Derivatives pyrrolidine and method of production thereof

 

(57) Abstract:

Usage: as substances having anti-hypertensive activity. The inventive product is a derivative of pyrrolidone f-ly I, where Y is the group -(CH2)nand when n=0; X=H, halogen, lower alkyl, R is phenyl, unsubstituted or substituted by halogen, lower alkyl, hydroxy - or alkoxygroup, trifluoromethyl; naphthyl; thiophene, unsubstituted or substituted lower alkyl; benzothiophen; pyridyl; imidazole, substituted lower alkyl. When n=1, X= H or halogen, R is phenyl, unsubstituted or substituted by halogen, hydroxy or alkoxygroup, lower alkyl; thiophene; Y IS S(O)pwhere p=0 or 2, -0 -, or NH, X is H, R is phenyl. Reagent 1: compound f-crystals II: R-Y-CHCOOR1where R above, R1is lower alkyl. Reagent 2: - nitroanilide f-ly III, where R2- hidroxizina group, X is specified. The compound obtained f-IV crystals reduced to the amino compounds, which cyclist, the resulting mixture of CIS - and TRANS-forms five-membered lactam f-ly V is heated in the presence or in the absence of base, in the environment of an organic solvent, obtained a five-membered lactam in the TRANS-form is reactivated by DIBORANE or a complex metal hydride, followed by removal of hydroc the teachings of the new derivatives pyrrolidine General formula

Y-Rwhere Y represents - (CH2)n-, whereby n = 0;

X is a hydrogen atom, halogen or lower alkyl group;

R is a phenyl group, phenyl group involved halogen, lower alkyl, hydroxy - or alkoxygroup, trifluoromethyl, naftalina group, thiophene, unsubstituted or substituted lower alkyl, benzothiophen, pyridyl, imidazole, substituted lower alkyl when n = 1;

X is H or halogen,

R is phenyl, unsubstituted or substituted by halogen, hydroxy or alkoxygroup, lower alkyl; thiophene; Y represents S(O)pwhere p = 0 or 2, -O - or-NH; X is hydrogen,

R-phenyl;

having hypotensive activity.

The aim of the invention is to develop on the basis of known methods method of obtaining new compounds pyrolidine series with a high antihypertensive activity with low toxicity.

The invention is illustrated by the following examples.

P R I m e R 1. /+-/-TRANS-3-(2-chlorine-3-hydroxyphenyl)-4-(3,4-dihydroxyphenyl)-PI-Ramadin hydrobromide.

I. 84 g of 2-chloro-3-methoxybenzaldehyde, 200 ml of nitromethane and 38 g of acetone ammonium was heated under reflux in 50 ml of acetic acid for 1.5 hours, the Reaction mixture was poured into Uchali 58 g of 2-chloro-3-methoxy-nitrostyrene; so pl. 98-100aboutC.

II. 19.3 g (to 0.19 mol) of dry Isopropylamine was dissolved in 100 ml of anhydrous tetrahydrofuran. The resulting solution was cooled to -60aboutC or lower in a bath containing dry ice and acetone and at this temperature and stirring was bury a solution of 1.6 M n-utility in n-hexane. The resulting mixture was stirred for 15 min at the same temperature bury solution 40,37 g (0.18 mol) of ethyl-3,4-dimethoxyphenylacetone in 200 ml of anhydrous tetrahydrofuran. After stirring for 15 min, under stirring was bury solution 38,45 g (0.18 mol) of 2-chloro-3-methoxy-nitrostyrene in 400 ml of anhydrous tetrahydrofuran with such speed that the temperature did not exceed -50aboutC. After stirring for 30 min was added a small amount of water and tetrahydrofuran drove in a vacuum. To the residue for acidification was added 6 n hydrochloric acid and the acidified residue was twice extracted with dichloromethane. The resulting organic phase is twice washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is kept in vacuum and the residue was purified chromatographically on a column of silica gel (elution was performed with a mixture of n-hexane/et the-acid)-4-nitrobutane.

III. 148,9 g (0.34 mol) of the above-described nitroethene and 200 ml of concentrated hydrochloric acid was dissolved in 1000 ml of ethanol and the resulting solution was stirred under reflux. Portions were added to 112.4 g (16,72 mol) of zinc dust. After stirring under reflux for 2 h, the solid was removed by filtration and the filtrate was concentrated in vacuum. To the residue was added dichloromethane and the resulting mixture was podslushivaet 10% aqueous solution of sodium hydroxide. Then the mixture was passed through Celite to remove precipitated solids by filtration and well washed with dichloromethane. The filtrate was separated into an organic phase and aqueous phase.

The aqueous phase was twice extracted with dichloromethane and the organic phase was combined with each other. The combined organic phase was twice washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is kept in vacuum to obtain 135 g of viscous crude ethyl-4-amino-3-(2-chloro-3-methoxyphenyl)-2(3,4-acid)of butyrate.

Part of the product was purified on a column of silica gel (carrying out elution with a mixture of chloroform with methanol in the ratio of 98:2 and transformed into the hydrochloride by the action of hydrogen chloride is,12; N 3,15.

Found, %: C 56,52; H Between 6.08; N 3,01.

IV. of 69.5 g (to 0.17 mol) of the above-described aminoether was heated under reflux in 500 ml of xylene for 5 hours After cooling, the reaction mixture xylene drove in vacuum and to the residue for solidification was added ether, resulting in received of 60.5 g of 3-(2-chloro-3-methoxyphenyl)-4-(3,4-acid)-2-pyrrolidon (mixture of the CIS(and TRANS-forms).

V. 108 g (0.3 mol) obtained above 2-pyrrolidinone derivative containing a mixture of CIS - and TRANS-forms, was dissolved in 1600 ml of xylene and parts, when heated under reflux and stirring, was added to 5.2 g (0.04 mol) trimethylsilanol potassium. After stirring under reflux for 2 h, xylene drove in vacuum and to the residue was added dichloromethane. The mixture was twice washed with diluted hydrochloric acid and then with saturated saline and dried over anhydrous magnesium sulfate. The solvent is kept off and the residue was recrystallized from ethanol to obtain 63,5 g of TRANS-3-(2-chloro-3-methoxyphenyl)-4-(3,4-dime-toxigenic)-2-pyrrolidone; so pl. 149-151aboutC.

VI. 18,5 g (0,051 mol) of the above TRANS-pyrrolidinone derivative was dissolved in 700 ml of hot tetrahydrofuran and the solution ol the system on the basis of ice water. After that, the mixture was stirred under reflux for 5 h and then stood to cool. In the reaction mixture was gradually added to 50 ml of 6 n hydrochloric acid and the resulting mixture was stirred under reflux for 1 h with the purpose of decomposition aminoborane complex. After cooling, a mixture of tetrahydrofuran drove in vacuum and to the residue for alkalizing was added 10% sodium hydroxide solution. Podelochnyj the residue was extracted three times with dichloromethane. The dichloromethane solution is washed twice with saturated saline and then dried over anhydrous magnesium sulfate. Dichloromethane drove away and the residue was purified by chromatography (medium pressure column of silica gel (initial elution with a mixture of chloroform/methanol in a ratio of 95:9 and subsequent elution with methanol) to obtain 11 g of a viscous TRANS-3-(2-chloro-3-methoxyphenyl)-4-(3,4-acid)pyrrolidine.

VII. 2.6 g of the above TRANS-pyrolidine derivative was dissolved in dry dichloromethane and cooled with ice water and with stirring in a stream of nitrogen was bury 33,7 ml of 1M solution tribromide boron in dichloromethane. After completion of the addition the temperature of the mixture was lowered to pick. The resulting solution was again distilled in a vacuum. This operation was repeated three times and the residue was recrystallized from a mixture of ethanol/acetonitrile with receipt of 1.36 g of TRANS-3-(lorlor-3-hydroxyphenyl)-4-(3,4-hydroxyphenyl)-PIR solidaritybased; so pl. 218-219aboutC.

P R I m m e R 2. The hydrobromide (+-)-TRANS-3(3,4-dihydroxyphenyl)-4-(3-methylthieno)pyrrolidine.

I. of 6.31 g (0.05 mol) of 3-methylthiosemicarbazone was dissolved in 40 ml of acetic acid was added 13 ml of nitromethane and 3.85 g of ammonium acetate. The mixture was stirred at reflux for 2.5 hours After cooling, the reaction mixture was concentrated in vacuo and added 70 ml of 70% ethanol. The resulting crystals were isolated by filtration to obtain 3-methyl-2-(2-nitrovinyl)thiophene. So pl.: 65-67aboutC.

(II) 2,44 ml Diisopropylamine was dissolved in 15 ml of anhydrous tetrahydrofuran and the solution was cooled to -60aboutC or lower in a bath of dry ice and acetate, 9,88 ml of 1.6 M n-utility in n-hexane was to bury the system under stirring. After complete addition, the mixture was stirred for 15 min at the same temperature was bury solution of 3.54 g (0,0158 mol) of ethyl 3,4-dimethoxyphenylacetone in 7 ml of anhydrous who) 3-methyl-2-(2-nitrovinyl)of thiophene in 16 ml of anhydrous tetrahydrofuran was bury at the same temperature. After termination of the addition the mixture was stirred for 30 min and was added 0.5 ml of water. The solvent is then kept in a vacuum. The residue was dissolved in 100 ml of dichloromethane and the solution washed 3h. solution of hydrochloric acid and then with saturated saline. The resulting dichloromethane phase was dried over anhydrous magnesium sulfate. The solvent is kept in vacuum to obtain crude ethyl 2-(3,4-acid)-3,-(3-methylthieno)-4-nitrobutane.

III. 3,68 g (9,35 mol) of the above-described nitrofura was dissolved in 17 ml of ethanol and 5,61 ml of concentrated hydrochloric acid and 0.61 g of powdered zinc was added to the system. The mixture was heated under reflux for 24 hours After cooling the mixture, the solid was removed by filtration and the filtrate was concentrated in vacuum. To the residue was added dichloromethane and the mixture was podslushivaet 2n. aqueous solution of sodium hydroxide. Then the mixture was passed through Celite to remove precipitated solids by filtration. The organic phase of the filtrate was separated. The aqueous phase was twice extracted with dichloromethane and the organic phases were combined. The combined organic phase was twice washed with saturated saline and dried over anhydrous Colnago pressure on a column of silica gel (dichloromethane: methanol = 95:5) to give 1.2 g of 3-(3,4-acid)-4-(3-methylthieno)-2-pyrrolidine and 1.6 g of ethyl-4-amino-2-(3,4-acid)-3-(3-methylthieno)-butyrate.

IV. 1.1 g of the above described derivative of 2-pyrrolidone was dissolved in 20 ml of ethanol. To the solution was added 50 mg of tert-butyrate, potassium and the mixture was heated under reflux for 2 hours, After cooling the mixture of solvent and drove to the residue for dissolution was added 50 ml of dichloromethane. The resulting solution was washed with 2n. hydrochloric acid and then with saturated saline. The organic phase was dried over anhydrous magnesium sulfate. Dichloromethane drove in vacuum and the residue was recrystallized from ethanol to obtain 0.9 g of TRANS-3-(3,4-acid)-4-(3-were)-2-pyrrolidine; so pl. 138-140aboutC.

V. Solution of 1.81 g (56,7 mol) of the above derived TRANS-2-pyrrolidone in 100 ml of tetrahydrofuran was to bury 22,8 ml of 1M borane in tetrahydrofuran, in a cooled state in a stream of nitrogen. The mixture was stirred for 15 min and was heated under reflux for 10 hours After cooling, the reaction mixture was added 5 ml of 6N. hydrochloric acid and the resulting mixture was heated for 30 min at 60aboutC. After cooling, the reaction mixture was concentrated in vacuo and to the residue was added 2n. an aqueous solution of sodium hydroxide. The mixture was extracted with dichloromethane and the extract was washed with saturated by chromatography (medium pressure column of silica gel (elution with a mixture of chloroform/methanol with a ratio of 95: 5 and then methanol) to give 0.96 g butter-like TRANS-3-(3,4-acid)-4-(3-methylthieno)pyrrolidine.

VI. 1,32 g (4.35 mol) of the above derived transferredin was dissolved in 5 ml dichloromethane and the resulting solution under ice cooling, was added 13.1 ml of a 1M solution of tribromide boron in dichloromethane. After complete addition the mixture was stirred at room temperature for 3 h and at -20aboutWith added 3 ml of methanol. The reaction mixture was concentrated in vacuo and was again added to the methanol. The mixture was concentrated and the residue was recrystallized from ethanol to obtain 16.4 g of the hydrobromide of TRANS-3-(3,4-dihydroxyphenyl)-4-(3-methylthieno)-pyrrolidine; so pl. 271-272aboutC (decomposition).

WITH15H17NO2SHBr.

Calculated, %: C 50,57; H 5,09; N 3,93.

Found, %: C 50,37; H 4,99; N 3,96.

P R I m e R 3. (+)-TRANS-3-(3,4-dihydroxyphenyl)-4-(3-methoxyphenyl)pyrrolidine hydrochloride.

I. Sitedisability was obtained at -70aboutWith in tetrahydrofuran in a stream of nitrogen of the 5.2 ml (37 mol) of Diisopropylamine and 23 ml (37 mol) of a solution of 1.5 M n-utility in 23 ml (37 mmol) of n-hexane, and this product was added dropwise a solution of 6.8 g (35 mol) of ethyl o-methoxyphenylacetate in 20 ml of tetrahydrofuran at -70aboutC. After 15 min to the mixture dropwise added 6,76 g (35 mmol) of 3,4-methylendioxy-N-nitro which was added to the mixture a small amount of water and the reaction mixture was concentrated in vacuum. Then to the residue was added 3n. hydrochloric acid for acidification and acidified residue was extracted with dichloromethane. The extract was washed with saturated saline solution and dried over anhydrous magnesium sulfate, and dichloromethane drove away. The residue was purified by chromatography on a column of silica gel (elwira a mixture of n-hexane/ethyl acetate in a ratio of 3:1 (to obtain ethyl-2-(2-methoxyphenyl)-3-(3,4-methylenedi-xifer)-4-nitrobutane.

II. at 8.36 g (21.6 mmol) of the above nitro-derivatives of ester was dissolved in 45 ml of ethanol. of 12.6 ml of concentrated hydrochloric acid and 4.2 g of zinc powder was added to the solution and the mixture was heated under reflux for 5.5 hours After cooling the mixture, the solid was filtered and the mother liquor was concentrated in vacuo. To the residue was added dichloromethane and the resulting solution was podslushivaet 10% aqueous solution of sodium hydroxide and passed through Celite to remove precipitated solids. The dichloromethane phase was separated and washed with saturated salt solution. The washed dichloromethane phase was dried over anhydrous magnesium sulfate and the solvent drove away. The residue was purified by chromatography with an average pressure on a column of silica gel (alumino-2-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)butyrate.

III. and 2.79 g (7.8 mmol) of the above linolenova ether was heated in 15 ml of xylene overnight under reflux. After cooling the mixture, the solvent is kept off and the residue was dissolved in 30 ml of ethanol. 0.1 g of tert-butoxide potassium added to the solution and the mixture was heated under reflux for 1.5 hours, the Solvent is kept in vacuum and a small amount of ethanol was added to the residue for solidification, thereby gaining 1.12 g of TRANS-3-(2-methoxyphenyl)-4-(3,4-methylazoxymethanol)-2-pyrrolidine.

IV. 1.1 g (of 3.53 mmol) of the above derivative TRANS-2-pyrrolidone was dissolved in 70 ml of tetrahydrofuran. The solution was cooled and then dropwise added to 11 ml of 1M solution of borane in tetrahydrofuran in a stream of nitrogen. The mixture was heated overnight under reflux. The reaction mixture is cooled and 5 ml of 6N. normal hydrochloric acid dropwise added thereto. The mixture was heated under reflux for 1.5 h and tetrahydrofuran drove away. To the residue was added dichloromethane and the mixture was podslushivaet 10% aqueous solution of sodium hydroxide. The organic phase was separated, washed with saturated saline solution and dried over anhydrous magnesium sulfate. The solvent is kept in vacuum and the residue cleaned the ri ratio of chloroform and methanol 96:4 and then methanol) to obtain 360 mg of 3-(2-methoxyphenyl)-4-(3,4-methylenedioxyphenyl)pyrrolidone.

V. 350 mg (1.18 mmol) of the above derivative of pyrrolidone was dissolved in 15 ml of dichloromethane and the solution cooled condition with stirring dropwise added to 4.7 ml of a 1M solution of trichloride boron in dichloromethane. After adding dropwise, the mixture was stirred at room temperature for 2 h and to the mixture at -20aboutWith added methanol. The solvent is kept in vacuum. Methanol was again added to the residue and drove in a vacuum. This technique was repeated several times, and the residue was recrystallized from acetone to obtain 250 mg of TRANS-3-(3,4-dihydroxyphenyl)-4-(3-methoxyphenyl)pyrrolidin-on hydrochloride, T. pl. 212-213aboutC.

WITH17H19NO3HCl

Calculated, %: C 61,72; H 6,41; N To 4.23.

Found, %: C 61,84; H 6,23; N 4,13.

P R I m e R 4. (-)-TRANS-3-(2-chloro-3-hydroxyphenyl)-4-(3,4-dihydroxyphenyl)-Pirro-lidine the hydrobromide and hydrochloride.

I. of 27.6 g of TRANS-3-(3-chloro-3-methoxyphenyl)-4-(3,4-acid)pyrrolidine obtained in stage VI of example 1, was dissolved in 210 ml of chloroform and 10 ml of triethylamine was added to the solution. Then a solution of 8.8 g of acetylchloride in 17 ml of chloroform dropwise added to the solution. The mixture was stirred over night at room temperature, washed with 2n. salt sour is if in a vacuum, and the resulting residue was purified by chromatography with an average pressure on a column of silica gel (chloroform: methanol = 99:1) to obtain 24.6 g of amorphous TRANS-1-acetyl-3-(2-chloro-3-methoxyphenyl)-4-(3,4-dime - toxigenic)pyrrolidine.

II. 4 g of the above acetylpyrrolidine loaded on a column for separating optical isomers were separated and purified using a mixed solvent comprising n-hexane, isopropyl alcohol and diethylamine (5: 2: 0,005) as eluent. From the first elyuirovaniya fraction was obtained 1,38 g (-) isomer, having the value [ ]D27- 38,6about(C = 1.0 in methanol), and later elyuirovaniya fraction was obtained (+) isomer, having the value [ ]D26+ 36,7about(C = 1.1 in methanol).

III. to 1.38 g of the above (-) isomer was heated in a 47% solution of Hydrobromic acid for 22 hours, After cooling, a mixture of Hydrobromic acid is kept in vacuum. To the residue was added methanol and kept in vacuum. This technique was repeated several times, and the residue was recrystallized from acetonitrile to obtain 0,82 g (-)-TRANS-3-(2-chloro-3-hydroxyphenyl)-4-(3,4-dihydroxyphenyl)pyrrolidine hydrobromide; so pl. 217-219aboutC.

[ ]D28- 55,0

Found, %: C 49,74; N 4,43; N 3,49.

IV. The above hydrochloride was dissolved in water and the solution pass through the ion exchange resin. So pl. 262aboutC.

[ ]D26to 62.8aboutC (C = 1.00 in methanol).

WITH16H17ClNO3SHCl.

Calculated, %: C 56,15; H 5,02; N 4.09 To.

Found, %: C 56,05; H 5,02; N 4.09 To.

P R I m e R 5. (+) isomer obtained in phase II of example 3 was processed according to the method of stage III to obtain (+)-TRANS-3-(2-chloro-3-hydroxyphenyl)-4-(3,4-dihydroxyphenyl peer - tolidine hydrobromide, so pl. 218-220aboutC.

[]D2650,7o(c = 0.96 in methanol).

The information obtained by the methods described in examples 1-5 are listed respectively in the form of examples in table 6-40.2-4.

P R I m e R 41. TRANS-3-benzyl-4-(3,4-hydroxyphenyl)pyrrolidine hydrobromide.

I. Ethyl-2-benzyl-3-(3,4-acid)4-nitrobutyl. 10 g (56,1 mmol) ethylenepropylene dropwise added at -78aboutWith 300 ml of tetrahydrofuran to sitedisability obtained from 9,04 ml (64,5 mmol) Diisopropylamine and 38.6 ml (64,5 mmol) of 1.6 n utility. The mixture was stirred at the same temperature for 15 min and a solution of 11,74 g (56,1 mmol) of 2-(3,4-acid)nitroethane in 200 ml tetrabutyl 20 ml of water to stop reaction and tetrahydrofuran drove in a vacuum. To the residue was added 100 ml of 3 N. hydrochloric acid and the mixture was extracted twice with 300 ml of methylene chloride. The obtained organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. The solvent is kept in vacuum, and the residue was subjected to chromatography on a column of silica gel (the solvent) ethyl acetate: n-hexane = 1:1 (receive 16,55 g of the target product) yield 80%. In this case, you first have suirable threo-isomer, and then Erythro-isomer (trio:Erythro = 8:6). Erythro-isomer was crystalline, while threo-isomer was oily.

Threo-isomer, so pl. 94-96aboutC.

(2) Ethyl-threo-4-amino-2-benzyl-3-/3,4-acid/-butyrate.

of 8.1 g of 20.9 mmol) ethyl-threo-2-benzyl-3-(3,4-acid)-4-nitrobutyl dissolved in 38 ml of ethanol and to the solution was added 12.5 ml of concentrated hydrochloric acid. To the mixture on a water bath portions added vs. 5.47 g of powdered zinc (84 mmol). After complete addition, the mixture is refluxed for 2 hours, the Reaction mixture was concentrated and alkalizing the residue was added 10% aqueous sodium hydroxide. The resulting solution was extracted 3 times with methylene chloride. The organic phase is washed of NASA is of the target of the crude product. The crude product was used in the next step without isolation and purification.

(3) TRANS-3-benzyl-4-(3,4-acid)-2-pyrrolidone. The crude product ethyl-trio-4-amino-2-benzyl-3-(3,4-acid)butyrate was dissolved in 200 ml of xylene and heated under reflux for 6 hours Xylene drove in vacuum to obtain the desired crude product. The crude product was purified from ethanol to obtain 2.55 g (yield 39%) of the target product; so pl. 116-118aboutC.

(4) TRANS-3-benzyl-4-(3,4-acid)pyrrolidin. 10 ml of the complex 1M borane/tetrahydrofuran was added to 10 ml of solution 0,81 g (2.6 mmol) of TRANS-3-benzyl-4-(3,4-acid)-2-pyrrolidone in tetrahydrofuran, and the mixture is boiled under reflux for 6 hours, After cooling, was added 10 ml of 6N. hydrochloric acid dropwise, gently at room temperature and the mixture was stirred at 60aboutC for 30 minutes Tetrahydrofuran drove in vacuum and the residue was podslushivaet 10% aqueous solution of sodium hydroxide and was extracted twice with methylene chloride. The obtained organic layer was dried over anhydrous sodium sulfate and the solvent is kept in vacuum to obtain the crude product. The crude product adsorbs of 0.37 g (yield 48%) of the target Poduct.

(5) TRANS-3-benzyl-4-(3,4-dihydroxyphenyl)pyrrolidine hydrobromide.

0,37 g (1,24 mmol) of TRANS-3-benzyl-4-(3,4-acid)pyrrolidine dissolved in methylene chloride and the resulting solution was added 10 ml of 1M tribromide boron in methylene chloride. The solution was stirred at room temperature for 3 hours the Reaction mixture was concentrated in vacuum. Then, the concentrate was added methylene chloride and added dropwise methanol (3 ml). The mixture was again concentrated under vacuum. (This technique was repeated several times and the precipitated crystals were removed by filtration to obtain 70 mg hydrobromide as a target product (yield 16%); so pl. 182-184aboutC.

C17H19NO2HBr.

Calculated, %: C 58,30; H 5,76; N 4,00.

Found, %: C 58,56; H 5,86; N 3,79.

P R I m e R 42. CIS-3-benzyl-4-(3,4-dihydroxyphenyl)-pyrrolidine hydrobromide.

(1) Ethyl-Erythro-4-amino-3-benzyl-3-(3,4-acid)-butyrate.

The target product was obtained according to the method of obtaining threo-isomer using 6,01 g (15,11 mmol) of ethyl Erythro-2-benzyl-3-(3,4-acid)-4-nitrobutane, 4,06 g (62,1 mmol) of powdered zinc, 28 ml of ethanol and 9.3 ml of concentrated hydrochloric acid; so pl. 74-80aboutC.

(2) CIS-3-one ethyl-Erythro-4-amino-2-benzyl-3-(3,4-acid)Butera - the method for producing threo-isomer, except that the reaction time was 12 o'clock Exit 3,18 g (66% in two stages); so pl. 137-139aboutC.

(3) CIS-benzyl-4-(3,4-acid)pyrrolidin.

0.45 g (yield 56% ) of the target product was obtained from 0.84 g (2,70 mmol) of CIS-3-benzyl-4-(3,4-acid)-2-Pirro - lidón according to the method of synthesis of TRANS-isomer.

(4) CIS-3-benzyl-4-(3,4-acid)pyrrolidine hydrobromide.

0.10 g (yield 22%) of the hydrobromide as the target product was obtained 0.45 g (1,51 mmol) of CIS-3-benzyl-4-(3,4-acid)pyrrolidine according to the method of synthesis of TRANS-isomer; so pl. 209-210aboutC (decomposition).

WITH17H19NO2HBrH2O.

Calculated, %: C 55,45; H 5,02; N 3,80.

Found, %: C 55,65; H 5,65; N 3,76.

P R I m e R 43. TRANS-3-(2-hydroxy-3-chloroformate)-4-(3,4-dihydroxyphenyl)pyrrolidine hydrobromide.

(1) 3-chloro-2-methoxybenzamide.

The mixture 20,36 g (0.13 mmol) of m-chloro-o-methoxytoluene with USD 237.2 g (0.13 mol) of N-bromosuccinimide, 0.6 g (2,47 mole) of peroxide of benzene and 200 ml of carbon tetrachloride was irradiated with light ( 300 nm) from a mercury high-pressure lamps (400 W) for 5 h using a Pyrex filter. The insoluble matter was separated by filtration and the filter was concentrated in WA is th magnesium sulfate, and the solvent is kept in vacuum to obtain 29,2 g of the desired product as an oily substance.

(2) Diethyl 2-(3-chloro-3-methoxybenzyl)malonate. 100 ml of the suspension was 4.76 g (0,116 mol) of sodium hydride in tetrahydrofuran was cooled with a mixture of ice/dry ice/methanol and 50 ml of 20,64 g (0,128 mol) of diethylmalonate in tetrahydrofuran was added to the mixture in portions with stirring. To the mixture then were added 50 ml of 29,2 g (0,124 mol) of colloid obtained in the above stage (I) in tetrahydrofuran, and the mixture was stirred at room temperature for 3 hours the Solvent is kept in vacuum, the residue was diluted with methylene chloride, washed with water and then with brine and dried over anhydrous magnesium sulfate. The solvent is kept in vacuum and the residue was subjected to vacuum distillation to obtain an 18.8 g of the target product, with so Kip. 144-155aboutC.

(3) 3-(3-Chloro-2-methoxyphenyl)propionic acid. A mixture of 18.8 g (59,7 mol) derivative of malonic acid obtained in the above stage 2, with 142 ml of 8h. hydrochloric acid is refluxed over night. The reaction mixture is cooled to extract the precipitated crystals by filtration. The crystals were washed with water and dried to obtained the) derivative of propionic acid, obtained in the above stage 3 of 0.96 ml of concentrated sulfuric acid and 40 ml of ethanol was heated under reflux for 2.5 hours, the Solvent is kept in vacuum, and the residue was plunged chromatography with an average pressure on a column of silica gel (hexane-ethyl acetate = 5:1 by volume) to obtain 7,37 g of the desired product as an oily substance.

(5) Ethyl 2-(3-chloro-2-methoxybenzyl)-3-(3,4-acid)-4-nitrobutyl.

11,1 ml (17.8 mmol) of 1.6 M n-utility in hexane was added in portions to 20 ml of a solution of 2.5 ml (17.8 mmol) of Diisopropylamine in tetrahydrofuran with stirring under conditions of cooling the mixture of dry ice/acetone. After 15 min after adding to the mixture in portions at -50aboutC or lower was added 30 ml of a solution of 4.13 g (17 mmol) of ester obtained in the above stage 4, in tetrahydrofuran. The mixture was stirred at the same temperature for 10 min and portions to the mixture was added 100 ml of a solution of 3.55 g (17 mmol) of nitroolefins in tetrahydrofuran. The mixture was stirred for 30 min and the reaction mixture was added water. The mixture was acidified using 2n. solution of hydrochloric acid and was extracted with methylene chloride. The methylene chloride phase was washed with brine and susirades pressure on a column of silica gel (hexane:ethyl acetate = 3:1 by volume) to obtain 3.8 g of the desired product as an oily substance.

6. Ethyl-4-amino-2-(3-chloro-2-methoxybenzyl)-3-(3,4-acid)butyrate.

2,73 g (of 41.7 mmol) of zinc was added in portions to a mixture of 3.73 g (8.25 mmol) netrokona ether obtained in the above stage 5, with 5.2 ml of concentrated hydrochloric acid and 35 ml of ethanol under stirring conditions of the cooling water with ice,and the mixture was heated under reflux for 3 hours, the Excess zinc was removed by filtration and the filtrate was concentrated in vacuum. To the residue was added methylene chloride, and the mixture was podslushivaet 10% sodium hydroxide solution. The basic mixture was passed through Celite to remove the precipitated insoluble substances by filtration. A mixture of methylene chloride was fractionally, washed with water and then with brine and dried over anhydrous magnesium sulfate. The solvent drove in vacume with 3 g of the desired product as an oily substance.

7. 3-(3-Chloro-2-methoxybenzyl)-4-(3,4-acid)-2-pyrrolidon.

30 ml of a solution of 3 g (7.1 mmol) linolenova ester obtained in stage 6 above in xylene was heated under reflux for 4 hours the Solvent is kept in vacuum and the residue was subjected to chromatography at an average pressure on the column of the tion.

8. TRANS-3-(3-chloro-2-methoxybenzyl)-4-(3,4-acid)-2-pyrrolidone.

A mixture of 1.85 g (to 4.92 mmol) of lactam obtained in stage 7, above, with 2.76 g (24.6 mmol) of tert-butoxide potassium, 30 ml of ethanol and 30 ml of xylene was heated under reflux overnight. The solvent is kept in vacuum. To the residue was added methylene chloride and the mixture was acidified using 2n. solution of hydrochloric acid. The methylene chloride phase was fractionally, washed with water and then with brine and dried over anhydrous magnesium sulfate. The solvent is kept in vacuum and the residue was subjected to chromatography at an average pressure on a column of silica gel (chloroform:methanol = 99:1, by volume) to obtain 1.06 g of the desired product as an oily substance.

9. 3,3-Chloro-2-methoxybenzyl)-4-(3,4-acid)-pyrrolidin.

30 ml of a solution of 1.06 g (2.82 mmol) of TRANS-pyrrolidone obtained at stage 6 above in tetrahydrofuran was added in a stream of nitrogen to 10 ml (10 mmol) of a 1M solution of the complex EXT/tetrahydrofuran in tetrahydrofuran under stirring conditions of the cooling water with ice, and the mixture was heated under reflux overnight. To the reaction mixture was added 6N. the hydrochloric acid solution with stirring at what these lamps within 2 hours The solvent is kept in vacuum and to the residue was added methylene chloride. The mixture was podslushivaet with 10% aqueous sodium hydroxide solution. The methylene chloride phase was fractionally, washed with brine and dried over anhydrous magnesium sulfate. The solvent is kept in vacuum and the residue was subjected to chromatography at an average pressure on a column of silica gel. Elution was performed first with a mixture of chloroform with methanol at a ratio of chloroform and methanol 97:3 (by volume) and then with methanol. Received 510 mg of the desired product as an oily substance from the fraction, elyuirovaniya methanol.

10. TRANS-3-(2-hidroxy-3-chlorophenyl)-4-(3,4-dihydroxyphenyl)pyrrolidine hydrobromide.

6,5 ml (6.5 mmol) of 1M solution of tribromide boron in methylene chloride was added in portions to 30 ml of a solution of 510 mg (1,41 mmol) pyrrolidine obtained at stage 9, as described above, in methylene chloride, in a stream of nitrogen with stirring, under conditions of cooling water with ice. After that, the mixture was stirred at room temperature for 4.5 hours, the Solvent is kept in vacuum and to the residue was added portions of methanol under stirring conditions of the cooling water with ice. Methanol drove in vacuum and to the East is crystallizable from a mixture of acetonitrile/benzene to obtain 250 mg of the target substance, so pl. 207-209aboutC.

C17H18NO3ClHBr.

Calculated, %: C 50,75; H 4,79; N 3,49.

Found, %: C 51,02; H 4,70; N 3,32.

P R I m e R 44. (+-)-TRANS-3-(3,5-debtor-2-hydroxybenzyl)-4-(3,4-dihydroxyphenyl) pyrrolidine hydrobromide.

(1) 3,5-debtor-2-hydroxy-N,N-dimethylbenzylamine.

51,72 g (0.40 mmol) of 2,4-differenoe dissolved in 46 ml of ethanol, and 91 ml of 50% aqueous solution of dinitramine and 40 ml of 37% formalin solution was added to the first solution. The mixture was boiled under reflux for 3 hours. After cooling, the reaction mixture was held by its extraction with ethyl acetate. The extract was washed with water and then saturated saline solution and dried over anhydrous sodium sulfate. The solvent is kept in vacuum to obtain 76 g (quantitatively) of the target product; so pl. 63-64aboutC (ethanol).

2. 3,5-Debtor-2-hydroxy-N,N,N-trimethylphenylammonium iodide.

74 g (x 0.40 mole) of 3,5-debtor-2-hydroxy-N,N-dimethylbenzylamine dissolved in 300 ml of chloroform and to the solution was added 200 ml under the conditions. The mixture was boiled under reflux for 3 hours for the deposition of a yellow precipitate. The precipitate was recovered by filtration to obtain 113 g (yield 87%) of the target product; so pl. 170-173aboutC.

4. 3,5-Debtor-2-methoxybenzaldehyde.

3,5-debtor-2-hydroxybenzaldehyde in the form of the crude product (corresponding to 0.35 mol) was dissolved in 800 ml of acetonitrile. 110 g (0.8 mol) of potassium carbonate and 61 ml (0.96 mol) under the conditions added to the solution and the mixture is boiled under reflux for 5 hours After cooling the mixture, insoluble materials were filtered off and the mother liquor was concentrated. To the concentrate was added to 1.3 liters of ether and the mixture is washed twice with 500 ml of water. Then the mixture was washed with saturated salt solution and the ether layer was dried over anhydrous magnesium sulfate. The solvent is kept in vacuum with getting to 39.6 g (yield 66%) of the whole is 9.6 g (0.23 mol) of 3,5-debtor-2-methoxybenzaldehyde dissolved in 80 ml of ethanol and to the solution is dropwise added 35 ml of a solution of 4.35 g (0,115 mol) sodium borohydride in ethanol at 0aboutC for 5 minutes and the Mixture was stirred at room temperature for 1 h and was added to the mixture of 115 ml of water to stop reaction. The reaction mixture was extracted four times with 115 ml of ether. The extract was washed with brine and dried over anhydrous magnesium sulfate. Ether drove in vacuum and the crude product obtained in this way, person to distil from the receipt of 21.2 g (yield 53%) of the target product.

Boiling point 108-110about(2 mm RT.cent.).

6. 3,5-Debtor-2-methoxybenzylidene.

10 g (57,4 mol) of 3,5-debtor-5-methoxybenzamido alcohol was dissolved in 100 ml of methylene chloride. To the solution was added 25 ml (287 mmol) of tielhard and 7 drops of dimethylformamide and the mixture is boiled under reflux for 1 h, the Reaction mixture was cooled, concentrated and subjected to azeotropic distillation twice with benzene. The residue was dissolved in ether, washed twice with water and then with brine, and dried over anhydrous magnesium sulfate. The solvent is kept in vacuum and the oily substance thus obtained, person to distil obtaining 9,72 g (yield 88%) of the target product (97-98aboutWith/on 24-25 mm RT.cent.).

7. Diethyl-2-(3,4-dimethoxybenzamide)malonate.

200 g (1.2 m is risotti 12 ml pyrrolidine and 6.6 g veratavou acid for 6 hours After cooling, the reaction mixture was added 700 ml of ethyl acetate and the mixture washed with water. Next, the organic phase was washed with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and with brine and dried over anhydrous magnesium sulfate. The solvent is kept in vacuum and the residue person to distil obtaining 360,0 g (yield 97%) of the target product (i.e Kip, 193-200aboutC) (0.5-2.0 mm RT.cent.).

8. Ethyl-3-cyano-3-(3,4-acid)propionate.

A solution of 40.4 g (0.61 mol) of potassium cyanide in 72 ml of water was added to the 1.44 l of a solution of 180.0 g (of 0.58 mol) dalonega ether (7) in ethanol, and the mixture was stirred at 70aboutC for 10 h, the Reaction mixture was cooled and concentrated to 0.5 l of water and 1.5 l of ethyl acetate was added to the mixture and the organic phase was separated from the mixture. The organic phase is washed with water and then saturated saline solution and dried over anhydrous magnesium sulfate. The person to distil the solvent in vacuo to obtain 201 g (0,76 mol) (yield 66%) of the target product.

9. 4-(3,4-Acid)-2-pyrrolidone.

100,5 g tiaokong ester (8) was hydrogenosomal under 100aboutC for 24 h in an atmosphere of hydrogen at a pressure of 50 kg/cm2in the presence of Raney cobalt in smallsville from ethanol with the receipt of 53.5 g (yield 64%) of the target product.

10. 1-(3,4-Dimethoxybenzyl)-4-(3,4-acid)-2-pyrrolidone.

30 g (0,136 mol) of pyrrolidone (9) was treated with Triton B (60 ml of a 40% methanolic solution of 400 ml of benzene). Benzene drove in vacuum and to the residue was added 40 ml of benzene again. This technique was repeated 3 times and was added to the mixture 25,31 g of 3,4-dimethoxybenzaldehyde at room temperature. The mixture was stirred at 60aboutC for 6 h and the reaction mixture was added water. The organic phase was separated and washed twice with water and once with saturated salt solution. The organic phase was dried over anhydrous sodium sulfate and the solvent person to distil under vacuum. The residue was recrystallized from ethanol to obtain 41,54 g (yield 82%) of the target product; so pl. 117-118aboutC.

11. 3-3,5-Debtor-2-methoxybenzyl)-N-(3,4-dimethoxybenzyl)-4-(3,4-dimethoxy - Neil)-2-pyrrolidone.

of 2.1 ml (15 mmol) of Diisopropylamine dissolved in 30 ml of tetrahydrofuran in a nitrogen atmosphere. of 9.4 ml (15 mmol) of 1.6 M n-utility dropwise added to this solution at -78aboutC and the mixture was defended at the same temperature for 10 minutes To this solution at -78aboutWith added dropwise 100 ml of a solution of 3,71 g (10 mmol) of N-(3,4-dimethoxybenzyl)-4-(3,4-demeton - Setenil)-2-p is eacli. The reaction mixture was concentrated and to the residue was added methylene chloride. The mixture was washed with water and then with brine and the organic phase was dried over anhydrous sodium sulfate. The solvent is kept in vacuum and the crude product thus obtained was subjected to chromatography on a column of silica gel (manifesting as a solvent ethyl acetate: n-hexane = 3:1) to obtain the 4.65 g (yield 88%) of the target product; so pl. 94-96aboutC.

12. 3-(3,5-Debtor-2-methoxybenzyl)-N-(3,4-dimethoxybenzyl)-4-(3,4-dimethoxy - nil)pyrrolidin.

200 ml 17,78 g (33 mmol) of 3,5-(3,5-debtor-2-methoxybenzyl-N-(3,4-dime-oxybenzyl)-4-(3,4-dimethoxyphenyl Il)PIR rolidone in tetrahydrofuran dropwise added at 0aboutC in nitrogen atmosphere to 150 ml of a 1M solution of a complex of borane/tetrahydrofuran in tetrahydrofuran. The mixture was boiled under reflux for 2 h and cooled, and to the mixture was added 50 ml of 6 n hydrochloric acid. The mixture was heated to 60aboutC. After stirring for 2 h, the tetrahydrofuran was concentrated in vacuo and extracted twice with methylene chloride. The organic phase is washed with brine and dried over anhydrous sodium sulfate, and the solvent is kept in vacuum. The rest of podvedut.

13. 3-(3,5-Debtor-2-methoxybenzyl)-4-(3,4-acid)-pyrrolidin.

2.5 g (5.9 mmol) of 3-(3,5-debtor-2-methoxybenzyl)-N-(3,4-dimethoxybenzyl)-4-(3,4-acid )pyrrolidine dissolved in ethanol and boiled under reflux for 10 h in the presence of 0.4 g of 10% palladium on coal. The crude product thus obtained was subjected to chromatography on a column of silica gel (elwira first with a mixture of methanol with methylene chloride at a ratio of methanol and methylene chloride 5:95 and then methanol) to give 1.07 g (yield 73%) of target compound.

14. (+-)-TRANS-3-(3,5-debtor-2-hydroxybenzyl)-4-(36,4-dihydroxyphenyl)Pirro - lidine hydrobromide.

Concentrated Hydrobromic acid was added 1.06 g of 3-(3,5-debtor-2-methoxy)-4-(3,4-acid)Pirro - litina, and the mixture was stirred at 100aboutC for 12 h in an oil bath. The solvent is kept in vacuum and to the residue was added benzene and twice held the azeotropic distillation. To the residue was added acetonitrile for the implementation of crystallization. Thus obtained crystals were removed by filtration to obtain 0,76 g (yield 63%) of the target product; so pl. 217-219aboutC.

C17H17F2NO3HBr.

1. TRANS-N-acetyl-3-(3,5-debtor-2-methoxybenzyl)-4-(3,4-acid)PIR role of the Dean.

2.17 g (6,17 mmol) of TRANS-3-(3,5-debtor-2-methoxybenzyl)-4-(3,4-acid)pyrrolidine obtained from stage 13 of example 4, was dissolved in 30 ml of chloroform and 0.75 g (7.4 mmol) of triethylamine was added to the mixture. Next, to the mixture was added dropwise 10 ml of a solution of 0.5 ml (7.0 mmol) of acetylchloride in chloroform under ice cooling, and the mixture was stirred at room temperature for 3 hours To the mixture was added 1 ml of water to stop reaction. The reaction mixture was washed with water, 2n. hydrochloric acid and saturated aqueous sodium bicarbonate solution successively and dried over anhydrous sodium sulfate. The solvent is kept in vacuum and the residue was subjected to chromatography on a column of silica gel (methylene chloride:methanol 97: 3) to obtain 2.5 g (quantitatively) of the target product.

2. 27.5 g of the above-described derivative of acetylpyrrolidine loaded into a column for separating optical isomers were separated and purified using a mixed solvent comprising n-hexane, isopropyl alcohol and diethylamine (5:2:0,005) as eluent, thereby obtaining 1.06 g (+) isomer []D28: +20,2o(c = 1,05 in methanol) and 1.09 g ( reflux in a 47% solution of Hydrobromic acid for 20 hours Hydrobromic acid is kept in vacuum and to the residue was added benzene with (twice) azeotropic distillation. The residue was dissolved in ethanol, treated with activated charcoal was removed by filtration. The solvent drove in vacuo from the filtrate with the receipt of 1.05 g of (-)-TRANS-3-(3,5-debtor-2-hydroxybenzyl)-4-(3,4-dihydroxyphenyl peer - tolidine hydrobromide.

[]D28:is 18.5o(c = 1,05 in methanol).

(+) isomer obtained in stage 2 of example 5, was treated by the same procedure as described above for stage 3, to obtain (+)-TRANS-3-(3,5-debtor-2-hydroxybenzyl)-4-(3,4-dihydroxyphenyl)pyrrolidine hydrobromide.

[]D28:+16,6o(c = 1.01 in methanol).

P R I m e R s 46-70. Derivatives of pyrrolidine listed in the following table.5 were obtained by the above methods.

P R I m e R 71. TRANS-3-(3,4-dihydroxyphenyl)-4-(2-hydroxy-3-trimethyl)Pirro-lidine the hydrobromide was obtained as amorphous compounds WITH17H21NO3HBr.

P R I m e R 72. Were obtained the following compounds: 3-(3-chlorophenyl)-4-(3,4-dihydroxyphenyl) pyrrolidine (1) 3-(3-bromophenyl)-4-(3,4-dihydroxyphenyl) pyrrolidine (2) 3-(3-chlorophenyl)-4-(3,4-dihydroxyphenyl) pyrrol the The last three compounds were obtained in the form of their salts of Hydrobromic.

Analytical data of these compounds are the following: (3) so pl. 184-185aboutC; weight 290 (M+); (4) so pl. 197-199aboutC; weight 334 (M+); (5) so pl. 190-191aboutC; weight 270 (M++1);

1. Tests for specic binding of D1 and D2 receptors warts rats.

Deleted the striatum (large inner gray nuclei in the brain, the striatum Corpus) in rats, homogenized them in 0.05 M Tris Buffer and then centrifuged speed Hg to collect synaptosomes faction. The precipitate is repeatedly washed with 0.25 M Tris-buffer and suspended in 0.05 M Tris-buffer containing 120 mm NaCl, 5 mm KCl, 2 mm CaCl2and 1 mm MgCl2.

The suspension portions were frozen at a temperature of -80aboutC. Simultaneously with the samples, portions to the suspension was added N-Sch 23390 with a final concentration of 0.3 pH in the case of3N-spiperone with a final concentration of 0.2 nm in the case of D2, respectively. The mixture is incubated at 37aboutC for 15 minutes After filtration on Whatman filter CrF/In these mixtures was studied using liquid-scintillation counter. KF-82526 and Spiperone used to determine nonspecific binding. IC50denotes the concentration of the test material, which can be replaced by epithemia compounds A-L are listed below.

Compound. Connection: the hydrobromide-3-(3,4-hydrofoil)-4-phenylpyrrolidine Connection: TRANS-3-(3,4-dihydroxyphenyl)-4-(2-were)pyrrolidin Connection: TRANS-3-(3,4-dihydroxyphenyl)-4-(2-were)pyrrolidine hydrobromide Connection With: the hydrobromide of TRANS-3-(2-chlorophenyl)-4-(3,4-dihydrogen)Pirro - lidine. Compound D: hydrobromide TRANS-3-/2-chloro-3-hydroxyphenyl/-4-(3,4-digidoc - Setenil)pyrrolidine. Compound E: the hydrobromide of TRANS-3-(3,4-hydroxyphenyl)-4-(3-metranil)Pirro - lidine Connection F: hydrogen bromide CIS-3-(3,4-dihydroxyphenyl)-4-(3-metranil)Pirro - lidine Connection G: hydrobromide TRANS-3-(7-benzothiophene)-4-(3,4-dihydroxyphenyl peer-tolidine Connection N: TRANS-3-(3-chloro-6-hydroxyphenyl)-methyl-4-(3,4-dihydroxyphenyl)PIR - Raiden Connection I: TRANS-3-2,6-dihydroxyphenyl/methyl-4-(3,4-dihydroxyphenyl peer - Raiden Compound J: TRANS-3-/3-chloro-2,6-dihydroxyphenyl)-methyl-4-/3,4-dihydroxy - nil)pyrrolidin Connection To: TRANS-3-/3.5-debtor-22-hydroxyphenyl)-methyl-4-(3,4-dihydroxyphenyl)pyrrolidin n Connection L: TRANS-3-(3-fluoro-2-hydroxyphenyl)methyl-4-(3,4-dihydroxyphenyl peer-Raiden

2. Impact kardiogemodinamicheskuyu agents on anastasiosandy dogs.

Half-dogs weighing about 10 kg anastasiou nitrous oxide and enflurane in conjunction with each other through endotracheally tube inserted for the purpose of artificial respiration using an artificial respirator ACOM ARF-E (togawaa name) and anesthetic device ACOM EAT-P (trade name) with the aim of implementing effective anesthesia. Blood pressure and intravenous pressure in the left ventricle were determined using microcutting pressure sensor MPC-500 (trade name of the firm Miller), which was inserted into the femoral artery. Blood pressure at points determined by inserting through laprotomy in the renal artery of the probe electromagnetic counter flow of blood MSU-2100 (trade name Nikon KOHDEN Bldg.). The results were processed using a polygraph system RM company Nihon KOHDEN Building.

The sample was dissolved in 0.9% saline and was used through the brachial vein inserted in her catheter. In the case where the application was made through the duodenum, it was cut in the longitudinal direction and inserted the catheter. The results obtained are given in table.2 interest in improving renal blood flow and decrease in percentage of the average blood pressure during the application of the test compounds.

3. Effect on acute heart failure is edu opened in the region of the fourth edge with the left-hand thoracotomy. To determine cardiac workload electromagnetic probe was then placed around the aorta. Expose the left anterior descending coronary artery (IAD) at the periphery relative to the first diagonal holes for the bonds around her wound thread. Acute heart failure was caused as follows. Within 2 h of intravenous poured into 500 ml of 0.9% saline, and then took an injection of 500 ml of 6% Dextran solution 50 (Midori Jui Co., Co., Ltd.) containing 10 mg propanol and 300 mg creatinine quickly poured for 30 min to improve the left gastric lower diastolic pressure (OEDR) to the value of 20 mm RT.article The rate of infusion solution dextranase reduced by approximately one third for the preservation of stagnation. After the occurrence of the blockage becomes stable, it was weakening latinoware IAD. Is WEDR increased to more than 25 mm RT. Art. then started an intravenous infusion of 0.3 ág/kg/min hydrochloride connection D. B the result of this infusion is WEDR was down by about 3 mm RT.article Cardiac activity and blood flow in the kidneys was reduced by 20 and 10%, respectively, as a result of ligatti IAD.

Infusion hydrochloride connected is. The results obtained show that the compounds of the present invention are effective agents in the case of heart failure.

1. Derivatives pyrrolidine General formula

where Y is the group - (CH2)nand when n = 0, X is hydrogen, halogen, lower alkyl;

R is phenyl, unsubstituted or substituted by halogen, lower alkyl, hydroxy - or alkoxygroup, trifluoromethyl, naphthyl, thiophene, unsubstituted or substituted lower alkyl, benzothiophen, pyridyl, imidazole, substituted lower alkyl;

when n = 1 X is hydrogen or halogen;

R is phenyl, unsubstituted or substituted by halogen, hydroxy or alkoxygroup, lower alkyl, thiophene;

Y - S(O)pwhere p = 0 or 2, -O - or - NH;

X is hydrogen;

R - phenyl.

2. The method of obtaining derivatives of pyrrolidine General formula

Y-R< / BR>
where Y is the group -(CH2)nand when n = 0 X is hydrogen, halogen, lower alkyl;

R is phenyl, unsubstituted or substituted by halogen, lower alkyl, hydroxy - or alkoxygroup, trifluoromethyl, naphthyl, thiophene, unsubstituted or substituted lower alkyl, benzothiophen, pyridyl, imidazole, substituted lower alkyl;

when n = 1 X is hydrogen or halogen;

R is phenyl, unsubstituted or samewe X - hydrogen;

R is phenyl,

characterized in that the compound of General formula

R - Y - CH2COOR1,

where R has the above meanings;

R1- lower alkyl,

subjected to interaction with nitroanilide General formula

Y-R< / BR>
where X has the above meanings;

R2- hidroxizina group,

the compound obtained of General formula

< / BR>
reduced to the amino compounds of General formula

< / BR>
which cyclist, the mixture of CIS - and TRANS-forms a 5-membered lactam of General formula

< / BR>
heated in the presence or absence of a base in an environment of organic solvent, the obtained 5-membered lactam in the TRANS-form

< / BR>
restore the DIBORANE or a complex metal hydride, followed by removal hydroxyamine groups in the resulting derived pyrrolidine General formula

< / BR>
where R and R2have the specified values.

 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of adamantane of the general formula:

wherein m = 1 or 2; each R1 represents independently hydrogen atom; A represents C(O)NH or NHC(O); Ar represents the group:

or

wherein X represents a bond, oxygen atom or group CO, (CH2)1-6, CH=, O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, CR'(OH), NR5, (CH2)1-6NR5, CONR5, S(O)n, S(O)nCH2, CH2S(O)n wherein n = 0, 1 or 2; R' represents hydrogen atom; one of R2 and R3 represents halogen atom, nitro-group, (C1-C6)-alkyl; and another is taken among R2 and R3 and represents hydrogen or halogen atom; either R4 represents 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system comprising one or two nitrogen atoms and oxygen atom optionally being heterocyclic ring system is substituted optionally with one or more substitutes taken independently among hydroxyl atoms, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, -NR6R7, -(CH2)rNR6R7; or R4 represents 3-8-membered saturated carbocyclic ring system substituted with one or more substitutes taken independently among -NR6R7, -(CH2)NR6R7 wherein r = 1; R5 represents hydrogen atom; R6 and R7 each represents independently hydrogen atom or (C1-C6)-alkyl, or (C2-C6)-hydroxyalkyl group eliciting antagonistic effect with respect to R2X7-receptors. Also, invention describes a method for their preparing, pharmaceutical composition comprising thereof, a method for preparing the pharmaceutical composition and their applying in therapy for treatment of rheumatic arthritis and obstructive diseases of respiratory ways.

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

13 cl, 88 ex

FIELD: biology, medicine.

SUBSTANCE: invention relates to chemical compounds and compositions that can be used as modulating agents of phototoxicity of skin cells. Proposed "modulators" relate to material that can either accelerate or decelerate damage of cells, for example, skin cells caused by effect (exposition) of light, for example, UV-rays of type A. Modulators are chosen from group consisting of 3-hydroxyproline pharmacophor or proline, 4-hydroxyproline or its alkyl ester. Invention provides modulating effect of phototoxicity of cells wherein modulators relate to molecule that can be molecule of skin components, in particular, collagen.

EFFECT: improved and enhanced method of modulation.

14 cl, 2 tbl, 13 dwg, 10 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new nitrogen-containing heterocyclic derivatives represented by the formula (I): where symbols have the following meaning: R1 and R2 can be equal or different and denote H-, C1-C6-alkyl, C3-C14-cycloalkyl, C1-C6-alkyl-CO-, HO-CO-, C1-C6-alkyl-O-CO-, H2N-CO-, C1-C6-alkyl-HN-CO-, (C1-C6-alkyl)2N-CO-, C1-C6-alkyl-O-, C1-C6-alkyl-CO-O-, H2N-, C1-C6-alkyl-HN-, (C1-C6-alkyl)2N-, C1-C6-alkyl-CO-NH-, halogen, nitro, morpholine, pyrrolidin, imidazol or cyano; R3 and R4 can be equal or different and denote C1-C6-alkyl, C1-C6-alkyl-O-, (C1-C6-alkyl)2N- or halogen; R5 and R6 can be equal or different and denote H-, C1-C6-alkyl or halogen; R7 and R8 can be equal or different and denote H-, C1-C6-alkyl, HO-, C1-C6-alkyl-O- or halogen; R7 and R8 together can form oxo (O=); R9 denotes heterocyclic group -C1-C6-alkyl-CO-, which can be optionally substituted for at least one substitute selected out of a group b described further, where heterocyclic group is selected out of morpholine, piperazine, pyrrolidin, piperidine, thiomorpholine, azepine, diazepine, oxyazepine, decahydroquinoline, decahydroisoquinoline, hexahydroazepine or 2,5-diazabicyclo[2.2.1]heptane; R10, R11, R12 and R13 can be equal or different and denote H- or C1-C6-alkyl; group b: (1) HO, (2) C1-C6-alkyl-O-, (3) R101 R102N (where R101 and R102 can be equal or different and denote (i) H, (ii) C1-C6-alkyl), (4) halogen, (5) oxo (O=), (6) C3-C14-cycloalkyl, (7) phenyl, (8) pyrrolidine, (9) C1-C6-alkyl, which can be optionally substituted for HO, C1-C6-alkyl-O-, phenyl, C1-C6-alkyl-CO- or morpholine, (10) acyl, which can be optionally substituted for oxo (O=), where acyl is C1-C6-alkyl-CO- or heterocyclic -CO group, where heterocyclic group is imidazol, pyridine or pyrazine, (11) H2N-CO- and (12) C1-C6-alkyl-SO2; A denotes heterocycloalkyl group selected out of piperidine, pyrrolidine or hexahydroazepine; n is 0, or its pharmaceutically acceptable salts. The invention also concerns pharmaceutical composition and application of nitrogen-containing heterocyclic derivatives from each of pp. 1-11.

EFFECT: obtaining new biologically active compounds and pharmaceutical composition based on there, with inhibition effect on sodium channel activity.

16 cl, 226 ex, 32 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the new compounds of general formula (II) , whereat values R1, R2, X, R11, R12, R18, R19, m, n are displayed in claim 1 of the formula.

EFFECT: compounds display agonistic and antagonistic activity which allows to propose their usage in pharmaceutical compositions for treatment of diseases and distresses connected with histamine H3 receptor.

38 cl, 80 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) in form of a separate stereoisomer, a mixture of stereoisomers or a racemic mixture of stereoisomers and their pharmaceutically acceptable salts. In formula (I) ring A, C or D is independently completely or partially saturated; each of C1, C4, C11, C12, C15 and C16 is independently substituted with two hydrogen atoms; each of C9 and C14 is independently substituted with a hydrogen atom; R1 represents -OR7 or -N(R7)2. Values of the rest of the radicals are given in the formula of invention. The invention also relates to a pharmaceutical composition with anti-inflammatory activity and contains an effective amount of the disclosed compound and to use of the said compounds to make a medicinal agent with anti-inflammatory activity.

EFFECT: disclosed compounds have anti-inflammatory activity.

23 cl, 47 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel phenyl methanone derivatives of the formula I: where R1 denote -OR1, heterocycle such as morpholinyl, pyrrolidinyl, tetrahydropyranyl, phenyl, heteoaryl such as pyrazolyl, which are not substituted or substituted with C1-6alkyl, halogen; R1 denote C1-6alkyl, C1-6alkyl substituted with halogen, or denotes a -(CH2)0-saturated C3-6cycloalkyl; R2 denotes -S(O)2-C1-6alkyl, -S(O)2NH-C1-6alkyl, NO2 or CN; R3 denotes pyridinyl, substituted with C1-6alkyl, substituted with halogen, or phenyl which is not substituted or substituted with one to three substitutes selected from a group consisting of C1-6alkyl, C1-6alkoxy, CN, NO2, halogen, C1-6alkyl, substituted with halogen, C1-6alkoxy, substituted with halogen, phenyl, sulphonamide; X denotes -CH2-, -NH-, -CH2O- or -OCH2-; n denotes 1, 2; m denotes 1, 2; o denotes 1 or 1; and pharmaceutically acceptable acid addition salt thereof.

EFFECT: compounds have glycine reuptake inhibition which enables their use to prepare a pharmaceutical composition.

9 cl, 2 tbl, 40 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclopropylamine derivatives of formula: or its pharmaceutically acceptable salt, wherein: one of R1 and R2 means a group of formula -L2-R6a-L3-R6b; the other of R1 and R2 means H, C1-10alkyl, C1-10alkoxy, halogen, CN; each R3, R3a R3b independently means H, C1-6alkyl, trifluoromethyl, C1-10alkoxy, CN; R4 and R5 taken together with a nitrogen atom whereto each attached form a non-aromatic cycle of formula: R7, R8, R9 and R10 each H, C1-10alkyl; R6a means cyanophenyl, phenyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, [1,2,3]triazolyl, [1,2,4]triazolyl, azepanyl, azetidinyl, azetidin-2-onyl, pyridazin-3(2H)-onyl, pyridin-2(1H)-onyl, pyrimidin-2(1H)-onyl, pyrrolidin-2-onyl, benzothiazolyl wherein the pyridinyl and pyrimidinyl groups optionally contain 1-3 substitutes specified in a group consisting of C1-10alkyl and C1-10alkoxy; R6b means H; L means - [C(R16)(R17)]k; L2 means a bond, C2-10alkylene, -O-, -C(=O)-, -NH-, -N(R16)C(=O), -C(=O)N(R16) and -N(C1-6alkyl)-;L3 means a bond; R15 means H, C1-6alkyl, C1-6alkoxycarbonyl, amido and formyl R16 , R17 in each specific case means H, C1-6alkyl; Rx and Ry in each specific case independently mean H, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, fluorine, diC1-6alkylamino; k is equal to 1, 2 or 3; m is equal to 2.

EFFECT: compounds show H3 receptor inhibitory activity that makes them applicable in a pharmaceutical composition.

10 cl, 7 dwg, 44 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to certain (R)-arylalkylamino derivatives of formula , wherein R is specified in the following values: - 2-thiazolyl substituted by a trifluoromethyl group; -CORa, SO2Ra, wherein Ra is specified in the following values -C1-C5-alkyl, C3-C6- cycloalkyl, phenyl, a heteroaryl group specified in thiophen, furan and pyridine with heteroaryl being unsubstituted or substituted by a group specified in COOH and C1-C4-acyloxy; - ω-aminoalkylamino group of formula , wherein X represents: - linear or branched C1-C6 alkylene; R2 and R3 together with N atom bound therewith form a 3-7-member nitrogen-containing heterocyclic ring of formula , wherein Y represents a single bond; and p is equal to 0 or represents an integer 1 to 3; R1 represents linear or branched C1-C5 alkyl; Ar represents a phenyl group substituted by one or more groups independently specified in benzoyl, heteroarylcarbonyl wherein the heteroaryl group represents furan, 4'-trifluoromethane sulphonyloxy-, 4'-[1-methyl-1-(phenylsulphonyl)ethyl]- and 4'-benzole sulphonyloxy-. The compounds under the invention provides unexpectedly strong inhibiting action on C5a-induced chemotaxis of human PMN.

EFFECT: preparing (R)-arylalkylamino derivatives applicable in treating the pathologies dependent from chemotaxic activity of neutrophils and monocytes induced by the C5a complement fraction.

6 cl, 1 tbl, 10 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I): wherein n = 1 or 2; R1 represents chlorine, fluorine, bromine atom, methyl or methoxy-group; R2 is taken among of one the following groups: (i) halogen atom, nitro-, hydroxy- amino- or cyano-group; (ii) -X1-R5 wherein X1 represents -O-, -S-, -SO-, -SO2-, NR6-, -CO-, -CONR6-, -NR6CO- wherein R6 represents hydrogen atom and R5 is taken among (C1-C6)-alkyl optionally substituted with one or some A, and so on; (iii) 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom and so on; R3 represents (C1-C6)-alkyl optionally substituted with one or some A and so on; A is taken among hydroxy-, amino-group, halogen atom, carboxy-, N-(C1-C4-alkyl)-amino-, N,N-di-(C1-C4-alkyl)-amino-group, carbamoyl and (C1-C6)-alkoxy-group; D is taken among: (i) -Xa-Rc wherein Xa represents -SO2, -CO-, -NRdCO-, -NRd- or -CONRd-; (iv) cyano-group or halogen atom; (v) -XcRf wherein Xc represents -C(O)- and Rf represents 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom with optionally additional heteroatom taken independently among oxygen atom (O), optionally substituted at ring carbon atom by the hydroxy-group, halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or cyano-group; G represents (C1-C6)-alkanoyl; R4 represents hydrogen or fluorine atom; or to its pharmaceutically acceptable salt or its ester hydrolyzed in vivo. Also, invention proposes a method for preparing compound of the formula (I). Also, invention proposes pharmaceutical composition enhancing activity of pyruvate dehydrogenase comprising substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I) or its pharmaceutically acceptable salt or ester hydrolyzed in vivo in combination with pharmaceutically acceptable vehicle or carrier. Invention provides preparing derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide enhancing activity of pyruvate dehydrogenase.

EFFECT: valuable medicinal and biochemical properties of compounds.

14 cl, 1 tbl, 85 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new inhibitors of farnesyltransferase of the formula (I):

wherein R1 means hydrogen atom (H), group of the formula R5C(O)- wherein R5 means phenyl, pyridyl or N-methylpiperidine; R2 means hydrogen atom (H), isopropyl, cyclopentyl or N-methyltetrahydropyridyl; R3 means hydrogen atom (H), halogen atom; R4 means hydrogen atom (H), halogen atom; L means -CH2-Z- wherein Z means NH; Y means sulfur atom (S), S(O) or S(O)2; or its salt. Compounds of the formula (I) inhibit activity of enzyme, farnesyl(protein)transferase, that allows their using in pharmaceutical composition in cancer treatment.

EFFECT: valuable medicinal properties of inhibitors.

18 cl, 3 tbl, 3 sch, 6 ex

New compounds // 2261245

FIELD: organic chemistry, medicine, pharmacy.

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

EFFECT: valuable medicinal properties of new compounds.

14 cl, 98 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to compounds that inhibit binding ligands with α4β1-integrin (VLA-4) selectively. Compounds have the formula (I):

wherein W means unsubstituted phenyl or phenyl substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom, (C1-C4)-alkoxy-group and halogen alkyl; W1 means unsubstituted phenylene or phenylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, pyridylene, pyridylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, 2-oxopyrrolylene or thiazolylene; A means oxygen atom (O); R means -(CH2)n- wherein n = 1 or 2; X means -C(O)-; M is taken among the following groups: a)

wherein means divalent 5- or 6-membered heterocyclic radical wherein nitrogen atom is located in the joining point to X wherein Q represents -CH2-, -O- or -S-; R1, R2 and R3 are taken independently among the group involving: hydrogen atom (-H), hydroxyl group (-OH), quinolinyloxy-group, -NH2, mono- or dialkylamino-group, (C1-C6)-alkylsulfonylamino-, arylsulfonylamino-, naphthyloxy-, phenyloxy-group substituted optionally with di-(C1-C6)-alkylamine, (C1-C6)-alkyl, benzyloxymethyl, halogen atom, phenyl, (C1-C4)-alkoxy-group; or two adjacent R1, R2 and R3 taken in common can form alkylene- or alkylenenedioxy-group substituted optionally with 1-3 alkyl groups; R4 means hydrogen atom (H), lower alkyl; Y is taken among a bond, (C2-C8)-alkenylene group, (C2-C8)-alkynylene group, -C(O)-, -C(O)NH- and -(CH2)kY2 wherein k is taken among 1, 2 and 3; Y2 means a direct bond or divalent radical taken among -O-, -S-, -S(O)-, -S(O)2- and -NY3- wherein Y3 is taken among hydrogen atom (H), lower alkyl; Z means (C3-C8)-cycloalkylene, optionally substituted phenylene, pyridylene, piperidylene, piperazinylene; A1 means a direct bond, -(CH2)t-alkynyl wherein t is taken among 1, 2 and 3; R5 means -OH, lower alkoxy-group, , ; b) means wherein R11 is taken among , -NR12- wherein R12 is taken among hydrogen atom (-H), optionally substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl; Z3 is taken among a direct bond, (C1-C12)-alkyl wherein one or some carbon atoms can be replaced with -O- or -NR13- wherein R13 means hydrogen atom (-H), lower alkyl, wherein x = 0 or 1; y = 1, 2 or 3; R14 means hydrogen atom (-H), ; and when R11 means NR12 then Z3 is taken among: wherein 14Ra means hydrogen (H), halogen atom; , and ; Q2 means wherein R17 and R18 mean hydrogen atom (H), lower alkyl; or phenylene that can be substituted; L1 means -COOH or -COOR19 wherein R19 means lower alkyl. Compounds of the formula (I) inhibit activity of VLA-4-mediated adhesion of cells that allows their using in pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and compositions.

21 cl, 11 tbl, 283 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds including all its enantiomeric and diastereomeric forms, and to their pharmaceutically acceptable salts wherein indicated compound corresponds to the formula: wherein A represents a conformationally limited ring system chosen from the group comprising the following formulae: (a) (d) and (e) wherein carbon atoms labeled by asterisks can be in any stereochemical configuration or their mixtures wherein Y has a formula: -(CH2)b-R15 wherein index b = 1-4, and R15 represents -OH, -NH2, guanidine-group, and Z has a formula: wherein R represents hydrogen atom; R9 represents naphthylmethyl; R10 represents -C(X)N(R16)2 wherein each R16 represents independently hydrogen atom or (C1-C10)-alkyl; X represents oxygen atom; or Z represents naphthylmethyl wherein W has a formula: wherein R represents phenyl substituted optionally with halogen atom of OH-group wherein fragment L is chosen from the group comprising: -NH- or -NHC(O)-; B represents hydrogen atom of fragment of the formula: wherein fragments R2, R3 and R4 are chosen independently among the group comprising hydrogen atom, -NHC(O)CH3, benzyl substituted optionally with hydroxy-group or halogen atom, imidazolylmethyl; or fragments R2, R3 and R represent in common naphthalinyl or isoquinolinyl; or one radical among R2, R3 and R4 represents hydrogen atom and two radical among R, R3 or R4 chosen in common form piperidine ring or tetrahydroisoquinoline ring substituted optionally with the group -C(O)CH3. Also, invention relates to a pharmaceutical composition possessing the agonistic activity with respect to MC-3/MC-4 receptors based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of disorders mediated by function of MC-3/MC-4 receptors.

EFFECT: valuable medicinal properties of compounds and compositions.

17 cl, 14 tbl, 12 ex

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

SUBSTANCE: invention relates to novel isoquinoline compounds of the general formula (I): wherein R1 represents hydrogen atom, halogen atom or alkyl; Y is absent or represents alkylene chain comprising from 1 to 8 carbon atoms wherein arbitrary carbon atom can comprise hydroxyl group as a substitute; R represents the following formula (II): wherein X represents -CH or nitrogen atom under condition that if Y absent in the formula (I) then X must represent -CH; W represents -CH or nitrogen atom under condition that if X represents -CH then W must represents nitrogen atom; s represents a whole number from 1 to 3; t represents a whole number from 1 to 3; if R3 represents hydrogen atom or alkyl then R2 represents hydrogen atom, alkyl, hydroxyl group or hydroxyalkyl, and R2' represents hydroxyl group or hydroxyalkyl, and if R3 represents hydroxyalkyl then R2 and R2' represent hydrogen atom. Also, invention relates to their optically active forms, pharmaceutically acceptable salts, aqueous adducts, hydrates and solvates. Compounds of the formula (I) elicit inhibitory effect on activity of poly-(ADP-ribose)-polymerase and can be used in prophylaxis of diseases associated with cerebral infarction.

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

40 cl, 4 tbl, 55 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of N-methyl-N-{(1S)-1-phenyl-1-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}-2,2-diphenylacetamide. Method involves the following steps: (a) interaction of N-substituted derivative of phenylglycine of the formula (I): , wherein R means -OR1, -SR1; R1 means A, benzyl, unsubstituted phenyl or phenyl, biphenyl or naphthyl mono- or disubstituted with halogen atom, -OA or (C1-C6)-alkyl; A means linear or branched (C1-C6)-alkyl; M means hydrogen atom (H) or a cation chosen from group comprising alkaline metals, earth-alkaline metals, ammonium or alkylammonium with compound of the formula (II): , wherein R2 means H, A, or with acid-additive salt of compound of the formula (II) of acids HCl, HBr, HJ, H2SO4, H3PO4, or with organic carboxylic acid to obtain compound of the formula (III): , wherein R and R2 have above given values; (b) synthesized compound is converted to compound of the formula (IV): , by reduction reaction that is converted optionally to acid-additive salt of acids HCl, HBr, HJ, H2SO4, H3PO4, or to salt of organic carboxylic acid, and (c) synthesized compound of the formula (IV) is subjected for interaction with activated carboxylic acid of the formula (V): , wherein R4 means F, Cl, Br, J, -OA or -O-CO-A to yield compound of the formula (VI): , that is converted to a corresponding acid-additive salt using inorganic acid chosen from group comprising HCl, HBr, HJ, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, ortho-phosphoric acid or using organic acid.

EFFECT: improved method of synthesis.

7 cl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrrolidinium of the general formula (I): possessing antagonistic effect with respect to muscarinic receptors M3 wherein B means phenyl or thienyl group; each radical among R1, R2 and R means independently hydrogen, fluorine, chlorine atom or hydroxyl; n means a whole number from 0 to 1; A means group chosen from groups -CH2 and -O-; m means a whole number from 0 to 6; R means (C1-C8)-alkyl; X- represents a pharmaceutically acceptable anion of mono- or multibasic acid, and involving all separate stereoisomers and their mixtures. Also, invention relates to methods for synthesis of such compounds, pharmaceutical compositions containing such compounds and to their using in therapy as antagonists of muscarinic receptors M3.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

17 cl, 51 ex

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