-methyl-4-cryptomaterial-3-carboxylic acid (1.9 g) and oxalicacid (0.9 ml) in methylene chloride (20 ml) was stirred at room temperature in the presence of catalytic amount of DMF. The solvent is evaporated under reduced pressure, obtaining a solid crystalline substance. This solid is dissolved in methylene chloride (10 ml) and added dropwise at 0°to a solution of 2-biphenylamine (1.7 g) and triethylamine (4,2 ml) in methylene chloride (20 ml). The reaction mixture was stirred at room temperature for 2 hours After evaporation of the solvent under reduced pressure, adding water and Phi is Tracii get N-(2-biphenylyl)-1-methyl-4-cryptomaterial-3-carboxamide.

1H-NMR (CDCl2): of 8.37 (d, 1H), 7,60 (s, br, 1H), of 7.48-7,14 (m, 8H), 7,03 (d, 1H), to 6.88 (d, 1H), 3,63 (s, 3H).

Example P 2: N-(2-biphenylyl)-1,5-dimethyl-4-cryptomaterial-3-carboxamide

a) 1,5-Dimethyl-4-cryptomaterial-3-carboxylic acid

The mixture containing the TOSMIC (20 g), methyliodide (18.5 g) and chloride N-benzyltriethylammonium (1 g) in methylene chloride (100 ml) and aqueous hydroxide solution (30 ml of a 50%aqueous solution), stirred at 5°C for 3 hours dropwise via addition funnel is added a solution of ethyl-4,4,4-trifurcation (20 g) in methylene chloride (50 ml) at such a rate that the temperature did not exceed 25°. After stirring the reaction mixture for a further 1 h at room temperature are added during the cooling excess methyliodide. After incubation for 2 h at room temperature the reaction mixture was poured onto ice chips. After re-extraction of simple ether, washing of the combined organic phases with brine and evaporation of the solvent to obtain the crude mixed product. Pure intermediate substance obtained after chromatography on silica gel. The hydrolysis is carried out under the conditions described in example 1 (a), receiving 1,5-dimethyl-4-cryptomaterial-3-carboxylic acid as a colourless solid crystalline substance.

1H-NMR (d6-DMSO): 12,04 (s, br, 1H), 7,50 (, 1H), to 3.58 (s, 3H), and 2.27 (s, 3H).

6) N-(2-biphenylyl)-1,5-dimethyl-4-cryptomaterial-3-carboxamide

A solution of 1,5-dimethyl-4-cryptomaterial-3-carboxylic acid (1.9 g) and oxalicacid (0.9 ml) in methylene chloride (20 ml) was stirred at room temperature in the presence of catalytic amount of DMF. The solvent is evaporated under reduced pressure, obtaining a solid crystalline substance. This solid is dissolved in methylene chloride (10 ml) and added dropwise at 0°to a solution of 2-biphenylamine (1.7 g) and triethylamine (4,2 ml) in methylene chloride (20 ml). The reaction mixture was stirred at room temperature for 2 hours After evaporation of the solvent under reduced pressure, adding water and filtering of receive N-(2-biphenylyl)-1,5-dimethyl-4-cryptomaterial-3-carboxamide.

1H-NMR (CDCl3): 8,39 (d, 1H), 7,58 (s, br, 1H), of 7.48-7,14 (m, 9H), to 3.58 (s, 3H), and 2.27 (s, 3H).

These compounds have a similar way, using similar methods.

Table 1: Compounds of formula I in which R1denotes hydrogen, R2denotes methyl and corresponds to one line of table A.

Table 2: Compounds of formula I in which R1and R2denote methyl and corresponds to one line of table A.

Table 3: Compounds of formula I in which R1denotes hydrogen, R2oznachaet ethyl and corresponds to one line of table A.

Table 4: Compounds of formula I in which R1denotes hydrogen, R2denotes methoxymethyl and corresponds to one line of table A.

Table 5: Compounds of the formula I, in which R1denotes hydrogen, R2denotes cyano and corresponds to one line of table A.

Table 6: Compounds of the formula I, in which R1denotes hydrogen, R2represents methylsulphonyl and corresponds to one line of table A.

Table 7: Compounds of the formula I, in which R1denotes hydrogen, R2means phenylsulfonyl and corresponds to one line of table A.

Table 8: Compounds of the formula I, in which R1denotes hydrogen, R2denotes acetyl and corresponds to one line of table A.

Table 9: Compounds of the formula I, in which R1denotes hydrogen, R2denotes methoxyacetyl and corresponds to one line of table A.

Table 10: Compounds of the formula I, in which R1denotes hydrogen, R2represents benzoyl and corresponds to one line of table A.

Table 11: Compounds of the formula I, in which R1denotes hydrogen, R2denotes 4-geobentoil and corresponds to one line of table A.

td align="center">
Conn. No.And
01
02
03

04
05
06
07
08
09
10
11
12
13
14

15
16
17
18
19
20
21
22
23
24
25
26

27
28
29
30
31
32
33
34
35
36
37

38
39
40
41
42
43
44
45
46
47
48

49
50
51
52
53
54
55
56
57
58
59

60
61
62
63
64
65
66
67
68
69
70

71
72
73
74
75
76

Table 12
Physico-chemical data of selected compounds from the above tables 1-11
Connection # Physico-chemical data tPL[°] or1H-NMR (CDCl3)
1.01of 8.37 (d, 1H), 7,60 (s, br, 1H), of 7.48-7,14 (m, 8H), 7,03 (s, 1H), to 6.88 (s, 1H), 3,63 (s, 3H); tPL100-102.
1.02of 8.27 (d, 1H), 7,50 (s, br, 1H), 7,46-to 7.18 (m, 7H), 7,10 (d, 1H), to 6.88 (s, 1H), 3,63 (s, 3H).
1.038,30 (d, 1H), 7,52 (s, br, 1H), 7,44 for 7.12 (m, 8H), to 6.88 (s, 1H),3,63 (s, 3H); tPL151-153.
1.04the 7.85 (d, 1H), 7,74 (s, br, 1H), 7,44 (dd, 2H), 7,30 (s, 1H), 7,28 (s, 1H), 7,13 (dd, 2H), 6,93 (s, 1H), 3,68 (s, 3H); tPL127-129.
1.05to 7.84 (d, 1H), 7,74 (s, br, 1H), 7,49 (s, 4H), 7,30 (d, 1H), 7,28 (d, 1H), of 6.96 (d, 1H), 3,68 (s, 3H); tPL142-145.
1.307,89 (d, 1H), 7,76-7,25 (m, 12H), to 6.95 (s, 1H), 3,69 (s, 3H); tPL168-169.
1.35tPL160-161.
1.38of 8.25 (d, 1H), 7,50 (s, br, 1H), 7,45-was 7.08 (m, 7H), of 6.68 (s, 1H), the 3.65 (s, 3H); resin
1.40tPL122-123.
1.42tPL142-143.
1.71tPL63-65.
1.72t PL112-114.
1.76resin
2.02tPL163-165.
2.03resin
2.05resin
2.35tPL124-125.
2.71resin
3.01resin
3.02resin
3.03resin
3.71resin

Connection # Physico-chemical data tPL[°C] or1H-NMR (CDCl3)
4.02resin
4.03resin
4.71resin
5.02resin
5.03resin
5.71resin
8.02resin
8.03resin
8.04resin
8.05resin
8.71resin

The processes to obtain compositions of compounds of formula I, such as emulsion concentrates, solutions, granules, dusty and wettable powders described in WO 97/33890.

Biological examples: Fungicidal Akti is ness

Example-1: Activity against Puccinia recondita on Spence (brown rust of wheat)

A one-week plant wheat cultivar Arina is treated with a composition of the test compound (0.02% of active substance) in the chamber for spraying. After 1 day after treatment of wheat plants inoculant by spraying pilot plant spore suspension (1×105uredospore/ml). After incubation for 2 days at 20°C and 95%relative humidity, the plants kept in the greenhouse for 8 days at 20°C and 60%relative humidity. The symptoms assessed 10 days after inoculation.

Compounds from tables 1 to 11 showed high activity in these experiments (defeat <20%).

Example b-2: Activity against Podosphaera leucotricha on Apple trees (powdery mildew of apples)

Five-week Apple varieties McIntosh is treated with a composition of the tested compounds (0,002% active ingredient) in the chamber for spraying. After 1 day after treatment plants Apple trees inoculant by shaking plants infected with powdery mildew of Apple, on experimental plants. After incubation for 12 days at 22°C and 60%relative humidity and a light regime of 14/10 h (day/night) assess the symptoms of the disease.

Compounds from tables 1-11 showed rather high active is to be in this experience. Connection 1.01, 1.02, 1.03, 1.04, 1.05, 1.30, 1.35, 1.38, 1.39, 1.40, 1.42, 1.71, 1.72, 1.76, 2.02, 2.03, 2.05, 2.35, 2.71, 3.01, 3.02, 3.03, 3.71, 4.02, 4.03, 4.71, 5.02, 5.03, 5.71, 8.02, 8.03, 8,04 and 8.71 showed very high efficiency (defeat <20%).

Example b-3: Activity against Venturia inaequalis on Apple trees (Apple scab)

Four weeks Apple varieties McIntosh is treated with a composition of the test compound (0.02% of active substance) in the chamber for spraying. After 1 day after treatment plants Apple trees inoculant by spraying pilot plant spore suspension (4×105conidia/ml). After incubation for 4 days at 21°C and 95%relative humidity, the plants kept in the greenhouse for 4 days at 21°C and 60%relative humidity. After additional incubation for 4 days at 21°C and 95%relative humidity assess the symptoms of the disease.

Compounds from tables 1 to 11 showed high activity in this experience. Connection 1.01, 1.02, 1.03, 1.04, 1.05, 1.30, 1.35, 1.38, 1.39, 1.40, 1.42, 1.71, 1.72, 1.76, 2.02, 2.03, 2.05, 2.35, 2.71, 3.01, 3.02, 3.03, 3.71, 4.02, 4.03, 4.71, 5.02, 5.03, 5.71, 8.02, 8.03, 8,04 and 8.71 showed high efficiency (defeat <20%).

Example b-4: Activity against Erysiphe graminis on barley (powdery mildew of barley)

Weekly plants of barley varieties Express is treated with a composition of the test compound (0.02% of active substance) in the camera for which prisciani. After 1 day after treatment of barley plants inoculant by shaking plants infected with powdery mildew, above the test plants. After incubation in the greenhouse for 6 days 20°/18°C (day/night) and 60%relative humidity assess the symptoms of the disease.

Compounds from tables 1 to 11 showed high activity in this experience. Connection 1.01, 1.02, 1.03, 1.04, 1.05, 1.30, 1.35, 1.38, 1.39, 1.40, 1.42, 1.71, 1.72, 1.76, 2.02, 2.03, 2.05, 2.35, 2.71, 3.01, 3.02, 3.03, 3.71, 4.02, 4.03, 4.71, 5.02, 5.03, 5.71, 8.02, 8.03, 8,04 and 8.71 showed high efficiency (defeat <20%).

Example B-5: Activity against Botrytis cinerea on Apple trees (grey rot of apples)

In apples Golden Delicious drill 3 holes and fill each dropwise 30 μl of the composition of the tested compounds (0,002% active ingredient). After 2 h after treatment in place of processing the pipette contribute 50 μl of a suspension of spores VSEGEI (4×105conidia/ml). After incubation for 7 days at 22°in growth chamber assess the symptoms of the disease.

Compounds from tables 1 to 11 showed high activity in this experience. Connection 1.01, 1.02, 1.03, 1.04, 1.05, 1.30, 1.35, 1.38, 1.39, 1.40, 1.42, 1.71, 1.72, 1.76, 2.02, 2.03, 2.05, 2.35, 2.71, 3.01, 3.02, 3.03, 3.71, 4.02, 4.03, 4.71, 5.02, 5.03, 5.71, 8.02, 8.03, 8,04 and 8.71 showed very high efficiency (defeat <10%).

Example B-6: Activity against Botrytis cinerea on grapes (grey rot wine is glad)

Five weeks shank grapes Gutedel is treated with a composition of the tested compounds (0,002% active ingredient) in the chamber for spraying. 2 days after treatment the plants grapes inoculant by spraying pilot plant spore suspension (1×10 conidia/ml). After incubation in the greenhouse for 4 days at 21°C and relative humidity of 95% evaluate the signs of the disease.

Compounds from tables 1 to 11 showed high activity in this experience. Connection 1.01, 1.02, 1.03, 1.04, 1.05, 1.30, 1.35, 1.38, 1.39, 1.40, 1.42, 1.71, 1.72, 1.76, 2.02, 2.03, 2.05, 2.35, 2.71, 3.01, 3.02, 3.03, 3.71, 4.02, 4.03, 4.71, 5.02, 5.03, 5.71, 8.02, 8.03, 8,04 and 8.71 showed very high efficiency (defeat <10%).

Example B-7: Activity against Botrytis cinerea on tomatoes (grey rot of tomatoes)

Four weeks old plants of tomato varieties Roter Gnom is treated with a composition of the tested compounds (0,002% active ingredient) in the chamber for spraying. 2 days after treatment the plants tomatoes inoculant by spraying pilot plant spore suspension (1×105conidia/ml). After incubation in a growth chamber for 4 days at 21°C and relative humidity of 95% evaluate the signs of the disease.

Compounds from tables 1 to 11 showed high activity in this experience. Connection 1.01, 1.02, 1.03, 1.04, 1.05, 1.30, 1.35, 1.38, 1.39, 1.40, 1.42, 1.71, 1.72, 1.76, 2.02, 2.03, 2.05, 2.35, 2.71, 3.01, 302, 3.03, 3.71, 4.02, 4.03, 4.71, 5.02, 5.03, 5.71, 8.02, 8.03, 8,04 and 8.71 showed very high efficiency (defeat <10%).

Example B-8: Activity against Pyrenophora teres on barley net blotch of barley)

Weekly plants of barley varieties Express is treated with a composition of the tested compounds (0,002% active ingredient) in the chamber for spraying. 2 days after processing barley plants inoculant by spraying pilot plant spore suspension (3×104conidia/ml). After incubation for 2 days at 20°C and relative humidity of 95% of the plants kept in the greenhouse for 2 days at 20°C and relative humidity of 60%. The symptoms assessed 4 days after inoculation.

Compounds from tables 1 to 11 showed high activity in this experience. Connection 1.01, 1.02, 1.03, 1.04, 1.05, 1.30, 1.35, 1.38, 1.39, 1.40, 1.42, 1.71, 1.72, 1.76, 2.02, 2.03, 2.05, 2.35, 2.71, 3.01, 3.02, 3.03, 3.71, 4.02, 4.03, 4.71, 5.02, 5.03, 5.71, 8.02, 8.03, 8,04 and 8.71 showed high efficiency (defeat <20%).

Example B-9: Activity against Septoria nodorum on wheat (Septoria leaf blotch of wheat)

A one-week plant wheat cultivar Arina is treated with a composition of the test compound (0.02% of active substance) in the chamber for spraying. After 1 day after treatment of wheat plants inoculant by spraying pilot plant spore suspension (5×105conid the th/ml). After incubation for 1 day at 20°C and 95%relative humidity, the plants kept in the greenhouse for 10 days at 20°C and 60%relative humidity. The symptoms assessed in 11 days after inoculation.

Compounds from tables 1 to 11 showed high activity in this experience. Connection 1.01, 1.02, 1.03, 1.04, 1.05, 1.30, 1.35, 1.38, 1.39, 1.40, 1.42, 1.71, 1.72, 1.76, 2.02, 2.03, 2.05, 2.35, 2.71, 3.01, 3.02, 3.03, 3.71, 4.02, 4.03, 4.71, 5.02, 5.03, 5.71, 8.02, 8.03, 8,04 and 8.71 showed high efficiency (defeat <20%).

Table
Physicochemical data for some compounds of the following structural formula
Conn-e No.R1R2R3R4The pace. pl., °
1NMeNresin
2NMeN127-29
3NMeNresin
4NMeN130-32
5NMeNresin
6NMeN116-19
7NMeNresin

Continuation of the table
8NMeH93-95
9NMeHOil
10NMeHoil
11NMeH73-75
12NMeCHFCH2CH(Me)2H105-07
13NMe CHF(CH2)4MeH108-10
14N.MeCHFCH2With(Me)3H136-38
15NMeCFMeCH2CH(Me)2H73-75
16NMeH86-88
17NMeH211-12
18NMeH164-68

1. Cryptomaterial formula I

where R1denotes hydrogen or C1-C4alkyl;

R2stands With1-C4alkyl, C1-C4haloalkyl,1-C4alkoxy-C1-C4alkyl, cyano or1-C6alkylsulphonyl;

And refers to a group

or

where

R3represents C1-C6alkyl, C1-C6haloalkyl,2-C6alkenyl,3-C7the cycle is alkyl, With1-C4alkyl-C3-C7cycloalkyl,4-C7cycloalkenyl,1-C4alkyl-C4-C7cycloalkenyl, phenyl, naphthyl or phenoxy, or substituted phenyl or substituted fenoxaprop, where the substituents are 1-3 groups independently of one another selected from the series comprising halogen, C1-C4alkyl, C1-C4alkoxy, cyano, C1-C4alkylsulphonyl,1-C4haloalkyl,1-C4haloalkoxy, methylenedioxy, diversitronics or phenyl;

R4denotes hydrogen, halogen or1-C4alkyl;

R5, R6and R7every means C1-C4alkyl.

2. The compound of formula I according to claim 1, where

R1denotes hydrogen or C1-C4alkyl,

R2stands With1-C4alkyl;

And refers to a group

or

where R3represents C1-C6alkyl, C1-C6haloalkyl,2-C6alkenyl,3-C7cycloalkyl,1-C4alkyl-C3-C7cycloalkyl,4-C7cycloalkenyl,1-C4alkyl-C4-C7cycloalkenyl, phenyl or naphthyl, phenyl, substituted with 1-3 groups, ezavisimo from each other chosen from the series including halogen, C1-C4alkyl, C1-C4alkoxy, cyano, C1-C4alkylsulphonyl,1-C4haloalkyl, C1-C4haloalkoxy, methylenedioxy, diversitronics or phenyl;

R4denotes hydrogen, halogen or1-C4alkyl;

R5, R6and R7every means C1-C6alkyl.

3. The compound according to claim 1 or 2, where R1denotes hydrogen or methyl.

4. The compound according to claim 1 or 2, where R2denotes methyl.

5. The compound according to claim 1 or 2, where R3denotes phenyl or phenyl substituted by halogen.

6. The compound according to claim 1 or 2, where R1denotes hydrogen or methyl, R2denotes methyl and R3denotes phenyl or phenyl substituted by halogen.

7. The compound according to claim 1, selected from the group including

N-(2-biphenylyl)-1-methyl-4-cryptomaterial-3-carboxamide,

N-(4'-chloro-2-biphenylyl)-4-cryptomaterial-3-carboxamide,

N-(4'-fluoro-2-biphenylyl)-4-cryptomaterial-3-carboxamide,

N-[2-(4-forfinal)-3-thienyl]-4-cryptomaterial-3-carboxamide,

N-[2-(4-chlorophenyl)-3-thienyl]-4-cryptomaterial-3-carboxamide,

N-(3',4'-debtor-2-biphenylyl)-4-cryptomaterial-3-carboxamide,

N-(3'-trifluoromethyl-2-biphenylyl)-4-cryptomaterial-3-carboxamide and

N-(4'-chloro-3'-ftor-biphenylyl)-4-cryptomaterial-3-carboxamide.

8. Method of producing compounds of the formula I according to claim 1, including interaction in the presence of base alkylacrylate formula

where alkyl denotes (ness.)alkyl,

with arylsulfonamides formula

where R1matter specified in claim 1 for formula I, and aryl denotes phenyl or tolyl,

obtaining terracarbon ether of the formula V

where R1matter specified in claim 1 for formula I, and alkyl denotes (ness.)alkyl,

subsequent N-alkylation in the presence of a base alkylating agent R2X, where R2matter specified in claim 1 for formula I, a X is a leaving group, to obtain the N-alkylated terracarbon ether of the formula IV

where R1and R2have the meanings indicated in claim 1 for formula I, and alkyl denotes (ness.)alkyl,

transform it by hydrolysis to carboxylic acid of the formula III

where R1and R2have the meanings indicated in claim 1 for formula I,

activation of the obtained carboxylic acid any known binding reaction and the subsequent processing is aktivirovannogo carboxylic acid derivative of the formula II

where R1and R2have the meanings indicated in claim 1 for formula I, a Y denotes a leaving group,

aromatic amine-NH2where a has the values specified in claim 1 for formula I, to obtain the target product.

9. The method of obtaining the compound of formula I according to claim 1, comprising the hydrolysis terracarbon ether of the formula V

where R1matter specified in claim 1 for formula I, and alkyl denotes (ness.)alkyl,

with the subsequent activation of the resulting carboxylic acid of formula VI

where R1matter specified in claim 1 for formula I,

any known reaction of binding processing of the activated carboxylic acid derivative of formula VII

where R1matter specified in claim 1 for formula I, a Y denotes a leaving group,

aromatic amine A-NH2where a has the values specified in claim 1 for formula I, with getting errorcorrected formula VIII

where R1and a have the meanings indicated in claim 1 for formula I,

and stage amidation can be carried out with the use of protective groups, and sleduushee alkylation errorcorrected formula VIII in the presence of a base alkylating agent R 2X, where R2matter specified in claim 1 for formula I, a X is a leaving group, to obtain the target product.

10. A method of combating phytopathogenic organisms or preventing the destruction of their cultivated plants by applying a compound of formula I according to claim 1 to the plants, their parts or their habitat.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

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

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

33 cl, 7 tbl, 42 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new taxanes of the general formula (I)

wherein R2 means benzoyloxy-group; R7 means hydroxyl (OH); R9 means keto-group; R10 means R10aCOO-; R10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl or 5-6-membered heteroaromatic group wherein heteroatom represents oxygen atom (O), sulfur atom (S) or nitrogen atom (N); R14 means hydrogen atom (H); X3 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl substituted possibly with nitro-group (-NO2), 5-6-membered heteroaromatic group wherein heteroatom represents O, S or N; X5 means -COX10, -COOX10; X10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl or 5-6-membered heteroaromatic group wherein heteroatom represents O, S, N; Ac means acetyl. Compounds of the formula (I) elicit antitumor activity.

EFFECT: valuable medicinal properties of compounds.

68 cl, 1 tbl, 6 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention relates to substituted thienocycloalk(ene)ylamino-1,3,5-triazines of the general formula (I): wherein R1 means hydrogen atom; R2 means hydrogen atom, formyl or alkylcarbonyl, group N(R1R2) denoting dialkylaminoalkylideneamine; R3 means unsubstituted or halogen-substituted alkyl; Z means one of the following thienocycloalkyl groups: and wherein A1, A2 and A3 mean alkylene. Also, invention describes a method for synthesis of indicated compounds and intermediate compounds used in the synthesis. Compounds can be used as herbicides.

EFFECT: improved method for synthesis, valuable agricultural properties of compounds.

8 cl, 4 tbl, 5 ex

New compounds // 2261245

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I): wherein m = 0, 1, 2 or 3; each R1 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C6)-halogenalkoxy-group, -NR9R10, (C3-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group or (C1-C6)-alkyl; X represents -O- or CH2-, OCH2-, CH2O-, CH2NH-, NH-; Y represents nitrogen atom (N) or group CH under condition that when X represents -O- or CH2O-, CH2NH- or NH-group then Y represents group CH; Z1 represents a bond or group (CH2)q wherein q = 1 or 2; Z2 represents a bond or group CH2 under condition that both Z1 and Z2 can't represent a bond simultaneously; Q represents -O- or sulfur atom (S) or group CH2 or NH; R2 represents group of the formula: n = 0; each R4, R5, R6 and R7 represents independently hydrogen atom (H), (C1-C6)-alkyl either R4, R5, R6 and R7 represent in common (C1-C4)-alkylene chain joining two carbon atoms to which they are bound to form 4-7-membered saturated carbon ring, either each R5, R6 and R7 represents hydrogen atom, and R4 and R8 in common with carbon atoms to which they are bound form 5-6-membered saturated carbon ring; R8 represents hydrogen atom (H), (C1-C6)-alkyl or it is bound with R4 as determined above; each R9 and R10 represents independently hydrogen atom (H), (C1-C6)-alkyl; R15 represents (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, adamantyl, phenyl or saturated or unsaturated 5-10-membered heterocyclic ring system comprising at least one heteroatom taken among nitrogen, oxygen and sulfur atoms wherein each group can be substituted with one or more substitute taken independently among nitro-group, hydroxyl, oxo-group, halogen atom, carboxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, phenyl and -NHC(O)-R17 under condition that R15 doesn't represent unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneiminyl group; t = 0, 1, 2 or 3; each R16 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C)-halogenalkoxy-group, -NR18R19, (C1-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group, (C1-C6)-alkyl; R17 means (C1-C6)-alkykl, amino-group, phenyl; each R18 and R19 means independently hydrogen atom (H), (C1-C6)-alkyl, or its pharmaceutically acceptable salt or solvate. Compounds of the formula (I) elicit activity of a modulating agent with respect to activity of chemokine MIP-1α receptors that allows their using in pharmaceutical composition in treatment of inflammatory diseases.

EFFECT: valuable medicinal properties of new compounds.

14 cl, 98 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

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

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: pharmaceutical industry, in particular new bioactive chalcones.

SUBSTANCE: invention relates to new chalcones of formula I

, pharmaceutically acceptable salts or solvates thereof, wherein Ar is optionally substituted C5-C10-carbocycle group or 5- or 6-membered heterocycle group having sulfur atom in cycle, and Ar substituents are selected independently from Cl, Br, F, CN, SCH3 and OR10, wherein R10 is linear or branched C1-C6-hydrocarbon; R is OH or R10; R2 and R3 are independently phenyl, saturated linear or branched C1-C6-hydrocarbon, or R2 and R3 together with carbon atom attached thereto form 5- or 6-membered carbocycle group with the proviso, that in compounds where R is OH and both R2 and R3 are methyl, Ar is not phenyl, 4-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 2-chlorophenyl, 3,4-dimethoxyphenyl, or 4-methoxyphenyl. Also disclosed are drug component for treatment or prophylaxis of neoplasm and pharmaceutical compositions with antiproliferation effect based on compounds of formula I.

EFFECT: new chalcone derivatives with value bioactive action.

26 cl, 2 tbl, 22 ex

FIELD: organic chemistry, pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new derivatives of S-substituted N-1-[(hetero)aryl]alkyl-N'-1-[(hetero)aryl]alkylisothioureas of general formula I

in form of free base and salts with pharmaceutically accepted acids, as well as racemate, individual optical isomers or mixture thereof. In formula R1, R2, R3, R4, Y and Z are as described in specification. Compounds of present invention are capable to potentiate (positively modulate) AMPA/KA glutamate receptors and simultaneously to block transmembrane currents induced by activation of NMDA glutamate receptors. Also disclosed are method for production of said compounds, including optical isomers; pharmaceutical composition; method for investigation of glutamatergic system, and method for Alzheimer's disease, treatment; as well as method for extreme retentiveness of memory by administering of effective amount of claimed compounds.

EFFECT: new pharmaceutically active compounds for Alzheimer's disease treatment.

23 cl, 1 tbl, 11 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to new derivatives of pyrrolopyrimidine of the formula (1) and their pharmaceutically acceptable salts possessing properties of selective inhibitor of specific cyclic guanosine 3',5'-monophosphate phosphodiesterase (specific cGMP PDE) (PDE V). In the formula (1) R1 represents hydrogen atom (H), (C1-C3)-alkyl substituted optionally with one or some fluorine atoms; R2 represents H, halogen atom, (C1-C6)-alkyl substituted optionally with hydroxyl group (-OH), (C1-C3)-alkoxy-group, (C3-C6)-cycloalkyl or one or some fluorine atoms, (C3-C6)-cycloalkyl; R3 represents (C1-C6)-alkyl substituted optionally with (C3-C6)-cycloalkyl or one or some fluorine atoms; R4 represents (C1-C6)-alkyl substituted optionally with one or some fluorine atoms; R5 represents -SO2NR6R, -NHSO2R8 or heterocyclyl such as tetrazolyl; each R6 and R7 represents independently H or (C1-C6)-alkyl substituted optionally with -CO2H or one or some fluorine atoms; or in common with nitrogen atom to which they are bound form monocylic ring, such as imidazole, pyrrolidine, piperidine, morpholine, piperazine and homopiperazine wherein indicated group is replaced optionally with R9 wherein R9 represents (C1-C6)-alkyl substituted optionally with one or some halogen atoms, hydroxyl group (OH), (C1-C3)-alkoxy-group that is replaced optionally with one or some fluorine atoms, -NR11R12, -C=NR13(NR14R15) or tetrazolyl group, 6-membered nitrogen-containing heteroaryl group; each R11 and R12 represents independently H or (C1-C4)-alkyl; R13represents H; each R14 and R15 represents independently H. Also, invention relates to intermediate compounds, methods for preparing compounds and pharmaceutical compositions. Proposed compounds can be used in treatment of impotency, sexual dysfunction in females, stable, nonstable and variant (Prinzmental) stenocardia and other diseases also.

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

15 cl, 1 tbl, 250 ex

FIELD: inorganic synthesis.

SUBSTANCE: invention relates to improved method of preparing amorphous calcium atorvastatine by dissolving crude calcium atorvastatine at heating in a lower alcohol containing 2-4 carbon atoms or in mixture of such alcohols followed by isolating amorphous calcium atorvastatine precipitated upon cooling.

EFFECT: improved preparation procedure.

4 cl, 2 dwg, 2 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides methods for preparing lamellarine compounds of general formula II: (II) via intramolecular cyclization of compounds having general formula I: (I), in which formulas moiety RA1RA2C-CRA3RA4 forms optionally monosubstituted aryl group or optionally monosubstituted aromatic 3-6-membered heteromonocyclic group with one nitrogen atom; Y represents hydrogen atom, optionally monosubstituted C1-C20-alkyl, optionally monosubstituted C2-C20-alkenyl, optionally monosubstituted C2-C20-alkynyl, hydroxy, optionally monosubstituted amino, optionally monosubstituted C1-C20-alkoxy, optionally monosubstituted C1-C20-alkenoxy, optionally monosubstituted C1-C20-alkynoxy, optionally monosubstituted aryl, optionally monosubstituted saturated or unsaturated 3-6-membered heteromonocyclic group with one nitrogen atom, carboxy, carboxyester, carboxamide, C1-C20-acyl, C1-C20-acyloxy, mercapto, optionally monosubstituted C1-C20-alkylthio, halogen, nitro, sulfate, phosphate, or cyano; W and X, together with nitrogen and carbon atoms to which they are linked, form group selected from quinoline, isoquinoline, dehydroquinoline, and pyridyl groups all optionally monosubstituted, dihydro- or tetrahydro-derivatives of indicated groups, and optionally monosubstituted phenantridine; wherein optional substituent is selected from C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, aryl, halogen, halo-C1-C20-alkyl, halo-C2-C20-alkenyl, halo-C2-C20-alkynyl, haloaryl, hydroxy, C1-C20-alkoxy, C2-C20-alkenyloxy, aryloxy, benzyloxy, halo-C1-C20-alkoxy, halo-C1-C20-alkenyloxy, haloaryloxy, nitro, nitro-C1-C20-alkyl, nitro-C2-C20-alkenyl, nitro-C2-C20-alkynyl, nitroaryl, nitro-substituted 3-6-membered heteromonocyclic group with one nitrogen atom, amino, C1-C20-alkylamino, di-C1-C20-alkylamino, C2-C20-alkenylamino, C2-C20-alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino, C1-C20-acyl, C2-C20-alkenylacyl, C2-C20-alkynylacyl, arylamino, diarylamino, benzylamino, dibenzylamino, C1-C20-acyl, C2-C20-alkenylacyl, C2-C20-alkynylacyl, arylacyl, C1-C20-acylamino, di-C1-C20-acylamino, C1-C20-acyloxy, C1-C20-alkylsulfonyloxy, arylsulfenyloxy, 3-6-membered heteromonocyclic group with one nitrogen atom, oxy-, amino-, and halogen-derivatives of the latter, C1-C20-alkylsulfenyl, arylsulfenyl, carbo-C1-C20-alkyloxy, carbo-C6-C24-aryloxy, mercapto, C1-C20-alkylthio, benzylthio, C1-C20-acylthio, cyano, sulfate, and phosphate; V represents halogen, hydrogen, or oxygen atom; and intermediates having general formulas Ia and Ib:

EFFECT: expanded synthetic possibilities in lamellarine series.

28 cl, 1 dwg, 2 tbl

FIELD: organic synthesis.

SUBSTANCE: invention provides new method for preparing amorphous atorvastatine, i.e. hemi-calcium salt of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-{(phenylamino)carbonyl]-1H-pyrrol -1-heptanoic acid. Method comprises (i) preparation of atorvastatine solution in one or several first-type solvents selected from low-molecular alcohols, ketones, and esters, in which atorvastatine is soluble; (ii) preparation of mixture of the above solution with one or several second-type solvents selected from ethers, resulting in precipitation of atorvastatine; and (iii) separation of above precipitate from solvent mixture.

EFFECT: expanded atorvastatine synthesis possibilities.

16 cl, 2 dwg, 5 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a new method for preparing 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrol-3-carboxylic acid phenylamide that involves conversion of methylcyano acetate to the end compound for 8 or less stages. Also, invention relates to value intermediate compounds that are synthesized as result of realization of above indicated stages of the claimed method. 5-(4-Fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrol-3-carboxylic acid phenylamide is a value intermediate compound used in synthesis of the drug atorvastatin calcium that is used as hypolipidemic and/or hypocholesterolemic agent. Proposed method allows avoiding usage of expensive chiral parent substances and to reduce the synthesis process time.

EFFECT: improved preparing method.

12 cl, 3 ex

The invention relates to new derivatives of guanidine and their pharmaceutically acceptable salts, used as medicines

The invention relates to pharmaceutical compositions for the treatment of inflammatory diseases, for example asthma, arthritis and allergies; fear; depression; fatigue syndrome; headache; pain; cancer; irritable bowel syndrome, including Crohn's disease, mucous colitis and symptoms of irritation of the colon; deregulation of the immune system; infections caused by human immunodeficiency virus (HIV); neurovirology diseases, such as Alzheimer's disease; gastrointestinal diseases; disorders of appetite, such as anorexia nervous system; stress caused by bleeding; symptoms of drug and alcohol withdrawal symptoms; addiction to the excessive use of drugs; stress-induced psychotic States and problems of fertilization, containing the above compound of formula I is effective for the treatment of these diseases the number and pharmaceutically acceptable carrier

The invention relates to agriculture and veterinary medicine
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