Ways to get lamotrigine, intermediate compounds and method for producing pharmaceutical compositions

 

(57) Abstract:

Describes how to obtain lamotrigine formula (I), which is used in the treatment of disorders of the Central nervous system, or its pharmaceutically acceptable salts obtained by the accession acid, characterized in that the compound of formula (II), where R represents CN, is subjected to irradiation with ultraviolet or visible light in an organic solvent under heating, followed, if necessary, redefine the target product in its pharmaceutically acceptable salt by treatment with an acid. Also describes intermediate compounds and method for producing the pharmaceutical composition. The technical result is simplification. 6 C. and 5 C.p. f-crystals, 2 PL.

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The invention relates to a method for lamotrigine and its pharmaceutically acceptable salts obtained by the addition of acids.

Lamotrigine is a 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine of the formula (I)

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This is a known compound described in patent application EP-A-0021121 and used in the treatment of disorders of the Central nervous system (CNS), in particular epilepsy. In patent application EP-A-0247892 described isetionate opisyvaetsja also a way to get lamotrigine, when the compound of the formula (II)

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subjected to cyclization, for example by heating in a vessel under reflux in ethanol in the presence of a base.

The present invention relates to a method for lamotrigine in which the compound of formula (II) in which R represents CN or CONH2in an organic solvent is subjected to irradiation with ultraviolet or visible light and, if R represents CN, then heat.

You can use any organic solvent in which is dissolved a compound of the formula (II). A preferred example is C1-C6-alkanol.

C1-C6-alkanol may represent alkanol with normal or branched chain. This can be, in particular, C1-C4-alkanol, for example methanol, ethanol, n-propanol, isopropanol, n-butanol, sec.-butanol or tert.-butanol or a mixture thereof.

If R in formula (II) represents a CN, the method according to the invention requires heating the compounds of formula (II). In this case, the method is preferably carried out by irradiating and heating the compounds of formula (II) in the solvent. The solution can be heated, for example, on a steam bath. E is at ambient temperature, and then heated, for example, before flavobacteria. An alternative solution may be first heated, for example, before flavoursome, and then irradiated. During irradiation the temperature of the solution it is convenient to maintain close to or equal to the temperature of distillation. For example, the solution can be heated before flavobacteria, and then subjected to circulation through the photochemical reactor with a falling film, in which he exposed to the appropriate intensity and duration.

If R in formula (II) represents CONH2the method according to the invention does not require heating. In this case, the solution of the compounds of formula (II) in an organic solvent can be irradiated at ambient temperature, for example at temperatures from 18oC to 25oC or from 20oC to 25oC, preferably at 25oC. However, this solution may possibly be heated before, during or after irradiation, for example, as described above for compounds of formula (II) in which R represents CN.

Irradiation of the compounds of formula (II) in an organic solvent can be carried out by exposure to sunlight, is the train to be carried out by exposing as sunlight, and under the lamp with a tungsten filament, or as in sunlight or under a lamp medium pressure. Lamp with a tungsten filament is, as a rule, the lamp power of 150 watts.

The irradiation is continued for a period of time sufficient to perform the cyclization of compounds of formula (II) in the lamotrigine. The duration of exposure will be dependent, among others, the source or sources of exposure, intensity of exposure, the nature of the reaction vessel and the temperature and pH of the irradiated solution. Irradiation may continue, for example, during the period of time from 2 hours to 5 days, in particular from 2 hours to 4 days, or from 2 hours to 2 days, or 2 hours to 1 day; or from 4 hours to 4 days, in particular from 4 hours to 4 days or 4 hours to 2 days, or from 4 hours to 1 day; or from 2 hours to 24 hours, in particular from 2 hours to 20 hours, or from 2 hours to 18 hours; or from 4 hours to 24 hours, in particular from 4 hours to 20 hours, or from 4 hours to 18 hours.

If R in formula (II) represents CONH2the method according to the invention, respectively, is carried out in the presence of a base. Can be used with any suitable base, such as hydroxide of alkali metal, toe pH, created by applying Foundation, activates the cyclization of the compounds of formula (II) in the lamotrigine in favor of possible competitive photochemical processes. An example of this competitive process is E/Z isomerization of the compounds of formula (II), the product of which is a mixture of the compounds of formula (II) and its Z-isomer, compounds of formula (III)

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in which R represents CN or CONH2.

I believe that the transformation of compounds of formula (II) in the lamotrigine is by photochemical isomerization of the Z-isomer of formula (III), which are not allocated, followed by cyclization of Z-isomer in itself lamotrigine.

If R in formula (II) represents CONH2then the other photochemical process can, under certain reaction conditions, to compete with cyclization in lamotrigine. This process represents a transformation of this compound 3-amino-5-hydroxy-6-(2,3 - dichlorophenyl)-1,2,4-truein formula (IV)

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As mentioned above, the temperature and pH at which the method according to the invention, can be significant when determining the progress of the reaction. For example, irradiation of a solution of compound II in which R represents CONH2in ethanol at neutral the ve main product of the cyclization, while lamotrigine is formed in a smaller number. In contrast, heating of the solution of compound II in which R represents CONH2in ethanol at alkaline pH, for example in the presence of KOH, followed by radiation for about 3 hours leads to the formation of lamotrigine when the actual exception hydroxy-compounds of the formula (IV).

The compound of formula (II) in which R represents CN, can be obtained by dehydration aminoguanidinium formula (V)

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This reaction is preferably carried out by treating compound of formula (V) with a suitable dehydrating agent, for example thionylchloride, in an appropriate organic solvent, for example dimethylformamide. It was established that in the dehydration of a mixture of (E)- and (Z)-isomers of compounds of formula (V) is essentially the only (E)-isomer of compounds of formula (II).

The compound of formula (V) is new. Therefore, the invention also applies to the above compounds of formula (V). The compound of formula (V) may be obtained by treating 2,3-dichlorophenylisocyanate formula (VI)

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aminoguanidine or its salt. The reaction is preferably carried out in a suitable solvent, such as what Laney acid, for example 8N hydrochloric acid. The reaction can be conducted at ambient temperature.

The compound of formula (VI) can be obtained by nitrotyrosine 2,3-dichloroacetophenone formula (VII)

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relevant nitrotyrosine agent, preferably C1-C6-alkylation or nitrous acid, more preferably a amilnitrita. The reaction is preferably carried out in the presence of an acidic or basic catalyst in a suitable organic solvent, for example in a simple ether or alcohol, preferably in diethyl ether or tert.-butanol, at a temperature in the range from approximately 15oC to the boiling point of the solvent. If used acidic catalyst, it is preferably carried out. If you're using a basic catalyst, it is preferably tert. -piperonyl potassium. The reaction can be conducted at room temperature.

The compound of formula (VII) can be obtained by treating 1,2-dichlorobenzene compound of the formula RM1or RM2X, in which R represents a C1-C6-alkyl, M1represents an alkali metal, M2represents an alkaline-earth metal, and X represents aborym anhydride. RM2X may represent, for example, the Grignard reagent (Grignard), such as methylmagnesium. Preferably used a compound of the formula RM1while utility is the most preferred, followed by reaction with acetic anhydride. This reaction is preferably carried out at a temperature of about -70oC.

The compound of formula (VII) can also be obtained by treating 2,3-dichlorobenzaldehyde connection RM1or RM2X, where R represents methyl, preferably by metalmilitia, and oxidation of the thus obtained-methyl-2,3-amyl-metacresol. Acceptable oxidizing agents include, for example, sodium hypochlorite. This reaction is preferably carried out at room temperature.

The compound of formula (VII) can also be obtained by treating 2,3-dichlorobenzoyl magnesium and interaction thus obtained compound with acetylchloride in the presence of anhydrous ferric chloride. This reaction is preferably carried out at a temperature of about -70oC.

The compound of formula (II) in which R represents CN, an alternative can be obtained by dehydration of the corresponding amide, which is soedinenii, for example pyrophosphorylase.

The original compound of formula (II) in which R represents CONH2get a way that enables handling of 2,3-dichlorophenylisocyanate formula (VIII)

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aminoguanidine or its salt.

If you apply salt aminoguanidine, it is preferably guanidine hydrochloride.

The reaction of interaction of the compounds of formula (VIII) with aminoguanidine or its salt is preferably carried out in a suitable organic solvent, such as C1-C6-alkanol, for example ethanol, in the presence of acid at elevated temperature. The acid is usually concentrated acid, for example concentrated hydrochloric acid. The reaction is respectively carried out at a temperature distillation of the used organic solvent.

The compound of formula (VIII) is new. Therefore, this invention also applies to the above compounds of formula (VIII).

The compound of formula (VIII) can be obtained by treating 1,2-dichlorobenzene compound of the formula RM1or RM2X, in which R represents a C1-C6-alkyl, M1represents an alkali metal, M2predstavlennogo thus compounds with C2-C6-alkylolamides. The compound of the formula RM2X may represent, for example, a Grignard reagent, such as methylmagnesium. Preferably used as a compound of the formula RM1most preferred is n-utillity. Alkyloxy preferably represents tilokarat.

The reaction of the interaction is preferably carried out by treatment of a solution of 1,2-dichlorobenzene in an appropriate organic solvent, for example ether, such as diethyl ether, dioxane or tetrahydrofuran, a solution of n-utility in a suitable organic solvent, such as hexane, at a temperature preferably below about -60oC. In the interaction of n-butyl chloride with lithium in situ may be formed of n-utillity.

The compound of formula (VIII) can also be obtained by activation of 2,3-dichlorophenylisocyanate acid by conversion into the corresponding anhydride or gelegenheid, and then the processing of the activated derivative with ammonia. Alternative ammonium salt of 2,3-dichlorophenylisocyanate acid can be digidrirovanne with obtaining the compounds of formula (VIII). Such methods are customary for reactions of acid amides, he shall nd ethyl ester of 2,3-dichlorophenylisocyanate acid of formula (IX)

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ammonium. The reaction of the interaction is preferably carried out in an appropriate solvent, for example, C1-C6-alkanol, such as methanol, ethanol, propan-1-ol or propan-2-ol, preferably in methanol.

Ethyl ester of 2,3-dichlorophenylisocyanate acid is new. Therefore, this invention concerns further the above compounds of formula (IX).

The compound of formula (IX) is preferably obtained by treatment of 1,2-dichlorobenzene compound of the formula RM1or RM2X, in which R represents a C2-C6-alkyl, M1represents an alkali metal, M2represents an alkaline earth metal, and X represents a halogen, with subsequent reaction of interaction of the thus obtained compound with heterocalixarenes, such as heterocalixarenes. RM2X may represent, for example, a Grignard reagent, such as methylmagnesium. Preferably used a compound of the formula RM1most preferred is n-utillity.

The invention also concerns a method which further includes obtaining pharmaceutically acceptable salt of lamotrigine formed by joining the m acid, include sulfate, phosphate, methanesulfonate, p-toluensulfonate, bansilalpet and isetionate. Isetionate lamotrigine most preferred for parenteral administration, as it has a high solubility in water.

Isetionate lamotrigine can be obtained by the interaction of lamotrigine with isetionate acid. Preferably the molar ratio of lamotrigine and isetionate acid is from 1:3 to 3:1, in particular approximately 1: 1.

Setinova acid is absent in the sale and therefore it is usually obtained in situ. For example, isetionate alkali metal in solution can be converted into isetionate acid, for example, by passing an aqueous solution of isetionate through H+-ion-exchange resin and subsequent mixing of the triazine with the resulting acidic solution. Usually the solvent in this reaction is water, and in this case, the reaction can be conducted at temperatures from 4 to 50oC, better at ambient temperature and without the use of any pH regulators, or other additives.

Formed isetionate can be recrystallized, for example, methylated industrial alcohol, obtaining crystals setit to be obtained by the interaction of salt lamotrigine, non-isetionate, with isethionate anion. Preferably, the ratio of salt to anion ranged from 1:50 to 50: 1. More preferably the ratio is about 1:10. Preferably this reaction is carried out by elution of the salt solution in methanol through the column with isethionate anion-exchange resin. In this case, the salt preferably represents methanesulfonate (mesilate) lamotrigine.

This invention also provides a method comprising preparing a pharmaceutical composition of compound of lamotrigine or its pharmaceutically acceptable salts obtained by the joining of the acid with a pharmaceutically acceptable diluent or carrier.

Lamotrigine should be present in the compositions obtained in accordance with the invention, in the form of an effective single dose, that is, in a quantity effective against disorders of the Central nervous system in vivo.

Pharmaceutically acceptable diluent or carrier present in the compositions prepared according to the invention can be a liquid or solid material that is inert or acceptable from the point of view of medicine and is compatible with lamotrigine or its salt.

For oral administration it is possible to use fine powders or granules that contain diluting, dispersing and/or surface-active substances, which can be represented in the form of dose in water or syrup, in capsules or tablets in a dry state or in the form of non-aqueous suspensions, which can be included suspendresume substances, and finally, in the form of a suspension in water or syrup. If it is desirable or necessary, can be included flavors, preservatives, suspendresume agents, thickening agents and emulsifying agents. If the suspension is prepared in water, in accordance with this invention preferably is at least one of these substances.

For parenteral administration, the active compound can be prepared in the form of a sterile aqueous solution for injection, which may contain antioxidants or buffers.

Lamotrigine or its salt can be introduced in pure form, not associated with other additives, and in this case, a preferred carrier is a capsule or toffee.

Alternative active connection megawide tablets, etc.

Other substances that can be included in the product are, for example, inert from the point of view of medicine ingredients, in particular solid and liquid diluents, such as lactose, starch or calcium phosphate for tablets or capsules; olive oil or etiloleat for soft capsules; and water or vegetable oil for suspensions or emulsions; softening agents such as talc or magnesium stearate; gelling agents such as colloidal clays; thickening agents such as gum Arabic or sodium alginate; and other therapeutically acceptable accessory ingredients such as moisturizers, preservatives, buffers and antioxidants that can be used as carriers in such preparations.

Tablets and other formulations of, presented in the form of separate units, may contain a number of lamotrigine or salts thereof, effective in the dose or in multiple doses, for example, units containing 5 mg to 500 mg, preferably from about 10 mg to 250 mg, in terms of free base.

Water drugs should generally contain pharmaceutically acceptable salt of lamotrigine in a quantity effective against disorders of the Central nervous system in vivo and such * up to 250 mg/ml of salt in terms of free base. However, the traditional concentration of salt in the solution is from 10 to 70 mg/ml, preferably from 10 to 50 mg/ml Salt for parenteral administration may be presented in the form of sterile aqueous solutions for injection, which may contain a therapeutically acceptable accessory ingredients, such as antioxidants, buffers and agents for regulating osmolarity solution. Preferably, anions such as chloride and phosphate, were not present in the solution as they tend to share with salt with the formation of precipitation.

Water preparation can be prepared by dissolving the salt in an aqueous environment, such as sterile water for injection. The solution before use can be diluted to the required concentration.

The following examples illustrate the steps of the method according to the invention.

Reference example 1. Obtaining (E)-2-(2',3'-dichlorophenyl)-2-(guanidinium)ndimethylacetamide (compound (II) with R=CONH2< / BR>
A mixture of 2,3-dichlorophenylisocyanate (54,5 g, 0.25 mol), hydrochloride aminoguanidine (33,15 g, 0.30 mol), ethanol (1 l) and concentrated hydrochloric acid (4 ml) was boiled under reflux for 6 h (pH = 1.5). The resulting solution was boiled away to (m/o) of aqueous sodium hydroxide (45 ml) at <15. The mixture was filtered, dark-yellow solid residue was washed with a solution of 0.88 to ammonium and dried to obtain a crude product (59,5 g, 87%), so PL 231-3o(FL. 233-4oRazlog. ). After recrystallization of this product (2.2 g) of propan-1-ol (60 ml) was obtained pure substance (1,83 g, 83%) so pl. 238-9o(Razlog.).

Reference example 2. Obtaining (E)-2-(2,3-dichlorophenyl)-2-(guanidinium)acetonitrile (compound (II) with R=CN)

Aminoguanidine formula (V), defined above, was dissolved in dimethylformamide and treated with thionyl chloride. Was obtained the crude product, which contained some minor impurities. These impurities are easily removed by rubbing with toluene and received in the result of (E)-2-(2,3-dichlorophenyl)-2-guanidinoacetate with the release of 24%.

Example 1. Receiving lamotrigine

(E)-2-(2', 3'- dichlorophenyl)-2-(guanidinium)ndimethylacetamide described in reference example 1 (0.3 g) was dissolved in ethanol (10 ml) and irradiated by exposing it to sunlight.

Thin layer chromatography (TLC) after 4 h exposure showed that in solution there is a mixture of compounds (II) and its Z-isomer compound (III), but the formation of lamotrigine has not occurred. However, after 2 days, TLC revealed the presence of spots, a line. After a total of 4 days, TLC analysis of the solution showed that lamotrigine is still present.

Suspended solid matter, which was formed at the pump was then filtered. It is established that at TLC, it gives you a spot at the baseline. In the remaining liquid by TLC was discovered lamotrigine. Therefore, the irradiation of the sample liquid was continued for one day. TLC revealed the presence of bright spots lamotrigine. The melting point of lamotrigine = 218oC.

Example 2. Receiving lamotrigine

(E)-2-(2',3'-dichlorophenyl)-2-(guanidinium)ndimethylacetamide (2.5 g) was dissolved in hot ethanol (40 ml). Added potassium hydroxide (2.0 g, equivalent to 5% m/o) and the resulting solution was irradiated by exposing it to the sun's glare and lamp with a tungsten filament (150 watts).

After 4-day exposure using a lamp TLC results showed the presence of spots of medium intensity corresponding to lamotrigine (Rf = 0,20).

Then alkaline ethanol solution was acidified with concentrated hydrochloric acid (3 ml) to pH 6. Added silica gel (2.0 g) and evaporated entire volume to dryness. Thin white powder was introduced into a column with silica gel and was suirable (see tab. 1).

oC).

Example 3. Receiving lamotrigine

(E)-2-(2',3'-dichlorophenyl)-2-(guanidinium)ndimethylacetamide (2.0 g) was dissolved in a solution of potassium hydroxide (5% m/o) in ethanol (40 ml). The resulting solution was irradiated at ambient temperature, using a medium pressure lamp for a full 12 hours the Solution was left to stand, and then warmed up on the steam bath at 70oC for 2 h

After 4 h, TLC analysis of the solution revealed the presence of trace amounts of lamotrigine (Rf = 0,20) together with a 50:50 mix of compound (II) and its Z isomer, compound III. TLC of the solution is repeated after 6.5 h, 9 h and 12 h Each time the plate was found a weak spot corresponding to lamotrigine, and more than a bright spot corresponding E/Z mixture of compounds II and III. These results suggested that the E/Z isomerization of compound II was very quick, and cyclization of the compound (II) in lamotrigine in the described reaction conditions has been slow.

Example 4. Receiving lamotrigine

Way

A solution of (E)-2-(2',3'-dichlorophenyl)-2-(guanidinium)ndimethylacetamide (2.2 g) in ethanol (100 ml) was heated before flavoursome and subjected to circulation through the photochemical reactor with a falling film. Solution during R the reaction for 10 h, the solution became dark yellow. After 13 h, the solution became orange and began to fall a white precipitate. At this point the reaction was stopped. White solid was filtered and examined by TLC.

Result

After 2.5 h after start of the reaction TLC of the solution showed that begins the formation of lamotrigine. Unreacted compound II was also present. After 5 h of unreacted compound II and lamotrigine were present still, but was also found additional spot with higher Rf value. In time, constituting 7.5, 10 and 13 h after start of the reaction, carried out the same observations.

White solid was identified by TLC as a pure sample of 3-amino-5-hydroxy-6-(2,3-dichlorophenyl)-1,2,4-triazine.

Example 5. Receiving lamotrigine

(E)-2-(2',3'-dichlorophenyl)-2-(guanidinium)ndimethylacetamide (5.0 g) was dissolved in hot ethanol (150 ml) containing potassium hydroxide (2% m/o). The obtained yellow solution was irradiated at 25oC, using a medium pressure lamp. TLC analysis of the solution after irradiation for 3 h and 5 h, respectively, showed that lamotrigine in detektiruya not formed.

Then the solution was heated to the beginning of phlegm by TLC revealed the presence of lamotrigine. 3-amino-5-hydroxy-6-(2,3-dichlorophenyl)-1,2,4-triazine has not been detected.

Recrystallization from ethanol containing 5 g of coal, resulted in the receipt of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine. EtOH (31 g, 56%) as a very pale yellow solids with so pl. 219-220oC (FL. 220-222oC). TLC in the system silica gel/ethyl acetate showed the presence of trace amounts of fluorescent impurities in the baseline.

Example 6. Receiving lamotrigine

(E)-2-(2,3-dichlorophenyl)-2-guanidinoacetate described in reference example 2 was dissolved in propan-1-Ola and irradiated by boiling under reflux, as shown in the table. 2. Evaporation of the resulting solution and recrystallization of the solid residue from ethanol resulted in colorless homogeneous 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine. EtOH in all except the last cases (see tab. 2).

In small-scale experiments, the conversion of 3,5-diamino-6-(2,3-dichlorophenyl)- 1,2,4-truein was very clean (TLC), and low outputs reflect losses during processing. In the final experiment with 47 g conversion of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine in 8 h was approximately 50%, but after 32 h, the reaction mixture became yellow and turbid. It was filtered, vipan (32,2 g, 68%) as a pale yellow solid. Recrystallization from ethanol containing 5 g of coal, resulted in the receipt of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine.EtOH (31 g, 56%) as a very pale yellow solids with so pl. 219-220oC (FL. 220-222oC). TLC in the system silica gel/ethyl acetate showed the presence of trace amounts of fluorescent impurities in the baseline.

Example 7. Getting aminoguanidinium formula (V)

Aldoxime 2,3-dichlorophenylamino are condensed with aminoguanidine in a mixture of dimethyl sulfoxide and 8 N hydrochloric acid at ambient temperature. The reaction mixture was podslushivaet concentrated ammonium hydroxide solution and was isolated oxime aminoguanidine with the release of 73% in the form of an equimolar mixture of (E)- and (Z)-isomers.

Reference example 3. Obtain 2,3-dichlorophenylisocyanate formula (VI)

Method AND

2,3-dichloroacetophenone (20,00 g, 0.104 g mol) was dissolved in dry diethyl ether (200 ml) and the solution for half an hour was barbotirovany hydrogen chloride. Slowly, dropwise, with stirring, was added amyl nitrate (24,36 g, 0,238 mol) so as to maintain the solution at a soft boil under reflux. After this, the solution was gently boiled OBR is the temperature during the night. The reaction mixture with exceptional care poured into 2 N sodium hydroxide solution (200 ml) (reaction is very rapid), and divided. The organic phase was extracted with 2 N sodium hydroxide solution (2 x 100 ml). The alkaline phase was combined, poured on ice (200 ml) and added with stirring, concentrated hydrochloric acid (100 ml). The obtained acidic mixture was left to stand at room temperature overnight, and the precipitate was filtered at the pump. 2,3-dichlorophenylisocyanate received in the form of a cream-colored substance (10.4 g, 46% yield). TLC (SiO2; CHCl3) showed the absence of impurities, therefore, further purification was not performed.

Method B

Tert. -piperonyl potassium (239,7 g 2,136 mol) was dissolved in tert.-butanol (1.5 l) and stirred at room temperature for 30 minutes In the form of a single portion was added 2,3-dichloroacetophenone (67,26 g, 0,356 mol) and the resulting mixture was stirred over night at room temperature. Slowly, dropwise, with stirring, was added amyl nitrate (83,41 g, 0,712 mol). When the addition was completed, the reaction mixture was stirred at room temperature for 22 h, and then was heated at 50oC for 2 hours the Solution is allowed to cool and was peremetallirovaniya diethyl ether (3 x 500 ml). The aqueous phase was acidified with concentrated hydrochloric acid and left to stand at room temperature overnight. The solid is deposited in the sediment was filtered at the pump, and dried in vacuum over anhydrous pjatiokisi phosphorus and got 2,3-dichlorophenylisocyanate systems (57.3 g, 53,8%) as a brown solid. TLC (SiO2, CHCl3) revealed the presence of small amounts of impurities, but subsequent dehydration of the oxime showed that recrystallization would be desirable. The oxime can be recrystallized from toluene, so pl. 109oC.

Reference example 4. Obtain 2,3-dichloroacetophenone

Method AND

Utility in hexane (300 ml, 0,474 mol) is slowly added dropwise, with stirring, were added to 1,2-dichlorobenzene (104,58 g, 0,711 mol) dissolved in dry tetrahydrofuran (2 l) and maintained at -70oC in nitrogen atmosphere. The resulting solution was stirred at -70oC for 1 h, This solution still at -70oC, in an atmosphere of nitrogen was added via needle with double end to acetic anhydride (290,35 g, 2,84 mol) dissolved in dry tetrahydrofuran (1 l) at -70oC. After complete addition, the resulting solution was stirred at -70oC probaly on the ice (5 l) and, after mixed well, left to stand overnight at room temperature. The aqueous mixture was extracted with ether (3 x 1.5 l). The ether phases were combined, washed with water (3 x 750 ml), saturated sodium bicarbonate solution (3 x 750 ml) and brine (1 x 750 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to obtain a yellow liquid. The crude product was placed in a high vacuum on a hot water bath for complete removal of 1,2-dichlorobenzene and acetic anhydride. Got 2,3-dichloroacetophenone (67,2 g, yield 73%). IR, NMR and TLC (SiO2; CHCl3) showed that this product contains little impurities, therefore, further purification was not performed.

Method B

Itmean (234,89 g 2,288 mol) was added dropwise with stirring to the magnesium shavings (54,88 g 2,288 mol) in dry ether to obtain metalmilitia. 2,3-dichlorobenzaldehyde (200 g, 1,144 mol), dissolved in a mixture of benzene/diethyl ether (1 l, 50:50) was added dropwise with stirring to the Grignard reagent. The reaction mixture was stirred at room temperature overnight. The solution was boiled under reflux for 2 h, and then gave it to cool. The reaction mixture was poured into a saturated solution of chloride is inali, washed with brine (1 x 2 l), dried over anhydrous magnesium sulfate, filtered and evaporated. Received - methyl-2,3-dichlorobenzoyl alcohol (196,4 g, yield 90%) as a yellow oil, which crystallized upon standing with the formation of a pale yellow solid. TLC (SiO2; CHCl3) did not reveal the presence of impurities, so that further purification is not carried out. However, if desired, the alcohol can be recrystallized from petroleum ether at 40-60oC obtaining white prisms with a melting point 53oC.

-Methyl-2,3-dichlorobenzoyl alcohol (5.0 g, was 0.026 mol) was dissolved in acetic acid (24 ml) and slowly added dropwise, under stirring at a temperature of 15-25oC added 12% (m/o) sodium hypochlorite solution (23,26 ml, 0,0314 mol). When the addition was completed, the reaction mixture was stirred at room temperature for about 1.5 hours, until the sample starch/iodide did not give a positive result. To the reaction mixture were added a saturated solution of sodium bisulfite until the sample starch/iodide did not become negative. This mixture is poured into ice-cold brine (100 ml) and was extracted with diethyl ether (3 x 75 ml). The ether phase was combined and washed with 2 N sodium hydroxide solution (3 x 75 ml) until the washing obtained 2,3-dichloroacetophenone (3.2 g, yield 65%) as a pale yellow oil. TLC (SiO2; CHCl3) and NMR showed that this material does not contain impurities.

The way IN

To obtain 2,3-dichlorophenylisocyanate 2,3-dichlorodibenzo (350 g, 1,282 mol), dissolved in dry ether (1250 ml) slowly with stirring was added to magnesium turnings (30,77 g 1,282 mol) in dry diethyl ether (300 ml) under nitrogen atmosphere. Dropwise with stirring, a Grignard reagent was added to acetylchloride (301,91 g 3,846 mol) dissolved in dry diethyl ether (1 l) and anhydrous ferric chloride (1,925 g, 0,0118 mol) in nitrogen atmosphere at -70oC. When the addition was completed, the resulting mixture was stirred at -70oC for another 5 min, and then allowed to warm to room temperature. The reaction mixture was poured on ice (5 l) and thoroughly mixed. The aqueous mixture was podslushivaet sodium carbonate and left to stand at room temperature overnight. The aqueous solution was extracted with diethyl ether (3 x 2 l), ether phases are combined, dried over anhydrous magnesium sulfate, filtered and evaporated. Received crude 2,3-dichloroacetophenone (KZT 235.7 g) as a yellow liquid. The crude substance drove under vacuum to obtain pure 2,3-dichloroacetophenone does not contain impurities.

Example 8. Obtain 2,3-dichlorophenylisocyanate (compound VIII)

1. Rapid laboratory method

Mix a solution of 1,2-dichlorobenzene (50.0 g, 0.34 mol) in dry tetrahydrofuran (500 ml) was cooled to -65oC in nitrogen atmosphere and treated dropwise over 1 hour a solution of n-utility in hexane (204 ml concentration 1,72 M = 0.35 mol) at a temperature after having been maintained below -60oC. After stirring for a further 1 h pale yellow solution was treated dropwise with a solution of atelocerata (19.9 g, to 0.17 mol) in warm tetrahydrofuran (200 ml). During this procedure, the color of the reaction mixture changed from yellow through orange to purple-red. After stirring for a further 1 h at -60oC and the mixture was left to warm to 0oC for 2 h, cautiously treated with water (250 ml) and hydrochloric acid was acidified to pH 6. The yellow organic phase was separated, washed with brine (2 x 250 ml), dried (magnesium sulfate) and boiled away with obtaining a yellow solid. His suspended in ethanol (300 ml) and was filtered to obtain crude 2,3-dichlorophenylisocyanate (12.0 g, 32.4 percent) as not quite white solids with so pl. 213-214oC (FL. so pl. 216-218oC). In the concentration of et is anti crude 2,3-dichlorophenylisocyanate (40 g, so pl. 199-203oC) was recrystallized from acetic acid (240 ml) and water (180 ml) with receipt of 33.4 g (83%) of the pure product (so pl. 216-218oC).

2,3-Dichlorophenylisocyanate had the following characteristics:

Molecular weight: 217,9

Melting point: 216-218oC

Microanalysis: C; H; N;

Calculated: 44,07; 2,31; 6.42 per;

Found: 44,79; 2,63; 6,09.

The formation of utility in situ

n-butyl chloride (55,5 g, 0.6 mol) was added dropwise in a nitrogen atmosphere to peremalyvavshaya suspension thin shavings of lithium (8,30 g, 1.2 mol) in dry ether (300 ml) thus, in order to maintain a low boil under reflux. After boiling under reflux for subsequent 3,75 h the mixture was cooled to room temperature and was stirred overnight. (The preceding analyses show that this method gives a 66% yield of utility ( 0.4 mol)). This mixture then was cooled to -60oC and maintained at this temperature during the following operations. Added dry tetrahydrofuran (400 ml), then added dropwise a solution of 1,2-dichlorobenzene (58,8 g, 0.4 mol) in dry tetrahydrofuran (300 ml) over 40 minutes After stirring the mixture for 1 h was added dropwise during St the 1 h at -60oC. After the mixture allowed to warm to 0oC carefully added water (300 ml), and the mixture was acidified to pH 6 with hydrochloric acid. The yellow organic phase was separated, washed with brine (2 x 300), dried (magnesium sulfate) and was evaporated to obtain a solid light yellow substance. His suspended in ethanol (250 ml), filtered, and dried to obtain crude 2,3-dichlorophenylisocyanate (22,5 g, 52%) with T. pl. 214-215oC (FL. 215-218oC).

Example 9. Getting ethyl-2,3-dichlorophenylisocyanate (compound IX)

Materials

- 2,3-dichlorodibenzo (0.1 M, 27,3 g) in 35 ml of dry ether;

- magnesium (2,43 g) in 15 ml of dry ether;

- chloride of cadmium (0.1 M, 9,8 g);

- ethoxysilane (0.079 in M, of 10.9 g of 8.92 ml);

- the reaction was carried out in nitrogen atmosphere.

Way

The Grignard reagent was prepared in the usual way as follows.

Dichlorobenzoyl was added to magnesium within 1-2 h and the resulting solution was boiled under reflux for about 4 hours because the Mg has not been dissolved, the Grignard reagent was allowed to mix at room temperature over night.

Then the flask was cooled in ice for 10 min added portions of dry chloride of cadmium. When was added all Ratnam refrigerator.

The ether was boiled away and the residue was washed twice with dry benzene, which, in turn, has boiled away.

The residue is collected and processed by heterocalixarenes in 20 ml of dry benzene. It was slowly added from a dropping funnel with stirring. This reaction is very rapid. When adding has finished and spontaneous boiling subsided, the reaction mixture is boiled under reflux for another hour.

Then the reaction mixture was cooled in an ice bath. Gently added to the mixture of ice/water. Then added an amount of 20% H2SO4sufficient to obtain two clear phases. The aqueous phase was separated and was extracted twice with benzene. The benzene layers were combined and extracted with 1 x water, 1 x solution of Na2CO3, 1 x water 1 x NaCl. The benzene solution is then dried over MgSO4was filtered and boiled away. Got to 17.5 g of crude product.

Were carried out by NMR and TLC analyses. TLC in SiO2/CHCl3gave two spots, one corresponding to the connection specified in the header (the product), and one - dichlorobenzene (source material).

Example 10. Getting ethyl-2,3-dichlorophenylisocyanate (compound (IX)

Materials

- 2,3-dichlorodibenzo (0.2 M, 54.6 g) in 50 ml of EF is 0.15 M, 21.8 g);

- the reaction was carried out in nitrogen atmosphere.

Way

Was carried out by the General method described in example 7. However, the Grignard reagent is not boiled under reflux during the night, as the reaction proceeded very rapidly due to the large volume of ether.

After addition of acrocallosal the reaction mixture was cooled with ice and the resulting mixture was stirred at room temperature over night.

The reaction mixture was decomposed by adding ice water was added in amount of 20% H2SO4sufficient to obtain two separate layers.

The mixture was separated and the aqueous layers were washed twice with benzene. The benzene layers were combined and washed with water. No alkaline washing is not conducted. The benzene layers were dried, filtered and evaporated. Received 39.5 g of product. NMR and TLC yielded results identical obtained in example 9.

Example 11. Getting isetionate 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine

The solution isetionate sodium (148 g, 1.0 mol) in water (4.9 liters) missed through a column of IR-120 (H) ion exchange resin and suirable water. 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine (256 g, 1.0 mol) was dissolved in the obtained Lenogo methylated alcohol with getting isetionate 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triamine.

Output 273,3 g (72%), so pl. 242oC.

Example 12. Getting isetionate 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine

50 mmol Amberlite (trade mark) IR-45 (OH) was mixed with 15 mmol (10 ml), water isetionate acid and the resulting product was filled in a column. Then the column was washed with methanol. 0.7 g (2 mmol) in methanol solution nelfinavir 3,5-diamino-6-(2,3-dichlorophenyl)- 1,2,4-triazine was suirable through this column. Eluant boiled away in vacuum and the residue was recrystallize from industrial methylated spirit and received isetionate 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine.

Yield 300 mg (40%), so pl. 242-243oC.

Example 13

74,625 g (of € 0.195 mol) of isetionate 3,5-diamino-6-(2,3-dichlorophenyl)- 1,2,4-triazine was added and dissolved in about 900 ml water for injection BP, and diluted to 1000 ml by adding water for injection BP, obtaining an aqueous solution containing isetionate in a quantity equivalent to 50 mg/ml base 3,5-diamino-6-(2,3 - dichlorophenyl)-1,2,4-triazine. This solution was acceptable on the basis of tone.

Example 14

14,925 g (0,039 mol) of isetionate 3,5-diamino-6-(2,3-dichlorophenyl)- 1,2,4-triazine was added to a solution of 438 g (0,221 mol) of dextrose monohydrate in about 900 ml of water for injection In the in number, equivalent to 10 mg/ml base 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine. This solution was acceptable on the basis of tone.

Example 15

Was prepared in a pharmaceutical composition, comprising the following ingredients.

3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine - 150 mg*< / BR>
Lactose 200 mg*< / BR>
Corn starch 50 mg*< / BR>
Polyvinylpyrrolidone 4 mg*< / BR>
Magnesium stearate 4 mg*< / BR>
*content on the pill

The drug was mixed with the lactose and starch and granulated with a solution of polyvinylpyrrolidone in water. The obtained granules were dried, mixed with magnesium stearate and extruded to obtain pellets of average weight 408 mg.

1. The way to get lamotrigine formula I

< / BR>
or its pharmaceutically acceptable salts obtained by the accession acid, characterized in that the compound of formula II

< / BR>
where R represents CN, is subjected to irradiation with ultraviolet or visible light in an organic solvent under heating, followed, if necessary, redefine the target product in its pharmaceutically acceptable salt by treatment with acid.

2. The way to get lamotrigine f the I, the compound of formula II

< / BR>
in which R represents CONH2in an organic solvent in the presence of a base is subjected to irradiation with ultraviolet or visible light.

3. The method according to p. 1 or 2, characterized in that the compound of formula II is subjected to irradiation by boiling under reflux in propane-1-Ola.

4. The method according to p. 1 or 3, characterized in that the compound of formula II in which R represents CN, obtained by dehydration of compounds of formula V

< / BR>
5. The method according to p. 2 or 3, characterized in that the compound of formula II in which R represents CONH2receive processing 2,3-dichlorophenylisocyanate formula VIII

< / BR>
aminoguanidine or its salt.

6. The method according to any of paragraphs. 1 to 5, characterized in that lamotrigine transformed into a pharmaceutically acceptable salt by treatment with acid.

7. The method according to p. 6, characterized in that the salt is isethionate lamotrigine.

8. A method of obtaining a pharmaceutical composition, characterized in that the method according to any one of paragraphs.1 - 7 of lamotrigine or its salt obtained by the accession acid, is mixed with a pharmaceutically acceptable carrier or time is/BR>< / BR>
11. Ethyl-2,3-dichlorophenylisocyanate formula IX



 

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FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of N,N-bis-acetoacetylarylamides that are used as azo-components in manufacturing high-strength azo-pigments. N,N-bis-acetoacetylarylamides are prepared by reaction of diketene with primary carbocyclic aromatic amines in a solvent medium, Carbocyclic aromatic amines represent unsubstituted phenylenediamines or substituted phenylenediamines wherein 2,5-dimethyl-1,4-phenylenediamine, 2-methyl-5-chloro-1,4-phenylenediamine and 2,5-dichloro-1,4-phenylenediamine are used. Reaction is carried out at temperature 35-75°C in the presence of acetone taken in the amount 0.5-1 mole/1 mole of used diamine, in 99.5-100% acetic acid medium that is recovered to cycle after isolation of the reaction end product. Invention provides enhancing yield and quality of end products.

EFFECT: improved method of synthesis.

5 cl, 1 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: disclosed is (carboxylalkylenephenyl)phenyloxamides of formula , where R3 denotes H, F, Cl, Br, CF3, phenyl, COOH, COO-(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, wherein the phenyl can be monosubstituted with: R12; R1, R5 independently denote H, F, Cl, Br, CF3, phenyl, COOH, COO-(C1-C6)-alkyl, (C1-C6)-alkyl; R2, R4 independently denote H, F, Cl, Br, CF3; R7, R8, independently denote H or (C1-C6)-alkyl; X denotes (C2-C3)-alkylene, which can be monosubstituted or multisubstituted with R11; m equals 0; R6 denotes OH, F, Cl, Br, CN, OCH3; OCF3, CH3, CF3, (C1-C6)-alkyl or O-(C1-C6)-alkyl, and the alkyl can be monosubstituted or multisubstituted with OH, F, Cl, Br or CN; R11 denotes (C2-C6)-alkynyl; R12 denotes (C1-C6)-alkyl; and physiologically acceptable salts thereof.

EFFECT: disclosed compounds have activity towards the GPR40 receptor and are suitable for preparing a medicinal agent for reducing blood sugar level, treating diabetes, increasing insulin release, treating diseases of the central nervous system, treating schizophrenia and Alzheimer's disease.

19 cl, 2 tbl, 35 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (3) which can be used in the method for synthesis of precursors to immunological adjuvant E6020. In formula (3), R1, R2, R3 denote a C5-C15 alkyl group, C5-C15 alkenyl group or C5-C15 alkynyl group. The invention also relates to compounds of formula (4), which can also be used in synthesis of precursors to said adjuvant. In formula (4) R4 is a C1-C6 alkyl group, C3-C5 alkenyl group, C3-C5 alkynyl group, cycloalkyl group, ethyl group substituted in position 2, halogen ethyl group, aryl group, benzyl group or silyl group; R5, R6 independently denote a C1-C6 alkyl group, C3-C6 alkenyl group or C3-C6 alkynyl group; or R5 and R6 together a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring.

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34 cl, 8 dwg, 2 tbl, 6 ex

FIELD: chemistry.

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EFFECT: method cuts the duration of the process, lowers the temperature thereof and increases the output of the end product.

3 cl, 2 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new method for production of m- or p-substituted α-arylalkanecarboxylic acids of general formula I

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EFFECT: new α-arylalkanecarboxylic acids and intermediates thereof.

6 cl, 5 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to synthesis of 1,3-dicarbonyl compounds and to a new method for preparing 4-substituted alkyl-3-oxobutanoates of the formula: wherein: R is C6H5CH2, 2-F-6-ClC6H3CH2, 2,6-Cl2C6H3CH2, 1-C10H7CH2, Ph2CH; Alk is Me; R is 1-AdCH2; Alk is i-Pr that are used precursors of antiviral agents of pyrimidine order. Method involves acylation of 2,2-dimethyl-1,3-dioxane-4,6-dione with acyl chlorides in dichloromethane in the presence of triethylamine followed by alcoholysis of 5-(1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione wherein acylation is carried out with acyl chlorides in the presence of trimethylsilyl chloride in the mole ratio 2,2-dimethyl-1,3-dioxane-4,6-dione : acyl chloride : trimethylsilyl chloride : triethylamine = (1-2):1:1.1:3.5, respectively, with formation of an intermediate product 5-[1-(trimethylsilyloxy)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione that is subjected for hydrolysis with formation of 5-(1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione and its following alcoholysis and formation of the end product. Method provides enhancing yield and purity of claimed compounds.

EFFECT: improved method for preparing.

2 cl, 8 ex

FIELD: organic chemistry, perfumery.

SUBSTANCE: invention relates to an aromatizing composition containing at least compound of the formula (I): as an active component wherein values w, m, P, X, G, Q and n are given in claim 1 of the invention description, and one or more aromatizing component. Also, invention relates to a method for improving, enhancing or modifying odor, to a method for aromatizing surface, method for enhancing or prolonging the diffusion effect of component on surface and to novel compounds of the formula (I) with exception of compounds enumerated in claim 10 of the invention description and to invention relating to aromatizing article using compounds of the formula (I).

EFFECT: valuable cosmetic properties of compounds.

13 cl, 14 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel intermediate compounds and inmproved method for synthesis of compound of the formula (C): . Proposed method is based on using inexpensive parent substances and provides synthesis of intermediate compounds with the high yield and high purity degree being without carrying out procedures for chromatographic purification and can be realized in large-scale industry manufacture. Invention relates to improved methods for synthesis of compound of the formula (I): , compound of the formula (II): , compound of the formula (III): , compound of the formula (VIII): , compound of the formula (IX): , and to a reagent consisting of boron tribromide and 2,6-dimethylpyridine. Method is used for a sparing and selective splitting a methyl group in aromatic methyl ethers.

EFFECT: improved method of synthesis.

12 cl, 8 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to photoinitiating agents of phenylglyoxylic acid order used in polymerizing compositions to be subjected for hardening. Invention describes a photoinitiating agent of the formula (I): wherein Y means (C3-C12)-alkylene, butenylene, butinylene or (C4-C12)-alkylene that are broken by groups -O- or -NR2- and not following in sequence; R1 means a reactive group of the following order: -OH, -SH, -HR3R4, -(CO)-OH, -(CO)-NH2, -SO3H, -C(R5)=CR6R7, oxiranyl, -O-(CO)-NH-R8-NCO and -O-(CO)-R-(CO)-X; R2 means hydrogen atom, (C1-C4)-alkyl, (C2-C4)-hydroxyalkyl; R3 and R4 mean hydrogen atom, (C1-C4)-alkyl, (C2-C4)-hydroxyalkyl; R, R and R mean hydrogen atom or methyl; R8 means linear or branched (C4-C12)-alkylene or phenylene; R9 means linear or branched (C1-C16)-alkylene, -CH=CH-, -CH=CH-CH2-, C6-cycloalkylene, phenylene or naphthylene; X, X1 and X2 mean -OH, Cl, -OCH3 or -OC2H5. Also, invention describes a method for synthesis of a photoinitiating agent, polymerizing composition and substrate covered by its. Proposed photoinitiating agent possesses the effective introducing capacity and absence of migration in thermal treatments.

EFFECT: improved and valuable properties of agent.

13 cl, 1 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: novel compounds of formulas , , , , , , (designation of all groups are given in invention formula) are used for treatment of different metabolic diseases, such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver, cachexia, obesity, atherosclerosis and arteriosclerosis.

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124 cl, 52 ex, 17 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: present invention refers to the new benzotropolone derivatives of general structural formula (A) as well to their pharmaceutically acceptable salts possessing anti hiv-activity, to the pharmaceutical composition thereof and to the method of HIV-integrase inhibition. formula (A) where R1 is selected from the group consisting of the hydrogen and halogen; R2 is selected from the group consisting of the hydrogen and OC1-6alkyl; each of R3, R4, R5 independently is hydrogen; G is selected from the group consisting of the structures I, II; R6 is hydrogen; R7 is COOR9; R8 is selected from C1-6alkyls substituted with one or more halogen atoms; W is O; R9 is selected from hydrogen or C1-6alkyl. The structures I, II are represented in the formula of invention.

EFFECT: claimed compounds possess anti HIV-activity.

5 cl, 6 dwg, 13 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new benzotropolone derivatives of general structural formula (A) as well to their pharmaceutically acceptable salts which are able to inhibit the replication of HIV-virus, to pharmaceutical composition thereof and to the method of inhibition of HIV-virus replication. formula (A) where R1 is hydrogen; R2 is OC1-6alkyl; each of R3, R4, R5 independently is hydrogen; G is selected from the group consisting of the structures I, II; R6 is hydrogen; R7 is (CH2)bCOOR9 where b takes up the integer values from 1 to 5; R8 is selected from C1-6alkyls substituted with one or more halogen atoms; W is O; R9 is selected from hydrogen or C1-6alkyl. The structures I, II are represented in the formula of invention.

EFFECT: claimed compounds inhibit the replication of HIV-virus.

4 cl, 6 dwg, 7 ex

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