Method for preparing sulfamide-substituted imidazotriazinones

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of sulfamide-substituted imidazotriazinones represented by the general formula (I): Method involves interaction of compound of the formula (II): with sulfuric acid followed by treatment of synthesized substances with thionyl chloride and interaction with amine without their isolation to yield the end compound that is converted if necessary to the corresponding salts or hydrates. Method provides the development of a simple realization of synthesis of sulfamide-substituted imidazotriazinones in large-scale and high yield being without isolation of hydrolysis-sensitive imidazotriazinone sulfonyl chloride in intermediate step with exception of variations in yield at intermediate step of synthesis.

EFFECT: improved method of synthesis.

5 cl, 2 ex

 

This invention relates to well-known sulfamethoxine imidazo-triazinones, more specifically to a new method of obtaining them.

It is known that compounds that are able to inhibit metabolizing cyclic guanosin-3',5'-monophosphate phosphodiesterase (cGMP-PDE), can be used for the treatment of impotence (see, for example, European patent application EP-IN-0702555; Knigga, Drugs, News & Perspectives 6 (1993), 150).

In the international patent application WO 99/24433 described sulfamethoxine imidazolidinone capable of inhibiting one or several metabolizing cyclic guanosin-3',5'-monophosphate phosphodiesterase (cGMP-PDE). In accordance with the nomenclature Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11, 150-155, 1990) in the case of these cGMP-PDE we are talking about the isoenzymes of phosphodiesterase PDE-I and PDE-II and PDE-V

According to the international patent application WO 99/24433 described there sulfamethoxine imidazolidinone obtained from the corresponding 2-ethoxybenzylidene imidazolidinone by their interaction with chlor-sulphonic acid and the subsequent interaction with the appropriate amine, as illustrated by the following scheme (R1-R6are specified in WO 99/24433 values):

In this way as a highly reactive reagent is used chlorosulfonic acid. Furthermore, formed appromiately step imidazolidinecarboxamide susceptible to hydrolysis, that can lead, in particular in the implementation of this method on an industrial scale, to significant fluctuations in the yield of the target product.

Therefore, the present invention is to provide a method of obtaining sulfamethoxine imidazolidinone devoid of the disadvantages known from the prior art of the above process.

This object is achieved by eliminating the use of chloro-sulfonic acid by introducing into the reaction with sulfuric acid, sulfonic acid and subsequent interaction with thionyl chloride. In addition, interaction with thionyl chloride and subsequent interaction with the amine is carried out in one reactor so that at an intermediate stage do not emit susceptible to hydrolysis imidazolidinecarboxamide. As a result, the intermediate stage are excluded fluctuations in output due to partial hydrolysis. Thus these benefits provide a more simple implementation described in the present invention process on an industrial scale than in the international application WO 99/24433.

Thus, the object of the invention is a method for sulfamethoxine imidazolidinone formula (I)

in which

R1means a straight or branched alkyl containing up to 4 atoms is of Pereda,

R2means a straight alkyl containing up to 4 carbon atoms,

R3and R4together with the nitrogen atom form a residue of the formula

where

R7means a straight or branched alkyl containing up to 6 carbon atoms,

R5and R6may be the same or different and denote hydrogen or straight or branched alkoxy containing up to 6 carbon atoms,

which lies in the fact that the compound of formula (II)

where

R1, R2, R5and R6have the above values,

subjected to the interaction of sulfuric acid with the formation of the compounds of formula (III)

where

R1, R2, R5and R6have the above values,

with its subsequent interaction with thionyl chloride, and the thus obtained product without allocation (in situ) in an inert solvent is subjected to interaction with the amine of formula (IV)

where

R3and R4have the above meaning,

and also, if necessary, transferred to salt or hydrates.

According to a preferred form of execution of this invention, the reactants and the final products have the following values:

R1means direct or rasvet is by alkyl, containing up to 4 carbon atoms,

R2means a straight alkyl containing up to 4 carbon atoms,

R3and R4together with the nitrogen atom form a residue of the formula

where

R7means a straight or branched alkyl containing up to 4 carbon atoms,

R5and R6may be the same or different and denote hydrogen or straight or branched alkyl containing up to 6 carbon atoms.

According to another preferred form of execution of this invention, the reactants and the final products have the following values:

R1means hydrogen or a straight or branched alkyl containing up to 4 carbon atoms,

R2means a straight alkyl containing up to 4 carbon atoms,

R3and R4together with the nitrogen atom form a residue of the formula

where

R7means methyl or ethyl,

R5and R6may be the same or different and denote hydrogen or straight or branched alkoxy containing up to 6 carbon atoms.

In particular, the above reactants and the final products of the proposed method have the following meanings:

R1means methyl or ethyl,

R2means n-propyl,

R3and R4together with the nitrogen atom form a residue of the formula

<>

where

R7means methyl or ethyl,

R5means hydrogen,

R6means ethoxy.

In accordance with the invention as a solvent to separate stages of the process using conventional organic solvents which do not change under the reaction conditions. These include ethers, preferably diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, or a hydrocarbon, such as benzene, toluene, xylene, hexane, cyclohexane or oils or kalogeropoulou, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethylene or chlorobenzene, or an ester of acetic acid, dimethylformamide, triamide hexamethylphosphoric acid, acetonitrile, acetone, dimethoxyethane or pyridine. You can also use mixtures of the mentioned solvents.

Especially, it is preferable to carry out the interaction of the compounds of the formula (II) with sulfuric acid without solvent with subsequent interaction of the reaction mass with thionyl chloride mainly without solvent and carrying out the subsequent reaction with the amine of formula (IV) in xylene.

In accordance with the invention the reaction temperature at different stages of the process may vary in a wide interval. Mainly working in the field from mine is 20° With up to 200°C, preferably from 0°C to 70°C.

In accordance with the invention stage of the process carried out mainly at normal pressure. You can also hold them at elevated pressure or at reduced pressure (for example, in the range from 0.5 to 5 bar).

In accordance with the invention in the first stage of the process, sulfuric acid is used in excess, for example in the 2-20-fold excess, mainly in the 2 to 10-fold excess, relative to 1 pray the compounds of formula (II).

In the second stage of the process in accordance with the invention thionyl chloride is used in excess, for example in the 2-20-fold excess, mainly in the 5-15-fold excess relative to 1 pray the compounds of formula (III). The amine (IV) is administered in equimolar amounts or in excess, for example, 2 to 10-fold excess, mainly in 2-5-fold excess relative to 1 pray the compounds of formula (III).

The interaction of the compounds of formula (III) with thionyl chloride occurs mainly in the presence of catalytic amounts of a base, with a catalytic amount you should understand much smaller number of reasons (for example, at least more than ten times) compared with the reagents. As the grounds are suitable mainly cyclic amines, such as piperidine, pyridine, 4-N,N-dimethylaminopyridine, or alkylamines followed with 1-4 atoms is carbon, as, for example, triethylamine, or, preferably, amides, such as N,N-dimethylformamide or N,N-dibutylformamide. Particularly preferred N,N-dimethylformamide.

The compounds of formula (II) can be obtained as described in international patent application WO 99/24433 manner by reacting compounds of the formula (V)

in which

R1and R2have the above significance and

L means a straight or branched alkyl containing up to 4 carbon atoms,

with a compound of General formula (VI)

in which

R5and R6have the above value.

This reaction can be conducted either as described in the international patent application WO 99/24433 in two stages in the system ethanol and oxytrichloride phosphorus/dichloroethane, or mainly according to the invention in two stages in a single reactor systems methanol and oxytrichloride phosphorus/acetic acid or, especially preferably, methanol and acetylchloride/acetic acid.

As the solvent for this reaction using conventional organic solvents which do not change under the reaction conditions. These include ethers, preferably diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, or a hydrocarbon, such as benzene, then the Wal, xylene, hexane, cyclohexane or oils or galvanoplastic, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethylene or chlorobenzene, or alcohols, such as methanol, ethanol, n-propanol, isopropanol or p-butanol, or an ester of acetic acid, acetonitrile, acetone, dimethoxyethane or pyridine, or an acid, for example acetic acid. You can also use mixtures of the mentioned solvents. For the first stage in accordance with the invention, the preferred alcohols, especially methanol, and for the second stage will use either dichloroethane (as described in the international patent application WO 99/24433), or particularly preferably acetic acid.

In this reaction temperature can vary in a wide interval. Mainly working in the field of -20°to 200°C, preferably from 0°C to 70°C.

This reaction is generally performed under normal pressure. You can also hold it at an elevated pressure or at reduced pressure (for example, in the range from 0.5 to 5 bar).

The reagents used in this reaction as the original products. Depending on the properties of the reagents can be used in equimolar amounts or with an excess of one of the reactants.

The compounds of formula (V) partially known or can be obtained according to the international patent application WO 9/24433 by the interaction of the compounds of General formula (VII)

in which

R2have the above significance and

T denotes halogen, mainly chlorine,

with a compound of General formula (VIII)

in which

R1has the above value

optionally, in inert solvents, optionally in the presence of a base and/or trimethylchlorosilane, to obtain the compounds of General formula (IX)

in which

R1and R2has the above value,

and the subsequent interaction with a compound of formula (X)

where

L has the above value,

in inert solvents, optionally in the presence of a base.

As a solvent to separate stages of the process using conventional organic solvents which do not change under the reaction conditions. These include ethers, preferably diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, or a hydrocarbon, such as benzene, toluene, xylene, hexane, cyclohexane or oils or kalogeropoulou, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethylene or chlorobenzene, or an ester of acetic acid, dimethylformamide, triamide GE is somethingstore acid, acetonitrile, acetone, dimethoxyethane or pyridine. You can also use mixtures of the mentioned solvents.

Especially preferred for the first stage is to carry out the interaction of the compounds of formula (VII) with the compound of the formula (VIII) in dichloromethane or process without an inert solvent in the presence of a base, preferably a hydroxide of an alkaline or alkaline earth metal, particularly preferably sodium hydroxide solution as a solvent.

For the second stage of the process, preferably the reactions of compounds of formula (IX) with the compound of the formula (X) in a mixture of tetrahydrofuran and pyridine.

As grounds mainly suitable cyclic amines, such as piperidine, pyridine, dimethylaminopyridine or alkylamines followed with 1-4 carbon atoms, such as, for example, triethylamine. Preferred triethylamine, pyridine and/or dimethylaminopyridine.

The base is used generally in an amount of from 1 to 5 mol equivalents, preferably 1 to 3 mol equivalents relative to the reactants.

The reaction temperature may vary within a wide range. Mainly working in the field of -20°to 200°C, preferably from 0°to 100°C.

The compounds of formula (VII), (VIII) and (X) are known or can be obtained by methods known in the art, for example, according to the SNO described in the international patent application WO 99/24433 processes.

The compounds of formula (VII) and (VIII) are used depending on the properties of the reactants in equimolar amounts or with an excess of one of the reactants.

The compounds of formula (VII) and (VIII) are used depending on the properties of the reactants in equimolar amounts or with an excess of one of the reagents. Predominantly the compound of formula (X) used in the 1.5-5-fold excess.

The compounds of formula (VI) can be obtained in various ways. For example, you can get them according to the international patent application WO 99/24433 by the interaction of the compounds of General formula (XI)

in which

R5and R6have the above meaning,

with ammonium chloride in toluene in the presence of trimethylaluminum in hexane at a temperature of from -20°C to room temperature, mainly at 0°C and normal pressure and subsequent interaction formed of amidine if necessary, without selection (in situ), with hydrazinehydrate.

Compounds of General formula (XI) by themselves are known or can be obtained by conventional methods. For example, get them, according to the international patent application WO 99/24433 from the corresponding phenol derivatives by interesterification. It is also possible the engagement of the respective benzamido in an inert organic solvent such as toluene, t is analgorithm when heated, for example, 50-100°mainly 70-100°With formation of compounds of formula (XI).

In addition, the compounds of formula (VI) can also be obtained by the interaction of the compounds of formula (XI) in the presence of a base in an inert organic solvent with hydroxylamine hydrochloride to form compounds of the formula (XII)

where

R5and R6have the above meaning,

with the subsequent recovery in an organic solvent to compounds of the formula (XIII)

where

R5and R6have the above meaning,

which then interact with hydrazinehydrate if necessary, without selection (in situ), translated into compounds of the formula (VI).

As solvents for these reactions are suitable ordinary organic solvents which do not change under the reaction conditions. To them mainly belong alcohols, such as methanol, ethanol or isopropanol, ethers, such as diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, or a hydrocarbon, such as benzene, toluene, xylene, hexane, cyclohexane or oils or kalogeropoulou, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethylene or chlorobenzene, or an ester of acetic acid, dimethyl rmaed, triamide hexamethylphosphoric acid, acetonitrile, acetone, dimethoxyethane or pyridine or acetic acid. You can also use mixtures of the mentioned solvents.

Especially preferably the conversion of compounds of formula (XI) in the compounds of formula (XII) in isopropanol. The conversion of compounds of formula (XII) in the compounds of formula (XIII) is particularly preferably carried out in acetic acid. The subsequent interaction of the compounds of formula (XIII) with hydrazinehydrate particularly preferably in methanol. These reactions are carried out mainly at normal pressure. You can also hold them at elevated pressure or at reduced pressure (for example, in the range from 0.5 to 5 bar).

The reaction temperature can vary in a wide interval. Mainly working in the field of -20°to 200°C, preferably from 0°to 100°C.

The conversion of compounds of formula (XI) to compounds of formula (XII) is carried out in the presence of a base. As bases are suitable, in particular, cyclic amines, such as piperidine, pyridine, dimethylaminopyridine, or alkylamines followed with 1-4 carbon atoms, such as, for example, triethylamine. Preferred triethylamine. The base is used generally in an amount of from 1 mole to 4 moles relative to 1 pray the compounds of formula (XI), respectively.

The no is the compounds of formula (XII) to compounds of formula (XIII) can be carried out with conventional for such reactions with reducing agents with well-known specialist conditions. Particularly preferably restoration by hydrogenation in the presence of a catalyst such as palladium on charcoal, in acetic acid.

Depending on the properties of the reagents, the compounds of formula (XI) and hydroxylamine hydrochloride, and accordingly, the compounds (XIII) and hydrazinehydrate used in equimolar amounts or hydroxylamine hydrochloride, and accordingly hydrazinehydrate used in excess.

Compounds of the invention are inhibitors metabolizing cyclic guanosin-3',5'-monophosphate phosphodiesterase (cGMP-PDE) and is described in the international patent application WO 99/24433.

The invention is illustrated by the following, not limiting the scope of invention preferred and comparative examples.

Unless otherwise noted, all listed quantities are mass percent.

Examples

1H-NMR spectra were taken on the spectrometer SY WP-200 Bruker) at room temperature. As a solvent used deuterated dimethylsulfoxide or deuterochloroform with tetramethylsilane was as an internal standard (if not noted otherwise).

Mass spectra were taken on the spectrometer 40 M company AMD and API 150 company PE/SCIEX. Specify the relative intensity of the signal (in percent relative to the base peak).

An analytical study was conducted with what omashu high-speed column liquid chromatography (SGH) on the chromatograph HP 1090 Hewlett Packard. The exact conditions are given in the examples.

The source connections

Example I: Getting 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo-[5,1-f][1,2,4]triazine-4-it

Ia) Obtaining 2-bouteillerie acid

A solution of 100 kg D,L-alanine in aqueous caustic soda solution is subjected to interaction with 119 kg harpalani acid in the cold. After adding butyl acetate, acidified with hydrochloric acid, the organic phase is separated and extracted with aqueous phase. The organic phase is dried by azeotropic distillation. Crystallized was separated, washed with butyl acetate and dried.

Output: to 132.6 kg (68%)

1H-NMR: δ=0,8 (t, 3H), of 1.25 (d, 3H), 1,5 (m, 2H), 2,1 (t, 2H), 4.2V (q, 1H), 8,1 (d, NH), 12,0-12,7 (s, COOH)

MC: 336 (2M+NH4, 40), 319 (2M+H, 15), 177 (M+NH4, 100), 160 (M+N, 20)

Ib) Obtaining 2-ethoxybenzonitrile

To a suspension of 250 kg 2-ethoxybenzene in toluene at 85-95°add 260 kg of thionyl chloride by dispensing. The reaction mixture was stirred under heating. Then distilled thionyl chloride and toluene in a vacuum. The product is used as starting material in the next stage.

Output: 228,5 kg (the original product)

1H-NMR: δ=1,45 (t, 3H), 4,15 (q, 2H), 7,0 (m, 2H, phenyl), and 7.5 (m, 2H, phenyl)

MC: 312 (2M+NH4, 35), 165 (M+NH4, 100), 147 (5)

Ic) Obtaining 2-ethoxy-N-hydroxybenzamide

111 kg 2-Ethoxybenzonitrile (original product) of example Ib is heated 164 l of triethylamine and 73 kg of hydroxylamine hydrochloride in isopropanol under reflux. The reaction mixture is mixed with water and cooled. Crystallized separated, washed and used as crude product in the next stage.

Output: 92,6 kg (wet product)

1H-NMR: δ=1,35 (t, 3H), 4,1 (q, 2H), 5,6 (s, 2H), from 6.9 to 7.4 (4H, phenyl), and 9.4 (s, 1H, OH)

MS: 361 (2M+N, 30), 198 (M+NH4, 30), 181 (M+H, 100)

Id) Obtaining 2-ethoxybenzylidene-hydrochloride

135 kg 2-Ethoxy-N-hydroxybenzamide (crude product from example Ic hydronaut in acetic acid in the presence of palladium on coal as a catalyst at 50-60°C. the Reaction product is freed from the catalyst, is mixed with hydrochloric acid and concentrated. The remaining acetic acid and water are removed by azeotropic distillation with toluene. Crystallized separated and dried in vacuum.

Output: to 136.4 kg

H-NMR: of 1.35 (t, 3H), 4,15 (q, 2H), and 7.1 to 7.7 (m, 4H, phenyl), from 9.1 to 9.4 (2×s, 3H), of 0.5 to 10.7 (s, 1H)

MS: 329 (2M+N, 10), 165 (M+H, 100)

Ie) Obtaining 2-(-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-it

231 kg 2-Bouteillerie acid from example Ia mixed in tetrahydrofuran with 341 kg of pyridine, a catalytic amount of 4-N,N-dimethyl-aminopyridine and 392 to the of atillaatalay and stirred while heating under reflux. The reaction mixture was diluted in ethyl acetate, washed with water and concentrate an ethyl acetate phase. The residue from the distillation is dissolved in methanol and mixed with the following solution.

192 kg 2-Ethoxybenzylidene-hydrochloride from example Id mix in methanol from 47.5 kg of hydrazine hydrate is added and stirred at room temperature. The solution is combined with vyshepredstavlennyh solution propenyl-ethyl ester 2-Butylimino-1-etoxycarbonyl-oxalic acid. Thus obtained reaction mixture is stirred while heating under reflux. The methanol is removed by distillation and mixed with acetic acid.

Option a:

Add 138,6 kg of phosphorus oxychloride and stirred under heating. Acetic acid is distilled off in vacuum. The residue is mixed with water and dichloro-methane, or optionally a mixture and neutralized with sodium hydroxide solution. The organic phase is concentrated and the residue is dissolved in acetone and crystallized by cooling. Crystallized separated, washed and dried.

Option B:

Add a minimum of 190 kg acetylchloride and stirred under heating. Acetic acid is distilled off in vacuum. The residue from the distillation is mixed with acetone and water and the product is crystallized by neutralizing with sodium hydroxide solution. The product is separated, washed and dried.

Output: 90-160 kg

1 H-NMR: δ=1,0 (t, 3H), 1,6 (t, 3H), and 1.9 (m, 2H), and 2.8 (s, 3H), 3,3 (t, 2H), 4,3 (q, 2H), 7,0-8,2 (Ar, 4H), 10,3 (CONH, 1H)

MS: 313 (M+H, 100), 149 (25), 151 (40), 121 (15)

SGH: Phase Kromasil C-18, a neutral phosphate buffer, acetonitrile, 233 nm, linear gradient 30% acetonitrile ->80% acetonitrile (30 min): 99 FI.% (Rt19,1)

Examples of production

Example 1a: 4-Ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazine-2-yl)-benzolsulfonat acid

194 kg 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-1][1,2,4]triazine-4-she's from example Ie mixed with 504 kg of concentrated sulfuric acid. To the reaction mixture, water is added, cooled, crystallized separated and dried in vacuum.

Output: 195,2 kg

1H-NMR: δ=of 0.95 (t, 3H)and 1.3 (t, 3H), 1.8 m (m, 2H), and 2.6 (s, 3H), 3,05 (t, 2H), 4,1 (q, 2H), 7,15 (Ar, 1H), to 7.75 (m, 2H), 12,3 (SO2OH)

MS: 393 (M+H, 100), 365 (25), 151 (40)

SGH: Phase X-Terra C-18, aqueous phosphoric acid, acetonitrile, 242 nm, a linear gradient of 10% acetonitrile ->90% acetonitrile (20 minutes): 98 FI. % (Rt9,2)

Example 1b): 2-[2-ethoxy-5-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-one

22.5 kg 4 Ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazine-2-yl)-benzosulfimide acid from example 1a is mixed with 74 kg of thionyl chloride and catalytic amounts of dimethylformamide until the termination of the generation of gas. To R the promotional mix add xylene and distilled thionyl chloride. To the suspension is added to 15.1 kg N-ethylpiperazine and mix. After adding water hydrochloric acid to bring the pH to 1 and the phases are separated. The aqueous phase is diluted with acetone and neutralized with sodium hydroxide solution. The mixture is cooled, crystallized separated, washed and dried in vacuum.

Output: 26,1 kg

1H-NMR: δ=1,0 (2xt, 6H), 1,6 (t, 3H), and 1.9 (m, 2H), 2,45 (q, 2H), by 2.55 (m, 4H), to 2.65 (s, 3H), 3,0 (t, 2H), 3,1 (m, 4H), 4,35 (q, 2H), 7,15 (Ar, 1H), 7,9 (Ar, 1H), 8.4 (Ar, 1H), 9.8 (CONH)

MS: 489 (M+H, 100), 345 (10), 313, (10), 285 (10), 113 (20)

SGH: Phase X-Terra C-18, a neutral phosphate buffer, acetonitrile, 242 nm, a linear gradient of 20% acetonitrile ->75% acetonitrile (20 minutes): 98 FI.% (Rt16,3)

1C) 2-[2-Ethoxy-5-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-one-hydrochloride-trihydrate

22.5 kg of 2-[2-Ethoxy-5-(4-ethyl-piperazin-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-she's from example 1b is dissolved in a 5.1 kg of concentrated hydrochloric acid and acetone/water (12:1 V/V) by heating. A clear solution is subjected to hot filtration and crystallized using the seed and cooling. Crystallized separated, washed and dried in vacuum at about 30°and about 300 mbar.

Output: 25,4 kg

MP. (VHI): 192°

SGH: Phase X-Terra C-18, a neutral phosphate buffer, acetonitrile, 242 nm, a linear gradient of 20% acetonitrile ->75% acetonitrile(20 minutes): 99 FI.% (R t16,3)

1. The method of obtaining sulfamethoxine imidazolidinone formula (I)

in which R1means hydrogen or a straight or branched alkyl containing up to 4 carbon atoms;

R2means a straight alkyl containing up to 4 carbon atoms;

R3and R4together with the nitrogen atom form a residue of the formula

where R7means a straight or branched alkyl containing up to 6 carbon atoms,

R5and R6may be the same or different and denote hydrogen or straight or branched alkoxy containing up to 6 carbon atoms,

characterized in that the compound of formula (II)

where R1, R2, R5and R6have the above values,

subjected to the interaction of sulfuric acid with the formation of the compounds of formula (III)

where R1, R2, R5and R6have the above values,

with its subsequent interaction with thionyl chloride, and the thus obtained product without selecting the inert solvent is subjected to interaction with the amine of formula (IV)

where R 3and R4have the above values,

and also, if necessary, transferred to salt or hydrates.

2. The method according to claim 1, in which obtain the compounds of formula (I), in which

R1means a straight or branched alkyl containing up to 4 carbon atoms;

R2means a straight alkyl containing up to 4 carbon atoms;

R3and R4together with the nitrogen atom form a residue of the formula

where R7straight or branched alkyl containing up to 4 carbon atoms,

R5and R6may be the same or different and denote hydrogen or straight or branched alkoxy containing up to 6 carbon atoms.

3. The method according to claim 1, in which obtain the compounds of formula (I), in which

R1means hydrogen or a straight or branched alkyl containing up to 4 carbon atoms;

R2means a straight alkyl containing up to 4 carbon atoms;

R3and R4together with the nitrogen atom form a residue of the formula

where R7means methyl or ethyl;

R5and R6may be the same or different and denote hydrogen or straight or branched alkoxy containing up to 6 carbon atoms.

4. The method according to claim 1, which produces the t of the compounds of formula (I), in which

R1means methyl or ethyl;

R2means n-propyl;

R3and R4together with the nitrogen atom to the remainder of formula

where R7means methyl or ethyl;

R5means hydrogen;

R6means ethoxy.

5. The method according to claim 1, characterized in that compounds of the formula (II) are obtained by reacting compounds of the formula (V)

in which R1and R2have specified in claim 1; and

L means a straight or branched alkyl containing up to 4 carbon atoms,

with a compound of General formula (VI)

in which R5and R6have specified in claim 1 value

in two stages in the systems methanol and oxytrichloride phosphorus/acetic acid or methanol and acetylchloride/acetic acid.



 

Same patents:

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel condensed derivatives of imidazole that are inhibitors of dipeptidyl peptidase IV. Invention describes compound represented by the following formula (I): or its salt or hydrate wherein T1 represents monocyclic 5-6-membered heterocyclic group comprising one or two nitrogen atoms in ring that can comprise one or more amino-groups as substitutes; X represents (C2-C6)-alkenyl group that can comprise one or more substitutes, (C2-C6)-alkynyl group, phenyl group that can comprise one or some substitutes chosen from alkyl group or halogen atom or phenyl-(C1-C6)-alkyl group; each Z1 and Z2 represents independently nitrogen atom or group of the formula -CR2=; each R1 and R2 represents independently group of the formula -A0-A1-A2 wherein A0 represents a single bond or (C1-C6)-alkylene group that can comprise 1-3 substitutes chosen from group B consisting of given below substitutes; A1 represents a single bond, oxygen atom, sulfur atom, sulfinyl group, sulfonyl group, carbonyl group, group represented by formula -O-CO-, group represented by formula -CO-O-, group represented by formula -NRA-, group represented by formula -CO-NRA-, group represented by formula -NRA-CO-, group represented by formula -SO2-NRA-, or group represented by formula -NRA-SO2-; each A2 and RA represents independently hydrogen atom, halogen atom, cyano-group, (C1-C6)-alkyl group, (C3-C8)-cycloalkyl group, (C2-C6)-alkenyl group, (C2-C6)-alkynyl group, (C6-C10)-aryl group, 5-10-membered heteroaryl group, 4-8-membered heterocyclic group, 5-10-membered heteroaryl-(C1-C6)-alkyl group, (C6-C10)-aryl-(C1-C6)-alkyl group or (C2-C7)-alkylcarbonyl group wherein each A2 and RA can comprise independently 1-3 substitutes chosen from the given below group of substitutes D: when Z2 represents group of the formula -CR2= then R1 and R2 can form in common 5-7-membered ring with exception cases when: [1] R1 represents hydrogen atom; Z1 represents nitrogen atom, and Z2 represents group -CH=; and [2] Z1 represents nitrogen atom and Z2 represents group -C(OH)=; <group of substitutes B>. Group of substitutes B represents group comprising: hydroxyl group, mercapto-group, cyano-group, nitro-group, halogen atom, trifluoromethyl group, (C1-C6)-alkyl group that can comprise one or some substitutes, (C3-C8)-cycloalkyl group, (C2-C6)-alkenyl group, (C2-C6)-alkynyl group, (C6-C10)-aryl group, 5-10-membered heteroaryl group, 4-8-membered heterocyclic group, (C1-C)-alkoxy-group, (C1-C6)-alkylthio-group, group represented by formula -SO2-NRB1-RB2, group represented by formula -NRB1-CO-RB2, group represented by formula -NRB1-RB2 (wherein each RB1 and RB2 represents independently hydrogen atom or (C1-C6)-alkyl group), group represented by formula -CO-RB3 (wherein RB3 represents 4-8-membered heterocyclic group), group represented by formula -CO-RB4-RB5, and group represented by formula -CH2-CO-RB4-RB5 wherein RB4 represents a single bond, oxygen atom or group represented by formula -NRB6- wherein each RB5 and RB6 represents independently hydrogen atom, (C1-C6)-alkyl group, (C3-C8)-cycloalkyl group, (C2-C6)-alkenyl group, (C2-C6)-alkynyl group, (C6-C10)-aryl group, 5-10-membered heteroaryl group, 4-8-membered heterocycle-(C1-C6)-alkyl group, (C6-C10)-aryl-(C1-C6)-alkyl group or 5-10-membered heteroaryl-(C1-C6)-alkyl group. Also, invention describes inhibitor, pharmaceutical composition, method of treatment and using based on thereof. Invention describes novel compounds possessing useful biological properties.

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

33 cl, 3 tbl, 352 ex

FIELD: organic chemistry, heterocyclic compounds, medicine.

SUBSTANCE: invention relates to dihydropyrimidine compounds of the formula (I*): their enantiomers, diastereoisomers and pharmaceutically acceptable salts wherein X1, X2 and X3 in common with atoms to which they are added form ring of the formula: or ; R1 represents hydrogen atom; R2, R3*, R4, R5, R6 and R7 have values given in cl. 1 of the invention claim. Also, invention relates to separate dihydropyrimidine compounds. Proposed compounds are inhibitors of calcium channel function being especially inhibitors of Kv1 subfamily of potential-overlapping K+-channels and especially inhibitors of Kv 1.5 that associated with super-rapid activating delayed cleaning K+-flow of Ikur and can be used in treatment of arrhythmia and Ikur-associated diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 589 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for improved synthesis of pharmacologically active compound of the formula (A): Method involves the following steps: (a) interaction of compound of the formula (I): with alkaline metal nitrite in the presence of suitable acid to yield compound of the formula (VII): (b) coupling compound of the formula (VII) with compound of the formula (VI): to yield compound of the formula (V): and (c) removal of protection from compound of the formula (V) to yield compound of the formula (A). Compound of the formula (A) possesses property of antagonist of R2T receptors, high metabolic stability and bioavailability. Also, invention relates to a novel intermediate substance of the formula (I) and methods for its synthesis, and to novel intermediate substances used in its synthesis.

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

12 cl, 4 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to biologically active compounds and concerns the development of a novel substance - 2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazine-7-(4H)-one sodium salt dihydrate of the formula: . This compound is designated for treatment and prophylaxis of diseases caused by viruses that are pathogenic form humans and animals. Proposed compound protects against infections caused by Rift Valley fever virus. Also, it shows activity against viruses of WEE(West Equine Encephalomyelitis), parainfluenza, respiratory-syncytium, Aujeszky's disease virus, avian infectious laryngotracheitis virus, avian influenza virus - totally against above 10 RNA- and DNA-containing viruses. The proposed compound is active in curative schedule of its using that is especially valuable.

EFFECT: valuable medicinal properties of compound.

1 cl, 6 tbl, 2 dwg, 7 ex

FIELD: organic chemistry, medicine, cardiology, pharmacy.

SUBSTANCE: invention relates to novel 3,7-diazabicyclo[3.3.0]octanes of the formula (I): wherein wavy lines mean the possible relative cis- or trans-stereochemistry; R means (C1-C12)-alkyl (possibly substituted and/or terminating by one or more groups chosen from aryl, Het1, -C(O)R5a, -OR5b, -N(R6)R5c, -C(O)XR7, -C(O)N(R8)R5d and -S(O)2R9), Het2, -C(O)R5a, -C(O)XR7 or -S(O)2R9 wherein R5a - R5d in each case mean independently hydrogen atom (H), (C1-C6)-alkyl (possibly substituted and/or terminating by one or more substitute chosen from -OH, (C1-C6)-alkoxy-group, cyano-group, aryl, Het3 and -NHC(O)R10), aryl or Het4; R10means H, (C1-C4)-alkyl; R6 means H, aryl; X means oxygen atom (O); R7 means in each case (C1-C12)-alkyl (wherein alkyl group can be substituted and/or terminating by one substitute chosen from -OH, cyano-group, (C1-C6)-alkoxy-group, -SO2R13a, -C(O)R13b and Het5) wherein R13a and R13b mean independently (C1-C6)-alkyl; R8 means in each case H, (C1-C12)-alkyl, (C1-C6)-alkoxy-group (wherein two latter groups are substituted possibly and/or terminating by one substitute chosen from -OH, (C1-C4)-alkyl and (C1-C4)-alkoxy-group), -D-aryl, -D-Het6, -D-S(O)2R15a wherein R15a means independently aryl; D means a direct bond or (C1-C6)-alkylene; R9 means in each case (C1-C6)-alkyl (possibly substituted and/or terminating by one substitute chosen from aryl) or aryl; R2 means H, -E-OR16, -E-N(R17)R18 or in common with R3 represent =O; R3 means H or in common with R2 represent =O; R16 means H, (C1-C6)-alkyl or -E-aryl; R17 means H; R18 means H; E means in each case a direct bond or (C1-C4)-alkylene; A means -G-; B means -Z-, -Z-N(R22)-Z-, -Z-S(O)n-. -Z-O- (wherein in two latter groups Z is bound to carbon atom carrying R2 and R3); G means a direct bond or (C1-C6)-alkylene; Z means a direct bond or (C1-C4)-alkylene; R22 means independently H; R4 means aryl or het13 wherein both these groups are substituted possibly with one or more substitute chosen from -OH, cyano-group, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -C(O)R24c or -S(O)nR23c; Het13 means 5-6-membered heterocyclic group comprising one or more heteroatoms chosen from oxygen, nitrogen and/or sulfur; Het1 - Het6 in each case mean independently 5-6-membered heterocyclic groups comprising one or more heteroatoms chosen from oxygen, nitrogen and/or sulfur wherein these heterocyclic groups are substituted possibly with one or more substitutes comprising (C1-C6)-alkyl or -C(O)R24c wherein R23c means in each case independently (C1-C6)-alkyl; R24c means in each case H or (C1-C6)-alkyl; n means 0, 1 or 2 in each case; Ra - R1 mean independently H or (C1-C4)-alkyl wherein each aryl or aryloxy-group (if not indicated otherwise) is substituted possibly with one or more substitutes chosen from -OH, cyano-group, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -C(O)R24c or -S(O)nR23c; or it pharmaceutically acceptable derivative under condition that: (a) when R2 means -E-OR16 or -E-N(R17)R18 wherein E means a direct bond then: (1) A can't mean a direct bond; and (2) B doesn't mean -N(R22)-, -S(O)n-. -O- or -N(R22)-Z- (wherein in the latter group -N(R22) is bound to carbon atom carrying R2 and R3; (b) this compound is not 3,7-bis-(1-phenylethyl)-3,7-diazabicyclo[3.3.0]octane, 3-methyl-7-benzyl-3,7-diazabicyclo[3.3.0], 3-cyclohexyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(thiazol-2-yl)-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(2-pyrimidyl)-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(5,5-dimethoxy)pentyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane; (c) when R in common with R3 represent =O, and B means -Z-N(R22)- or -N(R22)-Z- then G is not a direct bond. Compounds of the formula (I) can be used as components of a pharmaceutical composition in treatment or prophylaxis of arrhythmia. Also, invention describes methods for its synthesis and intermediate compounds used in these methods.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

38 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes a novel compound 4-(2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl)[1,5-a]-1,3,5-triazine of the formula (I):

, its steroisomeric forms or pharmaceutically acceptable salts, pharmaceutical composition comprising thereof and its using for preparing pharmaceutical composition used in treatment of anxiety in mammals.

EFFECT: valuable medicinal property of compound and pharmaceutical composition.

7 cl, 2 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and its pharmaceutically acceptable salts possessing properties of tumor necrosis factor (TNF-α) and to pharmaceutical composition based on thereof wherein R1 means substituted or unsubstituted phenyl wherein substitutes are chosen from halogen atoms or halide-(C1-C6)-alkyl; R4b is substituted or unsubstituted with 1-3 aryl substituted chosen from phenyl, naphthyl wherein substitutes are chosen from halogen atoms, (C1-C6)-alkyl, halide-(C1-C6)-alkyl, (C1-C6)-alkoxyl, cyano-, amino-, (C1-C6)-acylamino-group, (C1-C6)-alkanesulfonyl, or two adjacent substitutes in benzene ring form dioxol group, or unsubstituted or substituted 6-membered nitrogen-containing heteroaryl with 1-3 nitrogen atoms in ring wherein substitutes are chosen from halogen atoms.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 9 sch, 10 tbl, 15 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel pyrimidotriazines of the general formula (I):

wherein each R1 and R2 is chosen from the group comprising hydrogen atom, or R1 and R2 form in common chemical bond, -CH2-Ar and Ar is chosen from the group comprising unsubstituted phenyl, unsubstituted naphthyl, phenyl, mono- or disubstituted with (lower)-alkoxy-group and naphthyl mono- or disubstituted with (lower)-alkyl, or their pharmaceutically acceptable salts. Also, invention relates to a method for synthesis of these compounds, pharmaceutical composition based on thereof and to using novel pyrimidotriazines for prophylaxis and/or treatment of diabetes mellitus as these compounds possess the strong expressed inhibitory effect on activity of protein tyrosine phosphatase PTP1B.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 27 ex

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention relates to an agent used against acid-resistant microorganisms containing derivative of pyridone carboxylic acid as an active component, its pharmaceutically acceptable salt or its hydrate that elicits high antibacterial activity against Mycobacterium tuberculosis and atypical acid-resistant microorganisms. Invention describes agent used against acid-resistant microorganisms containing compound represented by the following formula (I) its salt or its hydrate as an active component wherein R1 represents cyclic alkyl group comprising 3-6 carbon atoms that can comprise substitute(s) chosen from halogen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; A1 represents incomplete structure represented by the formula (2): wherein X2 represents halogen atom, alkyl group comprising 1-6 carbon atoms or alkoxy-group comprising 1-6 carbon atoms; A1, A2 and A3 form incomplete structure of the formula: in common with carbon atoms combined with them; X1 represents halogen atom; Y represents hydrogen atom; Z represents phenylpiperazine substitute. Invention provides synthesis of pyridone carboxylic acid eliciting high antibacterial activity against Mycobacterium tuberculosis and atypical acid-resistant microorganisms in combination with good pharmacokinetics indices and safety.

EFFECT: valuable biological property of agent.

10 cl, 9 tbl, 10 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to group of novel derivatives of 4,5-dihydro-1H-pyrazole and their stereoisomers that are strong antagonists of cannabinoid (CB1) receptors. These compounds are useful in treatment of some diseases associated with cannabinoid system disorders. Compounds have the general formula (I) wherein R represents phenyl or thienyl substituted with halogen atom, or R represents pyridyl; R1 represents phenyl that can be substituted with 1-2 substitutes chosen from halogen atom and trifluoromethyl group; R2 represents hydrogen atom; R3 represents hydrogen atom or branched or direct (C1-C4)-alkyl group; R4 represents branched or direct (C2-C4)-alkyl group that is substituted with hydroxy-, amino-, monoalkylamino-, dialkylamino-, methoxy-, acetoxy-, aminooxy-group or one fluorine atom, or R4 represents branched or direct (C1-C8)-alkoxy-group that can be substituted with amino-group, monoalkylamino-group or dialkylamino-group, or R4 represents (C4-C8)-nonaromatic heterocyclic or (C4-C8)-nonaromatic heterocycloalkyl-alkyl group that comprise 1-2 heteroatoms chosen from nitrogen (N) and oxygen (O) atom that can be substituted with (C1-C3)-alkyl group, or R4 represents hydroxy-group or imidazolylalkyl group or pyridylmethyl group; or if R represents hydrogen atom or methyl then R4 can represent group -NR6R7 wherein R6 represents hydrogen atom and R7 represents (C2-C4)-trifluoroalkyl; or R3 and R4 in common with nitrogen atom to which they are bound form saturated or unsaturated monocyclic or bicyclic heterocyclic group comprising 4-10 atoms in cycle that comprises 1-2 heteroatoms chosen from N and O, or group -SO2 wherein indicated group can be substituted with (C1-C4)-alkyl, hydroxy-group, hydroxyalkyl, pyridyl, amino-, monoalkylamino-, dialkylamino-group, monoalkylaminoalkyl, dialkylaminoalkyl or piperidyl group; R5 represents phenyl group substituted with 1-3 substitutes Y wherein Y represents halogen atom, trifluoromethyl group or (C1-C3)-alkyl, or R5 represents branched or direct (C1-C8)-alkyl. Also, invention relates to pharmaceutical compositions containing one or some these compounds as an active component.

EFFECT: valuable biological and medicinal properties of compounds and pharmaceutical compositions.

5 cl, 4 tbl, 92 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel aromatic compounds that can be used in treatment of diseases or pathological states accompanying by inflammation, for example, chronic inflammation diseases. Invention describes compound of the formula (II): wherein G means phenyl, pyridinyl, pyrazolyl and wherein G is substituted with one or some groups R1, R2 or R3; Ar means naphthyl; X means (C5-C8)-cycloalkyl or cycloalkenyl optionally substituted with 1-2 oxo-groups, phenyl, furanyl, pyridinyl or pyrazolyl; Y means a bond or saturated either unsaturated branched or unbranched (C1-C4)-carbon chain wherein one or some methylene groups are optionally and independently substituted with oxygen (O) or nitrogen (N) atoms; Y is optionally substituted with oxo-group; Z means phenyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, morpholinyl, thiomorpholinyl, piperidinyl, piperidinonyl, piperazinyl, pentamethylenesulfoxidyl wherein each of them is optionally substituted with 1-3 (C1-C6)-alkyls or group -CONH2, (C1-C6)-alkyl, nitrile, hydroxy-group, (C1-C6)-alkoxy-group, secondary or tertiary amine wherein amine nitrogen is bound covalently with (C1-C3)-alkyl or (C1-C5)-alkoxyalkyl, tetrahydrofuranyl-(C1-C3)-alkyl, nitrile-(C1-C3)-alkyl, carboxamide-(C1-C3)-alkyl; R1 means independently in each case (C1-C10)-alkyl which is optionally partially or completely halogenated and optionally substituted with 1-3 hydroxy-groups, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl wherein each of them is optionally substituted with 1-3 groups -CN, halogen atom, (C3-C6)-alkynyl branched or unbranched carbon chain and one or some methylene groups is optionally replaced for atom O and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R2 means branched or unbranched (C1-C6)-alkyl that is optionally partially or completely halogenated, branched or unbranched (C1-C4)-alkoxy-group that in each case is optionally partially or completely halogenated, halogen atom, (C1-C6)-alkoxy-group, hydroxy-group, mono- or di-(C1-C4)-alkyl-amino-group, group -OR6, nitro-group or group mono- or di-(C1-C4)-alkyl-amino-S(O)2 that is optionally partially or completely halogenated, or group -H2NSO2; R3 in each case means independently phenyl, pyridinyl, pyrimidyl, pyrrolidinyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, (C1-C4)-alkynyl group or branched or unbranched (C1-C6)-alkoxy-group wherein each of them is optionally partially halogenated, -OR18 or (C1-C6)-alkyl optionally substituted with group -OR18, amino-group or mono- either di-(C1-C5)-alkyl-amino-group, (C2-C6)-alkynyl branched or unbranched carbon chain wherein one or some methylene groups are optionally replaced for atom O, and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R6 means (C1-C4)-alkyl that is optionally partially or completely halogenated; in each case R18 means independently hydrogen atom, (C1-C4)-alkyl; W means atom O, and its pharmaceutically acceptable derivatives. Also, invention describes a pharmaceutical composition containing these compounds and a method for treatment of disease mediated by cytokines and based on indicated compounds. Invention provides synthesis of novel compounds possessing valuable biological properties.

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

12 cl, 1 tbl, 38 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to a synthetic quinolone agent that is effective as medicinal agents, veterinary preparations, drugs used in fishing industry or as antibacterial preserving agents. Invention describes compound represented by the following general formula (I): as its separate isomers or their mixture, its salt and their hydrates wherein R1 represents cyclic alkyl group comprising 3-6 carbon atoms that can comprise a substitute chosen from halogen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; R4 represents hydrogen atom, amino-group, hydroxyl group; A represents nitrogen atom or part of structure as given in the invention claim; each R5 and R6 represents independently alkyl group comprising 1-6 carbon atoms or hydrogen atom; n means a whole number 1 or 2. Also, invention describes antibacterial agent and therapeutic agent based on compounds of the formula (I) used in treatment of infectious disease, a method for preparing antibacterial agent, a method for preparing a medicinal agent used in treatment of infectious disease and using compound of the formula (I) for preparing an antibacterial agent and using compound of the formula (I) for preparing a medicinal agent used in treatment of infectious disease. Invention provides novel compounds possessing useful biological properties.

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

35 cl, 2 tbl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes using the compound (R/S)-(-/+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or (S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or their salts for preparing a medicinal agent. This agent is used in treatment of extrapyramidal motor disorders, in particular, in treatment of unfavorable effects of anti-parkinsonic preparations and using (S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman in combination with an anti-parkinsonic preparation for preparing the combined medicinal agent. Also, invention relates to a pharmaceutical composition for treatment of extrapyramidal disorders and a set of the same designation. Proposed compounds are able to prevent catalepsy caused by usual anti-dopaminergic preparations and they are strong agonists of 5-HT1A-receptors in combination with antagonism to dopamine D2-receptors and interaction with D3-receptors that provides positive effects on extrapyramidal system in treatment of dyskinesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 10 ex

FIELD: chemistry of heterocyclic compounds, antibacterial agents.

SUBSTANCE: invention relates to agent used against acid-resistant microorganisms. Invention describes agent against acid-resistant microorganisms containing as an active component the compound represented by the general formula (1) or its hydrate wherein R2 represents hydrogen atom; R3 represents hydrogen atom; A1, A2 and A3 form incomplete structure of the formula: wherein A1 represent incomplete structure of the formula: wherein X2 and above described R1 can be combined to form six-membered cyclic structure comprising part of the parent nucleus wherein formed ring can comprise oxygen atom and, except for, can comprise alkyl group having 1-6 carbon atoms as a substitute; X1 represents halogen atom, hydrogen atom or amino-group; Y represents hydrogen atom; Z represents incomplete structure of the formula: . Agent elicits high antibacterial activity of broad spectrum and possesses good pharmacokinetics and safety also.

EFFECT: improved and valuable properties of agent.

3 cl, 9 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to biologically active compounds and concerns the development of a novel substance - 2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazine-7-(4H)-one sodium salt dihydrate of the formula: . This compound is designated for treatment and prophylaxis of diseases caused by viruses that are pathogenic form humans and animals. Proposed compound protects against infections caused by Rift Valley fever virus. Also, it shows activity against viruses of WEE(West Equine Encephalomyelitis), parainfluenza, respiratory-syncytium, Aujeszky's disease virus, avian infectious laryngotracheitis virus, avian influenza virus - totally against above 10 RNA- and DNA-containing viruses. The proposed compound is active in curative schedule of its using that is especially valuable.

EFFECT: valuable medicinal properties of compound.

1 cl, 6 tbl, 2 dwg, 7 ex

FIELD: chemical-pharmaceutical industry, biochemistry, medicine.

SUBSTANCE: invention relates to a liposome directly effecting on αvβ3-integrin receptors and comprising cationic amphiphilic substance including 1,2-dioleoyloxy-3-(N,N,N-trimethylammonium)propane chloride, neutral lipid, lipid with a direct effect having domain with a direct effect and hydrophobic domain bound with domain of a direct effect, and nucleic acid forming complex with cationic lipid. Cationic lipid presents in the amount from about 1 to about 50 molar % and indicated lipid with a direct effect presents in the amount from about 1 to about 20 molar % wherein molar percents are calculated as measured for the total number of lipid moles in liposome. Domain with a direct effect comprises a nonpeptide antagonist of αvβ3-integrin comprising 4-[2-(3,4,5,6-tetrahydropyrimidin-2-ylamino)ethyloxy]-benzoyl-2-(S)-aminoethylsulfonamino-β-alanine (compound 10) bound covalently with hydrophilic domain by amide bond. Also, invention relates to a method for inhibition of angiogenesis and involving administration to a patient needing in inhibition of angiogenesis a liposome in the therapeutically effective dose that directly effects on αvβ3-integrin receptors and comprising nucleic acid that is able to express a protein or peptide suppressing angiogenesis.

EFFECT: valuable properties of system.

27 cl, 2 tbl, 18 dwg, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention elates to derivatives of benzothiazole of the general formula (I): wherein R means hydrogen atom, -(CH2)n-phenyl optionally substituted with a substitute chosen from the following group: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, trifluoromethyl or -N(R')-C(O)-(lower)-alkyl, -(CH2)n-pyridinyl optionally substituted with (lower)-alkyl, -(CH2)n-(C3-C6)-cycloalkyl optionally substituted with hydroxy-group, -(CH2)n-benzo[1,3]dioxolyl, -(CR'2)-thiophenyl, -(CR'2)n-thiazolyl optionally substituted with (lower)-alkyl, -(CH2)n-C(O)-thiophenyl optionally substituted with halogen atom, -(CH2)-furanyl optionally substituted with (lower)-alkyl, -(CHR')n-benzofuran-1-yl, -(CH2)n-benzo[b]thiophenyl, -(CH2)n-N(R')-C(O)-phenyl optionally substituted with halogen atom or (lower)-alkoxy-group. -(CH2)n-C(O)-phenyl optionally substituted with (lower)-alkoxy-group, -(CH2)n-C(O)-2,3-dihydrobenzo[1,4]dioxine-6-yl, -(CH2)n-N(R')-C(O)-pyridinyl, -(CH2)n-tetrahydrofuranyl, -CH-biphenyl, -CH-(phenyl)pyridinyl, -(CH2)n-1-oxo-(CH2)n-CH-(phenyl)tetrahydropyranyl, -(CH2)n-1-oxo-1,2,3,4-tetrahydroquinoline-3-yl or -(CH2)n-S-[1,3,4]thiadiazol-2-yl optionally substituted with amino-group; R' means hydrogen atom or (lower)-alkyl and independently of one another in case R'2; n = 0, 1, 2, 3 or 4. Also, invention relates to a medicament possessing high affinity to adenosine A2A-receptors and high selectivity with respect to A1-receptors and comprising one or more derivatives of benzothiazole of the formula (I) and pharmaceutically acceptable excipients. Invention provides using derivatives of benzothiazole as ligands of adenosine receptors.

EFFECT: valuable medicinal properties of compounds and medicament.

13 cl, 2 tbl, 3 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention describes a method for prophylaxis or treatment of states wherein inhibition of enzyme activity is required wherein this enzyme catalyzes hydrolysis reaction of ester functional groups and wherein indicated disorder represents obesity or accompanying disease. Method involves prescribing compound of the formula (1):

or its pharmaceutically acceptable salt, ester, amide or precursor wherein in the formula (1) a means six-membered aromatic or heteroaromatic ring; R1 means a branched or unbranched alkyl (its carbon chain can be broken possibly by one or more oxygen atoms), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, reduced aryl, reduced heteroaryl, reduced heteroarylalkyl or their substituted derivative wherein a substitute represents one or more group taken independently among the following group: halogen atom, alkyl, halogen-substituted alkyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, reduced heteroarylalkyl, arylalkoxy-, cyano-, -C(O)R4, -CO2R4, -SOR4, -SO2R4, -NR6R7, -OR6, -SR6, -C(O)CX1X2NR6R7, -C(O)NR4R5, -C(O)N(OR5)R6, -NR6C(O)R4, -CR6(NH2)CO2R6, -NCX1X2CO2R6, -N(OH)C(O)NR6R7, -N(OH)C(O)R4, -NHC(O)NR6R7, -C(O)NHNR6R7, -C(O)N(OR5)R6, or lipid or steroid (natural or synthetic one) under condition that any substituting heteroatom in R1 or R2 must be segregated from nitrogen exocyclic atom by at least two carbon atoms (preferably, saturated ones); R2 means hydrogen atom or group, such as determined for R1 and wherein R4 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl, OR6, NHCX1X2CO2R6 or NR6R7; R5 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl; R6 and R7 are taken independently among hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylakyl, reduced heteroarylalkyl or -(CH2)n(OR5)m wherein n = from 1 to 12 but preferably from 2 to 10; m = from 1 to 3; for R5 (C2-C10)-alkyl is preferable; X1 and X2 represent independently hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylalkyl or reduced heteroarylalkyl. Also, invention describes compounds of formulas (II), (IIa), (IIb) given in the invention description, method for preparing compound of the formula (II), pharmaceutical composition used for prophylaxis or treatment of obesity or accompanying disorder, the nutrition foodstuff, method for prophylaxis or treatment of obesity or accompanying disorders, method for inhibition of enzymes activity, method for reducing the fat content in animals, cosmetic method for maintaining this weight of animals. Invention discloses the possibility for prophylaxis or treatment of obesity or accompanying disorders.

EFFECT: valuable medicinal properties of compounds.

30 cl, 1 dwg, 2 tbl, 5 ex

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