Derivatives of 2-imino-benzothiazoline, their enantiomers in the presence of an asymmetric center and their acid-additive pharmaceutically acceptable salts and pharmaceutical compositions on their basis

 

(57) Abstract:

The essence of the invention: derivatives of 2-aminobenzothiazole f-ly I, where R1-polyflor C1-C4alkyl or polyflor C1-C4alkoxygroup, R2group f-ly CH2[CH(R4)]n-R3where R3-qu-(C1-C4) alkylamino, 1-piperidinyl, 1-pyrrolidinyl, mercaptopropyl, C1-C4alltihopa, C1-C4allylthiourea, C1-C4alkylsulfonyl or C1-C4alkylsulfonyl: R4is a hydrogen atom or a C1-C4alkyl and n=0 or 1: or R2group f-crystals II, their enantiomers in the presence of asymmetric centre, their acid-additive pharmaceutically acceptable salt or pharmaceutical composition thereof. Connection structure of f-crystals I and II (see drawing). 2 S. p. f-crystals, 1 Il.

The invention relates to new derivatives of 2-aminobenzothiazole, and to their use in pharmaceutical compositions having activity against convulsions induced by glutamate.

From the literature known compound 2-amino-6-cryptomaterial with antiglutamate activity. However, the activity of this compound is not enough videosto.

Goal is achieved by derivatives of 2-aminobenzothiazole formula I

= NH (I) in which R1represents polyflor (C1-C4) alkyl or polyflor (C1-C4) alkoxygroup;

R2means or the group CH2[CH (R4)]nR3where

R3denotes di (C1-C4) alkylamino,

1-piperidinyl, 1-pyrrolidinyl, mercaptopropyl, (C2-C4) alltihopa, (C1-C4) allylthiourea (C1-C4) alkylsulfonyl or (C1-C4) alkylsulfonyl;

R4denotes a hydrogen atom or (C1-C4) alkyl and n is 0 or 1; or a group of formula II

CH2-CH2-S-S-CH2-CHN (II)

where R1has the specified values, their enantiomers in the presence of an asymmetric center and their acid-additive pharmaceutically acceptable salts.

The compounds of formula I, except those in which R2means a group of formula II, and R3denotes a radical alkylsulfanyl, alkylsulfonyl or mercaptopropyl can be obtained by reacting the amino derivatives of formula III

(III) in which R1has the specified values on derivatives of the formula

This reaction is usually conducted in an inert organic solvent such as alcohol (ethanol, propanol), ketone (acetone or methyl ethyl ketone) or dimethylformamide, at a temperature of from 10aboutC to the boiling point of the solvent, if necessary in the presence of sodium iodide or, if necessary, after melting a mixture of compounds of formulas (III) and (IV) at 130-140aboutC. the compounds of formula (I) in which R2is the chain-CH2-[CH(R4)]n R3in which R3is alkylsulfonyl or alkylsulfonyl radical, R4and n are defined above, can be obtained by oxidation of the corresponding derivative for which R3represents a radical of alkylthio.

Oxidation to alkylsulfanyl usually performed using m-chloroperbenzoic acid, in an environment of alcohol, for example methanol or ethanol, at a temperature of about -20aboutC.

Oxidation to alkylsulfonyl usually performed using hydrogen peroxide in acetic acid medium, at a temperature of about 100aboutS, Il is IU, at a temperature of about 20aboutC.

In accordance with the invention the compounds of formula (I) for which R2represents a chain of CH2-[CH(R4)]n-R3in which R3represents a mercapto radical, R4and n are defined above, can be obtained by hydrolysis of the corresponding derivative in which R3represents the radical tert-butylthio. This hydrolysis is usually carried out using Hydrobromic acid at a temperature of about 110aboutC.

The compounds of formula (I) and their salts are active against convulsions induced by glutamate, therefore, may find use in the treatment and prevention of convulsive phenomena, schizophrenic disorders, in particular deficient forms of schizophrenia, sleep disorders, phenomena associated with cerebral ischemia, as well as those of neurological disorders, which may be administered glutamate, for example in the cases of Alzheimer, Huntington's disease, side amiotroficheskii sclerosis and olivopontocerebellar atrophy.

The activity of compounds of the formula (I) in relation to convulsions induced by glutamate was determined by the method of [1] introduction glutamate in the brain ventricle of osushestvleniya formula (I) have low toxicity. The rate DL50exceed 15 mg/kg entrepreneuralism introduction in mice.

In the pharmaceutical compositions of the compounds of formula (I) can be used as they are or in the form of pharmaceutically acceptable salts, i.e., non-toxic, in acceptable doses.

As an example, pharmaceutically acceptable salts can be called additive salts with inorganic or organic acids, such as propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isothionate, theophyllinate, salicylate, phenolphthalein, methylene-bis-xinafoate, hydrochloride, sulfate, nitrate and phosphate.

P R I m e R 1. 7 g of 2-amino-6-cryptomaterial and 4.8 g of 2-chloro-N, N-dimethylethylamine heated for 1 h at 130aboutC. Add 10 cm32-propanol, and continue heating at boiling for 20 hours, After cooling to a temperature of about 20aboutWith the reaction medium was concentrated at 40aboutWith under reduced pressure (20 mm RT.article 2,7 kPa), the residue is treated with 40 cm31 N. lye sodium. After extraction 100 cm3dichloromethane, drying over magnesium sulfate and concentration under 40aboutWith under reduced pressure the residue is chromatographically purified on silicagel is 2-amino-6-triphtalocyaninine - Zolina in the form of a yellowish oil, which is transferred to dichlorhydrate, which sublimates at 200aboutC. 2-Amino-6-cryptomaterial can be obtained by the method of [3]

P R I m m e R 2. 9.4 g of 2-amino-6-cryptomaterial and 8.1 g of the hydrochloride of N-(2-chloroethyl) piperidine is heated for 1 h at 130aboutC. Then add 20 cm3of dimethylformamide and continue the reaction for 24 h at 130aboutC. After cooling to a temperature of about 20aboutWith the precipitate is filtered, then treated with 50 cm31 N. lye sodium 100 cm3of distilled water. After extraction with dichloromethane, drying over magnesium sulfate and concentrating to dryness under reduced pressure (20 mm RT.article 2,7 kPa), the residue is chromatographically purified in a column with silica gel, as eluant using first ethyl acetate and then a mixture of ethyl acetate with methanol (95-5 by volume). Obtain 2.9 g of 2-imino-3-(2-piperidinoethyl)-6-triphtalocyaninine in the form of a yellow oil, which was transferred to dichlorhydrate, which sublimates at 200aboutAfter recrystallization in 20 cm3in boiling absolute alcohol.

P R I m e R 3. 9.4 g of 2-amino-6-cryptomaterial and 7.5 g of the hydrochloride of N-(2-chloroethyl)pyrrolidine heated for 2 h at 130aboutaboutWith the precipitate is filtered, then treated with 20 cm31 N. lye sodium 100 cm3of distilled water. The residue obtained after extraction with dichloromethane, drying over magnesium sulfate and concentrating to dryness under reduced pressure (20 mm RT.article 2,7 kPa) consume 50 cm3ethyl ether and treated with 3.1 cm34,2 N. hydrochloric ether. After recrystallization 50 cm3boiling 2-propanol gain of 1.9 g of 3-[2-(1-pyrrolidinyl)ethyl]-2-amino-6-triphtalocyaninine, which melts at a temperature above 260aboutC.

P R I m e R 4. A mixture of 40 g of 2-amino-6-cryptomaterial and 22.2 g of 1-chloro-2-methylthioethyl 250 cm3methyl ethyl ketone is heated under refluxing for 18 h, then cooled to a temperature of about 20aboutC. the Formed precipitate was filtered, and the filtrate concentrated at 40aboutWith under reduced pressure (20 mm RT. Art. of 2.7 kPa) to a volume of about 100 cm3. Then the reaction continue boiling for 72 h, after cooling to a temperature of about 20aboutWith the new filter the obtained precipitate and attach to your earlier draft. After washing 200 cm3ethyl ether get to 31.9 g of the hydrochloride of 2-imino-3-(2-methylthioethyl)-6-Formatexception and 5.5 g of 1-chloro-2-ethylthioethyl 20 cm3methyl ethyl ketone is heated at boiling for 15 h Formed precipitate is filtered hot, washed with 2 times 20 cm3boiling methyl ethyl ketone. Gain of 11.5 g of the hydrochloride of 3-(2-ethylthioethyl)-2-imino-6-triptoreline - isothiazoline, which sublimates at 160aboutC.

P R I m e R 6. 1.5 g of the hydrochloride of 3-(2-tert-butylthioethyl)-2-imino-6-triptoreline - benzothiazoline and 15 cm3Hydrobromic acid (47%) are heated for 4 h at 100aboutC. After cooling to 0aboutWith the formed precipitate is filtered, washed with 2 times 25 cm3distilled water, then 2 times 30 cm3ethyl ether. Obtain 0.9 g of bromhidrosis 2-(2-imino-6-triptoreline-3-benzothiazoline)ethanthiol, which melts at 180aboutC. the Hydrochloride of 3-(2-tert-butylthioethyl)-2-imino-6-triphtalocyaninine can be obtained by the following procedure: 9.4 g of 2-amino-6-cryptomaterial and 6.7 g of 2-chloro-1-tert-butylthiourea 30 cm3methyl ethyl ketone is heated at boiling within 42 hours After cooling the reaction medium to the 0aboutWith the formed precipitate is filtered and washed with 2 times 20 cm3methyl ethyl ketone. Obtain 3.7 g of the hydrochloride of 3-(2-tert-butylthioethyl)-2-imino-6-triphtalocyaninine, which is on, 10.3 cm330% hydrogen peroxide and 70 cm3acetic acid is heated at 100aboutWith within 24 hours After cooling to a temperature of about 20aboutWith the reaction medium was injected into 200 cm3distilled water, cooled to 0aboutWith handle 120 cm330% alkali sodium, then extracted with 300 cm3ethyl acetate. The organic phase is washed with 150 cm3distilled water, then 2 times 150 cm3an aqueous solution of distilled water, then 2 times 150 cm3an aqueous solution of sodium bisulfite, dried over magnesium sulfate and concentrated to dryness under reduced pressure (20 mm RT.article 2,7 kPa). After the formation of the hydrochloride by adding 16 cm31 N. hydrochloric acid in 25 cm3chloroform gain of 1.9 g of the hydrochloride of 3-(2-ethylsulfonyl)-2-imino-6-triphtalocyaninine, which melts at 212aboutC.

P R I m e R 8.

To 1.7 g of 3(2-ethylthioethyl)-2-imino-6-triphtalocyaninine 25 cm3absolute ethanol cooled to -20aboutWith add 0.9 g m-chloroperbenzoic acid for 10 minutes the Reaction continued at the same temperature for 30 minutes the precipitate Formed is filtered, then treated with 50 cm3ethyl is-(2-ethylsulfinyl)-2-amino-6-triphtalocyaninine (RS), which melts at 174aboutC.

P R I m e R 9. Working as in example 8, but take 3.7 g of 2-imino-3-(2-methylthioethyl)-6-triphtalocyaninine and 2.3 g of m-chloroperbenzoic acid in 60 cm3absolute ethanol. After soaking for 30 min at -20aboutWith the formed precipitate was filtered, and the hydrochloride receive 60 cm3of acetone. Receive in the form of enantiomers 1.5 g of the hydrochloride of 2-imino-3-(2-methylsulfinylphenyl)-6-triphtalocyaninine (RS), which melts at 186aboutC. the resulting enantiomers separated by high-performance liquid chromatography on chiral phase CHIRACEL [Tris(3,5-dimethylphenylcarbamate)cellulo -] manufactured by DAICEL, with a mixture of ethano-hexane (20-80 V/V) as eluant.

Two enantiomers have the following characteristics:

the enantiomer (+) D +57o(1, it)

so pl. 125aboutWITH

the enantiomer (-) D -59o(1, Et)

So pl. 130aboutWITH

P R I m e R 10. 6,55 g 2-amino-6-triftoratsetofenona and of 7.48 g of 1-chloro-2-ethylthioethyl 20 cm3methyl ethyl ketone is heated under refluxing for 18 h, then the mixture is cooled to a temperature of about 20aboutC. After concentration to dryness at 50aboutWith under reduced pressure (20 mm RT.article 2,7 50 cm32-propanol. Obtain 3.1 g of the hydrochloride of 3-(2-ethylthioethyl)-2-imino-6-trifluoromethyl of benzothiazoline, which sublimates at 160aboutC.

P R I m e R 11. 16,8 g of the hydrochloride of 3-(2-tert-butylthioethyl)-2-imino-6-triptime - oxibendazole and 500 cm348% Hydrobromic acid is heated at 120aboutC for 18 hours the Formed precipitate is filtered, washed with 2 times 50 cm3distilled water, then 2 times 50 cm3ethyl ether. Obtain 10.0 g of debrominate disulfide bis-2-[2-imino-6-triptoreline-3-benzothiazoline]ethyl, melting point above 260aboutC.

P R I m e R 12. A mixture of 16.4 g of 2-amino-6-cryptomaterial and 8.1 g of chloromethylated and metilsulfate 30 cm3methyl ethyl ketone is stirred for 9 h at 20aboutC. the precipitate Formed is filtered and recrystallized 2 times in absolute ethanol. Obtain 5.5 g of the hydrochloride of 2-imino-3-methylthiomethyl-6-Cryptor - methoxybenzothiazole, which sublimates at 170aboutC.

P R I m e p 13. at 3.35 g of the Hydrochloride of 2-imino-3-methylthiomethyl-6-cryptomaterial - sitesonline added to 7.6 g of m-chloroperbenzoic acid in solution in 70 cm3dichloromethane, cooled to 0aboutC. the Reaction continues the atrium until neutral, and the organic phase is extracted with ethyl acetate. After chromatographic purification on a column of silica gel, as eluant uses a mixture of ethyl acetate and methanol (90-10 by volume), obtain 1.0 g of 2-imino-3-methylsulfonylmethyl-6-triptoreline - isothiazoline (RS), which is transformed into the form of the hydrochloride, which sublimates at 150-155aboutC.

P R I m e R 14. A mixture of 9.4 g of 2-amino-6-cryptomaterial and 6.1 g of 1-chloro-2-propylthiourea 30 cm3methyl ethyl ketone is maintained at boiling for 72 hours precipitate Formed is filtered off, washed with 2 times 20 cm3methyl ethyl ketone and recrystallized from 30 cm32-propanol. Obtain 5.8 g of the hydrochloride of 2-imino-3-(2-propylthiouracil)-6-triphtalocyaninine, which melts at 187aboutC.

P R I m e R 15. To 3.4 g of 2-imino-3-(2-methylsulfinylphenyl)-6-tripterococcus - thiazoline (RS) 70 cm3dichloromethane, cooled to 0aboutTo add 2.1 g m-chloroperbenzoic acid for a period of approximately 5 minutes the Reaction continued for 30 min at the same temperature. Formed precipitate is filtered off, then absorb a mixture of 100 cm3dichloromethane and 15 cm3absolute ethanol and treated with 6 cm34 N. of chlorestol therouanne water obtain 2.3 g of the hydrochloride of 2-imino-3-(2-methylsulfonylmethyl)-6-triptoreline - isothiazoline, which sublimates at 210aboutC.

P R I m e R 16. To 3.0 g of the hydrochloride of 3-(2-ethylthioethyl)-2-imino-6-trifluoromethyl - benzothiazoline in suspension 75 cm3dichloromethane, cooled to 0aboutWith, gradually add 6.6 g m-chloroperbenzoic acid. The reaction is carried out for 2 h at 20aboutC. the precipitate Formed is filtered, then recrystallized in 20 cm32-propanol. Obtain 0.8 g of the hydrochloride of 3-(2-ethylsulfonyl)-2-imino-6-triftoratsetofenona, which sublimates to 180aboutC.

P R I m e R 17. To by 5.87 g of 2-imino-3-(2-propylthiouracil)-6-tripterococcus - thiazoline in solution with 80 cm3absolute ethanol, cooled to -35aboutWith add for a period of approximately 10 min 4.3 g 70-75% m-chloroperbenzoic acid. The reaction continued for 10 min at the same temperature. Then the reaction mixture was added to 300 cm3ethyl ether and treated with 4.2 cm34,2 N. hydrochloric ether. Formed precipitate is filtered off, then absorb 50 cm3distilled water and neutralized 1 N. lye sodium. After extraction with ethyl acetate, drying over magnesium sulfate and concentrating to dryness under reduced pressure (20 mm RT.article 2,7 kPa) ProductName (90-10 by volume) as allentow. After conversion into the hydrochloride obtain 0.33 g of the hydrochloride of 2-imino-3-(2-propylsulfonyl)-6-triptime - moxibustion, which sublimates at 200aboutWith, and 2,63 g of the hydrochloride of 2-imino-3-(2-propylsulfonyl)-6-triptime - moxibustion (RS), which melts at 125aboutC.

P R I m e R 18. 14.2 g of 2-amino-6-cryptomaterial and 13.2 g of 2-bromo-1-methylthiophene 30 cm3methyl ethyl ketone is heated for 3 hours at the boil. Formed precipitate is filtered off, washed with 2 times 50 cm3methyl ethyl ketone and recrystallized in 50 cm32-propanol. Get 11.5g of bromhidrosis 2-imino-3-(2-methylthiouracil)-6-triptoreline - isothiazoline (RS), which sublimates to 180aboutC.

2-Bromo-1-methylthiophene can be obtained by the following method: to a 27.6 g of 1-methylthio-2-propanol, cooled to 0aboutWith add dropwise 9 ml of tribromide phosphorus. The reaction is performed for 4 h at the same temperature, then the reaction medium was hydrolized by slowly adding 50 cm3of distilled water. After extraction with ethyl ether, drying, filtering and concentrating to dryness under reduced pressure (20 mm RT.article 2,7 kPa) gain of 13.2 g of 2-bromo-1-methylthiopropionate sodium, stir at a temperature of 20aboutWith 100 cm3absolute ethanol is added dropwise 21.3 cm31-chloro-2-propanol. The reaction mixture was then heated at boiling temperature for 3 hours After concentration to dryness under reduced pressure, the residue is extracted with 300 cm3ethyl acetate, the organic phase is washed with distilled water, then dried, filtered and concentrated to dryness under reduced pressure. Get to 19.8 g of 1-methylthio-2-propanol as a yellow oil.

P R I m e R 19. To 6.2 g of 2-imino-3-(2-methylthiouracil)-6-triphtalocyaninine - Zolina (RS) 80 cm3absolute ethanol, cooled to -40aboutWith add for 10 min 4,74 g of 70% m-chloroperbenzoic acid. The reaction continued for 10 min at the same temperature. In the reaction medium was added 200 cm3ethyl ether and treated with 5 cm34,2 N. hydrochloric ether. Formed precipitate is filtered off, then absorb 50 cm3distilled water and treated with an aqueous alkali solution of sodium until neutral. After extraction with ethyl acetate and normal processing gain of 6.7 g of the crude product, which was chromatographically purified on a column of silica gel using phenylpropyl)-6 - triphtalocyaninine, hydrochloride which sublimates 200aboutWith 1.3 g of 2-imino-3-(2-methylsulfinylpropyl)-6-triphtalocyaninine (isomer A), the hydrochloride of which sublimates 200aboutWith, and 0.8 g of 2-imino-3-(2-methylsulfinylpropyl)-6-triphtalocyaninine (isomer B), the hydrochloride of which melts at 134aboutC.

P R I m e R 20. 3.0 g of 3-(2-acetylethyl)-2-vinyloxycarbonyl-6-triptime - moxibustion 30 cm3acetic acid is stirred at a temperature of about 20aboutC for 18 h in the presence of 3 cm347% Hydrobromic acid. After adding 100 cm3distilled water and neutralization using 30% alkali sodium, extraction with ethyl acetate and subsequent conventional processing gain of 1.2 g of oil which crystallized. After the formation of the hydrochloride in a mixture of ethyl ether and ethyl acetate and by treatment with hydrochloric ether are recrystallization in ethyl acetate, to obtain 0.5 g of the hydrochloride of 3-(2-acetylethyl)-2-imino-6-triftormetilfosfinov - Lin, which sublimates to 160aboutC.

3-(2-acetylethyl)-2-vinyloxycarbonyl - solimano-6-triftormetilfosfinov - Lin can be obtained in the following way: 17,6 g triphenyltetrazolium. Stirring is continued at this temperature for 30 minutes Then slowly add a solution of 4.8 cm3thioglucose acid and 11.7 g of 3-(2-hydroxyethyl)-2-vinyloxycarbonyl-6-three - formatexception 75 cm3tetrahydrofuran (THF). The reaction is continued at 0aboutC for 1 h, and then for 1 h at 20aboutC. After concentration to dryness under reduced pressure (20 mm RT.article 2,7 kPa) obtained residue absorb 50 cm3methanol, then filtered and washed 1 time 50 cm3of methanol. Obtain 10.4 g of 3-(2-acetylethyl)-2-vinyloxycarbonyl-but-6-triphtalocyaninine which melts at 173aboutC.

3-(2-Hydroxyethyl)-2-vinyloxycarbonyl - limina-6-triftormetilfosfinov can be obtained by the following method: to 20 g of 3-(2-hydroxyethyl)-2-imino-6-triptorelin - dibenzothiazepine dissolved in 200 cm3dichloromethane, in the presence of 7.9 cm3of triethylamine is added dropwise at 0aboutWith 4.8 cm3vinyloxycarbonyloxy. Mixing is carried out at 20aboutC for 2 h Formed precipitate is filtered, washed with water and dried. Get 11.7 g of 3-(2-hydroxyethyl)-2-vinyloxycarbonyl-6-triptorelin - dibenzothiazepine, which melts at 1903absolute ethanol is heated for 95 hours at the boil. The mixture is cooled to a temperature of about 20aboutC. the Formed precipitate was filtered and washed with 100 cm3ethyl ether. Get 6.4g of bromhidrosis 3-(2-hydroxyethyl)-2-imino-6-cryptomaterial, which melts at 219aboutC.

P R I m e R 21. To a cooled to -5aboutWith a solution of 0.4 g of 3-(2-ethylthioethyl)-2-imino-6-dataformatexception 6 cm3dichloromethane added with stirring for 15 min the solution, dried over magnesium sulfate and received from 0.75 g of 50% m-chloroperbenzoic acid and 5 cm3dichloromethane. Stirring is carried out for 1 h, keeping the temperature between -5 and 0aboutC, then filtered to remove the resulting benzoic acid, and then the filtrate is diluted with 50 cm3ethyl ether and acidified with ethereal solution of 5 G. hydrochloric acid. Obtain 0.25 g of the hydrochloride of 3-(2-ethylsulfonyl)-2-imino-6-pentafluorobenzonitrile, which melts at 230aboutC.

3-(2-Ethylthioethyl)-2-imino-6-pentaho - methoxybenzothiazole can be obtained by the following method: heated on an oil bath at 110aboutC for 25 h in a mixture of 0.5 g of 6-pentaverate-2-benzothiazoline, 15 cmWith under reduced pressure (20 mm RT.article 2,7 kPa), the residue from the evaporation process 30 cm3water, alkalinized 28% hydroxide ammonium and extracted 3 times with 60 cm3ethyl ester as a whole. After evaporation under reduced pressure (20 mm RT.article 2,7 kPa), the residue is dark red (0.7 g) chromatographically purified on a column of silica gel, eluant - a mixture of cyclohexane and ethyl acetate (70-30 by volume). Gain of 0.42 g of 3-(2-ethylthioethyl)-2-imino-6-pentafluorobenzonitrile in the form of oil, which crystallizes with a melting point of less than 50aboutC.

6 Pentaverate-2-benzothiazole can be obtained by the following method: to a solution of 4.8 g of 4-pentafluorostyrene 35 cm3acetic acid is added in an argon atmosphere of 8.15 g of potassium thiocyanate and stirred for 10 min at a temperature of about 20aboutC. To the thus obtained solution was added dropwise over 35 min a solution of 1.1 cm3bromine in 10 cm3acetic acid at a temperature of from 22 to 42aboutC, then stirred for 20 h at a temperature of about 20aboutC. the Reaction mixture was poured into a mixture of water and ice (250 cm3), alkalinized 50 cm328%-aqueous hydroxide ammonium and extracted 2 times with 250 the hell magnesium sulfate, filtered and evaporated at 50aboutWith under reduced pressure (20 mm RT.article 2,7 kPa). The resulting product (6.3 g) chromatographically purified on a column of silica gel (650 g, grain size distribution 0,063-0,200 mm), as eluant uses a mixture of cyclohexane and ethyl acetate (50-50 by volume) and recrystallized 400 cm3boiling cyclohexane. Obtain 3.25 g of 6-pentaverate-2-benzothiazoline, which melts at 156aboutC.

P R I m e R 22. Conduct operations as in example 21, take 6.6 g of 3-(2-ethylthioethyl)-2-imino-6-pentafluorobenzonitrile, 12 g metallocarboranes acid (80% ) and 200 cm3dichloromethane. After chromatography on a column of silica gel, eluent-ethyl acetate, to obtain 2.6 g of a pink solid, which is recrystallized twice in a mixture of cyclohexane and ethyl acetate (80-20 by volume). Receive 1 g of 3-(2-ethylsulfonyl)-2-imino-6 - pentafluorobenzonitrile, which melts at 125aboutC.

3-(2-ethylthioethyl)-2-imino-6-pentaho - nativisation can be obtained by the following method: heated under reflux for 18 h the mixture of 11.2 g of 6-pentafluoroethyl-2-benzothiazoline, 6 cm32-chloridesulfate and ethylsulfate and 20 cm3methyl ethyl ketone. Then dissolve the odes, alkalinized 28% hydroxide of ammonia, and extracted with a total number of 500 cm3ethyl acetate. After evaporation under reduced pressure (20 mm RT.article 2,7 kPa) orange residue is chromatographically purified on a column of silica gel, eluant-a mixture of cyclohexane and ethyl acetate (60-40 by volume). Get 7.5 g of 3-(2-ethylthioethyl)-2-imino-6-pentafluoroethyl - benzothiazoline in the form of an oil which crystallized, and receive a melting point less than 50aboutC.

6-Pentafluoroethyl-2-benzothiazole can be obtained by carrying out the operation as in example 21 when receiving 6 pentaverate-2-benzothiazoline, but take 14.6 g of 4-panafcortelone, 14 g of potassium thiocyanate and 3.6 cm3bromine in 150 cm3of acetic acid. After purification through column chromatography with silica gel eluent-a mixture of cyclohexane and ethyl acetate (50-50 by volume) to obtain 17 g of 6-pentafluoroethyl-2-benzothiazoline, which melts at 100aboutC.

P R I m e R 23. To a cooled to -5aboutFrom 30.8 g of a solution of 2-imino(2-ethylthio)-3-ethyl-6-triftoratsetofenona 300 cm3dichloromethane, is added dropwise with stirring, dried over magnesium sulfate solution obtained from 38 g of meta-chloroperbenzoic acid (50%) and 300 cm3dig deliciuous to pH 10 with 28% aqueous hydroxide ammonium, appeared a white precipitate is removed by filtration, the filtrate is decanted and the organic phase is dried over magnesium sulfate and evaporated under reduced pressure ( 20 mm RT.article 2,7 kPa).

After evaporation the residue chromatographic on a column of silica, elwira a mixture of ethyl acetate and ethanol (about 80-20.). Get 26 grams of solid cream color, which is transferred into the hydrochloride in the environment of ethyl ether. After three kristallizatsii in ethanol obtain 2.9 g of the hydrochloride of 2-imino-ethylsulfinyl-3-ethyl-6-triftormetilfosfinov (RS), melting at 150aboutC.

2-Imino-(2-ethylthio)-3-ethyl-6-Cryptor - methylbenzothiazole can be obtained as follows.

Heated under reflux for 16 h the mixture and 32.3 g of 6-trifluoromethyl-2-benzothiazoline, 18 cm32-chloridesulfate and ethylsulfate and 20 cm3methyl ethyl ketone. After cooling to 20aboutWith add 20 cm3acetone and the resulting solution was poured into a mixture of 200 cm3ethyl acetate and 200 cm3petroleum ether (40-60aboutC). Pop the precipitate is filtered, diluted with water and alkalinized 28% hydroxide ammonium. The base is extracted with a mixture of 150 cm3ethyl acetate and 150 cm3cyclohexane and clean it on to the o-(2-ethylthio)-3-ethyl-6-triftoratsetofenona, melting at 50aboutC.

The compounds of formula (I) form part of the pharmaceutical compositions that include any other pharmaceutically compatible products, which can be inert or physiologically active. The composition can be applied oral, parenteral, rectal or topical route.

As solid compositions for oral administration can use tablets, pills, powders (gelatin capsules, pills or granules. In these compositions, the active substance in accordance with the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica.

In these compositions can also contain substances other than diluents, for example one or more lubricants like magnesium stearate or talc, tinted substance, protective coating, glaze.

As liquid compositions for oral administration can be applied solutions, suspensions, emulsions, syrups and elixirs, pharmaceutically acceptable, which contain inert diluents as water, ethanol, glycerol, vegetable oils or paraffin oil. In these compositions may also comprise other substances 2">

For parenteral administration, sterile compositions can be preferably non-aqueous solutions, suspensions or emulsions. As solvent or base you can use water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive, organic esters for injection, for example etiloleat, or any other suitable organic solvents. In these compositions can also be additives, for example wetting agents, isotonic, emulsifying, dispersing or stabilizing agents. Sterilization can be done in various ways, for example asamisimasa filtering, by introducing a sterilizing composition of substances by irradiation or heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or other sterile environment for injection.

Compositions for rectal injection are candles or rectal capsules which contain, besides the active substance, excipients (indiferente substances), such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Compositions for topical introduction may be in the>In the treatment of people connection in accordance with the invention is particularly useful in the treatment and prevention of convulsive phenomena, schizophrenic disorders, in particular deficient forms of schizophrenia, sleep disorders, phenomena associated with cerebral ischemia and neurological diseases, which can be assigned glutamate, such as disease Alzheimer, Huntington's disease side amiotroficheskii sclerosis and olivopontocerebellar atropia.

Doses depend on the desired effect, the duration of treatment and used as a way of introduction, usually the dose from 30 to 300 mg / day in oral introduction for adults, with a single dose of 10 to 100 mg of active substance.

Typically, the physician determines the appropriate dosage depending on the age, weight and all other factors related to the treatment.

The following examples illustrate compositions in accordance with the invention.

P R I m e R A. In the usual manner made pills containing 50 mg of active substance, which have the following composition, mg: (ethylsulfinyl-2-ethyl)-3-imino-2-triptoreline-6-benzothiazolin 50; cellulose 18; lactose 55; silica gel 1; sodium carboxymethylamino 10; talc 10; walls the substances, the following composition, mg: imino-(2-methylthio-2-ethyl)-3-triptoreline-6-benzothiazolin 50; lactose 104; cellulose 40; polyvidone 10; sodium carboxymethylamino 22; talc 10; magnesium stearate 2; silica gel 2; a mixture of hydroxymethylcellulose, glycerin, titanium oxide (72-3,5-24,5) quantity sufficient for 1 tablet coated with a layer of, 245.

P R I m e R C. Prepare the solution for injection contains 10 mg of active substance of the following composition, mg: (ethylsulfonyl-2-ethyl)-3-imino-2-triptorelin - si-6-benzothiazolin 10; benzoic acid 80; benzyl alcohol 0,06 cm3; sodium benzoate 80; ethanol 95% 0.4 cm3; sodium hydroxide 24; propylene glycol 1.6 cm3; water, a sufficient quantity to 4 cm3.

Description pharmacological tests.

1. Convulsions induced by glutamate.

Used of male rats breed Sprague-Dawley/CD Charles River (mass 170-210 g Glutamate) 2.5 mmol per rat odnonatrieva salt of L-glutamic acid varieties Sigma was dissolved in saline and injected in a volume of 10 µl per rat through the ventricle of the brain according to the method of [1] the Test substance was administered in a volume of 5 ml/kg for half an hour before injection of glutamate (12.5 mmol/kg) injected into the lateral cerebral cavity of rats without anesthesia, polos 10 mm behind the line, drawn through the middle of the eye and about 2.5 mm away from the middle. Injection needle type 26G (microspec f-we Hamilton) with attached elastic band to limit the depth of the injection 4.5 mm, was introduced perpendicular to the surface of the skull. For the introduction of required continuous pressure for piercing skin and skull. After injection for rats was observed within 30 minutes Glutamate evoked convulsions immediately after the injection. Animals darted, strongly hopped and was observed clonic convulsions with pulling the front legs. Convulsions took place quickly, lasted less than a minute. Happened again cramps after 10 or 20 minutes the Results were reported as Yes and no. Rats were considered to be protected if there were convulsions, they were not running and not jumping for 30 min after injection of glutamate, even if it was behavior like "wet dog shaking or syndrome "swing to the head."

DA dose of the test substance, which protects 50% of the rats that participated in the experiment.

The comparison was conducted with the compound 2-amino-6-triftormetilfosfinov described in [4] and exhibiting similar activity. The results are summarized in the following table.

1. Derivatives of 2-imino-benzothiazoline oxygraph;

R2or a group of formula-CH2-[CH(R4)]n-R3where R3di (C1C4) alkylamino, 1-piperidinyl,

1-pyrrolidinyl, mercaptopropyl, C2C4-alltihopa, C1C4-allylthiourea, C1C4-alkylsulfonyl or C1C4-alkylsulfonyl;

R4hydrogen or C1C4-alkyl;

n is 0 or 1,

or a group of formula II

< / BR>
where R1has the specified values,

their enantiomers in the presence of an asymmetric center and their acid-additive pharmaceutically acceptable salt.

2. Pharmaceutical composition having activity against convulsions induced by glutamate containing the active principle and a pharmaceutically acceptable carrier, characterized in that it contains as active principle compounds of General formula I

< / BR>
where R1polyflor-(C1C4)-alkyl or polyflor-(C1C4)-alkoxygroup;

R2or the group CH2[CH (R4)]nR3where R3di(C1C4-alkylamino, 1-piperidinyl, 1-pyrrolidinyl, marketgraph, C2C4-alltihopa, C1- C4-allylthiourea, C1C4-alkyl;

n is 0 or 1,

or a group of the General formula II

< / BR>
where R1has the specified values,

their enantiomers in the presence of an asymmetric center and their acid-salt additive in an amount of 10 to 100 mg per unit dose.

Priority signs:

15.12.88 when R1polyflor-(C1C4-alkoxygroup and trifluoromethyl;

R2the group CH2[CH (R4)]nR3where R3di(C1C4-alkylamino, 1-piperidinyl, 1-pyrrolidinyl, mercaptopropyl, C1C4-allylthiourea, C1- C4-alkylsulfonyl and C1C4-alkylsulfonyl;

R4hydrogen;

n 1.

13.07.89 when R1polyflor-(C1C4-alkoxygroup and trifluoromethyl;

R2or the group CH2R3where R3C1- C4-allylthiourea, C1C4-alkylsulfonyl and C1- C4-alkylsulfonyl

or a group of the formula

< / BR>
14.12.89 when

1) R1polyflor-(C1C4-alkoxygroup or trifluoromethyl;

R2the group-CH2[CH (R4)]nR3where n 1;

R4C1-C4-alkyl;

R3di(C1C4)-alkylamino, 1-piperidinyl, 1-is B>1
C4-alkylsulfonyl;

2) R1polyflor-(C1C4-alkoxygroup or trifluoromethyl;

R2-CH2[CH (R4)]nR3where n 0;

R3di(C1C4-alkylamino, 1-piperidinyl, 1-pyrrolidinyl or mercaptopropyl;

3) R1polyflor-(C1-C4-alkoxygroup, except PERFLUORO-(C1C4-alkoxygroup;

R2-CH2[CH (R4)]nR3; n 1;

R3di(C1C4-alkylamino, 1-piperidinyl, 1-pyrrolidinyl, mercaptopropyl, allylthiourea, C1- C4-alkylsulfonyl or C1C4-alkylsulfonyl;

4) R1polyflor-(C1C4)-alkyl;

R2a group of the formula II or-CH2[CH (R4)]n- R3;

n is 0 or 1;

R4hydrogen or C1C4-alkyl;

R3di (C1C4alkylamino, 1-piperidinyl, 1-pyrrolidinyl, mercaptopropyl, C1C4-allylthiourea, C1- C4-alkylsulfonyl or C1C4-alkylsulfonyl;

5) R1polyflor-(C1C4)-alkyl or polyflor-(C1C4-alkoxygroup;

R2-CH2[CH (R4)]nR3; n 0 Il is

 

Same patents:

FIELD: medicine, organic chemistry.

SUBSTANCE: the present innovation deals with new benzothiazole derivatives and medicinal preparation containing these derivatives for treating diseases mediated by adenosine receptor A2.A.. The present innovation provides efficient treatment of the above-mentioned diseases.

EFFECT: higher efficiency of therapy.

14 cl, 354 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing a substituted alkylamine derivative from the 2-aminothiophenol compound with high industrial yield that can be used as an intermediate compound used in medicine or in agriculture. Invention proposes a method for preparing substituted alkylamine derivative represented by the following general formula (3): wherein X mean halogen atom, alkyl group, alkoxy-group, cyano-group or nitro-group; n means a whole number from 1 to 4; each R1 and R2 means independently hydrogen atom of phenyl-substituted, or unsubstituted alkyl group that can in common form 5- or 6-membered cycle, or its additive acid salt. Method involves addition of 2-aminothiophenol derivative salt represented by the following formula (1): wherein X and n have abovementioned values to acid to provide pH value 6 or less and to convert salt to free 2-aminothiophenol derivative of the general formula (1) followed by addition of 2-aminothiophenol derivative with amino-N-carboxyanhydride to the reaction represented by the following general formula (2): wherein each R1 and R2 have abovementioned values. Invention provides the development of a method for unimpeded preparing 1-(2-benzothiazolyl)-alkylamine derivative, i. e. substituted alkylamine derivative from the 2-aminothiophenol derivative with the satisfactory industrial yield and without pollution of the environment.

EFFECT: improved preparing method, valuable properties of compound.

8 cl, 13 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds that possess affinity for adenosine A2A-receptors and represent compounds of the general formula: wherein R1 and R2 represent independently hydrogen atom, lower alkyl, tetrahydropyrane-2,3- or 4-yl, -(CH2)n-O-lower alkyl, -C(O)-lower alkyl, -(CH2)n-C(O)-lower alkyl, -(CH2)n-C(O)-NR'R'', -(CH2)n-phenyl substituted optionally with lower alkyl, lower alkoxy-group or -(CH2)n-pyridinyl, -(CH2)n-tetrahydropyrane-2,3- or 4-yl, -C(O)-piperidine-1-yl; or R1 and R2 in common with nitrogen atom (N) to which they are added form the ring 2-oxa-5-azabicyclo[2,2,1]hept-5-yl; R3 represents lower alkoxy-group, phenyl substituted optionally with halogen atom, -(CH2)n-halogen or -(CH2)n-N(R')-(CH2)n+1-O-lower alkyl, or represents pyridinyl substituted optionally with lower alkyl, halogen atom or morpholinyl; n means 1 or 2; R'/R'' represent independently of one another hydrogen atom or lower alkyl, and their pharmaceutically acceptable acid-additive salt. Except for, invention relates to a medicinal agent showing affinity to adenosine A2A-receptors containing one or some compounds by any claims 1-11, and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of compounds and agents.

13 cl, 38 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole. Method involves the following successive steps: (i) interaction of bromine with 4-acetamidocyclohexanone an aqueous solution to yield 2-bromo-4-acetamidocyclohexanone; (ii) addition of thiourea to yield 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzothiazole; (iii) addition of hydrobromic acid an aqueous solution to yield 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole without isolation of 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzothiazole synthesized at stage (ii); (iv) isolation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole and if necessary separation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole isolated at stage (iv) for R-(+)- and S-(-)-enantiomers, and isolation of R-(+)- and/or S-(-)-enantiomer. 2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole is used for synthesis of pramipexole. Also, invention relates to a method for synthesis of pramipexole by synthesis of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole by using the method said and its conversion to pramipexole and if necessary by separation of pramipexole for its R-(+)- and S-(-)-enantiomers and isolation of R-(+)- and/or S-(-)-enantiomer.

EFFECT: improved method of synthesis.

15 cl, 1 sch, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula II as neuropeptide FF receptor antagonist, their pharmaceutically acceptable acid-additive salts, medication based on them, as well as their application. Compounds can be applied for treatment and prevention of diseases mediated by activity of neuropeptide FF receptor, such as pain, hyperalgesia, enuresis, for elimination of syndromes arising in case of alcohol, psychotropic and nicotine addiction, for regulation of insulin release, digestion, memory functions, blood pressure or electrolytic and energy exchange. In general formula II , A together with thiazole ring forms 4,5,6,7-tetrahydrobenzothiazole, 5,6,7,8-tetrahydro-4H-cycloheptathiazole, 5,6-dihydro-4H-cyclopentathiazole fragments; R1 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tret-butyl, 1,1-dimethylpropyl or phenyl; R2-R6 each represents hydrogen or methyl.

EFFECT: obtaining solutions, which ca be used for treatment and prevention of diseases, mediated by activity of neuropeptide FF receptor.

6 cl, 4 tbl, 106 ex

FIELD: chemistry.

SUBSTANCE: this invention refers to new compounds of formula (Ia) and to their pharmaceutically acceptable salts. Compounds of this invention are characterised by CB1 receptor antagonist properties. In formula (Ia) , R1 means phenyl independently mono-, di- or tri-substituted with haloid, (lower)alkoxy, (lower)alkyl, halogenated (lower)alkoxy or di(lower)alkylamino; R2 means phenyl, independently mono-, di- or tri-substituted with haloid, halogenated (lower)alkyl, nitro or cyano; R3 means hydrogen, nitro, amino, -NHSO2-R3a or -NHCO-R3b; R3a means (lower)alkyl, di(lower)alkylamino, benzyl, phenyl or phenyl monosubstituted with (lower)alkyl; R3b means benzyl or phenyl monosubstituted with (lower)alkyl.

EFFECT: application of compounds thereof as therapeutically active substance with CB1 receptor agonist properties and to relevant pharmaceutical composition.

18 cl, 1 dwg, 5 tbl, 70 ex

FIELD: chemistry.

SUBSTANCE: invention concerns benzothiazole derivatives of general formula (1) and their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands with high affinity to A2A adenosine receptor, and based medicine. Compounds can be applied in treatment and prevention of diseases mediated by A2A adenosine receptors, such as Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease. In general formula (I) , R is C5-C6-cycloalkyl non-substituted or substituted by hydroxy group, or is ethyl or isobutyl, or is tetrahydropyrane-4-yl or -(CH2)n-tetrahydrofurane-2 or 3-yl or is 5-hydroxybicyclo[2,2,1]hept-2-yl; X is CH or N; n is 0 or 1.

EFFECT: enhanced efficiency of composition and treatment method.

12 cl, 2 dwg, 14 ex

FIELD: chemistry.

SUBSTANCE: invention concerns benzothiazole derivatives of general formula (I) and their pharmaceutically acceptable salts as adenosine receptor ligands and based medicinal product. Compounds can be applied in treatment and prevention of diseases mediated by A2A adenosine receptors, such as Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease. In the general formula (I) , R1 is C5-C6-cycloalkyl substituted by CF3 group, lower alkyl, -(CH2)nOH or -(CH2)n-O- lower alkyl, or is 1-bicyclo[2,2,1]hept-2-yl, 1-(7-oxa-bicyclo[2,2,1]hept-2-yl, 1-(5-exo-hydroxybicyclo[2,2,1]hept-2-exo-yl, 1-(5-exo-hydroxybicyclo[2,2,1]hepto-2-endo-yl, or is 1-adamantane-1-yl; R2 is lower alkyl; or R1 and R2 together with N atom form 8-oxa-3-aza-bicyclo[3,2,1]octane group, n is 0 or 1.

EFFECT: improved efficiency of treatment.

9 cl, 2 dwg, 15 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of formula (I) and its pharmaceutically acceptable salts and esters. Compounds of the present invention are characterised with properties of DGAT-1 inhibitor. In general formula (I) , Q represents O, S or NR5; A represents a linker chosen from where p is equal to 1 or 2, and , where m is equal to 0, and n is equal to 1, 2, 3 or 4, or m is equal to 1, while n is equal to 1, 2 or 3, where specified linker is optionally substituted with one or two groups R8; R1 and R2 are independently chosen from hydrogen, haloid; R3 is chosen from hydrogen, (C1-C6)alkyl optionally substituted with hydroxyl and phenyl optionally substituted with haloid; R4 is chosen from hydrogen, nitro and (C1-C6)alkyl; or R3 and R4 together with carbon atoms whereto attached, can form benzene ring optionally substituted with 1-2 substitutes. The invention also concerns compounds of formula (Ia) and (Ib) with structural formulas presented in the patent claim, and also to a pharmaceutical composition, a medical product, to application of compounds for making a medical product and compound process.

EFFECT: new compounds possess useful biological activity.

19 cl, 2 tbl, 7 dwg, 215 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention relates to 3-phenylpropionic acid derivatives of formula (I) as ligand of peroxisome proliferator-activated gamma-receptor (PPARγ), to their pharmaceutically acceptable salts, as well as to their application, treatment method and based on them pharmaceutical composition. Compounds can be applied for treatment and prevention of diseases mediated by peroxisome proliferator-activated gamma-receptor (PPARγ), for instance type 2 diabetes, insulin-resistance, metabolic syndrome, complications resulting from or connected with diabetes, cardio-vascular dysfunctions, atherosclerosis, obesity, cognition disturbances and lipid metabolism derangements. In general formula (I): W represents COOH or -COO-C1 - C4-alkyl group; Y represents NH; Z represents S or O; X represents O; R1 - R8 each independently represents hydrogen atom or halogen atom; A represents mono-, bi- or tri-cyclic 5-13-member heteroaryl with 1 or 2 heteroatoms selected from N, S or O, aryl, selected from phenyl and naphtyl, or -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, where heteroaryl is optionally substituted with 1-3 substituents, independently selected from group, consisting of C1-C4-alkyl, CN, phenyl halogen and phenyl, optionally substituted with 1-3 substituents, independently selected from C1-C4alkoxy, halogen and ethylenedioxy-group; and n represents integer number from 0 to 3 including; and their pharmaceutically acceptable salts.

EFFECT: increased efficiency of composition and treatment method.

20 cl, 14 dwg, 10 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel 1,2,3-tris-[(ammonio)methylcarbonyloxypoly(alkyleneoxy)]-propane trichlorides of the general formula:

wherein at -X+ as -N+R1RR, R1 = R2 mean hydrogen atom (H), R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e (the general degree of oxypropylation) = 49,b + d + f (the general degree of oxyethylation) = 0; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e = 55, b + d + f = 0; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e = 80, b + d + f = 24; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, a + c + e = 90, b + d + f = 27; at -X+ as -N+R1R2R3, R1 = R2 means H, R3 means phenyl, a + c + e = 80, b + d + f = 24; at -X+ as -N+R1R2R3, R1 = R2 mean H, R3 means phenyl, a + c + e = 90, b + d + f = 27; at -X+ as , a + c + e = 80, b + d + f = 24; at -X+ as , a + c + e = 90, b + d + f =27. Also, invention relates to a method for synthesis of these compounds. Method involves interaction of 1,2,3-tris-[hydroxypoly(alkyleneoxy)]-propane of the formula:

wherein a + c + e = 49-90, b + d + f = 0-27 with monochloroacetic acid in the presence of acidic catalyst, in boiling organic solvent medium with azeotropic removal of water formed and the following treatment of synthesized reaction product in polar solvent medium at heating with amino-compounds of the formula: NR1R2R3 wherein R1 = R2 mean H, R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms, phenyl, or morpholine of the formula:

in the following mole ratios of reagents - propane hydroxyl derivative : monochloroacetic acid : amino-compound or morpholine = 1:(3.0-3.2):(3.0-3.2), respectively. New compounds show the bactericidal and fungicide activity and properties of demulsifying agents for petroleum emulsions.

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

7 cl, 3 tbl, 8 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel [(heterylonio)-methylcarbonyloxypoly(alkyleneoxy)]-[(ammonio)methylcarbonyloxypoly(alkyleneoxy)]propane trichlorides of the general formula: wherein: at X+ = Y+ means X+ means -N+R1R2R3 wherein R1 = R2 means hydrogen atom (H); R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e (total degree of oxypropylation) = 49; b + d + f (total degree of oxyethylation) = 9; at X+ = Y+ means Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 55; b + d + f = 10; at X+ means Y+ = Z+ means -N+R1R2R wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 49; b + d + f = 9; at X+ means Y+ = Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 55; b + d + f = 10; at X+ means Y+ = Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 49; b + d + f = 0; at X+ means Y+ = Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 55; b + d + f = 0; at X+ = Y+ means Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 49; b + d + f = 0; at X+ = Y+ means Z+ means -N+R1R2R3 wherein R1 = R2 means H; R3 means aliphatic hydrocarbon radical comprising 10-16 carbon atoms; a + c + e = 55; b + d + f = 0, and to a method for their synthesis. Method involves interaction of 1,2,3-tris-[hydroxypoly(alkyleneoxy)]propane of the formula: wherein a + c + e = 55; b + d + f = 0-10 with monochloroacetic acid in the presence of acid catalysts, in organic solvent medium and with azeotropic removal of formed water and the following treatment at heating of the synthesized reaction productwith a mixture of morpholine and aliphatic amine in the molar ratio of reagents - hydroxyl derivative of propane: monochloroacetic acid : morpholine : aliphatic amine = 1:(3.0-3.2):(1.0-2.1):(1.0-2.1), respectively and wherein the total amount of morpholine and aliphatic amine is 3.0-3.2 mole. Novel compounds possess emulsifying properties for aqueous-bitumen and aqueous-mazut emulsions.

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

6 cl, 2 tbl, 8 ex

.FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their physiologically acceptable salts also possessing properties for decrease the blood sugar content. In compound of the formula (I) A means phenyl wherein phenyl residue can be substituted up to three times with fluorine (F), chlorine (Cl) and bromine (Br) atoms; R1 and R2 mean hydrogen atom (H); R3, R4, R5 and R6 mean independently of one another H, F, Cl, Br, -NO2, -O-(C1-C6)-alkyl, (C1-C6)-alkyl, -COOH; R7 means H, (C1-C6)-alkyl wherein alkyl can be substituted up to three times with -OH, -CF3, -CN, COOH, -COO-(C1-C6)-alkyl, -CO-NH2, -NH2, -NH-(C1-C6)-alkyl, -N-[(C1-C6)-alkyl]2, -NHCO-(C1-C6)-alkyl, -NHCOO-(C1-C6)-alkyl or -NHCOO-(C1-C4)-alkylenephenyl; in (CH2)m m can mean 0-6 and aryl means phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, pyridyl, indolyl, piperidinyl, tetrahydronapthyl, 2,3-dihydrobenzo[1,4]dioxynyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, morpholinyl wherein aryl residue can be substituted mono- or multiple with R9 wherein R9 means F, Cl, Br, -OH, -NO2, -CF3, -OCF3, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, -O-(C1-C6)-alkyl, -COOH, -COO-(C1-C6)-alkyl. Also, invention relates to a pharmaceutical composition and a method for preparing a medicinal agent.

EFFECT: valuable medicinal properties of derivatives and pharmaceutical composition.

7 cl, 2 sch, 1 tbl, 293 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of substituted N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I): wherein R represents methyl or mesyl, or its salt. Also, invention describes methods for synthesis of these compounds, pharmaceutical compositions containing thereof and their using for increasing activity of PDH in warm-blooded animal. Proposed compounds are useful in treatment of diabetes mellitus in warm-blooded animals.

EFFECT: valuable medicinal properties of compounds, improved methods for synthesis.

10 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with general formula (I), in which X1 is phenyl, 9-member bicyclic heteroaryl, containing S or O as heteroatoms, or 5-member heteroaryl, containing S or O as heteroatoms, each of which is optionally substituted with one or more substitutes, chosen from halogen or C1-6alkyl, which is optionally substituted with one or more halogens. X2 is phenyl, which is optionally substituted with one or more substitutes, chosen from halogen, or 5-member heteroaryl, containing S or O as heteroatoms. Ar is phenylene, which is optionally substituted with one or more substitutes, chosen from halogen, or C1-6alkyl, phenyl, C1-6alkoxy, each of which is optionally substituted with one or more halogens. Y1 is O or S, and Y2 represents O, Z represents -(CH2)n-, where n equals 1, 2 or 3. R1 is hydrogen or C1-6alkoxy and R2 is hydrogen, C1-6alkyl. The invention also relates to pharmaceutical salts of these compounds or any of their tautomeric forms, stereoisomers, stereoisomer mixtures, including racemic mixtures.

EFFECT: invention also pertains to use of these compounds as pharmaceutical compositions, with effect on receptors, activated by the peroxisome proliferator PPARδ subtype, and to pharmaceutical compositions, containing these compounds (I).

36 cl, 41 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to new use of compounds of 2-arylacetic acid and amides with formula (I) and their pharmaceutically used salts, where A comprises an atom X and is phenyl or a 5-6 member heteroaromatic ring, optionally containing a heteroatom, chosen from N; corresponding positions on ring A are marked by numbers 1 and 2; atom X is chosen from N (nitrogen) and C (carbon); R represents a substituting group on ring A, chosen from: a group in 3 (meta) positions, chosen from a group comprising straight or branched C1-C5-alkyl, C2-C5-acyl; a group in 4 (para) positions, chosen from a group, comprising C1-C5-alkyl, C1-C5-alkanesulphonylamino, substituted with halogens; Hy represents a small hydrophobic group with steric inhibition constant ν between 0.5 and 0.9 (where ν is Charton steric constant for substitutes), comprising methyl, ethyl, chlorine, bromine, group Y chosen from O (oxygen) and NH; when Y represents O (oxygen), R' represents H (hydrogen); when Y represents NH, R' is chosen from groups: -H, - residue with formula SO2Rd, where Rd represents C1-C6-alkyl. The invention can be used in making medicinal agents, which are inhibitors of induced IL-8 PMN chemotaxis (CXCR1) or induced GRO-α PMN chemotaxis (CXCR2).

EFFECT: new use of compounds of 2-arylacetic acid and amides and their pharmaceutically used salts.

14 cl, 2 tbl, 44 ex, 4 dwg

FIELD: pharmaceutics.

SUBSTANCE: invention concerns novel compounds of the formula I , where R3 is (4-methylpiperazinyl)methyl and the other four radicals R1, R2, R4, and R5 are independently hydrogen; cyano; lower alkyl; hydroxy- or amino-substituted simple alkyl; trifluoromethyl; free or etherified hydroxy-group; (lower)alkoxy; (lower)alkanoyloxy; free, alkylated or acylated amino group; mono- or di(lower)alkylamino; (lower)alkanoylamino; benzoylamino; free or etherified carboxy-group; (lower)alkoxycarbonyl, and halogen; R6 is halogen, NH2, NO2, NHC(O)CF3, NHC(O)CH3 or NHC(NH)NH2, R7 is methyl, and R8 is hydrogen; or the compound salt, or crystalline form, method of obtainment, application in obtaining compound of the formula IV, and pharmaceutical composition for leukemia treatment, based on the claimed compounds.

EFFECT: novel compounds applicable in obtaining compounds inhibiting tyrosine kynase of epidermal growth factor (EGF) receptor.

13 cl, 12 ex

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