4/4/4/4/2-(2,4-differenl)-2-(1h-azolylmethyl)-1,3 - dioxolane-4-yl-(methoxy)-(phenyl)-1-piperazinil/-phenyl/- triazolone or imidazolone, the retrieval method, the antifungal composition and method of combating fungi in warm-blooded animals

 

(57) Abstract:

Usage: as an antifungal drug. The inventive compound of formula I specified in the text of the description, (radicals Q and Y have the respective meanings). The antifungal composition containing as an active ingredient an effective amount of compound I. a Method of combating fungi with use as antifungal agents of compound I in the amount of 0.001 - 5 mg/kg of body weight. The method of obtaining the compounds I. Reagent I: compound of formula I. Reagent 2: emilyrose agent in reactive inert solvent in the presence of a base. 3 s and 5 C. p. F.-ly.

Known some heterocyclic derivatives of (4-phenyl-1-piperazinecarboxamide-1,3-dioxolane-2-yl)methyl-1H - imidazoles and 1H-1,2,4-triazoles. These compounds have antifungal and antibacterial properties.

Compounds according to the invention show improved antifungal activity, particularly against type icrosporum and against species of Candida.

The invention relates to fungicidal compounds having the formula I

(I), their pharmaceutically acceptable salts accession acid and stereochemical isomeric forms, where

Q is Il5-C7or mono-, di-, tri-, Tetra - or pentachlorinated1-C4;

R2denotes alkyl WITH1-C6cycloalkyl5-C7or mono-, di-, tri-, Tetra - or pentachlorinated1-C4.

In the above definitions, the expression "halogen" is generic for fluorine, chlorine, bromine and iodine; the term "alkyl WITH1-C6" denotes unbranched and branched hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, 1-methylethyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, butyl, pentyl, hexyl and the like; the term "cycloalkyl5-C7" indicates cyclopentyl, cyclohexyl and cycloheptyl; and the expression "mono-, di-, tri-, Tetra - or interleukin1-C4" denotes unbranched and branched hydrocarbon radicals having from 1 to 4 carbon atoms, in which one, two, three, four or five hydrogen atoms substituted by halo, such as, for example, trifluoromethyl, 2-foretel, 2,2,2-triptorelin, 2-fluoro-1-methylethyl, 2-fluoro-1-(permitil)ethyl, 2,2,2-Cryptor-1-methylethyl, 2,2,3,3-pendaftar-1 - methylpropyl and the like.

From the formula (1), it is evident that the compounds according to the invention have, the Institute of 2 - and 4-core dioxolane. Depending on the structure of R1and R2may be other asymmetric centers. Therefore, the compounds of formula (I) may exist in various stereochemical isomeric forms. Unless otherwise mentioned or indicated, the chemical designation of compounds celebrates the mixture of all possible stereochemical isomeric forms, and these mixtures containing all diastereomers and mirror isomers basic molecular structure. The absolute configuration of each chiral center may be indicated stereochemical descriptors R and S, and the symbol R and S corresponds to the rules described in Riga Appl. Chem. 1976, 45, 11-30. The relative configuration of the asymmetric centers in the diastereomeric racemates of formula (I) marked descriptors CIS and TRANS according to the rules described in J. Org. Chem. 1970, 35(9), 2849-2867. Stereochemical isomeric forms of the compounds of formula (I) is obviously intended to be included in the scope of the invention.

The compounds of formula (I) have basic properties and, consequently, they can be converted into their therapeutically active salts accession acid as a result of processing corresponding acids such as, for example, inorganic acids, Naya acid and the like; or organic acids, such as, for example, acetic, propanoic, oxiana, 2-oxopropanal, 2-oxopropanoic, oxalic acid, metandienone, atindimubona, (Z)-2-atindimubona, (E)-2-atindimubona, 2-tanadoona, 2,3-diethanolammonium, 2-hydroxy-1,2,3-propane - carboxylic, methansulfonate, econsultation, benzosulfimide, 4-methylbenzenesulfonate, cyclohexane - sulfamic, 2-oxybenzone, 4-amino-2-oxybenzone and the like acids. On the contrary, the form of a salt may be converted as a result of processing by the free alkali in the main form.

The term "pharmaceutically acceptable salts join acid" also includes a solvate, which can form compounds of formula (I), and these solvate intended to be included in the scope of the invention. Examples of the solvate include, for example, hydrates, alcoholate, and the like.

Interesting are compounds of the formula (I) in which Q denotes N, and/or the substituents on the dioxolane core have the CIS configuration. Particularly interesting compounds are those compounds in which R1and R2denote a mono-, di-, tri-, Tetra - or pentaverate1-C4the Kie particularly interesting connec - tion, in which R1and R2denote 2,2,2-triptorelin, 2,2,3,3-tetrafluoropropyl, cyclopentyl or R2denotes propyl, 1-methylpropyl, 2-methylpropyl or butyl.

The most preferred compounds are CIS-2-cyclopentyl-4-/4-/4-/4-//2-(2,4-differenl)-2-(1H-1,2,4 - triazole - 1-ylmethyl)-1,3-dioxolane-4-yl/methoxy/phenyl/-1-piperazinil/phenyl/-2,4 - dihydro-3H-1,2,4-triazole-3-one; CIS-4-/4-/4-/4-//2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3 - dioxolane-4-yl/methoxy/phenyl/-1-piperazinil/-phenyl/-2,4-dihydro-2-(2,2,2 - triptorelin)-3H-1,2,4-triazole-3-one; CIS-1-/4-/4-/4-//2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3 - dioxolane-4-yl/methoxy/phenyl/-1-piperazinil/-phenyl/-1,3-dihydro-3-(1 - methylpropyl)-2H-imidazol-2-he, their pharmaceutically acceptable salts and stereochemical isomeric form of them.

To simplify the structural representations of the compounds of formula (I) and of certain starting materials and intermediates used in their preparation, group 2-(2,4-differenl)-2-(1H-1,2,4-azole-1-ilma-Tyl)-1,3-dioxolane-4-yl will be further depicted the sign D:

(D)

The compounds of formula (I) can be obtained by O-alkylation of suitably substituted phenol of the formula (III) with an alkylating reagent of formula (II).

D-W + HONY (I)

In forms, is for example, halogen, preferably chlorine, bromine or iodine, or a group of sulfonyloxy, such as, for example, methanesulfonate, 2-naphthalenesulfonate or 4 methylbenzenesulfonate and the like.

The alkylation reaction of compounds (II) and (III) can be carried out under known conditions of the reactions of O-alkylation. This reaction of O-alkylation may be carried out in the usual way in a suitable reactionnaire solvent in the presence of an appropriate base. Suitable reaction-inert solvent is, for example, aromatic hydrocarbons such as benzene, methylbenzol, xylene and the like; halogenated hydrocarbons such as dichloromethane, trichloromethane and the like; lower alkanol, for example methanol, ethanol, 1-butanol and the like; a ketone, e.g. 2-propanone, 4-methyl-2-pentanone and the like; a simple ether, e.g. 1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran and the like; dipolar appreticeship solvent, for example N,N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, dimethyl sulfoxide, nitrobenzene, 1-methyl-2-pyrrolidinone and the like, or a mixture of these solvents. Acid, which visw or carbonate of alkaline earth metal, the hydrogen carbonate, hydroxide, alkoxide, hydride or amide, e.g. sodium carbonate, potassium carbonate, sodium hydroxide, sodium methoxide, sodium hydride, sodium amide and the like, or an organic base, such as, for example, amine, e.g. N,N-diethylamin, N-(1-methylethyl)-2-propanamine, 4-ethylmorpholine and the like. In some cases it may be appropriate to convert the substituted phenol (III) beginning in his metal salt, preferably the sodium salt, for example, through reaction of the compound (III) with a metal base such as sodium hydride, sodium hydroxide, and the like, and the use of said metal salt is then reacted with (II).

Stirring and a slight fever can increase the speed of reaction, in particular the reaction may be conducted at a temperature of from about 50aboutWith up to approximately 60aboutC. In addition, it may be expedient to carry out the specified O-alkylation under an inert atmosphere, such as, for example, free from oxygen, nitrogen or gaseous argon.

Alternatively, the compounds of formula (I) can be obtained according to known procedure, in particular by reaction of acetylation calculatescore, 4-methylbenzenesulfonate, methanesulfonate and the like acids.

< / BR>
This acetylation reaction can be carried out in the usual way in a reaction-inert solvent such as aromatic hydrocarbons, for example benzene, methylbenzol, halogenated hydrocarbon, such as trichloromethane; alkanol, for example ethanol, propanol, butanol and the like, or a mixture of such solvents. Preferably, the water that is released during the reaction is removed by azeotropic distilling. Similarly, compounds of formula (I) can also be obtained by transacetalization of the compound (IV) using acetone acetal compound (V) or by azetilirovanie of the compound (IV) using the derived 2,3-epoxidic - pilifera corresponding to (V) in the presence of acid and reaction-inert solvent, as described above.

Or the compounds of formula (I) can also be synthesized by N-alkylation of asola (VI) with an intermediate of formula (VII).

+

This reaction of N-alkylation can be properly carried out in a suitable reaction-inert solvent or in mixtures of such solvents in the presence of the corresponding end, such as benzene, methylbenzol, xylene and the like; lower alkanol, such as methanol, ethanol, 1-butanol and the like; a ketone, such as 2-propanone, 4-methyl-2-pentanone and the like; a simple ether such as 1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran and the like; dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, nitrobenzene, 1-methyl-2-pyrrolidinone and the like; halogenated hydrocarbon such as dichloromethane, trichloromethane and the like. The addition of an appropriate base, such as, for example, alkali or carbonate of alkaline earth metal, carbonate, halogen, hydroxide, amide or hydride, such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydride and the like, or an organic base, such as, for example, N, N-dimethyl-4-pyridylamine, N,N-diethylethanamine or N-(1-methylethyl)-2-propanamine, can be used to neutralize the acid which is liberated during the reaction. In some cases, it may be desirable to use an excess of azole (VI) or to transform it into the form of a metal salt, in particular, its form of salts of alkaline metal, following well-known in this field processes, still the>The compounds of formula (I) can also be obtained by cyclization of the intermediate compounds of formula (VIII) with an appropriately substituted benzoylamino formula (IX) or cyclization benzoylamino formula (X) with a reagent of formula (XI).

implementation (I)

This cyclization reaction can be carried out by stirring the reactants in the presence of an appropriate polar solvent, such as, for example, 2-propanol, 2-propanone and the like, preferably at an elevated temperature and preferably in the presence of alkali or alkali earth metal iodide, such as, for example, modesty potassium. In addition, the compounds of formula (I) can be prepared by N-alkylation of the piperazine of the formula (XII) with a benzene of the formula (XIII), or by N-alkylation of the piperazine of the formula (XV) with a benzene of the formula (XIV), following the standard procedures of N-alkylation. In formulas (XIII) and (XIV) WIdenotes the corresponding outgoing reactive group, such as, for example, halo, such as chloro or bromo and, in particular, fluorescent, or sulfonyloxy, such as tripterocalyx.

melirovanie (I)

Specified N-alkylation may be carried out under stirring re is e, such as, for example, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide and the like, in the presence of an appropriate base, such as, for example, alkali metal hydride or carbonate, and the like bases.

The compounds of formula (I) in which Y denotes a radical of the formula (a), and these compounds are represented by formula (I) can usually be obtained by cyclization of the intermediate of formula (XVI) with an appropriate reagent of formula (XVII), and compounds in which Y denotes a radical of the formula (b), and these compounds denoted by the formula (I,b) can be obtained by cyclization of an intermediate compound of formula (XVI) with an appropriate reagent of formula (XVIII).

HR1--L1___

-NR2--L1___

In formulas (XVII) and (XVIII) and below L1and L2both represent an appropriate leaving group, such as, for example, alkyloxy1-C6aryloxy, di(alkyl C1-C4)amino and the like groups, and R1and R2have the specified values. This cyclization reaction can usually be carried out in a suitable reaction-inert solvent such as, for example, alcohol such as butanol and the like; p is such solvents. Although the cyclization reaction can be conducted at room temperature, several desirable elevated temperature to increase the reaction rate. Preferably the reaction is carried out at the temperature of boiling under reflux the reaction mixture.

The compounds of formula I, a) can alternatively be obtained by cyclization of an intermediate compound of formula (XIX) c amidino formula (XX) or its salt accession acid, and N-alkylation of the thus obtained intermediate compound with a reagent of formula (XXI).

D-CH2-ONNH--NH-NH2(I,a)

This cyclization can be carried out by mixing and heating the reactants, preferably in the presence of an appropriate reaction-inert organic solvent having a relatively high boiling point, such as, for example, 1,1'-oxybis-(2-methoxyethane). This reaction of N-alkylation can be carried out following the same procedure as described for obtaining the compounds of formula (I) from (VI) and (VII). However, it may be appropriate to convert this intermediate connection is first in its shape metal salt, preferably sodium salt, in the usual way, e.g. the, and the use of said salt of the metal subsequently in the reaction with (XXI). The addition of the iodide salt, preferably alkali iodide, may be appropriate. Several elevated temperatures and mixing can increase the speed of reaction.

The compounds of formula I,b) can be alternatively obtained by cyclization of an intermediate compound of formula (XXII) with a reagent of formula (XXIII).

-CH2-ONNH-C-L1+(L2)-OTHER2__(I,b)

This cyclization reaction can be carried out under stirring and heating the reactants in a reaction-inert solvent such as, for example, a simple ether, such as tetrahydrofuran, 1,4-dioxane and the like, in the presence of an appropriate acid, such as, for example, formic, acetic, propanoic, benzoic acid and the like acid.

A number of intermediates and starting materials used in these reactions preparation, representation allows a known connection, others can be obtained according to known engineering methodologies for the preparation of these or similar compounds, while others are new. Some of these cooking methods will be described in more detail below. .

Starting materials of the formula (II) can be produced from 1-(2,4-differenl)-2-halogenation by introducing the latter in response to azole (VI) in a reaction-inert solvent, if necessary in the presence of a base, and the consequent introduction into the reaction thus obtained 1-(2,4-differenl)-2-(azole-1-yl)alanon (IV) with 1,2,3-propantriol in a suitable acatalasemia environment. It may be particularly desirable to separate form CIS and TRANS at this early stage. Appropriate methods that can be used include, for example, selective crystallization, chromatographic forms of separation, such as column chromatography and the like methods. The desired alkylating reagents of formula (II) can be easily obtained by converting the remaining hydroxyl group in the thus obtained intermediate substance in a reactive leaving group according to known methods. These reactive derivatives of the formula (II) can be alternatively prepared according to the sequence of reactions. Intermediate substances of the formula (VII) are obtained following the procedures for example acetalization diol of the formula (V) with 1-(2,4-differenl)-2-halogenated (III) with (chloromethyl)oxirane and subsequent hydrolysis of the epoxide. The previously described intermediate and raw materials can also be converted into each other following well-known in this field procedures of transformation of functional groups.

The compounds of formula (I) and some of the intermediate compounds according to the invention may contain an asymmetric carbon atom. Pure stereochemical isomeric forms of these compounds and these intermediate compounds can be obtained by applying known in this field procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Mirror isomers can be obtained from racemic mixtures by translating the first of these racemic mixtures with suitable solvent agents, such as, for example, chiral acids, mixtures diastereoisomeric salts or compounds, then the physical separation of these mixtures diastereoisomeric salts or compounds with, for example, selective crystallization or chromatographic technologies, such as liquid chromatography and t is dtweedie mirror isomers. Mirror isomers can also be separated by chromatography of the racemate after chiral stationary phase.

Pure stereochemical isomeric forms of the compounds of the formula [1] can also be obtained from pure stereochemical forms of the corresponding intermediates and starting materials, provided that the reactions proceed stereospecific. Pure and mixed stereochemical isomeric forms of the compounds of formula (I) are included in the scope of the invention.

The compounds of formula (I), their salts attaching a biologically acceptable acids and stereochemical isomeric form exhibit antifungal activity. This activity of the compounds of formula (I) can be demonstrated in the experience of Local and oral treatment of vaginal candidiasis in rats"; in the experience of Local and oral treatment of microspores in Guinea pigs, Local and oral treatment of candidiasis of the skin in Guinea pigs" and "Local treatment of deep (systemic) candidiasis in Guinea pigs".

From the point of view of useful antifungal activity of compounds that are the subject of the invention may be prepared in the form of various pharmaceutical forms for the purposes vvedeno special connection, perhaps in the form of salt accession acid, as an active ingredient, is combined in a mixture with a pharmaceutically acceptable carrier, and this carrier allows for a wide variety of forms depending on the desired option introduction. These pharmaceutical compositions are preferably provided in the form of a unit dosage, suitable for administration orally, rectally or parenterally by injection. For example, in the preparation of compositions in the form of oral dosages may be used any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols and the like, in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, destructive agents and the like in the case of powders, granules, capsules and tablets. Because of the ease of their administration tablets and capsules represent the most suitable oral dosage units, in this case solid pharmaceutical carriers, clearly, and used. For parenteral compositions, the carrier should usually contain sterile water, at least in significant Stepan, for example, can be prepared in which the medium contains a salt solution, a glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared, in this case, you can use the appropriate liquid carriers, suspendresume agents and the like. In the compositions suitable for percutaneous administration, the carrier can contain a means of improving the penetration and/or a suitable wetting agent, possibly combined with suitable additives of any nature in minor proportions, and these additives do not cause significant adverse effects on the skin. These supplements can facilitate the introduction into the skin and/or may be useful in the preparation of the desired compounds. These compositions can be administered in various ways, for example in the form of transdermal patches, in the form of a coating on a local site, in the form of ointments. Salt accession acids (I), due to their increased water solubility over the corresponding base form, are obviously more suitable for aqueous compositions. Especially is advisable to prepare pharmaceutical compositions in the form of a unit dosage for ease of administration and uniformity of dosage. Form ecem each unit contains a predetermined quantity of active component, designed to obtain the desired therapeutic effect in combination with the required pharmaceutical carrier. Examples of such forms of dosage units are tablets (including tablets with slots or coated), capsules, pills, powder packets, wafers, injectable solutions or suspensions, the volumes of the size of a teaspoon, the volume value in a tablespoon, and the like, and their separated components.

The compounds of formula (I), their pharmaceutically acceptable salts accession acid and stereochemical isomeric forms are useful agents for combating fungi. For example, these compounds were highly active against wide range of fungi, such as, for example, Microsporum eanis, Pityrosporum ovale, etenomyces mentagropytes, Trichophytn rubrum, Phialophora verrucosa, Cryptococcus neoformans, Candida tropicalis, Candida albicans, Mucor species, Aspergillus fumigatus, Sporotrichum schenckii and Saprolegnia specie. From the point of view of their potential as a General and a local antifungal activity of the compounds according to the invention constitute useful tools for the destruction of fungi or for inhibiting or preventing the growth or development of fungi. In particular, they can be used effectively in the treatment of warm-blooded animals, Straz, perionychia, paracoccidioidomycosis, histoplasmosis, coccidioidomycosis, cryptococcosis, chronomics, monorails, sporotrichosis, seborrheic eczema, and the like. Some of the proposed compounds are particularly attractive because of their superior local action against species of Microsporum. Specific examples of these warm-blooded animals are Pets, such as dogs, cats and horses as well as people infected with Microsporum. In addition, the proposed compounds also show improved activity against Candida infections. Therefore, the compounds are especially useful in the local treatment of vaginal thrush and candidiasis of the skin and in General the treatment of candidiasis of the skin and especially deep (or system) of candidiasis. Professionals working in the field of treatment of warm-blooded animals suffering from diseases caused by fungi, can easily determine the effective amount from the test results presented here. In General it is believed that an effective amount should be from 0.01 to 50 mg/kg body weight, more preferably from 0.05 to 20 mg/kg of body weight. For local applications, it is considered that the effective amount will be in the range from 0.001 to 5% by mass, and more preferably from.

The experimental part.

A. Preparation of intermediate compounds

P R I m e R 1. a) To boiling under reflux and stirred solution of 457,6 wt.h. 1H-imidazole 2400 wt.h. trichloromethane was added dropwise a solution of 320 hours of 2-chloro-1-(2,4-differenl)ethanone in 1440 wt.h. trichlormethane. After stirring for 1/2 at the boiling point under reflux, the reaction mixture was poured into water. The organic layer was washed with water (2x), dried, filtered and evaporated. The residue was led from 2-propanol, which gave 244 wt.h. (69%) 1-(2,4-differenl)-2-(1H-imidazol-1-yl)ethanone; melting point 125about(Intermediate compound 1).

b). A mixture of 100 wt.h. 1,2,3-propantriol, 70 wt.h. intermediate compounds (1), 450 hours of methansulfonate and 108 wt.h. benzene was stirred for 2 h at the boiling point under reflux using a water separator. After cooling, the reaction mixture was added dropwise to a mixed solution of sodium bicarbonate. The product was extracted with trichloromethane and the extract was washed with water, dried, filtered and evaporated, which gave 80 wt.h. (100%) of (CIS+TRANS)-2-(2,4-differenl)-2-(1H-them - Gasol-1-ylmethyl)-1,3-dioc the compounds (2), 234 wt. including N,N-diethylethanamine, 8 mass.h. N,N-dimethyl-4-pyridylamine 1950 and Mac. including dichloromethane was added portions 227 wt.h. 2-naphthalenesulfonate. Stirring is continued overnight at room temperature. The reaction mixture was diluted with water and was extracted with dichloromethane (3x). The combined extracts were washed with water, dried, filtered and evaporated. The residue was twice purified column chromatography (silica gel; l3-CH3HE 99:1; high performance liquid chromatograph; silica gel, CH2CL2-CH3HE 99:1). Eluent of the desired fraction evaporated and the residue was led from 4-methyl-2-pentanone. The product was filtered and dried, which gave 100 wt.h. (22,8%) of CIS-[(2,4-differenl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolane-4-yl] methyl-2-naphthalenesulfonate; melting point 125,0about(Intermediate compound 3).

P R I m m e R 2. A mixture of 44,6 wt.h. 1-(2,4-differenl)-2-(1H-1,2,4-triazole-1-yl)ethanone, 56,0 mAh.h. (2S)-1,2,3-propanetriol 1-(4-methylbenzenesulfonate) (ether), 296 mass.h. methansulfonate and 200 wt.h. dichloromethane was stirred at the boiling temperature under reflux using a water separator. After cooling, the reaction mixture was added dropwise to the mixture laravale dichloromethane. United dichloromethane layers were dried, filtered and evaporated. The residue was purified column chromatography (silica gel; l3). Eluent of the desired fraction evaporated and the residue was converted into 4-methylbenzenesulfonate salt in 4-methyl-2 - pentanone. The salt was recrystallized from 4-methyl-2-pentanone that was given to 20.5 wt. h (16,4%) of (-)-(2S, CIS)-2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane - 4-methanol 4-methylbenzenesulfonate (ester) 4-methylbenzenesulfonate (salt) (1:1); melting point 182,5aboutWITH; ()D20=-13,78about(C=1% in CH3HE) (intermediate compound 4).

P R I m e R 3. A mixture of 40.0 wt.h. 1-(2,4-differenl)-2-(1H-1,2,4-triazole-1-yl)this is Nona, 56,0 wt.h. (2R)-1,2,3-propanetriol 1-(4-methylbenzenesulfonate) (ester), 370 mass.h. methansulfonate and 133 wt.h. dichloromethane was stirred for 24 h at boiling temperature under reflux and using the water separator. After cooling, the reaction mixture was added dropwise to a mixture of potassium carbonate, ice water and dichloromethane. The organic layer was separated, washed with water, filtered and evaporated. The residue was purified column chromatography (silica gel; l3). Eluent desired fractions evaporated and the residue transformed what about the gave of 23.1 wt. h (20,6%) of (+)-(2R, CIS)-2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxol-on - 4-methanol 4-methylbenzenesulfonate (ester) 4-methylbenzenesulfonate (Sol, 1:1); melting point 183,5aboutWITH; ()D20=+14,43about(C=1% in CH3HE) (intermediate compound 5).

P R I m e R 4. a). 40 wt.h. 2,2-(dimethoxy)ethanamine alkilirovanie with dilution, using 35 wt.h. 3 pentanone in a mixture of 4 wt.h. the catalyst of palladium on charcoal (10%), 2 wt.h. solution of thiophene in methanol (4%) and 395 mass.h. of methanol. The reaction mixture was filtered and the filtrate evaporated. The residue was subjected to distillation (water-jet pump; 76about(C) that gave 55,7 wt. h (83.6 percent) of N-(2,2-dimethoxymethyl)-1-ethylpropylamine (intermediate compound 6).

b). A mixture of 36 wt. including phenyl (4-(4-(4-methoxyphenyl)-1-piperazinil)phenyl)-carb - Mat monohydrochloride, and 19.2 wt.h. intermediate compound (6), 4 wt.h. N,N-dimethyl-4-pyridylamine, of 14.6 wt.h. N,N-diethylethanamine and 412 wt.h. 1,4-dioxane was stirred for 3 h at boiling temperature under reflux. After cooling, the reaction mixture was diluted with water and all was left to crystallize. The product was filtered, washed with water, dried and stirred in 122 wt.h. formic acid in Cografya (silica gel; CH2CL2-CH3HE 99:1). Eluent desired fractions evaporated and the residue was ground into powder in 2-propanol. The product was filtered and dried, which gave to 29.3 wt.h. (85,0% ) 1-(1-ethylpropyl)-1,3-dihydro-3-(4-(4-(4-IU-toxigenic)-1-piperazinil)phenyl - 2H-imidazole-2-he; melting point 195,8about(Intermediate compound 7).

P R I m e R 5. a). A mixture of 10 wt.h. phenyl (4-(4-(4-methoxyphenyl)-1-piperazinil)Fe-nil)carbamate monohydrochloride, 3 wt.h. 2,2-diethoxyethane and 100 wt.h. 1,4-dioxane was stirred for 6 h at boiling temperature under reflux. After cooling, the precipitate was filtered, washed with 1,4-dioxane and purified column chromatography (silica gel; l3-CH3HE 99: 1). Eluent of the desired fraction was subjected to evaporation and the residue was led from 1,4-dioxane, which gave to 3.9 wt.h. N-(2,2-dimethoxymethyl)-N'-(4-(4-(4-methoxyphenyl)-1-piperazinil)Fe-nil)-mohavi us; melting point 225about(Intermediate compound 8).

b). A mixture of 70 wt.h. intermediate compound (8), 84 wt.h. hydrochloric acid, 300 wt.h. water and 280 wt.h. methanol was stirred for 1/2 h at 80aboutC. After cooling, the reaction mixture was left to crystallize. Prusiner)phenyl)-2H-imidazol-2-he monohydrochloride monohydrate; melting point 256,2about(Intermediate compound 9).

in). To a stirred mixture of 12 wt.h. the intermediate (9), 6.75 in weight.h. 1-bromopropane and 250 wt.h. dimethyl sulfoxide was added 3 wt.h. dispersion of sodium hydride in mineral oil (50%). After stirring for 2 h at 60aboutC and subsequent cooling, the reaction mixture was poured into water. The precipitate was filtered and was purified column chromatography (silica gel; l3). Eluent of the desired fraction evaporated and the residue was led from 1-butanol. The product was filtered and dried, which gave it a 7.2 wt. hours (61% ) of 1,3-dihydro-1-(4-(4-(4-methoxyphenyl)-1-piperazinil)-phenyl)-3-propyl - 2H-imidazol-2-it; melting point 214,1about(Intermediate compound 10). Similarly, the intermediate compound (9) was transformed into 1,3-dihydro-1-(4-(4-(4-methoxyphenyl)-1-piperazinil)phenyl)-3-(1-methylpropyl)- 2H-imidazol-2-he; melting point 184,0about(Intermediate compound 11).

P R I m e R 6. a). To mix the solution of 25.0 wt.h. 2,2,2-triptoreline 175 wt.h. N,N-diethylethanamine was added in portions to 62.2 wt.h. 2-naphthalenesulfonate and then a mixture of 1.5 wt.h. N,N-dimethyl-4-pyridylamine and 25 wt.h. ethyl acetate. After paramashiva ivali in the water. The solid was filtered and dissolved in dichloromethane. This solution was dried, filtered and evaporated. The residue was consistently rasmalai in powder with petroleum ether and was led from 2-propanol. The product was filtered and dried, which gave 65,3 wt.h. (89%) of 2,2,2-triptorelin-2-naphthalenesulfonate; temperature Pavle of 72,7about(Intermediate compound 12).

b). A mixture of 17.5 wt. including intermediate compounds (9), 16.1 wt.h. the intermediate (12), 10.6 wt.h. carbothane sodium,

261 wt.h. 1,3-dimethyl-2-imidazolidinone and 130,5 wt.h. methylbenzene was stirred for 48 h at the boiling point under reflux using a water separator. After cooling, the reaction mixture was diluted with water. After adding a certain amount of petroleum ether and 4.2 wt. including acetic acid, the product crystallized. It was dried and purified column chromatography (silica gel; CH2CL2/CH3HE of 99.5:0.5 to). Eluent of the desired fraction evaporated and the residue was led from 4-methyl-2-pentanone. The product was filtered and dried, obtaining of 9.0 wt.h. (41,6%) of 1,3-dihydro-1-(4-(4-(4-methoxyphenyl)-1-piperazinil)phenyl)-3-(2,2,2 - triptorelin)-2H-imidazol-2-she; temperature Plavi - n bath) quantity 200 ml trichromate boron 1M in dichloromethane) was added dropwise a solution of 14.6 wt.h. 1,3-dihydro-1-(4-(4-(4-methoxyphenyl)-1-piperazinil)phenyl)-3-methyl-2H - imidazol-2-she 665 wt.h. dichloromethane. Stirring was continued for 5 days at room temperature and then the reaction mixture was poured into a mixture of 200 wt.h. water, 158 mass.h. methanol and 180 wt.h. the ammonium hydroxide. After stirring for 1 h, the precipitate was filtered, washed with dichloromethane and water, and dried (the first product fraction). The organic layer of the filtrate was separated and evaporated. The residue was rasmalai into powder in dichloromethane. The solid was filtered and dried (second fraction). Both fractions were combined and were led from N,N-dimethylformamide, getting to 9.6 wt.h. (68,5%) of 1,3-dihydro-1-(4-(4-(4-oxyphenyl)-1-piperazinil)-phenyl)-3-methyl-2H - imidazol-2-it; melting point 283,1about(Intermediate compound 14).

According to the same procedure were also obtained intermediate substances that are listed in the table. 1.

P R I m e R 8. The mixture of 52.8 wt.h. 2,2,3,3-titrator-1-propanol, 117,8 wt. h 2-naphthalenesulfonate, 294 mass.h. pyridine and 2.0 wt.h. N,N-dimethyl-4-pyridylamine was stirred for 48 h at room temperature. The reaction mixture was diluted with water and all was left to crystallize. The product was filtered, promegranate; melting point 89,6about(Intermediate compound 27).

P R I m e R 9. a). To a chilled (ice bath) suspension of 41.7 wt.h. 2-naphthalenesulfonate 174 wt. hours of methylbenzene was added dropwise 20.0 wt. including 1,1,1-Cryptor-2-propanol. After stirring for 1 h was added dropwise a mixture of 9.6 wt.h. dispersion of sodium hydride in mineral oil (50%) and a number of methylbenzol while cooling on ice. After that, all was diluted dropwise with water. The organic layer was separated, dried and evaporated, giving a 53.2 wt.h. (99.9% of) (2,2,2-Cryptor-1-methylethyl)-2-naphthalenesulfonate (intermediate compound 28).

b). A mixture of 17.5 wt.h. 2,4-dihydro-(4- (4-(4-methoxyphenyl)-1-piperazinil)-phenyl)- 3H-1,2,4-triazole - 3-it, to 22.0 wt.h. intermediate compound (28), 5.0 wt.h. lithium carbonate, 10.0 wt.h. sodium carbonate, 261 mass.h. 1,3-dimethyl-2-imidazolidone and 130,5 wt.h. methylbenzene was stirred for 4 days at the boiling temperature under reflux. After cooling, the reaction mixture was diluted with 1500 wt. water. After adding 218 wt.h. 2,2'-oxybisethane product vykristallizovyvalas. The mother liquor was filtered and the product was dissolved in dichloromethane. The last solution was filtered 2,2'-oxybisethane and methylbenzene (1:1). The extract was dried, filtered and evaporated, which gave it a second product fraction. United fractions was purified column chromatography (silica gel; l3). Eluent of the desired fraction evaporated and the residue was vykristallizovyvalas of 4-methyl-2-pentanone, which gave it a 6 wt.h. (26,8%) of 2,4-dihydro-4(4-(4-(4-methoxyphenyl)-1-piperazinil)-phenyl)-2-(2,2,2 - Cryptor-1-methylethyl)-3H-1,2,4-triazole-3-one; melting point 198,7about(Intermediate compound 29).

in). A mixture of 11.5 wt. including intermediate compounds (29), 522 wt.h. Hydrobromic acid concentration of 48% and 3.0 wt.h. sodium sulfite was stirred all night at the boiling point under reflux. After cooling, the reaction mixture was diluted with 1000 wt.h. water and subsequently neutralized with ammonia. The precipitate was filtered, dried and purified column chromatography (silica gel; l3-CH3SOOS2H5-hexane-CH3HE 498,5:300: 200:1,5). Eluent of the desired fraction evaporated and the residue was led from 1-butanol. The product was filtered and dried, which gave it an 8.4 wt. h (74,5%) of 2,4-dihydro-4-(4-(4-(4-oxyphenyl)-1-piperazinil) phenyl)-2-(2,2,2-Cryptor-1-methylethyl)- 3H-1,2,4-triazole-3-one; melting point 230,4about(Between the oksifenil)-1-piperazinil)phenyl)-2-(2,2,3,3 - tetrafluoropropyl)-3H-1,2,4-triazole-3-one; melting point 214,7about(Intermediate compound 31).

B. obtain the final compounds.

P R I m e R 10. A mixture of 4.2 wt.h. 2,4-dihydro-4-(4-(4-(4-oxyphenyl)-1-Pipera - sinil)phenyl)-2-(2,2,2-triptorelin)-3H-1,2,4-triazole-3-one, 1,0 wt. ch. of sodium hydroxide and 135 wt.h. N,N-dimethylformamide was stirred at 50aboutC in nitrogen atmosphere. After adding water and 1.6 wt.h. acetic acid precipitate was filtered and dissolved in trichloromethane. The organic layer was dried, filtered and evaporated. The residue was purified column chromatography (silica gel; l3-CH3HE 98,5:1,5). Eluent of the desired fraction evaporated and the residue was led from 4-methyl-2-pentanone that gave 4.3 wt.h. (62%) of CIS-4-(4-(4-(4-((2-(2,4-differenl)-2-(1H-1, 2,4-triazole-1-ylmethyl)-1,3 - dioxolane-4-yl)methoxy)-phenyl)-1-piperazinil)phenyl)- 2,4-dihydro-2- (2,2,2-triptorelin)-3H-1,2,4-triazole-3-one; melting point 177,6about(Compound 2).

Similarly, using an equivalent amount of 2-cyclopentyl-2,4-dihydro-4-(4-(4-(4-oxyphenyl)-1-piperazinil) phenyl)-3H - 1,2,4-triazole-3-she also received CIS-2-cyclopentyl-4-(4-(4-(4-((2-(2,4-differenl)-2-(1H-1,2,4-triazole-1 - ylmethyl)- 1,3-dioxolane-4-yl)methoxy)phenyl)-1-piperazinil)phenyl)-2,4-dihydro - 3H-1,2,4-Tr-Tria-Zol-1-ylmethyl)-1,3 - dioxolane-4-yl)methoxy)phenyl)-1-piperazinil)phenyl)carbamate, 1.8 wt.h. N-(2,2-dimethoxymethyl)-2-butanamine, 1 wt.h. N, N-dimethyl-4-pyridylamine and 100 wt.h. 1,4-dioxane was stirred all night at the boiling point under reflux. The reaction mixture is evaporated and the residue is stirred for 2 h at 120 wt.h. formic acid at 60aboutC. After evaporation the residue was dissolved in dichloromethane and everything was neutralized with sodium bicarbonate solution. The organic layer was separated, dried, filtered and evaporated. The residue was purified column chromatography (silica gel; l3-CH3HE 99:1). Eluent of the desired fraction evaporated and the residue was twice led from 4-methyl-2-pentanone that gave 2.8 wt.h. (55,5%) CIS-1-(4-(4-(4-((2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3 - dioxolane-4-yl)methoxy)phenyl)-1-piperazinil)phenyl)-1,3-dihydro-3-(1 - methylpropyl)-2H-imidazol-2-it; melting point 159,0about(Connection 3).

All compounds are given in table. 2 were obtained according to the procedure described in example 10.

Pharmacological examples.

Antifungal activity of the compounds of formula (I) clearly confirmed by the data obtained in the following experiments. These data are presented to illustrate useful antifungal the microorganisms, and not in respect of the scope of formula (I).

P R I m e R 12. a) Local and oral treatment of vaginal candidiasis in rats.

Female Wistar rats weighing 100 g were used for the experiment. They were subjected to the operation of removal of the ovaries and hysterectomy and after a three-week recovery period they were administered 100 mg of astrogeological in sesame oil subcutaneously once a week for 3 consecutive weeks. The result of this pseudo-estrus was monitored by analysis under a microscope vaginal smears. Food and water were provided ad libitum. Rats infected vnutrivaginalno with 8 to 105cells of Candida albicans grown in nutrient solution Saburo within 48 h at 37aboutWith and dilution of the salt solution. Date of infection varied from day 25 to day +32 after surgery, depending on the appearance of signs of pseudo-oestrus. Investigational drugs used locally in 0.2 ml of polyethylene glycol RES 200 twice a day or orally in REES 200 once daily for three consecutive days, starting from the third day after infection. For each experiment there were control specimens treated with placebo. The results were evaluated p is promised in the nutrient solution Saburo in Petri dishes and incubated for 48 h at 37aboutC. When the animals had a negative reaction to the end of the experiment, i.e. there was no growth of Candida albicans, it was thanks to the use of drugs as the control specimens treated with placebo have always had a positive reaction. In table. 3 shows the minimum effective dose (MED) and the minimum effective local concentration (MÈLK) of study medication, which was active until 7 days after the last topical application of drugs.

b). Local and oral treatment microspores in Guinea pigs.

Preparing adult Guinea pigs-albinos by clamping their backs and infection on scarificing the skin by scratching the five transverse cuts a length of 3 cm using Microsporum canis (strain RV 14314). Animals were housed individually in wire mesh cages, food and water were provided ad libitum. The investigational drug was administered locally once a day for 14 consecutive days, starting from the third day after infection. Oral treatment was started on the day of infection and continued once a day for 14 consecutive days. For each experiment were controlled specimens treated with placebo. Animals were evaluated 21 days later by the bacterial antibiotic and suitable agent for removal of contaminating fungi.

In table. 4 illustrates the minimum effective oral dose (MED) and the minimum effective local concentration (MÈLK) investigational drugs, which was not observed in lesions and in which culture is not growing.

Examples of drugs.

P R I m e p 13. Drops orally.

500 wt.h. A. K. was dissolved in 0.5 l of 2-proparoxytone and 1.5 liters of 2-proparoxytone and 1.5 l of the polyethylene glycol at 60-80aboutC. After cooling to 30-40aboutWith added 35 l of polyethylene glycol and the mixture well stirred. Then was added a solution of 1750 wt.h. sodium saccharin in 2.5 l of purified water and while stirring was added 2.5 l flavorings, cocoa butter and polyethylene glycol, in an amount sufficient to volume of 50 l, obtaining the solution for oral drip containing 10 mg/ml A. K. the resulting solution was poured into suitable vessels.

P R I m e R 14. Oral solution.

9 wt.h. methyl-4-oxybenzoates and 1 wt.h. propyl-4-oxybenzoates was dissolved in 4 l of boiling purified water. In 3 l of this solution were dissolved first 10 wt.h. 2,3-dioxabicyclo and then 20 wt.h. A. K. the Latter solution was combined with the remaining part of the previous solution, 12 l 1,2,3-propanetriol and 3 l of 70% aqueous solution of the l essences gooseberry. The latter solution was combined with the previous, water was added in an amount necessary up to a volume of 20 l, obtaining a solution for oral administration containing 5 mg of active component on a teaspoon (5 ml). The resulting solution was poured into suitable vessels.

P R I m e R 15. The capsule.

20 wt. H. A. K. 6 wt.h. acrylourethane and 56 wt.h. starch, 56 wt.h. lactose, 0.8 wt.h. colloidal silicon dioxide, and 1.2 wt.h. the stearate strongly mixed together. The resulting mixture was then poured into 1000 suitable hardened gelatin capsules, each of which contains 20 mg of the active component.

P R I m e R 16. The tablets are film-coated.

Preparation of core tablets.

A mixture of 100 wt.h. A. K. 570 wt.h. lactose and 200 wt.h. starch was well mixed and then moistened with a solution of 5 wt.h. nitrilotriacetate and 10 wt. including polyvinylpyrrolidone (Kollidon-K 90 in about 200 ml of water. Wet powder mixture was sieved, dried and again sieved. Then was added 100 wt. including microcrystalline cellulose (Avical) and 15 wt.h. hydrogenated vegetable oil (Sterotex). All this was well mixed and extruded into pellets, receiving 10,000 tablets, each of which is cellulose (Methocel 60 HG) in 75 ml of denatured ethanol was added a solution of 5 wt.h. ethyl cellulose (Ethoul 22 cps in 150 ml of dichloromethane. Then added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. Was dissolved 10 wt.h. poly (ethylene glycol) in 75 ml dichloromethane. The latter solution was added to the first and then added 2.5 wt.h. octadecanoate magnesium, 5 wt. including polyvinylpyrrolidone and 30 ml of concentrated dye suspension (Opaspray K-1-2109) and all homogenized. The core tablets were coated thus obtained mixture in the apparatus for applying the coating.

P R I m e R 17. Injectable solution.

1.8 wt.h. methyl-4-oxybenzoates and 0.2 wt.h. propyl 4-oxybenzoates was dissolved in about 0.5 l of boiling water for injection. After cooling to about 50aboutWith added while stirring 4 wt.h. lactic acid; 0,05 wt. including propylene glycol and 4 wt.h. A. K. the Solution was cooled to room temperature and supplemented with water for injection in a quantity sufficient for 1 l, giving a solution containing 4 mg/ml A. K. the Solution was sterilized by filtration and poured into sterile vessels.

P R I m e R 18. Suppositories.

3 wt.h. A. K. was dissolved in a solution of 3 wt.h. 2,3-dioxabicyclo in 25 ml of polyethylene glycol 400. Together melted 12 wt.h. surface-active substances is tworoom. The resulting mixture was poured into moulds at a temperature of 37-38aboutTo obtain suppositories, each containing 30 mg/ml A. K.

P R I m e R 19. Injectively solution.

60 wt.h. A. K., and 12 wt.h. benzyl alcohol is well mixed and added sesame oil in sufficient quantity to 1 l, giving a solution containing 60 mg/ml A. K. the Solution was sterilized and poured into sterile vessels.

P R I m e R 20. 2% paste.

75 mg stearyl alcohol, 20 ml of cetyl alcohol, 20 mg servicemonitoring and 10 ml of isopropylmyristate injected into the vessel with double-walled jacket and heated until complete melting of the mixture. This mixture was added to a separately prepared mixture of purified water, 200 mg of propylene glycol and 15 mg of Polysorbate 60, having a temperature of from 70 to 75aboutSince, when using a homogenizer for liquids. The resulting emulsion is allowed to cool below the 25aboutWith constant mixing. Then to this emulsion is added a solution of 20 mg A. K. formula (I), 1 mg of Polysorbate 80 and 637 mg of purified water and a solution of 1 mg of anhydrous sodium sulfite in purified water with constant mixing. The paste is homogenized and placed into the appropriate tubes.

is Noah the treatment of vaginal candidiasis in rats (example 12A);

Test B: local and oral treatment of microspores in Guinea pigs (example 12B);

Test: local and oral treatment of candidiasis of the skin in Guinea pigs as described by van Kastama in J. and Thienpont, D. in Sabonraudia 9,17-20,1971;

Test G: oral systemic treatment of candidiasis in Guinea pigs as described by van Kastama and others in Sabourandia, J. Med. Vet. Myc. 23, 189-198, 1985.

The results of the tests are presented in table. 5 as the minimum effective dose for receiving oral (minutes E. D.) and the minimum concentration for local use (minutes E. K.).

The results prove that the compounds according to the invention, generally, superior to their activity in vivo is known compounds in various tests, especially when taken orally. The most excellent activity of the compounds according to the invention exhibit a systematic treatment of candidiasis in Guinea pigs.

1. 4/4/4/4/2-(2,4-differenl) -2-(1H-azolylmethyl)-1,3-dioxolane - 4-yl-(methoxy-phenyl)-1-piperazinil/ -phenyl/-triazolone or imidazolone General formula I

< / BR>
where Q is CH or N;

Y is a radical of the formula

< / BR>
where R1- C5- C7- cyclooctyl or mono - di - tri-, Tetra -, or C1- C4-pentachlorinated;

R2- halogenated.

2. Connection on p. 1, in which Q is N and the substituents on the nucleus of the dioxolane have the CIS - configuration.

3. Connection on p. 2, in which R1and R2- mono-, di-, tri-, Tetra -, or C1- C4-pentaverate, cyclohexyl or cyclopentyl or R2- C1- C4-alkyl.

4. Connection on p. 3 in which R1and R2- 2,2,2-triptorelin, 2,2,3,3-tetrafluoropropanol or R2- propyl, 1-methylpropyl, 2-methylpropyl or butyl.

5. Connection on p. 1: CIS-2-cyclopentyl-4-/4/4/-/4-[[2-(2,4-differenl) -2-(1H - 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl (-methoxyphenyl)-1-(piperazinil)phenyl] -2,4-dihydro-3H-1,2,4 - triazole-3-one; CIS-1-/4-/4-/4-[[2-(2,4-differenl)-1 - piperazinylmethyl] -2,4-dihydro-2-(2,2,2 - triptorelin)-3H-1,2,4-triazole-3-one; CIS-1-/4-/4-/4-[ [2-(2,4-differenl)-2-(1H-1,2,4-triazole-1-ylmethyl) -1,3-dihydro-3-(1-methylpropyl) -2H-imidazol-2-IT.

6. The antifungal composition consisting of the active ingredient and a physiologically acceptable excipient, characterized in that the active ingredient it contains an effective amount of compound 1 on PP. 1 - 5.

7. A method of combating fungi in warm-blooded animals by systemic or local injection of antifungal agents for the inhibition of the de the new tools use connection PP.1 - 5 in the amount of 0.001 - 5% mg/kg body weight.

8. The method of obtaining compounds on p. 1, characterized in that the O-alkylate the phenol of the formula

< / BR>
where Y has the value

alkylating reagent of the formula

D - CH2- W,

where W is a reactive tsepliaeva group, and D has formula

< / BR>
in a reaction-inert solvent in the presence of a base.

 

Same patents:

The invention relates to new derivatives of benzopyran that have protivogipertenzin activity and can be used in the treatment and prevention of cardiovascular diseases

The invention relates to compounds of the formula I

(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where

-A1= AND2- A3= AND4- bivalent radical having the formula

-CH=CH-CH=CH- (a-1)

-N=CH-CH=CH- (a-2)

-CH=CH-CH=N (a-5) or

-N=CH-N=CH- (and-6),

n=1 or 2

IN - NR4or CH2< / BR>
R4is hydrogen or C1-C6alkyl

L is hydrogen, C1-C6alkyl, C1-C6allyloxycarbonyl, or a radical of the formula

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Gwhere G2- CH=CH-CH=CH-, -S-(CH2)3,- -S-(CH2)/2-, -S-CH=CH - or-CH=C(CH3)-O-;

R6- C1-C6-alkyl, pyridinyl optionally substituted by nitro; pyrimidinyl; feast
R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;

R8- halophenol;

Y is O or NH;

Z1or Z2each independently NH or a direct link X-O

each Аlk independently - C1-C6alcander

The invention relates to optical active derivative triazolinones alcohol having optical activity (+), General formula (I):

(I) where X means a hydrogen atom or a chlorine atom, and the asterisk shows the asymmetric carbon atom, which can be used as a herbicide active ingredient

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< / BR>
(I) where X means a hydrogen atom or a chlorine atom, and the asterisk shows the asymmetric carbon atom, which can be used as fungicidal active ingredient

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The invention relates to new derivatives of 1-phenylimidazole formula 1

CFN< / BR>
where R represents a hydrogen atom or methyl;

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< / BR>
(I) where R1in position 4 means fluorine atom, chlorine or bromine, alkyl with 1-4 carbon atoms, cycloalkyl, vermeil, deformity or trifluoromethyl;

R2alkoxyl with 3-5 carbon atoms, substituted imidazolium in position 3, 4 or 5, alkoxyl with 2-5 carbon atoms, a substituted benzimidazole or tetrahydroimidazo in position 2, 3, 4 or 5, 2-(imidazol-1-yl)-ethoxyl provided that R4means 1H-tetrazolyl, alkylsulfonate with 1-4 carbon atoms, benzosulfimide or generalconclusions, unsubstituted or substituted at the nitrogen atom by alkyl with 1-6 carbon atoms, phenyl, cycloalkyl, phenylalkyl, cycloalkylation, bicyclohexyl or the biphenyl alluminare, in which the acyl radical is alkanoyl with 1-7 carbon atoms, alkoxycarbonyl with a total of 2-4 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, benzoyl, benzazolyl, generalkonsulin, naphthalenesulfonyl, cycloalkylcarbonyl, phenylalkanoic or Central electoral commissions substituents from the group includes fluorine atom, chlorine or bromine, methyl, methoxy, phthalimido, hemophthalmia, 2-carboxymethylamino or 2-carboxymethylamino, and one carbonyl group in phthalimidopropyl replaced by methylene, alkylamino or dialkylamino, one methylene group in hoofdlijnen may be substituted by one or two alkyl groups, and the phenyl nucleus may be optionally mono - or tizamidine the alkyl or alkoxyl, and the substituents may be the same or different and are wholly or partially gidrirovanny, unsubstituted or substituted by one or two alkyl groups or one tetramethylenebis or pentamethylene group 5-, 6 - or 7-membered, alkylamino or alkenylamine in which one methylene group may be replaced by a carbonyl or sulfonyl, imides bicycloalkyl-2,3-dicarboxylic acid and imine bicycloalkyl-2,3-dicarboxylic acid, where bicycloalkanes and bicycloalkanes part can contain 9 or 10 carbon atoms can be substituted by 1, 2 or 3 methyl groups, and endometrioma group may be replaced by oxygen atom, amidinopropane, unsubstituted or substituted by one or two alkyl groups is whether the two alkyl groups or tetramethylene or pentamethylene, maleinimide, unsubstituted or mono - or disubstituted by identical or different substituents from among alkyl and phenyl, linked through a carbon atom or aminogroup 5-membered heteroaromatic ring containing aminogroup, oxygen atom or sulfur, or aminogroup and atom oxygen, sulfur or nitrogen, or bound via a carbon atom of the 6-membered heteroaromatic ring containing 1 or 2 nitrogen atom, and mentioned heteroaromatic rings in the carbon skeleton may be substituted by alkyl with 1-6 carbon atoms or phenylalkyl to 5-membered and 6-membered heteroaromatic ring connected n-propylene, n-butylene or 1,3-butadienyl group via two adjacent carbon atom or n-propylene or n-butylene group through aminogroup and the adjacent carbon atom, resulting anilinophenol pyridine ring one methylene group may be replaced by a nitrogen atom, venelinova group in position 3 or 4 to the nitrogen atom of the formed pyridine ring with the sulfur atom, or formed anilinophenol phenyl ring by one or two methyl groups may be replaced by nitrogen atoms, and mentioned precondensation aromatic or heteroalkyl, alkoxyl, hydroxyl, phenyl, nitro, amino, alkylamino, dialkylamino, alkanolamine, cyano, carboxyla, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, formation, deformation, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, or tizamidine fluorine atoms or chlorine, stands, metaxylem or hydroxyl, and two methyl substituent can be connected to each other in position 1,2 via a methylene or ethylene bridge, and available if needed in the imidazole ring NH group may be substituted by an alkyl group with 1-6 carbon atoms, phenylalkyl or cycloalkyl; bound through a carbon atom pyrolidine, piperidine or pyridine ring, and the pyridine ring via two adjacent carbon atoms may be precondensation phenyl, and the neighboring nitrogen atom of the methylene group in pyrolidine or piperidinium the ring may be replaced by carbonyl, imidazolidinedione group, unsubstituted or substituted alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene, pyridazin-3-one and dihydropyridin-3-one, which is in position 2 can be substituted and,

the group R7-NR6CO NR5where R5a hydrogen atom, alkyl with 1-8 carbon atoms, cycloalkyl with 5-7 carbon atoms or phenylalkyl;

R6a hydrogen atom, alkyl with 1-8 carbon atoms, alkenyl with 3-5 carbon atoms, phenyl, phenylalkyl or cycloalkyl with 5-7 carbon atoms,

R7a hydrogen atom or alkyl with 1-6 carbon atoms,

one of the radicals R5, R6or R7may mean bicyclohexyl or diphenylol, R6and R7together with the enclosed nitrogen atoms means the unbranched alkalinising with 4-6 carbon atoms, or R5and R6ashamed mean alkylen with 2-4 carbon atoms, 1H, 3H-hinzelin-2,4-Dion-3-yl, pentamethylene-oxazoline-2-yl, or R1a hydrogen atom or is in position 5, 6 or 7 atoms fluorine, chlorine or bromine, an alkyl group with 1-4 carbon atoms, vermeil, deformity or trifluoromethyl; R2bound through a carbon atom or aminogroup 5-membered heteroaromatic ring containing aminogroup and the oxygen atom or sulfur, or aminogroup and atom oxygen, sulfur or nitrogen, or bound via a carbon atom of the 6-membered heteroaromatic ring containing 1 or 2 nitrogen atom, and said heteroaromatics and 6-membered heteroaromatic ring connected n-propylene, n-butylene or 1,3-butadienyl group via two adjacent carbon atom, or n-propylene or n-butylene group through aminogroup and the adjacent carbon atom, resulting anilinophenol pyridine ring one methine group may be replaced by a nitrogen atom, venelinova group in position 3 or 4 to the nitrogen atom formed piperidino ring sulfur atom, or formed anilinophenol phenyl ring, one or two methine groups may be replaced by nitrogen atoms, and mentioned precondensation aromatic or heteroaromatic rings in the carbon skeleton may additionally be monogamist fluorine atom, chlorine or bromine, the alkyl, alkoxyl, hydroxyl, phenyl, nitro, amino, alkylamino, dialkylamino, alkanolamine, cyano, carboxyla, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, formation, deformation, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, or tizamidine fluorine atoms or chlorine, stands, metaxylem or hydroxyl, and two methyl substituent can be connected to each other in position 1,2 via a methylene or ethylene my with 1-6 carbon atoms, phenylalkyl or cycloalkyl; bound through a carbon atom pyrolidine, piperidine or pyridine ring, and the pyridine ring via two adjacent carbon atoms may be precondensation phenyl, and the neighboring nitrogen atom of the methylene group in pyrolidine or piperidinium the ring may be replaced by carbonyl,

R3a hydrogen atom, an alkyl group with 1-5 carbon atoms in which one methylene group may be replaced by oxygen atom or sulfur, or cycloalkyl with 3-5 carbon atoms,

R4carboxyl, cyano, 1H-tetrazolyl, 1-triphenyl-methyl-tetrazolyl, alkoxycarbonyl with the total number of carbon atoms 2-5, alkanesulfonyl, arylsulfonamides, triftormetilfullerenov, and if nothing else is specified, then the above alcoolica, alkyl and CNS part can contain 1-3 carbon atoms, and cycloalkyl part of 3-7 carbon atoms, and moreover, if (a) R1a hydrogen atom, R3N-propyl and R4carboxyl, R2in position 6 does not mean 3-methylimidazo[4,5-b]pyridine-2-yl or 3-n-hexyl-imidazo[4,5-b]pyridine-2-yl, or if (b) R1a hydrogen atom, R3n-propyl or n-butyl and R41H-tetraza the sawdust and R4carboxyl, R2in position 5 or 6 does not mean 1-methylbenzimidazole-2-yl or 6 position 1H-butylbenzothiazole-2-yl, 1,5-dimethylbenzimidazole-2-yl or 1-methyl-5-trifluoromethyl-benzimidazole-2-yl, or if g) R1a hydrogen atom, R3n-butyl and R4carboxy or 1H-tetrazolyl, R2in position 6 does not mean 1-methylbenzimidazole-2-yl, or if d) R1a hydrogen atom, R3n-butyl and R4carboxyl, R2in position 6 does not mean benzimidazole-2-yl, mixtures of them 1-, 3-isomers or individual isomers and hydrates and salts, in particular their physiologically tolerated salts with inorganic or organic acids or bases which are used, for example, as antagonists of angiotensin II, the method of obtaining derivatives of benzimidazole containing the substances, medicinal product and method of its production

The invention relates to medicine, in particular to pharmacology and Oncology

The invention relates to new derivatives of benzimidazole, with a strong pharmacological action, as well as to intermediate compounds for their production
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