The method of obtaining nitrogen-containing heterocyclic compounds or their salts farmatsevticheskii

 

(57) Abstract:

Usage: in medicine, as the product has pharmacological activity. The inventive method of obtaining new heterocyclic nitrogen-containing compounds of the formula I where the radicals R1-R4have different values; X= CH2or their pharmaceutically-acceptable salts. Reagent 1: compound of formula II, where R is H. the Reagent 2: R2-Y. table 1.

The invention relates to methods for new nitrogen-containing compounds of General formula I

R where R1is hydroxy, lower alkanoyloxy, OCOT1Y2where: Y1, Y2is hydrogen, lower alkyl when X = CH2; R2group of the formula

or or or

or where n' is 0,1,2,3; n = 2,1,0, where: Y3Y4is hydrogen, lower alkyl, Y5- phenyl-lower alkoxy, hydrogen, lower alkoxy when X is - S R2group

CHY5or where Y3, Y5have the specified values;

R3lowest alkoxyl, lower alkyl, hydrogen, halogen, trifluoromethyl, lower alkylsulfonyl, R4lowest alkoxyl or their pharmaceutically acceptable salts.

The compounds of formula I and their pharmaceutically acceptable salts act as vasodilator agents, bespaltnaya composition, containing one (or more) compounds of the formula I in patients reduced blood pressure (hypertensive mammal). For lowering blood pressure is suitable single dose or daily dose divided into two or four portions, providing a dosage of about 0.1-100 mg per 1 kg of body weight per day, preferably about 1 to 50 mg per 1 kg per day. Preferred substances are prescribed orally, but can also be used parenteral methods of purposes, such as subcutaneous, intramuscular, or intravenous.

Substances of this invention can also be used in combination with a beta-adrenergic agent, or anti-arrhythmic agent, diuretin, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trifloromethyl, polythiazide, or benzthiazide, as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, muzolimine, bumetanide triamterene, amiloride and spironolactone and salts of such compounds, inhibitors of the enzyme that turns antiotensin, such as captopril, zofenopril, fosinopril, enalapril, delapril, pentopril, inapril, ramipril, lisinopril, and salts of such compounds, thrombolytic agent and Antilibanus complex plasminogen streptokinase activator (APSAC, Aminata, Bencham Of Labratories). In such products combinations, if they are made as a fixed dose, the substance of this invention are used within the described range of doses, and the other pharmaceutically active agent within the approved doses.

The substances of formula I can be prepared in a formulation for use in the reduction of blood pressure in such compositions as tablets, capsules or elixirs for oral destination or in sterile solutions or suspensions for parenterale destination. Substances of the formula I can also be administered via a transdermal patch or nasal inhalation solutions. Approximately 10-500 mg of the substances of the formula I compounder with a physiologically acceptable carrier, means for amplifying the drug, binder, preservative agent, stabilizer, perfume, etc. in the form of a unit dose, as provided by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that it turns out the right dosage at the specified interval.

The table shows the results of the tests according to the following procedure for the claimed compounds.

The test method.

The value of the IC50represents the concentration of the tested compound in the presence of 50% relaxation for contractions of the thoracic aorta of a rabbit caused by KCl in vitro. Then by the method of least squares was built curves describing the logarithmic relationship between concentration and transformation of the relaxation response.

Known benzodiazepine formula I where X = S

R4-H, Hal; alkyl, alkanoyloxy, R1= OY3, Y3-alkanoyl,

R3= H, Hal, R2= -(CH2)n---N ,

(CH2)n-Y-N

(CH2)nY-N , where n=0,1 Y4,Y5-H, lower alkyl, Y6- alkyl; Y7- aralkyl (1) exhibiting similar activity.

Known compounds containing at position I benzothiazepine ring alkalescence or cyclic residues exhibiting hypotensive activity.

These inventions allow us to expand the range of derivatives benzdiazepine having hypotensive activity.

The proposed method patrali II

R where X, R3, R4, R1have the specified values, is treated with a base in an inert organic solvent followed by treatment of the compound of formula III R2Y, where R2- has the specified values, Y - tsepliaeva group, with selection of the target product in free form or in pharmaceutically acceptable salt.

Most preferred are compounds where R3is 6-trifluoromethyl-or 7-methoxy-group in benzazepine core, or 8-methoxy group in benzodiazepinovom the nucleus and R4is a methoxy group.

P R I m e R 1. [1(TRANS),3A,4A]-1-[2-(dimethylamino)cyclohexyl]-1,3,4,5 - tetrahydro-4-(4-methoxyphenyl)-3-methyl-6-(trifluoromethyl)-2H-1 - benzazepin-2-it, monohydrochloride.

To a suspension of 0.3 g of sodium hydride (6.3 mmol, 50% dispersion in oil) in 20 ml of dry dimethylformamide added 2.0 g of (CIS)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl) -3-methyl-6-(trifluoromethyl) -2H-1-benzazepin-2-it (5,73 mmol) at once into a solid form. The solution is stirred for 45 min and then added dropwise a solution of 1.59 g (6.3 mmol) of (TRANS)1-iodine-2-(dimethylamino)cyclohexane in 12 ml of dry dimethylformamide for 15 minutes the solution was stirred at room temperature is dimethylamino)cyclohexane and continue heating for another 30 minutes The solution is allowed to cool and the dimethylformamide removed in vacuo. To the residue water is added, the aqueous solution extracted twice with ethyl acetate and the combined organic phases are washed with brine and dried with magnesium sulfate to obtain 3.15 g of semi-solid substances.

When chromatographicaliy on silica gel with 1% of triethylamine mixture of 2% methanol in dichloromethane obtain 0.74 g of the free base is specified in the header of the substance, in the form of a foamy solid white. This free base was dissolved in diethyl ether and adding ether saturated with hydrogen chloride, to obtain a white precipitate. The solution is evaporated and washed twice with ether to remove excess hydrogen chloride. The remaining white solid is subjected to recrystallization from a mixture of isopropanol-diisopropyl ether to obtain 0.68 g of the specified header connection so pl. above 250aboutC.

Calculated,%: C 62,51; N 6,77; N Of 5.40; Cl 6,83, F 10,99.

C27H34ClF3N2O21,5 H2O

Found,%: C 62,59; H6,84, N 5,30, Cl 6,70, F 10,99.

P R I m m e R 2. (CIS)-1-[2-(dimethylamino)propyl]-1,3,4,5-tetrahydro-4-(4 - methoxyphenyl)-3-methyl-6-(trifluoromethyl)-2H-1 - benzazepin-2-it, isomer a, monohydrochloride who yl)-2H-1-benzazepin-2-it in 90 ml of 2-butanone treated with 1.7 g (of 10.75 mmol) of N,N-dimethyl-2-chloro-1-(methyl) ethylamine and then 3.0 g (2,17 mmol) powdered potassium carbonate and heated to boiling under reflux. After approximately 2 days of heating still has a significant amount of (CIS)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-3-methyl-6- (trifluoromethyl)-2H-1-benzazepin-2-it. Add 1.2 g of N,N-dimethyl-2-chloro-1-(methyl)ethylamine and 2.2 g of potassium carbonate, and heating continued for another day. After cooling, the solids filtered off, washed with 2-butanone, and the combined filtrates evaporated. The residue is shaken with 90 ml of ethyl acetate and 30 ml of water, the layers separated, and an ethyl acetate layer was washed with 30 ml water and 30 ml brine, dried with magnesium sulfate and evaporated. The residue is dissolved in diethyl ether, repeat the evaporation and the residue is dried by using a pump, receiving 3,86 g solids. After two kristallizatsii from diisopropyl ether gain of 1.05 g of solid substance with a melting point 154-157aboutC. Thin layer chromatography: the main product, Rfof 0.51, a secondary product of Rf0,42 (eluent to 90:10 dichloromethane: methanol). The main product of Rf0,27, a secondary product of Rf0,17 (30:70 acetone-hexane).

This material chromatographic 40 g Balcerowski silica gel, elute with a mixture of 30: 70 acetone-hexane to obtain 0.6 g of a single isomer in the form of bestwe/SUB>F3N2O2.

Found,%: C 66,50; H 7,02; N 6,32.

The residue from the second crystallization from diisopropyl ether, and the fraction of described chromatography was carried out, which is rich isomer A, unite and chromatographic to additionally obtain 0.36 g of identical material.

The two portions join (for a total of 0.92 g), suspended in 25 ml of methanol, treated with 0.45 ml 5 N. ethanol solution of hydrogen chloride (solution), the solvent is evaporated, and dried using a pump. This process is repeated to obtain 0,92 g specified in the header colorless proof, non-hygroscopic salt with hydrochloric so pl. 101-104about(Foaming), sinters at 88aboutC. Thin layer chromatography: Rf0,40 (eluent 40:60 acetone-hexane) Rf0,25 (eluent - 8:1 dichloromethane-methanol-acetic acid).

Calculated,%: C 60,05; N 6,51; N Of 5.84; Cl 7,39.

Found,%: C24H29F3N2O2HCl 0.5 H2O

Found,%: C 59,93; H 6,87, N 6,04; Cl 7,14.

P R I m e R 3. (CIS)-1-[2-(Dimethylamino)propyl]-1,3,4,5-tetrahydro-4-(4 - methoxyphenyl)-3-methyl-6-(trifluoromethyl)-2H-1 - benzazepin-2-it, isomer b, monohydrochloride.

Royal solutions in diisopropyl ether after Chris According to thin-layer chromatography (eluent 40:60 acetone-hexane) this material is approximately 40:60 mixture of isomer a and isomer Century

This mixture chromatographic 40 g Balcerowski silica gel, elute with a mixture of 40:60 acetone-hexane to obtain 0,49 g of the isomer In-base in the form of a waxy solid. The solution of this base (0,48 g) in methanol process of 0.24 ml of 5 N. ethanol solution of hydrogen chloride and the solvent is evaporated. The residue is triturated under ether, evaporated and dried using a pump. This process is repeated to obtain 0.50 g of colourless, slightly hygroscopic hydrochloric salt with a melting point 83-86about(Foaming), sinters at 76aboutC. Thin layer chromatography: Rf0,22 (eluent to 40:60 acetone-hexane).

Calculated,%: C 60,05; N. Of 6.71; N Of 5.84, Cl 7,39.

C24H29F3N2O2HCl 0.5 H2O

Found,%: C 60,30; H 7,00; N 5,62; Cl 7,17.

P R I m e R 4. (CIS)-1-[2-Amino-1-methylethyl]-1,3,4,5-tetrahydro-4-(4-methoxyphenyl) -3-methyl-6-(trifluoromethyl)-2H-1-benzazepin - 2-it, isomer b, monohydrochloride.

A) (CIS)-1,3,4,5-Tetrahydro-4-(4-methoxyphenyl)-d,3-dimethyl-2-oxo - 6-(trifluoromethyl)-1H-1-benzazepin-1-acetonitrile, more mobile isomer.

To the suspension is 0.22 g of sodium hydride (5.37 mmol, 60% dispersion in oil) in 15 ml of dry dimethylformamide added 1.50 g (4,29 mmol) (atoi temperature, cooled to 0aboutAnd then add exactly at 0.42 ml (5.37 mmol) of 2-chloropropionitrile. The solution was stirred at 0about10 min, warmed to room temperature for 15 min and heated to 45aboutC for 90 min Add 50 mg of sodium hydride and 0.15 ml of chloropropionitrile, the solution is stirred at 45aboutWith 20 minutes the Reaction is interrupted by addition of 1 M solution of ammonium chloride, dimethylformamide removed under high vacuum with gentle heating. The residue is partitioned between ether and 1 M solution of ammonium chloride, and the EOS - organic layer washed with brine, dried with magnesium sulfate and evaporated to obtain a brown foamy solid, which was combined with the crude product from a similar reaction mixture obtained in the calculation by 1.68 mmol. This crude product consists of two diastereoisomeric product is identified as the more mobile isomer (BPI, Rf = 0,74, 50% ethyl acetate/hexane). This solid chromatographic on silica gel (60% ether/hexane) to obtain 0,90 g of pure BPI in the form of a white solid. When chromatographicaliy also obtain 0.34 g of almost pure less rolling isomer (DIF), which is soluble in hot hexane containing 5% UP>C. When chromatographicaliy mixed fractions receive an additional of 0.44 g of pure VPI (total weight of 1.34 g) and 0.31 g DIF (total weight of 0.60 g).

In) (CIS)-1-(2-amino-1-methylethyl)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl) -3-methyl-6-(trifluoromethyl)-2H-1-benzazepin-2-it, isomer b, monohydrochloride.

A solution of 0.87 g more rolling isomer (CIS)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-, 3-dimethyl-2-oxo- (trifluoromethyl)-1H-1-benzazepin-1-acetonitrile (2,16 mmol) and 0.87 g of 5% rhodium on aluminium oxide in the environment 125 ml of a mixture of 1:1 methanol : saturated ammonia methanol hydronaut under pressure of 50 psi (3,5 MPa) hydrogen for 25 hours the Solution is filtered through Celite, and the Celite washed twice with methanol, combined fractions are evaporated. Semi-solid residue is dissolved in dichloromethane, filtered through Celite and evaporated, getting 0,89 g of solid substance in the form of a white foam. To a solution of 0.34 g of this material in the air adding ether saturated with hydrogen chloride. The solution becomes milky white, it is evaporated and the residue is dissolved in methanol and evaporated. The residue is dissolved in 1 ml of methanol, add 20 ml of ether and then with 20 ml of hexane, and the solution is frozen. White solid filtered and dried to obtain 0,30 g specified in ASS="ptx2">

Calculated,%: C 59,15; H 5,96; N 6,27; Cl 7,93; F 12,76.

C22H26ClF3N2O20,60 H2O

Found,%: C 59,84; H Of 6.52; N 5,76; Cl 7,27; F 11,93.

P R I m e R 6. (CIS)-1-(2-(Dimethylamino))-1-methylethyl)-1,3,4,5-tetrahydro-4- (4-methoxyphenyl)-3-methyl-6-(trifluoromethyl)-2H-1 - benzazepin-2-it, isomer a, monohydrochloride.

A) (CIS)-1-(2-amino-1-methylethyl)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl) -3-methyl-6-(trifluoromethyl)-2H-1-benzazepin-2-it.

A solution of 0.60 g less rolling isomer (CIS)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl) -, 3-dimethyl-2-oxo-6-(trifluoromethyl)-1H-1-Ben - Zacepin-1-acetonitrile (1,49 mmol) and 0.49 g of 5% rhodium on aluminium oxide in the environment 125 ml of a mixture of 1:1 methanol:saturated ammonia methanol hydronaut hydrogen at a pressure of 3.5 MPa for 20 hours the Solution is filtered through Celite. Celite is washed twice with methanol and the combined filtrates evaporated. Semi-solid residue is dissolved in dichloromethane, filtered through Celite and evaporated, getting 0.56 g specified in the connection header in the form of a foamy white solid.

In) (CIS)-1-(2-dimethylamino)-1-methylethyl)-1,3,4,5-tetrahydro-4-(4 oksifenil)-3-methyl-6-(trifluoromethyl)-2H-1-benzazepin-2-it, isomer a, monohydrochloride.

A solution of 0.56 g of the crude (C in 10 ml of acetonitrile, containing 1.2 ml of 37% formaldehyde by adding with stirring to 0.28 g of solid cyanoborohydride sodium (of 4.44 mmol) and then add 0,145 ml of acetic acid. The solution is stirred for 2 hours, add another 0,145 ml of acetic acid, and the solution is stirred for 30 minutes, the Reaction mixture was partitioned between ether and 10% aqueous potassium carbonate solution, the organic layer washed with brine, dried with magnesium sulfate and evaporated to obtain 0,70 g of oil. This material is subjected to flash chromatography on silica gel (eluent 1% methanol /0.5% triethylamine/dichloromethane) to obtain 0.32 g of pure free base (specified in the header of the substance) as a foamy solid white. This material is dissolved in ether and adding ether saturated with hydrogen chloride, obtaining a white precipitate. The ether is evaporated, the solid is dissolved in methanol, and the solvent is evaporated. The solid is again dissolved in methanol, the solution is filtered through Celite and evaporated. The solid is dissolved in 2 ml of warm methanol and add hot diisopropyl ether until no starts blushing. The solution is cooled, and the solid is collected by filtration, getting 0.27 g ukazannoj is.

Calculated,%: C 61,20; N, 6.42 Per; N 5,95, Cl 7,53; F 12,10.

C24H30ClF3N2O2HCl.

Found,%: C 61,15; H Of 6.52; N 5,88; Cl 7,71; F 11,78.

P R I m e R 7. (3R-(1(R*)-3A, 4A))-3-(atomic charges)-1,3,4,5-tetrahydro-4-(4 - methoxyphenyl)-1-((1-methyl-2-pyrrolidinyl)methyl)-6- (trifluoromethyl)- 2H-1-benzazepin-2-it, monohydrochloride.

A) R-N-(tert-Butoxycarbonyl)-2-pyrrolidineethanol.

A solution of R-2-pyrrolidineethanol (5.0 g, 50 mmol) in dry dichloromethane (125 ml) at 0aboutWith treated dropwise with a solution of di-tert-BUTYLCARBAMATE (13 g, 59.5 mmol) in 50 ml of dichloromethane for 15 minutes Is immediate emissions of carbon dioxide. The cooling bath is removed, and the mixture is stirred at room temperature for 6 hours Then the reaction mixture was concentrated under reduced pressure to obtain specified in the title compound as light yellow viscous oil (13 g). This crude material was used in subsequent reactions without further purification.

C) R-N-methyl-2-pyrrolidineethanol.

Sociallyengaged (7.6 g, 200 mmol) is added in small portions to dry tetrahydrofuran (200 ml), cooled to 0-5aboutC. and Then added dropwise a solution of R-N-(tert-butoxycarbonyl within 45 minutes After 30 min at 0aboutTo room temperature, the reaction mixture is heated to boiling (under reflux) for 16 hours Then the reaction mixture was cooled to 0aboutWith the excess hydride is decomposed by the slow addition of a saturated aqueous solution of sodium sulfate. The addition continues until all the inorganic salt will not precipitate in the form of granular solids in white. The mixture is diluted with 500 ml ethyl acetate, dried with magnesium sulfate, filtered and concentrated, obtaining mentioned in the title compound as a colourless oil (5.7 g). This crude product was used without purification in the next reaction.

C) R-2-(chloromethyl)-1-methylpyrrolidine, hydrochloride.

To a solution of R-N-methyl-2-pyrrolidineethanol (2.0 g, to 17.4 mmol) in chloroform (18 ml) at 0aboutWith added dropwise chloride thionyl (0.74 g, to 52.1 mmol). The reaction mixture is heated to boiling for 2 h and then cooled to room temperature and concentrated under reduced pressure, the residue is subjected to recrystallization from a mixture of acetone-ether, getting mentioned in the title compound as a pale yellow solid (1,14 g).

D) (3R-(1R*)-3A, 4A))-1-((1-methyl-2-p/P> Sodium hydride (0,19 g, 8.1 mmol) are added to a solution of (3-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it (of 1.05 g, 3.0 mmol) in 30 ml of dried DMF (dimethylformamide). The mixture is stirred at room temperature for 1 h, then add R-2-(chloromethyl)-1-methylpyrrolidine, hydrochloride (0,78 g, 4.5 mmol), the mixture is heated to 80aboutC for 1 h Then the reaction mixture is cooled and the reaction is interrupted by the addition of saturated aqueous solution of potassium bicarbonate and extracted three times with ethyl acetate. The combined extracts are washed with 10% aqueous solution of lithium chloride, dried with magnesium sulfate and concentrate. The crude yellow liquid chromatographic on a column of silica gel and elute with a mixture of 1-3% methanol in dichloromethane, to obtain specified in the title compound in the form of a viscous liquid (0.24 g).

(E) (3R-(1(R*),3 ,4 ))-3-(the atomic charges)-1,3,4,5-tetrahydro-4-(4 - methoxyphenyl)-1-((1-methyl-2-pyrrolidinyl)methyl-6-(trifluoromethyl)- 2H-1-benzazepin-2-it, monohydrochloride.

A solution of (3R-(1(R*), 3 , 4 ))-1-((1-methyl-2-pyrrolidinyl)-methyl)-3-(hydroxy)-1,3,4,5 - tetrahydro-4-(4-methoxyphenyl)-1-((1-methyl - 2-pyrrolidinyl)methyl-6- (trifluoromethyl)-2H-1-benzazepin-2-it (0.24 g, 0.54 mmol), acetic anhydride (0.27 g, 2.68 mmol) and 4-di is e 60 hours The reaction mixture is then absorbed by the silica gel (60-200 mesh), poured into a column of silica gel and elute with a mixture of 1-3% methanol in dichloromethane, getting mentioned in the title compound as free base. This viscous oil was dissolved in ether and treated with a saturated ethereal solution of hydrogen chloride. A white precipitate is subjected to recrystallization from a mixture of toluene-hexane to obtain specified in the title compound as a white solid (0,23 g) so pl. 158-162aboutC.

[ ]D= +to 126.8about(C = 1.0 mol/l in methanol).

Calculated,%: C 57,31; H Of 5.92; N 5,14; Cl 6,51; F 10,46.

C26H30ClF3N2O41,0 H2O.

Found,%: C 57,63; H Of 5.68; N 5,23; Cl 6,34; F Of 10.21.

P R I m e R 8. (3R(1(S*),3 ,4 ))-3-(Aza-tilaki)-1-(2- (dimethylamino)-3-phenyl - propyl)-1,3,4,5-tetrahydro-4-(4 - methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

A) S-2-(dimethylamino)-3-phenyl-1-propanol.

To a solution of S-2-amino-3-phenyl-1-propanol (6.0 g, 4.0 mmol) and 37% aqueous formaldehyde (20 ml) in 200 ml of acetonitrile is added under stirring cyanoborohydride sodium (4.0 g, 64 mmol) in small portions. This mixture is stirred for 30 min, then added dropwise, lepri room temperature for 2 h with periodic addition of glacial acetic acid, in order to maintain the neutral pH of the mixture. Then the reaction mixture was concentrated and the residual oil was diluted with 2 N. a solution of sodium hydroxide (250 ml). The mixture is extracted with ethyl acetate three times and the combined extracts washed with 1N. potassium hydroxide solution and extracted three times with 1H. aqueous hydrochloric acid. The extracts are combined, dried over anhydrous magnesium sulfate and concentrated receiving specified in the title compound as a viscous oil (6,48 g).

In) S-1-chloro-2-(dimethylamino)-3-phenylpropane, hydrochloride.

To S-2-(dimethylamino)-3-phenyl-1-propanol (3.0 g, and 16.7 mmol) in 20 ml of chloroform at 0aboutWith added dropwise chloride thionyl (5,97 g of 50.2 mmol). The reaction mixture is heated (reflux) to the boil for 2 h and then evaporated to dryness under reduced pressure. The residue is subjected to recrystallization from a mixture of acetone-ether, receiving specified in the title compound in the form of not-quite-white solid (2.38 g) with a melting point 167,5-168,5aboutC.

(C) (3R-(1(S*), 3 ,4 ))-3-(hydroxy)-1-(2-(dimethylamino)-3-phenylpropyl)-1,3,4,5 - tetrahydro-4-(4-methoxyphenyl)-6-(trifluoromethyl) -2H-1-benzazepin - 2-it.

Sodium hydride (0,22 g, 9.0 mmol) are added to a solution of (3R-CIS)-3-(GESMES stirred at room temperature for 1 h, then add 0,89 g (4.5 mmol) of the hydrochloride of (S)-1-chloro-2-(dimethylamino)-3-phenylpropane, and the mixture is heat - Ute to 85aboutC for 2 h, the Reaction mixture is cooled, terminate the reaction by adding water and extracted three times with ethyl acetate. The combined extracts are washed with 10% aqueous solution of lithium chloride, brine and dried over anhydrous magnesium sulfate. After concentration the crude product chromatografic on a column of silica gel and elute with a mixture of 10-30% ethyl acetate in hexane, getting mentioned in the title compound as a white foam (1,16 g).

D) (3R-(1(S*), 3 ,4 ))-3-(the atomic charges)-1-(2-dimethylamino)-3-phenylpropyl)-1,3,4,5 - tetrahydro-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin - 2-it, monohydrochloride.

A solution of (3R-(1(S*),3 , 4 ))-3-(hydroxy)-1-(2-(dimethylamino)-3-phenylpropyl)-1,3,4,5 - tetrahydro-4-(4-methoxyphenyl)-6-trifluoromethyl)-2H-1-benzazepin-2 - it (1,16 g of 2.26 mmol), acetic anhydride (1,16 g, 11,32 mmol) and 4-dimethylaminopyridine (0.55 g, a 4.53 mmol) in dry dichloromethane (25 ml) stirred at room temperature for 16 hours, the Reaction mixture absorb silicagel (60-200 mesh), poured into a column of silica gel and elute with a mixture of 5-25% ethyl acetate in hexane, in the case specified in the header joint is REGO solution of hydrogen chloride, to get listed in the title compound as a white solid (0.96 g), so pl. 144-147aboutC.

[ ]D= +52,40about(C = 1.0 mmol/l in methanol).

Calculated,%: C 61,56; H Of 5.92; N 4,63; Cl 5,86; F 9,42.

C31H34ClF3N2O4 0,76 H2O.

Found,%: C 61,60; H 6,00; N 4,59; Cl To 5.93; F 9,23.

P R I m e R 9. (3R-(1(R*),3 ,4 ))-3-(the atomic charges)-1-(2-(dimethylamino)-3-phenylpro-saws)-1,3,4,5 - tetrahydro-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

A) R-2-(dimethylamino)-3-phenyl-1-propanol.

To a solution of S-2-amino-3-phenyl-1-propanol (6.0 g, 4.0 mmol) and 37% aqueous formaldehyde (20 ml) in 200 ml of acetonitrile is added under stirring cyanoborohydride sodium (4.0 g, 64 mmol) in small portions. This mixture is stirred for 30 min, then added dropwise glacial acetic acid to the solution until it becomes neutral (pH paper). The mixture is stirred at room temperature for 2 hours with periodic addition of glacial acetic acid to maintain the neutral pH of the mixture. Then the reaction mixture was concentrated and the residual oil was diluted with 2 N. potassium hydroxide solution (250 ml). The mixture is extracted with etilatsetatom hydrochloric acid. The acid extracts are combined neutralized with solid potassium hydroxide and extracted three times with ethyl acetate. The extracts are combined, dried over anhydrous magnesium sulfate and concentrated, obtaining mentioned in the title compound as a viscous oil (6,23 g).

In the R-1-chloro-2-(dimethylamino)-3-phenylpropane, hydrochloride.

R-2-(dimethylamino)-3-phenyl-1-propanol (3.0 g, and 16.7 mmol) in 20 ml of chloroform at 0aboutWith added dropwise chloride thionyl (6.0 g, a 50.2 mmol). The reaction mixture is heated (reflux) to the boil for 2 h and then evaporated to dryness under reduced pressure. The residue is subjected to recrystallization from a mixture of acetone-ether, receiving specified in the title compound in the form of not-quite-white solid (2,27 g) so pl. 170-171,5aboutC.

(C) (3R-(1(R*), 3 , 4 ))-3-(hydroxy)-1-(2-dimethylamino)-3-phenylpropyl)-1,3,4,5 - tetrahydro-4-(4-methoxyphenyl)-6-(triptime-Tyl) -2H-1-benzazepin - 2-it.

Sodium hydride (0,13 g, 5.4 mmol) are added to a solution of (3R-CIS)-3-(hydroxy)-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it (0,70 g, 2.0 mmol) in 20 ml of dry dimethylformamide. This mixture was stirred at room temperature for 1 h, after which add 0,60 g (3.0 mmol) of hydrochloride (what up, terminate the reaction by adding water and extracted three times with ethyl acetate. The combined extracts are washed with 10% aqueous solution of lithium chloride and brine. Filtered, dried over anhydrous magnesium sulfate and concentrated. The crude product chromatografic on a column of silica gel and elute with a mixture of 20-50% ethyl acetate in hexane, getting mentioned in the title compound as a white foam (0,60 g).

D) (3R-(1(R*), 3 , 4 ))-3-(the atomic charges)-1-(2-dimethylamino)-3-phenylpropyl)-1,3,4,5 - tetrahydro-4-(4-methoxyphenyl)-6-(triptime-Tyl)-2H-1-benzazepin - 2-it, monohydrochloride.

A solution of (3R-(1(R*), 3 ,4 ))-3-(hydroxy)-1-(2-(dimethylamino)-3-phenylpropyl)-1,3,4,5 - tetrahydro-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin - 2-she (1.0 g, 1,95 mmol) acetic anhydride (1.0 g, 9.8 mmol) and 4-dimethylaminopyridine (0,48 g, 3.90 mmol) in dry dichloromethane (20 ml) stirred at room temperature for 14 hours, the Reaction mixture absorb silica gel (60-200 mesh), poured on a column of silica gel and elute with a mixture of 5-25% ethyl acetate in hexane, obtaining the free base as a white foam. This free base is dissolved in ether and adding an excess of ethereal solution of hydrogen chloride, to obtain specified in the header of the connection in anole).

Calculated,%: C 61,93; H Of 5.89; N 4,66; Cl 5,90; F 9,48.

C31H34ClF3N2O40,56 H2O.

Found,%: C 62,02; H 6,21; N 4,67; Cl Of 5.83; F Was 9.33.

P R I m e R 10. (3R-CIS)-1-(2-(dimethylamino)-2-methylpropyl)-1,3,4,5-tetrahydro - 3-hydroxy-4-(4-methoxyphenyl)-6-(trifter - methyl)-2H-1-benzazepin - 2-it, monohydrochloride.

The preparation is carried out in an argon atmosphere. Stir a solution of (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-(trif - tormentil)-2H-1 - benzazepin-2-she (2.5 g, 7,12 mmol) in 75 ml of dimethylformamide is treated with 60% sodium hydride (0.3 g, 7.5 mmol) and stirred for 1 h To this solution was added dry toluene solution of 1-chloro-2-(dimethylamino)-2-methylpropane (isolated from 3.75 g (to 21.8 mmol) hydrochloric salts of potassium carbonate in toluene) and the mixture is heated in an oil bath at 71-78aboutWith in 1.25 hours and After cooling the mass of dimethylformamide is removed at the rotary at a pressure of 0.2 mm RT.article The residue is shaken with 125 ml ethyl acetate and 50 ml of water. Separate the layers, and the organic phase is washed 2 times with water (50 ml), brine (25 ml), dried with magnesium sulfate and evaporated. The solid residue is suspended in ether, repeat the evaporation and the solid is dried at the pump pumping; the weight of 3.33, It colchest. The solid residue (3.94 g) is shaken with 60 ml of ethyl acetate and 40 ml of water containing 17 ml of 1 N. hydrochloric acid. The layers are separated and the organic layer extracted with 40 ml of water. The combined aqueous phase is washed with ether (washing pour), cover with 40 ml of ethyl acetate, add 19 ml of 1 n sodium hydroxide solution, the mixture is shaken and separated. The aqueous phase is extracted with ethyl acetate (2 x 30 ml), combined an ethyl acetate layers washed with 20 ml brine, dried with magnesium sulfate and finally evaporated at a pressure of 0.2 mm receiving 3,66 g solids. During the subsequent crystallization from 25 ml of hot isopropanol get colorless material (free base compounds; specified in the header), the weight of 2.36 g so pl. 157-159about(Sinters at 155aboutC).

Calculated, %: C 63,98; H Of 6.49; N 6,22; F 12,65.

C24H29F3N2O3.

Found, %: C 64,17; H 6,53; N Between 6.08; F 12,93.

This Foundation (of 2.34 g) in 50 ml of ethyl acetate is treated with 1.2 ml of a 5 n solution of hydrogen chloride in ethanol, and the solvent is finally evaporated at 0.2 mm RT.article Almost solid residue triturated under a layer of ethyl ether and repeat the evaporation, will rest after drying when the pump pumping 2.67 g specified in sagola>the. [ ]D= +114about(C = 1.00 mol/l, methanol).

Calculated,%: C 58,12; H 6,30; N 5,64; Cl 7,15.

C24H29F3N2O3HCl 0.5 H2O.

Found, %: C 58,06; H 6,53; N Lower Than The 5.37; Cl 7,00.

P R I m e R 11. (3R-CIS)-1-(2-dimethylamino)-1-phenylethyl)-1,3,4,5-tetrahydro-3 - hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl) -2H-1-benzazepin - 2-it, isomer a, monohydrochloride.

Toluene solution of N, N-dimethyl-2-chloro-2-phenethylamine is prepared by distribution 3,59 g hydrochloric salt (16.3 mmol) of between 15 ml of toluene and 100 ml of an aqueous solution of sodium bicarbonate. The aqueous phase is washed with an additional quantity (10 ml) of toluene, the combined organic phases are dried with magnesium sulfate and filtered. To a stirred suspension of 0.75 g of sodium hydride (15.6 mmol, 50% dispersion in oil) in 30 ml of dried DMF (dimethylformamide) add 5.0 g of (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-(triptime - Tyl)-2H-1 - benzazepin-2-it (of 14.2 mmol) at one time, in the form of solids. The solution is stirred for 1 h at room temperature, heated to 70aboutWith, and a toluene solution of N,N-dimethyl-2-chloro-2-phenethylamine is added dropwise over 2 hours a Solution of 1 g of the above hydrochloric salt (4.5 mmol) and 0.51 g of tert-butoxide potassium (4,5 Xia solution stirred at 70aboutEven in the course of 2.25 hours and the reaction is interrupted by addition of an aqueous solution of sodium bicarbonate. The solvents are removed under high vacuum with gentle heating. The residue is distributed between ethyl acetate and aqueous sodium bicarbonate solution, the organic phase is washed with brine, dried with magnesium sulfate, filtered and evaporated, receiving light yellow foamy resin. The crude product is dissolved in 25 ml of ether, introducing a seed crystal of (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1 - benzazepin-2-it is rapidly cooled to obtain (after filtering) 0.25 g selected (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it. Upon evaporation of the mother liquor gain of 7.23 g of a foamy solid, which chromatographic on silica gel (eluent: 2% methanol /0.5% triethylamine/dichloromethane) receiving 1.90 grams, more pure rolling isomer (BPI) as a pale yellow foamy solid. A solution of 0.41 g of pure BPI is dissolved in ether and treated with ether saturated hydrogen chloride. Solid white is filtered off, washed twice with ether, and dried in the air, getting 0,41 g of a white solid. This material is dissolved in a mixture of 2 ml of isopropanol/6 ml desertrat treated with hexane, and the resulting white solid is collected by filtration and dried, obtaining 0.39 g is specified in the header of a substance with so pl. 136-142aboutC.

[ ]D= +146,2about(C = 1 mol/l, methanol).

Calculated, %: C 61,77; H Of 5.75; N 5,14; Cl 6,51; F 10,47.

C28H30ClF3N2O30.52 mol H2.

Found, %: C 61,77; H Of 6.02; N 5,26; Cl 6,46; F 10,63.

P R I m e R 12. (3R-CIS)-1-(2-(dimethylamino)-1-phenylethyl)-1,3,4,5-tetrahydro-3 - hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, isomer b, monohydrochloride.

When chromatographicaliy of monohydrochloride (3R-CIS)-1-(2-dimethylamino)-1-phenylethyl)1,3,4,5-tetrahydro-3 - hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, isomer And there was no fractions containing the less mobile isomer (DIF). The fractions containing DIF (contaminated BPI and (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-one) are combined and evaporated to obtain 3,40 g of crude RAC. This material is re-chromatographic on silica gel (eluent: 2% methanol /0.5% triethylamine/dichloromethane) to give 0,81 g DIF, containing trace amounts of BPI and a significant number of (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-(trif - turmuhambetova (eluent 5% methanol/dichloromethane), the main strip is removed, extracted twice with a mixture of 5% methanol (1% triethylamine/dichloromethane, and the combined extracts evaporated and expanded three times with carbon tetrachloride to obtain 0,41 g of pure free base connection specified in the header. This material is dissolved in ether, filtered through Celite to remove turbidity, and adding ether saturated with hydrogen chloride. The resulting solid white filtered, washed 2 times with ether, and dried in the air, getting 0,42 g is specified in the header of a substance in the form of a white solid with so pl. 165-171aboutC. [ ]D= + 221,8about(C = 1 mol/l, methanol).

Calculated,%: C 61,84; H 5,74; N 5,15; Cl 6,51; F 0,48.

C28H30N2O3ClF30,49 H2O.

Found,%: C 61,84; H Of 5.81; N 5,07; Cl 6,12; F 10,18.

P R I m e p 13. (3R-(1(S*),3 ,4 ))-3-(the atomic charges)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1-(2 - pyrrolidinyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

A) S-N-(benzyloxycarbonyl)-2-pyrrolidineethanol.

Powdered, anhydrous potassium carbonate (41 g, 297 mmol) is added under stirring to a solution of 5-2-pyrrolidineethanol (6 g, 59,32 mmol) in 20 ml of acetone. The mixture is cooled to 0aboutwhat tatom and water. The organic layer is separated and the aqueous layer extracted with ethyl acetate. The organic extracts are combined, dried with magnesium sulfate and concentrate. The crude oil is subjected to chromatographicaliy on a column of silica gel and elute with 25% ethyl acetate in hexane, to obtain 12,22 g specified in segalove substances in the form of a light yellow oil.

In) S-1-(benzyloxycarbonyl)-2-(methyl bromide) pyrrolidin.

Triphenylphosphine (4,46 g, 17 mmol) and 5,64 g (17 mmol) of tetrabromide carbon are added to a solution of S-N-(benzyloxycarbonyl)-2-pyrrolidineethanol (2 g, 8.5 mmol) in 100 ml of ether. This mixture was stirred at room temperature for 19 h, cooled and precipitated in the sludge solids filtered off. The remaining solid washed with hexane. The filtrate is concentrated and purified chromatographically on a column of silica gel. When the elution of 10-20% ethyl acetate in hexane get mentioned in the title substance (2,11 g) as a colourless oil.

(C) (3R-(1(S*), 3 ,4 ))-1-(benzyloxycarbonyl-2-pyrrolidinyl)methyl)-3-hydroxy - 1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1 - benzazepin-2-it.

To a suspension of sodium hydride (of 0.066 g, 2.7 mmol) in dimethylformamide (23 ml) was added (3R-CIS)-3-(hydroxy)-4-(4T 0.97 g (3.4 mmol) of (S)-1-(benzyloxycarbonyl)-2-(methyl bromide)-pyrrolidine. The reaction mixture is heated at 65aboutC for 2.5 h, then add an additional amount of sodium hydride (0,028 g to 1.14 mmol) and S-1-(benzyloxycarbonyl)-2-(bromoethylamine)pyrrole (0.33 g, to 1.14 mmol). After another 1 h at 65aboutC, cooled, then diluted with water and extracted three times with ethyl acetate. United an ethyl acetate extracts are washed with 10% aqueous lithium chloride, dried with anhydrous magnesium sulfate and concentrated. The crude residue chromatographic on a column of silica gel and elute with a mixture of 20-40% ethyl acetate in hexane, getting mentioned in the title compound (0.8 g).

D) (3R(1(S*),3 , 4 ))-3-acetoxy-1-((1-benzyloxycarbonyl)-2-pyrrolidinyl)IU - Tyl)- 1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it.

To a solution of (3R(1(S*), 3 ,4 ))-1-((1-benzyloxycarbonyl-2-pyrrolidinyl)methyl)-3-hydroxy - 1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it (1,14 g of 1.85 mmol) and acetic anhydride (0.87 g, 9,24 mmol) in dichloromethane (20 ml) is added N,N-dimethylaminopyridine (0.45 g, 3.7 mmol). The mixture is stirred at room temperature for 4 days, consume silica gel (60 mesh), and subjected to flash chromatography on a column of silica gel. When elution with a mixture of 1) (3R-(1(S*), 3 ,4 ))-3-(atomic charges)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1-(2 - pyrrolidinyl)methyl)-trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

The ammonium formate (0,23 g of 3.64 mmol) is added at once to a suspension of the catalyst is 10% palladium on coal (0.05 g) and (3R-(1(S*),3 , 4 ))-3-acetoxy-1-((1-benzyloxycarbonyl-2-pyrrolidinyl)methyl)- 1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1 - benzazepin-2-it (0,48 g, 0.73 mmol) in 10 ml of methanol. The mixture is heated to boiling for 30 min, then cooled and filtered through Celite. The remainder of the solids washed with ethyl acetate. The filtrate is concentrated to obtain a white foam, which was dissolved in ether and treated with excess ethereal solution of hydrogen chloride. The solution is concentrated and crystallized from a mixture of toluene and hexane, to obtain specified in the title compound in the form of not-quite-white solid (0,325 g), so pl. 217-219aboutC.

[ ]D= +78,7about(C = 1.0 mol/l in methanol).

Calculated,%: C 58,06; H Lower Than The 5.37; N 5,42; Cl 6,86; F 11,02.

WITH25H27F3N2O4HCl 0,29 H2O

Found,%: C 58,37; H Lower Than The 5.37; N, 5,54; Cl 7,05; F Of 10.58.

P R I m e R 14. (3R-(1(S*),3 ,4 ))-3-(the atomic charges)-1,3,4,5-tetrahydro-4-(4-methoxide - nil) -1-((1 - methyl-2-pyrrolidinyl)inmethanol.

A solution of S-2-pyrrolidineethanol (10 g, 100 mmol) in dry dichloromethane (250 ml) is treated at 0-5aboutWith added dropwise a solution of di-tert-BUTYLCARBAMATE (26 g, 119 mmol) in 100 ml dichloromethane for 30 minutes After 6 h at room temperature, the reaction mixture was concentrated, to obtain specified in the header connection (23,5 g) as a viscous oil.

In) S-N-methyl-2-pyrrolidineethanol.

A solution of the crude S-N-(tert-butyloxycarbonyl)-2-pyrrolidineethanol (17.5 g, 87 mmol) in dry tetrahydrofuran (100 ml) added dropwise at 0-5aboutWith the suspension of sociallyengaged (11.4 g, 6,300 mmol). The mixture is refluxed for 16 hours Then cooled in a bath of ice water, the excess hydride is destroyed by adding dropwise a saturated solution of sodium sulfate. The mixture is diluted with ethyl acetate and filtered through anhydrous magnesium sulfate. The remainder of the solids washed thoroughly with ethyl acetate. The combined filtrate is concentrated under reduced pressure, obtaining a yellow oil which is distilled to obtain specified in the title compound with a boiling point 97aboutC/50 mm RT.article.

C) S-2-(chloromethyl)-1-methylpyrrolidine.

Chloride thionyl is 0-5aboutC. the Mixture is refluxed for 2 h and then concentrated. The crude residue is subjected to crystallization from a mixture of acetone and ether to obtain specified in the title compound (1.48 g) in the form of a hydrochloric salt.

D) (3R-(1(S*),3 , 4 ))-1-((1-methyl-2-pyrrolidinyl)methyl)-3-hydroxy-1,3,4,5-Tetra - hydro - 4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it.

To a suspension of sodium hydride (0,13 g, 5.4 mmol) in dimethylformamide (20 ml) was added (3R-CIS)-3-(hydroxy)-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-he (0.7 g, 2.0 mmol). The mixture is stirred for 1 h at room temperature, cooled at 0aboutWith and add hydrochloric salt (S)-2-(chloromethyl)-1-methylpyrrolidine (0.52 g, 3 mmol). After stirring at room temperature for 1 h, add additional sodium hydride (0,012 g, 0.5 mmol). The mixture is stirred for another 3 h and then diluted with water and extracted with ethyl acetate. An ethyl acetate extract is washed with 10% aqueous lithium chloride, dried over anhydrous magnesium sulfate and concentrated. The crude residue chromatographic on a column of silica gel and elute with a mixture of 2-5% methanol in dichloromethane, getting mentioned in the title compound (0,65 is dinyl)methyl-6-(trifter-methyl)-2H-1-benzazepin-2-it, monohydrochloride.

N, N-Dimethylaminopyridine (0,41 g, to 3.34 mmol) are added to a solution of (3R-(1(S*), 3, 4 ))-1-((1-methyl-2-pyrrolidinyl)-methyl)-3-(hydroxy)-1,3,4,5 - tetrahydro-4-(4-methoxyphenyl)-1-((1-methyl-2-pyrrolidinyl)methyl-6- (trifluoromethyl)-2H-1-benzazepin-2-she (0.75 g, to 1.67 mmol) and acetic anhydride (0,79 ml, 8.4 mmol) in dichloromethane (18 ml). The mixture is stirred at room temperature for 24 h, the Reaction mixture absorb large silica gel and subjected to flash column chromatography with silica gel, which elute with a mixture of 2-3% methanol in dichloromethane. Get listed in the title compound as free base. This free base is dissolved in ether and then treated with a saturated ethereal solution of hydrogen chloride. Add another 20 ml of ether and precipitated precipitated salt is decanted and dried in vacuum at 70aboutWith to get listed in the title compound as a white solid (0,536 g), so pl. 151-154aboutC.

[ ]D= +80,0about(C = 1.0 mol/l in methanol).

Calculated, %: C 58,00; H 5,20; Cl 6,59; F 10,59.

C26H29F3N2O4HCl 0,63 H2O

Found, %: C 57,74; H 5,56; N 4,93; Cl 7,01; F 10,16.

P R I m e R 15. (3R-(1(R*),3 ,4 ))-1,3,4,5-tetrahydro-3-hydroxy-4-(4 is selecterror)-2-pyrrolidineethanol.

Benzyl ether of Harborview acid (6 ml, to 39.5 mmol) added dropwise at 0aboutTo a suspension of powdered anhydrous potassium carbonate (13,7 g, 99 mmol) and (R)-2-pyrrolidineethanol (2 g, and 19.8 mmol) in 100 ml of acetone. After 1 h the reaction mixture was diluted with water and ethyl acetate. The organic layer is separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts are dried with magnesium sulfate, filtered and concentrated. Crude oil chromatographic on a column of silica gel and elute 20-60% ethyl acetate in hexane, to obtain specified in the header of the connection (of 4.57 g).

In the R-1-(benzyloxycarbonyl)-2-(methyl bromide) pyrrolidin.

A solution of R-N-(benzyloxycarbonyl)-2-pyrrolidineethanol (4,55 g, and 19.3 mmol, triphenylphosphine (10.2 g, of 38.7 mmol) and tetrabromide carbon (12.8 g, of 38.7 mmol) in 200 ml of ether is stirred at room temperature overnight. The reaction mixture was diluted with hexane and filtered. The filtrate is concentrated and the residue chromatographic on a column of silica gel. When the elution of 5-10% ethyl acetate in hexane get mentioned in the title compound as a colourless solid (3,59 g).

(C) (3R-(1(R*),3 , 4)-1-(Benzyloxycarbonyl-2-pyrrolidinyl)metida sodium (0.25 g, 10.5 mmol) in dimethylformamide (70 ml) was added (3R-CIS)-3-(hydroxy)-4-(4 - methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-he (2,46 g, 7 mmol). The mixture is stirred for 1 h at room temperature and add 3 g (10.5 mmol) of (R)-1-(benzyloxycarbonyl)-2-(methyl bromide)pyrrolidine. The reaction mixture is heated at 80aboutC for 4 h and add a further quantity of methanol (0.08 g, 3.5 mmol). After another 2 h at 80aboutThe mixture is cooled and then interrupt the reaction water. The mixture is extracted three times with ethyl acetate. The combined extracts are washed with 10% aqueous lithium chloride, dried with anhydrous magnesium sulfate and concentrated. The crude residue chromatographic on a column of silica gel and elute with a mixture of 1% methanol in dichloromethane, getting mentioned in the title compound (4,32 g contaminated with unreacted (3R-(CIS)-3-(hydroxy)-4-(methoxyphenyl)-6-(trifluoromethyl)- 2H)-1 - benzazepin-2-one.

D) (3R-(1-(R*), 3 , 4))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-1-(2 - pyrrolidinyl)2)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it, monohydrochloride.

The ammonium formate (1.8 g, 28.3 mmol) is added at once to a suspension of the catalyst is 10% palladium on coal (1 g, and (3R(1(R*),3 , 4 ))-1-((1-benzyloxy - bonyl-2-pyrrolidinyl)-methyl)-3-Mixture is refluxed for 90 min, cooled and filtered through Celite. The remainder of the solids washed with chloroform. The combined filtrates are concentrated and the residue chromatographic on a column of silica gel. When elution with a mixture of 3-10% methanol in dichloromethane receive free basis specified in the connection header. This free base is dissolved in ether and treated with excess ethereal solution of hydrogen chloride. When the concentration of the solution under reduced pressure and finally under vacuum get mentioned in the title compound in the form of not-quite-white solid (0.21 g), so pl. 147-151aboutC.

[ ]D= +108,5about(C = 1.0 mol/l in methanol).

Calculated, %: C 56,50; H 5,77; N 5,73; Cl 7,25; F 11,66.

C23H25F3N2O3HCl and 1.0 H2O

Found, %: C 56,76; H 5,74; N Of 5.50; Cl 7,12; F 11,36.

P R I m e R 16. (3R-(1(S*),3 ,4 ))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)- 1-(2 - pyrrolidinyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

A) (3R-(1(R*),3 , 4 ))-1-((benzyloxycarbonyl-2-pyrrolidinyl)methyl)-3-hydroxy - 1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1 - benzazepin-2-it.

To a suspension of sodium hydride (0,19 g, 4.8 mmol) in dimethylformamide (40 ml) add mmol) of (S)-1-(benzyloxycarbonyl)-2-(methyl bromide) pyrrolidine and the mixture is heated to 80aboutWith for 1.5 hours Add an additional amount of sodium hydride (0.05 g, 2 mmol) and (3R-CIS)-3-(hydroxy)-4-(4-methoxyphenyl)-6-(trifter - methyl)-2H-1 - benzazepin-2-she (or 0.57 g, 2 mmol). The reaction mixture is heated for another 2 h, cooled, and terminate the reaction by adding water. The mixture is extracted three times with ethyl acetate. United an ethyl acetate extracts are washed with 10% aqueous lithium chloride, dried with magnesium sulfate and concentrate. The crude residue chromatographic on a column of silica gel and elute with a mixture of 30-50% ethyl acetate in hexane, getting mentioned in the title compound (1.12 g) as a white foam.

B) (3R-(1(R*), 3, 4 ))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-1-(2 - pyrrolidinyl)-6-(trifluoromethyl)-2H-1-Ben - Zacepin-2-it, monohydrochloride.

The ammonium formate (0,57 g, 9 mmol) are added to a suspension of the catalyst -10% palladium on coal (0.34 g) and (3R-(1(S*),3 , 4))-1-((1-benzyloxycarbonyl-2-Pirro - leinil)-methyl)-3-hydroxy - 1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6-(triptime - Tyl)-2H-1 - benzazepin-2-it (1.12 g, 1.82 mmol) in 40 ml of methanol. The mixture is heated to boiling for 30 min, cooled and filtered through anhydrous magnesium sulfate. The remainder of the solids washed with ethyl acetate. The combined filtrate control in dichloromethane, get listed in the title free base (0,72 g). This free base is dissolved in ethyl acetate and treated with excess ethereal solution of hydrogen chloride. The solution is concentrated and dried in vacuum at 70aboutWith to get listed in the title compound (0.64 g) so pl. 159-163aboutC.

[ ]D= +71,3about(C = 1.0 mol/l in methanol).

Calculated, %: C 57,56; H 5,67; N Of 5.84; Cl 7,39; F 11,88.

C23H25F3N2O3HCl 0.5 H2O

Found, %: C 57,34; H Of 5.84; N 5,62; Cl 7,31; F 12,17.

P R I m e R 17. (3R-CIS)-3-(atomic charges)-1-(2-(dimethylamino)-2-methylpropyl)-1,3,4,5 - tetrahydro-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

Mix a solution of 1.9 g (3.9 mmol) of monohydrochloride (3R-CIS)-1-(2-methylpropyl)-1,3,4,5-tetrahydro-3-hydroxy-4-(4 - methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it (see example 10) are heated in 50 ml of acetic anhydride, heated to 110-124aboutC (bath temperature) in an oil bath. Acetylation occurs relatively slowly, and it is necessary to heat the mixture to about 4.25 in h until starting material (analysis thin-layer chromatography). In parallel, gradually in the course of heating the formed side davlenie 0.2 mm RT. Art. and the residual oil (3.6 g) dissolved in 10 ml of ethyl acetate. Because there is no crystallization, the ethyl acetate is evaporated and the oil triturated under ether layer to obtain a solid substance. The greater part of the ether is decanted, and the material is rubbed under the fresh air and cool during the night.

Colourless solid, which becomes gelatinous, filtered in an atmosphere of argon, washed with ether (hygroscopic), dried in vacuum. When a solid substance contains no solvent, it loses hygroscopicity and can be exposed to the atmosphere. The mass of 1.23 g, so pl. 88-91about(Bubbles) are sintered at 81aboutC.

[ ]D= +104about(C = 1.0 mol/l in methanol).

Calculated, %: C 57,09; H Of 6.26; N 5,12; Cl 6,48.

C26H31N2O4HCl H2O

Found,%: C 57,46; H 6,46; N 4,84; Cl 6,33.

P R I m e R 18. (3R-CIS)-1-(1-(dimethylamino)methyl)propyl)-1,3,4,5-tetrahydro-3 - hydroxy-4-(4-methoxyphenyl)-6-(triptime-Tyl)-2H-1-benzazepin-2-he isomer In= monohydrochloride.

A) (3R-CIS)-3-(tert-butyldimethylsilyloxy)-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1-benzazepin-2-it.

To a mixed solution of 10 g of (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-(three - Vtormet the add 5.10 g of tert-butyldimethylsilyloxy. The solution is stirred overnight at 35aboutC, cooled to room temperature and partitioned between ether and water. The organic phase is washed with water and brine, dried with magnesium sulfate and evaporated, receiving 14.2 g specified in the connection header in the form of amorphous solids with so pl. 114-116aboutC.

B) (3R-CIS)-3-(tert-butyldimethylsilyloxy)-1-(1-cyano)propyl)-4 - methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it.

To a stirred suspension of sodium hydride (0.54 g, and 11.2 mmol, 50% dispersion in oil) in dry dimethylformamide (10 ml) is added at once 4 g of (3R-CIS)-3-(tert-butyldimethylsilyloxy)-4-(4-labels - Setenil)-6- (trifluoromethyl)-2H-1-benzazepin-2-she (8.6 mmol) as a solid. The solution is stirred for 30 min, add 1,33 g (12.9 mmol) of pure 2-chlorobutyronitrile, the solution is heated to 75aboutC for 1 h Add an additional 0.15 g of sodium hydride and 0.3 g of 2-chlorobutyronitrile, and the solution is heated to 75aboutWith over 45 minutes the Solution is cooled odnomernym solution of ammonium chloride, and the dimethylformamide removed in vacuo with gentle heating. The residue is partitioned between ether and odnomernym solution of ammonium chloride, the organic phase is washed with water and brine, article 50% ether in hexane) shows the product is a mixture of 3: 2 diastereoisomers, more mobile isomer has Rf = 0,63, and less mobile isomer Rf = 0,56. Method Flash chromatography on silica gel (30% ether in hexane) get mentioned in the title compound (1.10 g), more mobile isomer in the form of a white solid with so pl. 54-57aboutC.

(C) (3R-CIS)-1-(1-((amino)methyl)propyl)-3-(tert-butyldimethylsilyloxy)- 1-(1-cyano)propyl)-4-(4-methoxyphenyl)-6-(trifter-methyl)-2H-1 - benzazepin-2-it. A solution of 1.10 g of (3R-CIS)-3-(tert-butyldimethylsilyloxy)-1- (1-cyano)propyl)-4-(4 - methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-she (to 2.06 mmol) and 0.27 g of catalyst is rhodium on aluminium oxide in 100 ml of methanol, saturated with ammonia, hydronaut at a pressure of 50 psi (3,5 MPa) for 6 hours Add 0.10 g of rhodium on aluminium oxide, the solution again is saturated with ammonia and hydronaut at a pressure of 3.5 MPa additionally for 2 hours the Solution is filtered through Celite, which is washed 2 times with methanol, and the combined filtrates evaporated, getting 1,17 g of a foamy solid. Method Flash chromatography on silica gel (2% methanol /0.5% triethylamine/dichloromethane) receive specified in the title compound in the form of resin (0,70 g).

D) (3R-CIS)-1-(1-((amino)methyl)propyl)-3-(tert-buggered sodium (4.2 mmol) at 0aboutWith added with stirring in small portions a solution to 0.70 g of (3R-CIS)-1-(1-((amino)methyl)propyl)-3-(tert-butyldimethylsilyloxy-si) -4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-she (1.3 mmol) and 1.2 ml of 37% aqueous formaldehyde in 10 ml of acetonitrile, and then add pure acetic acid. Remove the ice bath, the solution is stirred for 2 h and add 0.05 ml of acetic acid, and the solution is stirred for further 30 minutes the Solution is partitioned between ether and 10% aqueous solution of potassium carbonate, the ether layer washed with brine, dried over anhydrous magnesium sulfate and concentrated, obtaining of 0.91 g of a thick oil. Method Flash chromatography on silica gel (1% methanol/0.2% triethylamine/dichloromethane) receive specified in the title compound in the form of a transparent resin (0,49 g).

(E) (3R-CIS)-1-(1-(dimethylamino)methyl)propyl)-1,3,4,5-tetrahydro-3 - hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it, isomer b, monohydrochloride.

To a solution of 0.49 g of (3R-CIS)-1-(1-((dimethylamino)methyl)propyl)-3-(tert - butyldimethylsilyloxy)-4-(4-methoxyphenyl)-6-(tri - vermeil)-2H-1 - benzazepin-2-it (0.87 mmol) in 10 ml of dry dimethylformamide added 0.55 g of three-hydrate tetrabutylammonium fluoride (1,74 mmol) at one time, raybaut brine, dried with magnesium sulfate and evaporated, getting 0,49 g of semi-solid substances. By the method of preparative thin-layer chromatography (3 plates, eluent: 5% methanol in dichloromethane) to obtain 0.35 g of the specified header connection in the form of free base - white crystals. This free base is suspended in the air, add ethyl acetate to dissolve the substance and then adding ether saturated with hydrogen chloride . The resulting white solid is quickly collected by filtration, washed with ether and dried in vacuum, obtaining 0.24 g specified in the title compound as a white solid with a melting point 144-148aboutC.

[ ]D= +89,60about(C = 1 mol/l in methanol).

Calculated, %: C 56,96; H 6,38; N The 5.45; Cl 7,24; F Is 11.11.

C24H30ClF3N2O31,06 H2O.

Found,%: C 56,96; H 6,40; N 5,54; Cl 7,00; F Of 11.26.

P R I m e R 19. (3R-CIS)-1-(1-(dimethylamino)methyl)propyl)-1,3,4,5-tetrahydro-3 - hydroxy-4-(4-methoxyphenyl)-6-(triptime - Tyl)-2H-1-benzazepin-2-it, isomer a, monohydrochloride.

A) (3R-CIS)-3-(tert-butyldimethylsilyloxy)-1-(1-cyano)propyl)-4-(4 - methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it.

Not received any cystagon)methyl)propyl)-1,3,4,5-tetrahydro-3 - hydroxy-4-(4-methoxyphenyl)-6-(trifter - methyl)-2H-1-benzazepin-2-it, monohydrochloride (see example 18). The fractions containing DIF, are combined and evaporated, getting 1,91 g solids. This material is purified by the method of Flash chromatography on silica gel (25% ether in hexane) to give to 1.21 g of almost pure DIF specified in the title compound as a white solid.

B) (3R-CIS)-1-(1-((amino)methyl)propyl-3-(tert-butyldimethylsilyloxy) -4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzene-pin-2-it.

A solution of 1.21 g of (3R-CIS)-3-(tert-butyldimethylsilyloxy(-1-(1-cyano)propyl)-4-(4 - methoxyphenyl)-6-(trifluoromethyl)-2H-1-Ben - Zacepin-2-she of 2.27 mmol) and 0.30 g of catalyst is rhodium on aluminium oxide in 75 ml of methanol, saturated with ammonia, hydronaut at a pressure of 50 psi (3,5 MPa) for 5 hours the Solution is filtered through Celite, who washed 2 times with methanol, and the combined filtrates evaporated, receiving of 1.36 g of the crude solids in the form of a transparent resin.

(C) (3R-CIS)-1-(1-((dimethylamino)methyl)propyl)-3-(tert - butyldimethylsilyloxy)-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it.

To 0,46 g hard cyanoborohydride sodium (7,26 mmol) at 0aboutWith added with stirring in small portions a solution of 1.36 g of (3R-CIS)-1-(1-((amino)methyl)propyl-3-(tert-Boutilimit is in 20 ml of acetonitrile, then add pure acetic acid. Remove the ice bath, the solution is stirred for 2 h and add 0.15 ml of acetic acid, the solution is stirred for further 2 hours the Solution is partitioned between ether and 10% aqueous solution of potassium carbonate, the ether layer washed with 10% aqueous potassium carbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated, getting 1,31 g of a clear oil. Method Flash chromatography on silica gel (1% methanol/ 0.5% triethylamine/dichloromethane) gain of 1.02 g of a white foamy solid substance containing specified in the header connection. This material chromatographic 6 preparative thin-layer plates (eluent 25% ethyl acetate in hexane) and the band with Rf = 0.52 in cut out and extracted with a mixture of 5% methanol in dichloromethane. The extract is filtered, and the filtrate is evaporated, receiving of 0.44 g specified in the connection header in the form of a light brown resin.

D) (3R-CIS)-1-(1-(dimethylamino)methyl)propyl)-1,3,4,5-tetrahydro-3 - hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it, isomer a, monohydrochloride.

To a solution of 0.44 g of (3R-CIS)-3-(tert-butyldimethylsilyloxy)-1-(1- ((dimethylene)methyl)propyl)-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H - 1-benzazepin-2-it (0,7 is based (1.56 mmol) as a solid. The solution is stirred for 25 min, partitioned between ether and water, the organic phase is washed with brine, dried with magnesium sulfate and evaporated, gaining 0.45 g of a brown resin. By the method of preparative thin-layer chromatography (3 preparative thin-layer plates, eluent 2% methanol in dichloromethane) to obtain 0.36 g of the free base is specified in the title compound as a white crystalline substance. This free base is dissolved in ether, the solution is filtered through Celite and to the filtrate add ether saturated with hydrogen chloride, the resulting white solid is collected by filtration, washed 2 times with ether and dried in vacuum, obtaining 0.35 g specified in the title compounds as white solids with so pl. 126-131aboutC.

[ ]D= +106,8about(C = 1 mol/l in methanol).

Calculated,%: C 57,54; H 6,35; N 5,59; Cl 7,08; F 11,38

C24H30ClF3N2O30,78 H2O

Found,%: C 57,54; H To 6.39; N 5,64; Cl Of 6.96; F 11,09.

P R I m e R 20. (3R-CIS)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-1-(1 - methyl)-2-(methylamino)ethyl)-6-(trifluoromethyl)--2H-1-benzazepin-2 - he isomer In monohydrochloride.

A) (3R-CIS)-3-(tert-butyldimethylsilyloxy)-1-(1-cyano-ethyl)-4-sildenafilcitrate)-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1-benzazepin-2-she (8.6 mmol, see example 18) in dry dimethylformamide (40 ml) is added 380 mg of sodium hydride (9.5 mmol, 60% dispersion in oil). The solution is stirred for 30 min at room temperature and added 0.68 ml (8,66 mmol) of pure 2-chloropropionitrile. The solution is heated to 50aboutC for 1 h Add an additional 0.02 g of sodium hydride and 0.07 ml of 2-chloropropionitrile, and the solution is heated at 50aboutC for 3 hours the Solution is cooled to room temperature, concentrated in vacuo to remove dimethylformamide and the brown residue is distributed between ethyl acetate and water. The organic phase is washed with water and brine, dried with magnesium sulfate and evaporated, and the residue is served on a column of silica gel. When elution with a mixture of 5% ethyl acetate in hexane get 1,76 g more rolling isomer specified in the connection header and 1.0 g less rolling isomer.

B) (3R-CIS)-1-(1-((amino)methyl)ethyl)-3-(tert-butyldimethylsilyloxy)- 4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzene-pin-2-it.

A solution of 0.8 g of (3R-CIS)-3-(tert-butyldimethylsilyloxy)-1-(1-cyano)ethyl)-4-(4 - methoxyphenyl)-6-(trifluoromethyl)-2H)-1-Benza - zipin-2-she (1.5 mmol) in 100 ml of methanol, saturated with ammonia at 0aboutC for 5 min, and add 0.2 g of catalyst (5% rhodium on " OK " the Torah and the solution again hydronaut at a pressure of 3.8 MPa additionally within 1 hour The mixture is filtered through a layer of Celite, which is washed with methanol and the combined filtrates evaporated, receiving 0.75 g specified in the header of the substance.

(C) (3R-CIS)-1-(1-((triptorelin)methyl)ethyl)-3-(tert - butyldimethylsilyloxy)-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it.

To a solution of (3R-CIS)-1-(1-((amino)methyl)ethyl)-3-(tert-butyldimethylsilyloxy) -4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it (0,76 g of 1.46 mmol) and pyridine (0.37 sq ml of 4.66 mmol) in 10 ml of dichloromethane add a solution triperoxonane anhydride (0,41 ml, only 2.91 mmol) in 5 ml of dichloromethane for 2 min, and the solution is stirred at room temperature overnight. Add pyridine (0,37 ml of 4.66 mmol) and triperoxonane anhydride (0,41 ml, only 2.91 mmol) in 5 ml of dichloromethane for 2 min and the solution stirred for 20 minutes the Solution is extracted with water and brine, dried with magnesium sulfate and evaporated, getting 0,77 g is specified in the header of the substance in the form of a red oil.

D) (3R-CIS)-1-(1-(((TRIFLUOROACETYL)methylamino)methyl)ethyl))-3-(tert - butyldimethylsilyloxy)-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it.

To a solution of (3R-CIS)-1-(1-((triptorelin)methyl)ethyl-3-(tert - butyldimethylsilyloxy)-4-(4-netoxygen the IDA sodium (1.12 mmol, 60% dispersion in oil). The solution is stirred for 30 min at room temperature, add 0,07 ml (1.12 mmol) iodotope bromide, and the solution is heated to 50aboutC for 1 h Add an additional 0.02 g of sodium hydride and 0.07 ml of 2-chloropropionitrile and the solution stirred for 2 h at room temperature. The solution is distributed between ethyl acetate and water. The organic phase is washed with water and brine, dried with magnesium sulfate and evaporated, receiving 450 mg specified in the title compound as a red oil.

(E) (3R-CIS)-1-(1-((methylamino)methyl)ethyl)-3-(tert - butyldimethylsilyloxy)-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it.

A mixture of (3R-CIS)-1-(1-(((TRIFLUOROACETYL)methylamino)methyl)-ethyl)-3-(tert - butyldimethylsilyloxy)-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1 - benzazepin-2-she (450 mg, to 0.72 mmol) and sodium carbonate (0.5 g, 4,72 mmol) in 20 ml of methanol is refluxed over night. The reaction mixture is cooled to room temperature and evaporated, and the residue partitioned between dichloromethane and water, the organic phase is washed with water and brine, dried with magnesium sulfate and evaporated. The residue is purified by the method of preparative thin-layer chromatography on 3 plates with silica gel,ethylamine in dichloromethane. The mixture is filtered through a layer of Celite, which is washed with dichloromethane and the combined filtrates evaporated. The rest scatter toluene, getting 230 mg specified in the title compound as a yellow oil.

F) (3R-CIS)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-1-(1 - methyl-2-(methylamino)ethyl)-6-(trifluoromethyl)-2H-1-benzo - zipin-2-he isomer In monohydrochloride.

To a solution of (3R-CIS)-1-(1-((methylamino)methyl)ethyl)-3-(tert - butyldimethylsilyloxy)-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-she (1.2 g, 2,24 mmol) in 50 ml of dried DMF (dimethylformamide) added 1.06 g of three-hydrate tetrabutylammonium fluoride (3,36 mmol). The solution is stirred overnight, evaporated and the residue partitioned between dichloromethane and water. The organic phase is washed with water and brine, dried with magnesium sulfate and evaporated, getting 0,86 g yellow oil. The residue is purified on 4 preparative plates with silica gel, which elute with 10% methanol in dichloromethane. Strip product cut out and extracted with a mixture of 15% methanol: 0.5% triethylamine in dichloromethane. The substance is dissolved in ether and to the solution was added ether saturated with hydrogen chloride. Obtained by filtering white solid was washed with ether, receiving 0,3 who, in ethanol).

Calculated,%: C 55,45; H 5,90; N 5,73; Cl 7,94; F Of 11.61.

C22H25F3N2O3HCl 0,98 H2O.

Found,%: C 55,45; H 5,91; N 5,88; Cl 7,44; F 11,96.

P R I m e R 21. (CIS)-1-(2-AMINOPHENYL)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl-3 - methyl-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

A) (CIS)-1-(2-Nitrophenyl)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-3 - methyl-6-(trifluoromethyl)-2H-1-benzazepin-2-it.

Add 1.0 g (2,86 mmol) of (CIS)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)3-me - til-2-oxo-6- (trifluoromethyl)-2H-1-benzazepin-2-she to a solution of 125 mg of sodium hydride (3,15 mmol, 60% dispersion in oil) in 5 ml of dry dimethylformamide. The solution is stirred for 35 min at room temperature, and added dropwise of 0.32 ml (3.0 mmol) of pure 2-peritrabecular. The solution is stirred for 105 minutes at room temperature and heated to 45aboutWith over 40 minutes the Solvent is removed under high vacuum with gentle heating and the residue partitioned between ether and odnomernym solution of ammonium chloride. The organic phase is washed with water (twice) and brine, dried and evaporated, receiving a yellow solid foam, which was dissolved in 25 ml of ether. After adding 175 ml of hexane and cooling during the night receive the-tetrahydro-4-(4-methoxyphenyl)-3 - methyl-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

A solution of 0.73 g (1.55 mmol) of the substance specified in the header, and 146 mg of catalyst (10% palladium on coal in 110 ml of absolute ethanol hydronaut within 4,25 h and filtered through Celite. Celite is washed 2 times with ethanol and the combined filtrates concentrated. The residue is twice dissolved in carbon tetrachloride and evaporated, getting 0.73 g of a white solid foam. According to the analysis of NMR nuclei 1H and 13 C product is almost pure free base. The residue is dissolved in 50 ml of ether and filtered from Muti through Celite. After adding ether solution of hydrogen chloride and incubation for 30 min a white precipitate is collected by filtration, washed 2 times with ether and dried in vacuum at 75aboutWith in a few days, in order to obtain specified in the header connection (0,58 g, 79%) as white solid powder with so pl. 165-170aboutC.

Calculated,%: C 63,00; H 5,13; N 5,88; Cl 6,69; F 11,96.

C25H23F3N2O20,9 HCl 0,19 H2O.

Found,%: C 63,00; H To 4.87; N 6,03; Cl 6,55; F To 11.79.

P R I m e R 22. (3R-CIS)-1-(2-Dimethylamino)phenyl)-1,3,4,5-tetrahydro-4-(4 - methoxyphenyl)-3-hydroxy-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

A) (3R-Castoro 2.0 g (5,69 mmol) (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-(trifter - methyl)-2H-1 - benzazepin-2-it in 10 ml of dry dimethylformamide added 230 mg of sodium hydride (5,69 mmol, 60% dispersion in oil). The solution is stirred for 60 min at room temperature and added dropwise to a solution of 1.2 ml (11,38 mmol) of pure 1-fluoro-2-nitrobenzene in 5 ml of dimethylformamide for 2 hours the Reaction mixture was stirred over night at room temperature, concentrated in vacuo to remove dimethylformamide and the residue distributed between ethyl acetate and odnomestnoi hydrochloric acid. The organic phase is washed with water and brine, dried over magnesium sulfate and evaporated, receiving a yellow oil. This oil is dissolved in warm ethyl acetate, and the yellow solid, crystallized from solution, filtered and washed with cold ethyl acetate. Obtain 1.68 g (63%) specified in the header And connection.

B) (3R-CIS)-1-(2-nitrophenyl)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)- 3-atomic charges-6-(trifluoromethyl)-2H-1-benzazepin-2-it.

To a stirred solution of the substance from heading And (1.68 g, of 3.56 mmol) and 4-dimethylaminopyridine (50 mg) in tetrahydrofuran (50 ml) is added pyridine (0,32 ml, to 3.92 mmol) and then acetic anhydride (of 0.44 ml, 4,63 mmol). The mixture is stirred at room temperature overnight. The solution is distributed between ethyl acetate and water. The aqueous phase is extracted with etilize - tatom (ia and brine and dried over magnesium sulfate. The solvent is removed in vacuum, obtaining of 0.85 g (46%) specified in title In connection in the form of a yellow solid.

(C) (3R-CIS)-1-(2-AMINOPHENYL)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-3 - atomic charges-6-(trifluoromethyl)-2H-1-benzazepin-2-it.

To a solution of 0.85 g (of 1.65 mmol) substances specified in the header In 100 ml of acetonitrile, add 0.2 g of catalyst (10% palladium on coal. The solution hydronaut under pressure of 3.5 MPa for 3 hours the Mixture is filtered through a layer of Celite. Celite is washed with acetonitrile and the combined filtrates evaporated, receiving of 0.60 g (75%) specified in the header With the connection.

D) (3R-CIS)-1-(2-dimethylaminophenyl)-1,3,4,5-tetrahydro-4-(4 - methoxyphenyl)-3-atomic charges-6-(trifluoromethyl)-2H-1-benzene - pin 2-he, monohydrochloride.

Hard cyanoborohydride sodium (62 mg, 0.98 mmol) is added a solution of 120 mg (0.25 mmol) of the compound of the header and 0.6 ml of 37% formaldehyde in 5 ml of acetonitrile. The reaction mixture was stirred at room temperature for 5 minutes, then add 0.1 ml of acetic acid. After 2 h, add 0.1 ml of acetic acid. The solution is distributed between ethyl acetate and aqueous potassium carbonate solution. The organic phase is washed with aqueous potassium carbonate solution, water and R is the thief of hydrogen chloride obtain a white solid compound. According to the analysis of NMR nuclei 1H acetyl group is partially hydrolyzed.

(E) (3R-CIS)-1-(2-(dimethylamino)phenyl)-1,3,4,5-tetrahydro-4-(4 - methoxyphenyl)-3-hydroxy-6-(trifluoromethyl)-2H-1-benzene-pin 2-he, monohydrochloride.

A mixture of the compound of the title D (420 mg, of 0.79 mmol) and potassium carbonate (0.5 g, 4,72 mmol) in 30 ml of methanol is refluxed for 5 h in an argon atmosphere. The reaction mixture is cooled to room temperature, concentrated in vacuo and the residue extracted with dichloromethane. The organic phase is washed with water and brine, dried with magnesium sulfate and evaporated. The residue is purified by the method of preparative thin-layer chromatography on 4 plates with silica gel, which elute with a mixture of 1:1 ethyl acetate and hexane. Strip product cut out and extracted with dichloromethane. The combined filtrates evaporated. The yellow solid is dissolved in ether and to the solution was added ether saturated with hydrogen chloride. Filtered light yellow solid, washed with ether, receiving 302 mg (74%) of the net specified in the header of a substance with so pl. 217 to 220aboutC.

[ ]D= +243,4about(C = 1 mol/l in ethanol).

Calculated,%: C 60,07; H 5,31; N 5,38; Cl For 6.81; F 10,96.

C

Mix a solution of 5.0 g (of 14.2 mmol) of (3R-CIS)-4-(4-methoxyphenyl)-3-hydroxy-6-(trifluoromethyl)-2H-1 - benzazepin-2-it in 150 ml of butanone treated with 2.8 g (17,1 mmol) of the hydrochloride of 2-chloromethylpyridine and 5.0 g (36,2 mmol) powdered potassium carbonate and refluxed over night. According to thin-layer chromatography (mixture of 95:5 methylene chloride: methanol) and the reaction is complete. After combining with the previously carried out by the experience in the amount of 0.5 g of the solid substance is filtered off, washed Bhutan, and the mass of the solvent is removed on a rotary evaporator. The residue is shaken with 150 ml of ethyl acetate and 50 ml of water, separate the layers, and the organic phase is washed with 50 ml water, 50 ml brine, dried with magnesium sulfate and finally the solvent is evaporated at a pressure of 0.2 mm RT.article Get to 7.3 g of a light yellow foamy residue. The residue after curing for Saturday and Sunday is dissolved in ether, filtered to remove insoluble orange material is evaporated and dried by pumping of the pump, getting to 6.9 g of light yellow brittle foam. According to thin-layer chromatography (TC shall provide 3.5 ml of a solution of hydrogen chloride (5 BC) in ethanol and the solvent is evaporated finally at 0.2 mm RT. Art. Partially solid residue triturated under ether layer and repeat the evaporation getting after drying with a pump pumping of 8.3 g of a light yellow solid. During the subsequent crystallization from 90 ml of hot isopropanol get of 6.95 g (93%) of colorless product with so pl. 184-186about(Foaming).

[ ]D= +97,0about(C = 1 mol/l in methanol).

Calculated,%: C 58,54; H To 4.81; N 5,69; Cl 7,20.

C24H21F3N2O3HCl 0,75 H2O.

Found,%: C 58,46; H 5,15; N 5,34; Cl 7,24.

P R I m e R 24. (3R-CIS)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-3-hydroxy-1-(2 - piperidinylmethyl)-6-(trifluoromethyl) -2H-1 - benzazepin-2-it, monohydrochloride, isomer A.

A solution of 3.00 g (6,09 mmol) substances specified in the header of example 23, in 200 ml of ethanol is treated of 0.30 g of platinum dioxide and placed for 2 h in a Parr autoclave under hydrogen pressure of 3.5 MPa, according to TLC at this point rehabilitated completely peredelnoj group. The catalyst is filtered off under nitrogen atmosphere and the solvent is evaporated, obtaining a solid residue. This residue is dissolved in 30 ml of acetonitrile and diluted with 330 ml of ether, obtaining a solid substance. The mixture is cooled overnight and filtered, obtaining 1.29 g (43%) from (to remove traces of catalyst), cooled overnight and filtered, getting to 0.72 g of nearly colorless solid, []D= +112about(C = 1 mol/l in methanol). After recrystallization from 18 ml of hot isopropanol product weight equal to 0.63 g (21%), so pl. 177-180aboutC [ ]D= +113about(C = 1 mol/l in methanol), (TLC): Rf = 0,59 (eluent is a mixture of 80:20 methylene chloride:methanol).

Calculated,%: C 58,89; H By 5.87; N 5,72; Cl 7,24.

C24H27F3N2O3HCl 0,25 H2O.

Found,%: C 58,82; H 5,90; N 5,68; Cl 7.23 Percent.

(3R-CIS)-1,3,4,5-tetrahydro-4-(4-labels-Setenil)-3-hydroxy-1-(2 - piperidinylmethyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride, isomer Century

Upon evaporation of the filtrate obtained in the first crystallization of the isomer A, gain of 1.46 g of the crude isomer Century After converting a free base, followed by chromatographytandem on the column with 35 g of silica gel (eluent is a mixture of 15:1 methylene chloride and methanol) gain of 0.48 g of pure isomer 7. This material was dissolved in 5 ml of chloroform and treated to 0.22 ml alcohol 5,1 n solution of hydrogen chloride in 3 ml of chloroform - mA. When removing the solvent in vacuo get solid, which is triturated with ether, receiving of 0.54 g of the product with so pl. 130-14024
H27F3N2O3HCl 1,25 H2O.

Found,%: C 56,77; H 5,77; N 5,39; Cl 6,93.

P R I m e R 25. (3R-(1(R*),3 ,4 ))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)- 1-(3 - piperidinylmethyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

A) (3R-(1(S*), 3 , 4 ))-1-((Benzyl-2-pyrrolidinyl)methyl-3-hydroxy-1,3,4,5-Tetra - guide-ro-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-he

B) (3R-(1(R*), 3 , 4 ))-1-((Benzyl-3-pyrrolidinyl)methyl-3-hydroxy-1,3,4,5-Tetra-hydro - 4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it.

Sodium hydride (1.44 g, was 59.9 mmol) is added under stirring to a solution of (3R)-CIS)-3-(hydroxy)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1-benzazepin-2-it (10 g, 28.5 mmol) in dried dimethylformamide (250 ml). After 1 h at room temperature, the mixture is cooled to 0aboutAnd add one of 7.36 g (30 mmol) of (S)-1-(benzyl-2-(chloromethyl)pyrrolidine. The mixture is heated to room temperature and stirred for 4 h the Mixture was diluted with saturated aqueous potassium bicarbonate and extracted three times with ethyl acetate. United an ethyl acetate extracts are washed with 10% aqueous solution of sodium chloride, dried with sodium sulfate, filtered and concentrated. Solid prophetic the button to remove unreacted (3R-CIS)-3-(hydroxy)-1,3,4,5-tetrahydro-4-(4-methoxide - nil)-6- (trifluoromethyl)-2H-1-benzazepin-2-it. Add solid sodium chloride and the aqueous layer was extracted 3 times with ethyl acetate. The combined extracts are dried with magnesium sulfate, filtered and concentrated. Get the crude compound a and b specified in the header, in the form of solids light orange color. Adducts of these compounds a and b cannot be separated at this stage, and they were taken to the next stage without additional purification.

(C) (3R-(1(S*), 3 ,4 ))-1-((2-pyrrolidinyl)methyl-3-hydroxy-1,3,4,5-tetrahed - ro-4-(4 - methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-he

D) (3R-(1(R*), 3, 4 ))-1-((3-piperidinyl)methyl-3-hydroxy-1,3,4,5-tetrahydro-4-(4 - methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it.

The ammonium formate (9,58 g, 151,9 mmol is added to a suspension of 10% palladium on coal (3.7 g) and a mixture of compounds specified in the headers a and b (18.5 g, 33 mmol) in 350 ml of anhydrous methanol in an atmosphere of argon. This mixture is refluxed 5 h, cooled and filtered through anhydrous magnesium sulfate. The remaining solid is washed with methanol. The filtrate is concentrated, dissolved in minimum amount of water and washed three times with ether. The aqueous layer was alkalinized water potassium bicarbonate and extracted with 3 so Get a mixture of compounds C and D, indicated in the header, in the form of a light yellow foam (10,89 g, 76%). Isomers of these compounds cannot be separated and they were taken to the next stage without additional purification.

(E) (3R-(1(S*),3 ,4 ))-1-(Benzyloxycarbonyl-2-pyrrolidinyl)methyl-3-hydroxy-1,3, 4,5 - tetrahydro-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-he

F) (3R-(1(R*),3, 4 ))-1-((Benzyloxycarbonyl-3-piperidinyl)methyl-3-hydroxy-1,3, 4,5 - tetrahydro-4-(4-methoxyphenyl)-6-(trifluoromethyl-2H-1-benzazepin-2-it.

To a mixture of connections specified in the headings C and D (7,07 g, 16.3 mmol) in 1,4-dioxane (80 ml) and saturated aqueous solution of potassium bicarbonate (30 ml) at room temperature is added dropwise benzylchloride (of 5.84 g, 32.5 mmol). The reaction mixture was immediately diluted with water and extracted 3 times with ethyl acetate. The combined extract washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude yellow liquid chromatographic on a column of silica gel and elute 15-30% ethyl acetate in hexane to obtain the connection specified in the header of the E (7,89 g, 85% ); Rf = 0,38 (silica gel, 50% ethyl acetate in hexane) and the connection specified in the header of F (0.87 g, 9,4); Rf = 0.50 in (silica gel, 50% ethyl acetate in ekberzade-pin 2-he, monohydrochloride.

To a solution of the compound indicated in the heading F (800 mg, of 1.41 mmol) in 25 ml of ethyl acetate and 1 ml triperoxonane acid was added with stirring to 160 mg of palladium hydroxide on carbon. The reaction flask is filled with hydrogen from a balloon. This vaccum flask under reduced pressure and filled with hydrogen (3 times). The mixture is then stirred at room temperature overnight, to remove hydrogen, and add anhydrous magnesium sulfate. Solids are removed by filtration and well washed them with ethyl acetate. The filtrate is washed with an aqueous solution of potassium bicarbonate (3 times). The combined aqueous layers are extracted with ethyl acetate and the organic extracts are combined, dried over magnesium sulfate, filtered and concentrated. The crude residue is triturated with 20 ml of ether and precipitated in the sediment free amine is filtered, collected and dried, obtaining 420 mg of white solid, which was dissolved in 5 ml methylene chloride and add 5 ml of ethereal HCl solution. The solution is concentrated under reduced pressure and finally under vacuum to obtain specified in the title compound (450 mg, 68%) as a white solid with so pl. 183-188aboutC.

[ ]D= +102,6N2O3HCl H2O.

Found,%: C 56,58; H Of 5.75; N Of 5.53; Cl 7,02.

P R I m e R 26. (3R-(1(R*),3 , 4 )-3-the atomic charges)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1-(3 - piperidinyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

A) (3R-(1(R*), 3 , 4 ))1-(benzyloxycarbonyl-3-piperidinyl)-3-atomic charges-1,3,4,5 - tetrahydro-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin - 2-it.

To a solution of the compound from example 25, F (880 mg, 1.53 mmol) in 20 ml of ethyl acetate are added dropwise to 700 ml of acetyl chloride. The reaction mixture is heated at 70aboutWith during the day, after which it is cooled, and the excess acetyl chloride destroy the addition of 2 ml of methanol. The mixture is diluted with ethyl acetate and washed 3 times with an aqueous solution of potassium bicarbonate. The combined aqueous wash extracted 1 time with ethyl acetate. The organic extracts are combined, dried with magnesium sulfate, filtered and concentrated under reduced pressure, obtaining the connection specified in the header (920 mg, 100%) as a white foam.

B) (3R-(1(R*), 3, 4 ))-3-the atomic charges)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1- (3 - piperidinyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

To a solution of the compound indicated in the title And, (920 mg, 1.53 mmol) in 25 ml alladia on coal. The reaction flask is connected with a balloon filled with hydrogen. This vaccum flask under reduced pressure and filled with hydrogen from a balloon (3 times). The mixture is then stirred at room temperature overnight, after which the balloon is removed. To the reaction mixture add anhydrous magnesium sulfate and filtered the mixture through a layer of magnesium sulfate. Solid well washed with ethyl acetate. The filtrate is washed 3 times with an aqueous solution of potassium bicarbonate. The combined aqueous layers extracted 2 times with ethyl acetate. The organic extracts are combined, dried with magnesium sulfate, filtered and concentrated. The brown oily residue (770 mg) chromatographic on a column of silica gel (pretreated with 1%) of triethylamine and elute with a mixture of 5% methanol in ethyl acetate to obtain 430 ml free base as a white foam. This free amine was dissolved in methylene chloride and added an excess of ethereal HCl solution. The solution is concentrated under reduced pressure, getting 420 mg specified in the title compound (65%) as white solids with so pl. 177-180aboutC.

[ ]D= +107,9about(C = 1, methanol).

Calculated,%: C 56,91; H 5,66; N 5,31; Cl 6,72; F 10,80.

C25

A) S-N-tert-butoxycarbonyl-2-pyrrolidineethanol.

S-2-pyrrolidineethanol (15 g, 148,3 mmol) and di-tert-BUTYLCARBAMATE (40 g, 178 mmol) in 500 ml of methylene chloride is stirred for 5 h at room temperature. The solvent is evaporated under reduced pressure, and the crude product turn at the next stage (B) without further purification.

In) S-N-tert-butoxycarbonyl-(methyl bromide)pyrrolidin.

Specified in the header And the connection (29,8 g, 148,3 mmol), triphenylphosphine (77,8 g, 297 mmol) and chetyrehhloristy carbon (99 g, 297 mmol) in 1000 ml of ether is stirred at room temperature for 18 hours Solid precipitate is removed by filtration and the solid westwa well washed with hexane. When the concentration of the filtrate receives a yellow liquid, which after chromatography was carried out on a column of silica gel and elution 0-5% ethyl acetate in hexane gives 17,49 g of compound indicated in heading (45%), as colourless liquid.

(C) (3R-(1(S*),3 a,4 a))-1-((tert-butoxycarbonyl-2-pyrrolidinyl)methyl)-3-hydroxy - 1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6 - trifluoromethyl)-2H-1 - benzazepin-2-it.

(cirid sodium (0.27 g, 11,33 mmol) in 95 ml of dimethylformamide (sustained over molecular sieve 4A) and stirred for 1 hour Add the connection specified in the header (3.0 g, 11,33 mmol), the mixture is heated 3 hours at 80aboutC. Add an additional 0.11 g (4,58 mmol) of sodium hydride and the connection of the header (1,25 g, 4,72 mmol). The reaction mixture is heated for 2 h at 80aboutWith cool and terminate the reaction by adding water and extracted 3 times with ethyl acetate. The combined extract is washed 3 times with 10% aqueous lithium chloride, dried over magnesium sulfate and concentrated. The crude yellow liquid chromatographic on a column of silica gel, which elute 5-20% ethyl acetate in hexane, to highlight the connection specified in the header (0.65 g, 13.7 percent).

[ ]D= +to 135.2about(C = 1 mol/l in methanol).

D) 3R-(1(S*), 3 , 4 )-6-chloro-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-1- (2 - pyrrolidinyl-methyl)-2H-1-benzazepin-2-it.

A solution of the compound of the title (of 0.67 g of 1.34 mmol) and 1 ml (of 13.1 mmol) triperoxonane acid in 10 ml of methylene chloride is stirred at room temperature for 6 hours Add saturated aqueous solution of potassium bicarbonate to podselect the reaction mixture, which is then Rabaul tryout, receiving the crude product, which chromatographic on preparative plates with silica gel, to obtain 0.28 g specified in the title compound (52%) as a pale yellow foam with so pl. 80-84aboutC.

[ ]D= +148,0about(C = 1 mol/l in methanol).

Calculated,%: C 64,70; H 6,38; N 6,86; Cl 8,68.

C22H25ClN2O30,42 H2O.

Found,%: C 64,96; H 6,34; N 6,60; Cl 8,78.

P R I m e R 28. (3R-(1(S*),3 , 4 )-3-(the atomic charges)-6-chloro-1,3,4,5-tetrahydro-4-(4-IU-toxigenic)-1- (2-pyrrolidinyl)-2H-1-benzazepin-2-it.

A) (3R-(1(S*),3, 4 )-1-((tert-butoxycarbonyl-2-pyrrolidinyl)methyl)-3-acyloxy)- 1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1 - benzazepin-2-it.

N, N-Dimethylaminopyridine (0.35 g, is 2.88 mmol) are added to a solution of compound header) from example 27 (0,72 g, 1.44 mmol) and acetic anhydride (0.68 g, 7.2 mmol) in 20 ml of methylene chloride. The mixture is stirred 18 h at room temperature, absorb silica gel (60-200 mesh), chromatographic on a column of silica gel and elute 10-20% ethyl acetate in hexane, to obtain 0.66 g of the compound indicated in the title And, (85%) as a white foam.

B) (3R(1(S*),3, 4 ))-3-(the atomic charges)-6-chloro-1,3,4,5-tetrahydro-4-(4-methoxyphenyl) -1- (2-pyrrole oruktusai acid (1,37 ml, 18.0 mmol) in 15 ml of methylene chloride is stirred for 1.5 h at room temperature. To the reaction mixture is added saturated aqueous solution of potassium bicarbonate, then water, before you extracted it with ethyl acetate (3 times). Dried over magnesium sulfate, filtered and concentrated, obtaining mentioned in the title compound (0.53 per share, 100% ) as a white foam, so pl. 74-78aboutC; [ ]D= +130,0about(C = 1, methanol).

Calculated,%: C 64,35; H 6,20; N 6,25; Cl To $ 7.91.

C24H27ClN2O40,29 H2O.

Found,%: C 64,61; H 6,09; N 5,97; Cl 7,51.

P R I m e R 29. (3R-(1(2R*),3 ,4 ))-1-(2-dimethylamino)-1-phenylpropyl)-1,3,4,5-tet - rehydro-3-hydroxy - 4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, isomer A.

A) 1S,2R-2-(N,N-dimethylamino)-1-phenyl-1-propanol.

To a suspension of 20 g of 1S, 2R-norephedrine-hydrochloride (106 mmol) in 50 ml of ether added 21 g of a 25% aqueous solution of sodium methoxide in 100 ml of methanol. Additionally, add 50 ml of methanol and the solution is stirred for several minutes and filtered. A white precipitate is washed several times with ether and the combined filtrates evaporated, receiving 16.6 g of free base - 1S,2R-norephedrine in the form of a clear oil (100%). This free base is dissolved in 125 ml Aceto is added to 10.5 g cyanoborohydride sodium (167 mmol) in solid form. Again with periodic cooling, added dropwise glacial acetic acid, until the pH of the solution drops to 8. The solution was stirred at room temperature for 30 min and evaporated. The residue is extracted three times with 2 n sodium hydroxide solution with ether and the combined ether extracts are washed with 0.5 N. the sodium hydroxide solution and extracted 3 times with 10% hydrochloric acid. The combined acid washing is neutralized with solid sodium hydroxide and extracted 3 times with ether. The combined ether washings washed with brine, dried over potassium carbonate and evaporated to obtain 15.6 g (82% ) specified in the header And connection in the form of a white crystalline substance.

In) 1R,2R-2-(N,N-dimethylamino)-1-phenyl-1-chloro-propane.

To a solution of the compound of the title (15.2 g, 70.5 mmol) in 100 ml of methylene chloride add to 20.6 ml chloride taanila (282 mmol) in 100 ml of methylene chloride, is added dropwise within one hour. After adding 200 ml of carbon tetrachloride and cooled to 0aboutWith not allocated a solid product. Distilled methylene chloride, and the remaining solution was freeze during the night, receiving a mixture of 1:1 1R, 2R and 1S, 2R-isomers of the compounds of the header) in the form of pink by recrystallization from 150 ml of acetone and 5 ml of methanol receive 0,98 g connection specified in the header) (isomer A) as a pale brown prisms.

[ ]D= -110,9about(C = 1 mol/l in methanol).

(C) (3R-(1(2R*),3 , 4 ))-1-(2-dimethylamino)-1-phenylpropyl)-3-(tert-butultimately-siloxy)- 1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it, isomer A.

To a suspension of 93 mg of sodium hydride (1,93 mmol, 50% dispersion in oil) in 4 ml of dry dimethylformamide added 0.75 g of 3-tert-butyldimethylsilyl ether (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-(tri - vermeil)-2H-1 - benzazepin-2-she (to 1.61 mmol). The solution is stirred for 10 min, heated to 70aboutAnd add a solution of 0.87 g (3,22 mmol) of the compound of the title In and 0.36 g of potassium tert-butylate (3,22 mmol) in 2 ml of dry dimethylformamide. Heating and stirring is continued for 70 min,add 45 mg of sodium hydride and 0.22 g of compound of the header and the solution is heated for 90 minutes the Reaction is interrupted by addition of an aqueous solution of potassium carbonate, dimethylformamide is removed under high vacuum with gentle heating, and the residue partitioned between ether and aqueous potassium carbonate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated, getting 1.51 g light yellow oil. Flash chromatography white foam, contaminated approximately 20% of imidate formed by alkylation of the amide carbonyl oxygen.

D) (3R-(1(2R*)3 , 4 ))-1-(2-dimethylamino)-1-phenylpropyl)-1,3,4,5-tetrahydro-3 - hydroxy - 4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, isomer A.

To a solution of 0.58 g of the crude compound header) less of 1.02 mmol) in 25 ml of dried tetrahydrofuran type of 0.68 g of solid three-hydrate tetrabutylammonium fluoride (1.56 mmol) at once. The solution is stirred for 20 min and partitioned between ether and water. The aqueous layer was washed with ether, and the combined organic layers washed with brine, dried with magnesium sulfate and evaporated, getting 0.51 g of a transparent resin. This material is purified on three preparative plates for thin-layer chromatography (eluent of 5% methanol: methylene chloride). The band corresponding to the Rf value of 0.48 (10% methanol in methylene chloride), extracted with a mixture of 10% methanol: 0.5% triethylamine: methylene chloride and the solution is filtered and evaporated to obtain and 0.37 g of the free base specified in the title compound, as a white solid foam. This free base is dissolved in ether, filtered through a layer of Celite and add the ether, NASA concurrent HCl. Obrtalova compound as a white solid foam with so pl. above 220aboutC [ ]D= +180about(C = 1 mol/l in methanol).

Calculated,%: C 60,92; H 6,09; N 4,90; Cl 6,20; F Becomes 9.97.

C22H31F3O3HCl 1,26 H2O.

Found,%: C 60,92; H Equal To 6.05; N 4,74; Cl 6,11; F 9,76.

P R I m e R 30. (3R-(1(2R*),3 ,4 ))-1-(2-(dimethylamino)-1-phenylpropyl)-1,3,4,5-Tetra - hydro-3 - hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride, isomer Century

A) (3R-(1(2R*), 3 ,4 ))-1-(2-dimethylamino)-1-phenylpropyl)-3-(tert-butyldimethylsiloxy)- 1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)- 2H-1-benzazepin-2-it, isomer Century

To a suspension of 1.08 g of sodium hydride (at 22.6 mmol of a 50% dispersion in oil) in 10 ml of dried DMF (dimethylformamide) add 3.5 g of 3-tert-butyldimethylsilyl ether (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1 - benzazepin-2-it (7,52 mmol). The solution is stirred for 30 min, add 3,05 g of a mixture of 1:1 1R,2R and 1S,2R - (N,N-dimethylamino)-1-phenyl-1-chloropropane (13 mmol, see example 29) in solid form and the solution is stirred and heated at 65aboutWith 1 h the Solution is cooled by addition of an aqueous solution of sodium bicarbonate, the dimethylformamide is removed under high vacuum with gentle heating and the residue partitioned between ether and aqueous solution of the CSOs brown oil. Method Flash chromatography on silica gel (eluent - 75% ether in hexane and then 75% ethyl acetate in hexane) to obtain 1.18 g of crude compound indicated in the heading And (a value of Rf = 0,41 50% ethyl acetate in hexane) contaminated with a small amount over the rolling isomer (compound C) in example 29(. Flash chromatography on silica gel (eluent 50% ethyl acetate in hexane) to give 0.84 g is specified in the header) connection (18%), as a yellow solid foam.

B) (3R-(1(2R*), 3, 4 ))-1-(2-dimethylamino)-1-phenylpropyl)-1,3,4,5-tetrahydro-3 - hydroxy - 4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, isomer b, monohydrochloride.

To a solution of 0.84 g of the crude compound of the title (of 1.34 mmol) in 25 ml of dried tetrahydrofuran type of 0.90 g of solid three-hydrate tetrabutylammonium fluoride (2,86 mmol) at once. The solution is stirred for 30 min and partitioned between ether and water. The aqueous layer was washed with ether and the combined organic layers washed with brine, dried with magnesium sulfate and evaporated, receiving of 0.85 g of a transparent resin. This material is purified on four preparative plates for thin-layer chromatography (eluent - 75% ethyl acetate in hexane). The band corresponding to the Rf value is 0.19 (75% ethyl acetate the process of 0.50 g of the free base specified in the connection header, in the form of a white solid foam. This free base is dissolved in ether, filtered through a layer of Celite and add ether saturated with HCl. The resulting white precipitate is collected by filtration, washed with ether and dried, but when standing appears hygroscopicity. This solid is dissolved in methanol, evaporated, suspended in hot isopropyl ether and added dropwise methanol, until the dissolution. The solution is cooled, and the resulting white solid is collected by filtration and dried, obtaining 0,42 g specified in the title compound as white solid powder with so pl. 191-192aboutC.

[ ]D= +242,6about(C = 1.05 mol/l in methanol).

Calculated,%: C 62,98; H 5,91; N 5,06; Cl 6,41; F 10,30.

C29H31F3N2O3HCl 0,22 H2O.

Found,%: C 62,98; H 5,79; N 5,04; Cl 6,21; F Of 10.58.

P R I m e R 31. (3R-(1(2S*),3 ,4 ))-1-(2-(dimethylamino)-1-phenylpropyl)-1,3,4,5-the - trihydro-3 - hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin - 2-it, monohydrochloride, isomer Century

A) 1R-2S-2-(N,N-dimethylamino)-1-phenyl-1-propanol.

To a stirred solution of 1R, 25-norephedrine (25 g, 0,165 mol) and 50 ml of formaldehyde (37% solution in water) in 150 ml and is in add 35 ml of glacial acetic acid. The reaction mixture was stirred at room temperature for 1 h, concentrated to 1/3 volume and neutralized to pH 10 odnomomentnym solution of sodium hydroxide. The combined organic phases are washed with water and brine, dried over magnesium sulfate and evaporated. The product is subjected to recrystallization from a mixture of ethanol and water, getting 7,01 g (24%) of the compound indicated in the heading A.

In) 1R,2S-2-(N,N-dimethylamino)-1-phenyl-1-chloropropane.

To a stirred solution of the compound indicated in the heading And (2,19 g, 12,22 mmol) in 25 ml of chloroform is added dropwise over 5 min a solution 8,89 ml chloride Tignale (122 mmol) in 15 ml of chloroform. The reaction mixture was stirred for 15 min and evaporated. The dark residue scatter chloroform (2 times 100 ml) and triturated with a mixture of 1:1 ether-hexane (3 times 100 ml), to obtain 2.28 g (80%) of the compound indicated in the title, in the form of a yellow solid, containing 15% 1S,2S-isomer.

(C) (3R-(1-(2S*), 3 ,4 ))-1-(2-dimethylamino)-1-phenylpropyl)-1,3,4,5-tetrahydro-3- (tert-butyldimethylsiloxy)-4-(4-methoxyphenyl)-6-(trifluoromethyl-2H - 1-benzazepin-2-it, isomer Century

To a stirred solution of the compound indicated in the heading And example 18 (1.5 g, up 3.22 mmol) in 20 ml of su is camping stirred for 1 h in argon atmosphere at room temperature. Add 0,76 g (3,22 mmol) undiluted substance of the header and the reaction mixture is stirred at 50aboutWith during the night. The solution is cooled to room temperature and evaporated. The residue is distributed between water and methylene chloride, the organic phase is washed with water and brine, dried over magnesium sulfate and evaporated. The residue is purified on a column of silica gel, which elute with a mixture of 1:1 ether-hexane, obtaining 1.18 g (56%) of the compound indicated in the title of S.

D) (3R-(1(2S*), 3 ,4 ))-1-(2-(dimethylamino)-1-phenylpropyl)-1,3,4,5-tetrahydro-3 - hydroxy-4-(4-methoxyphenyl)-6-(triptime - Tyl)-2H-1-benzazepin - 2-it, monohydrochloride, isomer Century

To a stirred solution of 1.18 g of the compound from header) (1.78 mmol) in 20 ml of dried tetrahydrofuran added 1.12 g of three-hydrate tetrabutylammonium fluoride (of 3.56 mmol). The solution is stirred at room temperature for 1 h and diluted with ether. The organic phase is washed with water and brine, dried with magnesium sulfate and evaporated. The residue is purified on a column of silica gel, which elute with ether. Get a solid substance, which is dissolved in ether. Add ether saturated with HCl, to obtain a white precipitate, which is filtered and washed with ether, prochymal/l, in methanol).

Calculated,%: C 59,77; H 6,18; N 4,80; Cl Between 6.08; F 9,78.

C29H31F3N2O3HCl 1,87 H2O.

Found,%: C 59,37; H 5,78; N 4,90; Cl 6,51; F 9,84.

P R I m e R 32. (3R (1-((2S*),3 ,4 ))-1 -(2-(dimethylamino)-1-phenylpropyl)-1,3,4,5 - tetrahydro-3-hydroxy - 4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride, isomer A.

A) 1S,2S-2-(N,N-Dimethylamino)-1-phenyl-1-chloropropane.

To a stirred solution of compound specified in part a of example 31 (2,19 g, 12,22 mmol) in 25 ml of chloroform is added dropwise over 5 min a solution 8,89 ml chloride taanila (122 mmol) in 15 ml of chloroform. The reaction mixture was stirred 1 h at room temperature and evaporated. The rest scatter chloroform (3 times 100 ml) and triturated with a mixture of 1:1 ether-hexane (4 x 100 ml) to obtain a 1:1 mixture of 1R,2S-isomer and 1S,2S-isomer as a yellow amorphous solid. Recrystallization from acetone gives 0.8 g of pure compound indicated in the heading A.

In) (3-(1(2S*), 3 ,4 ))-1-(2-dimethylamino)-1-phenylpropyl)-1,3,4,5-tetrahydro-3- (tert - butyldimethylsiloxy)-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it, monohydrochloride, isomer A.

The mixture of compounds specified in tugaloo of dimethylformamide is heated under 55aboutC for 2 h, the Reaction mixture was concentrated in vacuo and the residue triturated in water. The solid is collected and dissolved in ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated. The residue is purified on a column of silica gel, which elute with a mixture of 1:1 ether-hexane, gaining 0.7 g of pure compound indicated in the heading of the Century

(C) (3R-(1(2S*), 3 ,4 ))-1-(2-(dimethylamino)-1-phenylpropyl-1,3,4,5-tetrahydro-3-GI - droxy - 4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

To a stirred solution of 0.7 g of compound header) (1.12 mmol) in 20 ml of dried tetrahydrofuran added 0.35 g of three-hydrate tetrabutylammonium fluoride (1.12 mmol). The solution is stirred for 2 h at room temperature and evaporated. The residue is dissolved between ethyl acetate and water. The organic phase is washed with water and brine, dried with magnesium sulfate and evaporated. The residue is purified on four preparative plates with silica gel, which elute methylene chloride.

Strip product cut out and extracted with a mixture of 10% methanol in methylene chloride. The product is dissolved in ether, and adding ether saturated with hydrogen chloride. The solution is evaporated, and the residue Rasse CLASS="ptx2">

Calculated,%: C 61,83; H 6,01; N Equal To 4.97; Cl 6,29; F 10,12.

C29H31F3N2O3HCl 0,8 H2O.

Found,%: C 61,77; H Of 5.81; N 5,03; Cl 6,54; F 10,00.

P R I m e R 33. (3R-(1(S*),3 ,4 ))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)- 1-(3 - pyrrolidinyl)-6-(trifluoromethyl-2H-1-benzazepin-2-he, salt fumaric acid (1:1).

A) 3R-1-Benzyl-3-(para-toluensulfonate)pyrrolidin.

A mixture of 3R-1-benzyl-3-hydroxypyrrolidine (1 g, 5.6 mmol) and para-toluensulfonate (1.6 g, 8.4 mmol) is stirred in 10 ml of pyridine, 4 h, the Reaction mixture was partitioned between aqueous sodium hydrogen carbonate solution and methylene chloride. The organic layer is washed with sodium hydrogen carbonate solution, then brine. Then dried with magnesium sulfate and evaporated first with shallow vacuum and finally high vacuum pumping to remove traces of pyridine. The resulting yellow residue purified by the method of flash chromatography on silikagelevye column h cm (eluent is a mixture of 1:1 ethyl acetate and hexane). Pure fractions concentrated to obtain 933 mg specified in the header And connections, in the form of a colorless oil.

Br(3R-(1(S*), 3 , 4 ))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-1-(benzyl-3 - pyrrolidinyl)-6-(trifluoromethyl-2 is ethoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it (911 mg, 2.6 mmol) and cesium carbonate (to 4.23 g, 13 mmol) in 26 ml of distilled methyl ethyl ketone is refluxed for 8 h and stirred at room temperature for 18 hours Add ethyl acetate (60 ml) and the suspension filtered. The filtrate is concentrated and the residue purified by the method of flash chromatography on silikagelevye column h cm, using the following elution scheme: 2 liters of a mixture of 1:1 ethyl acetate:hexane:1 ml of a mixture of 3:1 ethyl acetate: hexane; 0.5 liters of 1% methanol in ethyl acetate. Pure fractions concentrated to obtain 1.24 g of almost white solid. This substance is recrystallized from ethyl ether, receiving 935 mg (71%) specified in the header connections, in the form of white crystalline powder with so pl. 147-149aboutC.

(C) (3R-(1(S*), 3 , 4 ))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-1-(3 - pyrrolidinyl)-6-trifluoromethyl)-2H-1-benzene - pin-2-it.

A mixture of substances from part (865 mg, 1.7 mmol), ammonium formate (552 mg, 8,76 mmol and 10% palladium on coal (150 mg) is refluxed in 25 ml of a mixture of 4:1 methanol: acetic acid for 4 hours then impose additional 220 mg of ammonium formate (3.5 mmol) and 120 mg of palladium (10 coal). This mixture is boiled for 30 min and then the catalyst is filtered off through Celite.control solution of sodium carbonate and ethyl acetate.

The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue is purified by the method of flash chromatography on silikagelevye column (5 × 20 cm, which is pretreated with a mixture of dichloromethane: methanol and triethylamine, 94:5:1. Column elute first 2 l of a mixture of 5% methanol in dichloromethane and then 2 l of 10% methanol in dichloromethane. Pure fractions concentrated to obtain 60 mg (yield 84% indicated in the title compound as a colourless foam.

D) (3R-(1(S*), 3 , 4 ))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl-1-(3 - pyrrolidinyl-6-(trifluoromethyl-2H-1-benzene - pin 2-he, salt fumaric acid (1:1).

Substance specified in the header (600 mg, of 1.43 mmol), dissolved in 5 ml of methanol and added 166 mg (1,43 mmol) of fumaric acid in solution in hot methanol. The solution is concentrated to dryness and the solid residue is crystallized from methanol:ether to obtain 650 mg (86%) indicated in the title compound as a colourless crystalline substance with so pl. 228-231aboutC.

[ ]D= +57,86about(C = 1.0 mol/l acetic acid)

Calculated, %: C 58,20; H 5,07; N 5,22; F To 10.62.

C22H23F3N2O3C4H4O4.

N is pirrolidone)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, salt of fumaric acid (1:1).

A) 3S-1-Benzyl-3-(benzoyloxy)pyrrolidin.

Diethylazodicarboxylate (4.8 ml, 30 mmol) is added dropwise to a stirred solution of 3R-1-benzyl-3-hydroxypyrrolidine (3.5 g, 20 mmol), triphenylphosphine (7,86 g, 30 mmol) and benzoic acid (6,12 g, 50 mmol in 200 ml of tetrahydrofuran at room temperature. After stirring for 1.5 h, the tetrahydrofuran is removed in vacuo and the residue partitioned between 1 N. hydrochloric acid and ethyl acetate. The organic layer is again extracted with 1 N. hydrochloric acid and the combined acid layers is alkalinized with solid sodium carbonate. The formed base layer is extracted with ethyl acetate. An ethyl acetate layer washed with water, then brine and then dried with magnesium sulfate. The organic layer is evaporated, and the residue purified by the method of flash chromatography on silikagelevye column 5x30 cm using a mixture of 1:3 ethyl acetate and hexane as mobile phase. Pure fractions concentrated to obtain 3.3 g (yield 59%) specified in the header And connections, in the form of a colorless oil.

C) 3S-1-Benzyl-3-hydroxypyrrolidine.

Add odnokorennye solution of sodium hydroxide (25 ml, 25 mmol) to a solution of compounds ukazannoj is 30 minutes After stirring for 30 min, the methanol is removed in vacuo and the remaining aqueous mixture is extracted with ethyl acetate. The organic phase is washed with water, then brine. After drying over sodium sulfate, the ethyl acetate is removed under vacuum, to obtain 1.5 g (yield 77%) of the compound indicated in the title, in the form of a colorless oil.

(C) 3S-1-Benzyl-3-(para-toluensulfonate)pyrrolidin.

A mixture of 3R-1-benzyl-3-hydroxypyrrolidine (1.45 g, 8.2 mmol) and para-toluensulfonate (2.35 g, 12.3 mmol) is stirred in 16 ml of pyridine for 20 hours then the reaction mixture is partitioned between aqueous sodium hydrogen carbonate solution and ethyl ether. The organic layer is washed with sodium hydrogen carbonate solution, water, then brine. After drying with sodium sulfate the organic layer is evaporated first with shallow vacuum and finally high vacuum pumping to remove traces of pyridine. The resulting residue is purified by the method of flash chromatography on silikagelevye column h cm (eluent is a mixture of 1:3 ethyl acetate and hexane). Pure fractions concentrated to obtain 2,31 g (yield 85%) indicated in the title compound, a pale yellow oil.

D) (3R-(1(R*), 3, 4))-1,3,4,5-tetrahydroazepine, specified in the header (2.2 g, only 6.64 mmol), (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it (1.86 g, 5,31 mmol) and cesium carbonate (8.65 g, of 26.5 mmol) in 75 ml of methyl ethyl ketone is refluxed for 18 hours, the Reaction mixture was cooled, diluted with 150 ml of ethyl ether and filtered through Celite. The filtrate is concentrated and the residue purified by the method of Flash chromatography on silikagelevye column h cm using a mixture of 3:1 ethyl acetate:hexane as eluent. This column is only achieved partial purification. Therefore, the concentrated fraction (2.35 g, 88% purity) chromatographic again silikagelevye column h cm, using as eluent a mixture of 2.5% methanol in dichloromethane. Pure fractions are concentrated, receiving 1.64 g (yield 61%) indicated in the title D compound as a white foam.

(E) (3R(1(R*),3 ,4 ))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)- 1-(3 - pyrrolidinyl)- 6-(trifluoromethyl)-2H-1-benzazepin-2-he, salt fumaric acid (1:1).

The solution of the substance from part D (1,58 g, 3.1 mmol) in 30 ml glacial acetic acid hydronaut over the catalyst of 20% palladium hydroxide on coal at room temperature for 3 h, using a balloon device. Then the catalyst from acid and the mixture is alkalinized with solid sodium carbonate. This basic mixture is extracted with 150 ml of ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue is purified by the method of flash chromatography on silikagelevye column h cm, which is pretreated with a mixture of dichloromethane: methanol and triethylamine, 94:5:1. Column elute first 2 l of a mixture of 5% methanol in dichloromethane and then 1 l of 10% methanol in dichloromethane. Pure fractions concentrated to a semi-solid residue which is dissolved in a mixture of 5% methanol in dichloromethane and filtered through Celite. The filtrate is concentrated to obtain 1,173 g (yield 90%) of free base as a white foam.

This free base (1.08 g, 2.57 mmol) was dissolved in methanol and add 298 mg (2.57 mmol) of fumaric acid in solution in hot methanol. The solution is concentrated to a white foam which crystallized from hot isopropanol. After filtration and drying in vacuo receive 925 mg (yield 68%) indicated in the title compound as a white crystalline substance with so pl. 228-231aboutC.

[ ]D= +58,9about(C = 0.50 mol/l, in methanol).

Calculated,%: C 58,22; H 5,17; N 5,16; F 10,51.

C22H23F3N2O3C4H4O4

(3R-(1(S*), 3 , 4 ))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-metoxyphenyl)-1-(3 - pyrrolidinyl)-6-(trifluoromethyl)-(2N-1-benzene-pin 2-he, monohydrochloride.

A) S-1-(benzyloxycarbonyl)-2-((pair-toluensulfonate)methyl) pyrrolidin.

To S-1-(benzyloxycarbonyl)-2-pyrrolidineethanol (105,7 g, 449 mmol) in 400 ml of pyridine at 0aboutSlowly add the pair-toluensulfonate (102,8 g, 539 mmol). The reaction mixture is allowed to warm to room temperature and stirred for 20 h half of the pyridine is removed under reduced pressure to dilute the mixture with water and extraction with ether (3 times). The combined extract was washed with diluted hydrochloric acid - aqueous solution of copper sulfate (3 times), dried with magnesium sulfate, filtered and concentrated to a crude viscous liquid, which is extracted with warm hexane (3 times). Dark orange viscous liquid (a 147.7 g, 84%) slowly hardens in 5aboutWith giving specified in the header And the connection, in the form of a light purple solid.

B) (3R-(1(S*), 3 , 4 ))-1-((1-benzyloxy - carbonyl-2-pyrrolidinyl)methyl)-1,3,4,5 - tetrahydro-3-hydroxy-4-(4-methoxyphenyl)- 6-(Tr is ahydro-3-hydroxy-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1-benzazepin-2-he (25 g, 71,2 mmol) and cesium carbonate (34.8 g, 106,7 mmol) in 200 ml of dimethylformamide is heated to 50aboutC. After 8 h add another connection header And (2.8 g, 7.2 mmol) and continue stirring for another 12 h, the Reaction mixture was cooled to room temperature, diluted with water and extracted 3 times with ethyl acetate. The combined extract was washed with 10% aqueous solution of lithium chloride (3 times), dried with magnesium sulfate, filtered and concentrated. The light yellow solid is triturated with 100 ml of ether for 30 min before adding 100 ml of hexane, and stirred for further 30 minutes Filtration gives 34,5 g is specified in the header connections, in the form of light yellow powder.

(C) (3R-(1)S*), 3, 4 )-1,3,4,5))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-1- (2-pyrrolidinyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it, monohydrochloride.

The solution of the substance from part b (35 g, 61,61 mmol) in 700 ml of absolute ethanol and 7 g of palladium hydroxide on coal is placed in shake a Parr autoclave and shaken under hydrogen pressure of 3.5 MPa for 1 hour and 40 minutes After pumping all of the hydrogen added anhydrous magnesium sulfate and filtered off the catalyst, sucking the reaction mixture. The solids on the filter, well washed with absolute floor the Aza with ethyl acetate. The combined extract is dried with magnesium sulfate, filtered and concentrated, obtaining a light yellow foam, which was dissolved in 350 ml of methanol and filtered. Add to 7.15 g (61,6 mmol) of fumaric acid and heated on the steam bath until the formation of homogeneous solution. The solution is allowed to cool, and during the night crystallization does occur.

The white crystalline substance is filtered and well washed with ethyl acetate, get 29,76 g (yield 88%) of fumaric salt specified in the connection header. This fumaric salt is converted into the free base by washing with a saturated aqueous solution of potassium bicarbonate and extraction with a mixture of ether/ ethyl acetate (3 times). To the free base dissolved in ether, is added an excess of ethereal solution of hydrogen chloride. A white precipitate collected and dried to obtain specified in the header connection (to 21.6 g, 100% yield from fumarata). So pl. 165-167aboutC [ ]D= +75,3about(C = 1.0 mol/l in methanol).

Calculated,%: C 57,07; H 5,72; N 5,79; Cl 7,32; F 11,78.

C23H25F3N2O3HCl 0,73 H2O.

Found,%: C 57,31; H 5,56; N 5,55; Cl 7,42; F A 12.03.

P R I m e R 36. (3R-(1(S*),3 ,4 ))-3-(the atomic charges)-1,3,4,5-tetrahydro-7-methoxime - XI-4-(4 - methoxyphenyl)-1-(2-dinyl)methyl)-1,3,4,5 - tetrahydro-3-hydroxy-4-(4-methoxyphenyl)- 7-(methoxyethoxy)-2H - 1-benzazepin-2-it.

A suspension of CIS-3-hydroxy-7-methoxyethoxy-4-(4-methoxyphenyl)-2H-1-benzene - pin 2-she (1.5 g, 4,37 mmol), anhydrous cesium carbonate (2,84 g is 8.75 mmol) and the connection specified in the header And example 35 (2.55 g, 6,56 mmol) in 50 ml of dimethylformamide is heated to 58aboutWith over 28 hours, the Reaction mixture was cooled, diluted with water and extracted 3 times with ethyl acetate. The combined extract was washed with 10% aqueous lithium chloride, dried with magnesium sulfate, filtered and concentrated give crude product. Was tested a number of silikagelevye speakers to highlight the desired (+) isomer, the connection specified in the header A. the First column elute with a mixture of 20% ethyl acetate in dichloromethane to highlight clean () diastereoisomer. The second column elute 1-10% ether in methylene chloride to obtain more mobile isomer of the compound indicated in the heading And (0,44 g, Rf ) of 0.64, eluent of 50% ether in methylene chloride, []D= +161,31about(=To 1.0, methanol)), less mobile isomer (0.08 g, Rf = 0,55, eluent 50% ether in methylene chloride, []D= 81,81about(C = 1.0 in methanol)) and some mixed fractions (0,57 g). In the final chromatographicaliy these mixed fractions and elution 4-10% ether in methylene chloride receive d the S*,3, 4 ))-1-(1-benzyloxycarbonyl-2-pyrrolidinyl)methyl)-3-(aceti - Loxy)- 1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-7-(methoxyethoxy)-2H-1 - benzazepin-2-it.

The connection specified in the header And (0,70 g, 1.25 mmol), 4-dimethylaminopyridine (0.31 g, 2.5 mmol) and acetic anhydride (0.64 g, 6.24 mmole) was stirred at room temperature in an argon atmosphere for 14 hours, the Reaction solution absorb silica gel (60-200 mesh) and chromatographic on a column of silica gel. When the elution of 20-40% ethyl acetate in hexane get the connection specified in the header, in the form of a white foam (0.74 g).

(C) (3R-(1(S*),3,4 ))-3-(the atomic charges)-1,3,4,5-tetrahydro-7-methoxyethoxy-4-(4 - methoxyphenyl)-1-(2-pyrrolidinyl)-2H-1-benzazepine-2-he, salt fumaric acid (1:1).

To a solution of the compound indicated in heading (0.64 g, of 1.06 mmole) in 10 ml of ethyl acetate and 0.4 ml triperoxonane acids are added with stirring to 130 mg of palladium hydroxide on carbon. The reaction vessel is connected with a balloon filled with hydrogen. The vacuum vessel under reduced pressure and filled with hydrogen. Then the mixture is intensively stirred at room temperature for 6 h to remove hydrogen and add anhydrous magnesium sulfate. Solids are removed by suction and filthaut in ethyl acetate. The organic layer was washed with an aqueous solution of potassium bicarbonate and distribute. The aqueous layer was extracted 2 times with ethyl acetate and the combined organic layers dried with magnesium sulfate, filtered and concentrated, obtaining the free amine as a pale orange foam (0.32 g). This free amine was dissolved in 20 ml of methanol and add to 79.3 mg (of 0.68 mmol) of fumaric acid, and stirred until the solution becomes homogeneous. When you get the specified concentration in the title compound (0,41 g) as a pale yellow foam with so pl. 126-130aboutC.

[ ]D= 89,7about(C = 1 mol/l in methanol).

Calculated,%: C Of 60.50; H 6,30; N 4,71.

C26H32N2O6C4H4O40,6 H2O.

Found,%: C 60,44; H 6,00; N 4,74.

P R I m e R 37. (3R-(1(2S*,4R*)-3,4 ))-1,3,4,5-Tetrahydro-3-hydroxy-4-(4-labels-Setenil)-1-((4 - phenylmethoxy(-2-pyrrolidinyl)methyl-6-(trifluoromethyl)-2H-1 - benzazepin-2-it, monohydrochloride.

A) (2S, 4R)-4-hydroxy-1-(tert-butoxycarbonyl)-2-pyrrolidinecarbonyl acid.

A suspension of 20.0 g (0,152 mol) of TRANS-4-hydroxy-Z-Proline and 38.0 g (0,174 mol) di-tert-BUTYLCARBAMATE in 250 ml of dioxane is slowly treated with 350 ml odnopolyarnogo of sodium hydroxide solution, per ml, then diluted with 150 ml of water. After washing with ethyl acetate, the aqueous layer was acidified with 6-normal hydrochloric acid and saturated with sodium chloride prior to the extraction with ethyl acetate (2 times). The organic solution was washed with water and brine, and evaporated, receiving of 30.9 g of compound indicated in the heading And in the form of a brown solid with so pl. 104-106aboutC.

Calculated,%: C 51,94; H 7,40; N 6,05.

C10H17NO5.

Found,%: C 51,31; H Of 7.55; N 5,67.

C) (2S, 4R)-4-(phenylmethoxy)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarbonyl acid.

Solution? 7.04 baby mortality g (ě 0.030 mol) of the compound indicated in the title And, and 5.2 g (0.30 mol) benzyl bromide (also responds well and benzyl chloride in 70 ml of dimethylformamide (in the bath with a temperature of -78aboutC) process of 0.38 g (0,009 mol) of a 60% dispersion of sodium hydride and stirred at room temperature for 3 h, then poured on ice. The solution is washed with ethyl acetate and acidified with it to pH 2 using 6-normal hydrochloric acid, saturated with sodium chloride. Extraction with ethyl acetate (2 times) gives 7,16 g of oil. Method flash chromatography using ethyl acetate receive 4.44 g of the compound indicated in the heading of the Century

Calculated,%: C 63,53; H 7,21; N 4,35.

Solution and 4.40 g (13 mmol) of the compound of the title) and 1.47 g (13 mmol) of ethylchloride in 65 ml of tetrahydrofuran (151) is treated dropwise with a solution of 1.40 g (13 mol) of triethylamine in 10 ml of tetrahydrofurane. After stirring for 1 h at room temperature the mixture is filtered directly into a three-neck flask. Stir the solution is treated dropwise with a solution of 0.75 g (20 mmol) of sodium borohydride in 8 ml of water. After 1 h the solvent is evaporated and the residue in ethyl acetate solution is washed odnomomentnoe hydrochloric acid, water, 1 N. a sodium hydroxide solution, water and brine. The dried solution is evaporated, receiving of 3.23 g of oil. Method flash chromatography using the eluent mixture of ethyl acetate and hexane 1:2 to obtain 2.76 g of the compound indicated in the heading, []D= -28,3about(C = 1,86, in chloroform).

D) (2S,4R)-4-(phenylmethoxy)-1-(tert-butoxycarbonyl)-2-methyl bromide) pyrrolidin.

A solution of 2.7 g (8,7 mmol) of the compound from header), 5.8 g a (17.4 mmol) chetyrehpostovye carbon and 4.5 g of a (17.4 mmole) of triphenylphosphine in 150 ml of ether is stirred over night at room temperature. The ether is decanted and the residual solid washed 2 times with hot hexane. Hexane extracts abhirama 2 times with boiling hexane. Oily residue after evaporation of the hexane dissolved in ethyl acetate and treated balcerowski silica gel (60-200 mesh). The solvent is evaporated, and the resulting powder was placed on a column with the same silica gel and elute with hexane to remove excess chetyrehpostovye carbon. Elution with a mixture of 1:2 ethyl acetate:hexane gives 2.3 g of target compound indicated in the title Doctor

[]D= -37,9about(C = 2,59, in chloroform).

(E) (3R-(1(2S*,4R*),3A,4A))-1-((1-(tert-butoxycarbonyl)-4- (phenylmethoxy)-2-pyrrolidinyl)methyl-3-hydroxy-1,3,4,5-tetrahed - ro - 4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it.

Mix a solution of 0.93 g (2.6 mmole) of (3-R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it in 10 ml of dimethylformamide is treated with 0.13 g (3.3 mmol) of potassium hydride (of 0.39 ml of a 35% suspension in oil). After 1 h a solution of 1.23 g (3.3 mmol) of the compound indicated in the heading On in 2 ml of dimethylformamide is gradually added to the reaction mixture, and then heated (oil bath temperature 60aboutC) for 18 hours, the Cooled mixture is diluted with ethyl acetate, washed 2 times with water and brine. After drying the solvent is evaporated and obtain 2.2 g of semi-solid material. This neo material. Method flash chromatography of the remaining solution in 400 ml of silica gel using the eluent is a mixture of 1:1.5 ethyl acetate:hexane get 0,57 g of compound indicated in the heading of the E, in the form of a glassy solid.

[]D= +116,9about(C = 1,95, in chloroform).

F) (3R-(1(2S*, 4R*), 3, 4 ))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-1-((4 - phenylmethoxy)-(2-pyrrolidinyl)methyl)-6- (trifluoromethyl)-2H-1 - benzazepin-2-it, monohydrochloride.

The compound from part E) of 0.85 g of 14.8 mmol) is dissolved in dichloromethane, containing 0.84 g (7.4 mmol) triperoxonane acid. The solution is stirred over night at room temperature. The solvent is evaporated. The residue is dissolved in toluene and the solvent is evaporated in vacuum to remove excess acid. A solution of the residue in ethyl acetate was washed with 1 N. solution hydroida sodium, water, and brine. The solution is dried and evaporated, to obtain 510 mg specified in the connection header in the form of oil

[ ]D= +137,0about(C = 1.0 mol/l in chloroform).

Calculated,%: C 66,65; H 5,77; N 5,18.

C30H31F3N2O4.

Found,%: C 65,13; H 5,69; N 5,04.

Above is dissolved in 15 ml of ether and treated with 1 equivalent of efern/SUP> (C = 1.15 mol/l in methanol).

Calculated,%: C 60,55; H To 5.93; N 4,70; Cl 5,95.

C30H31F3N2O4HCl.

Found,%: C 60,79; H 5,59; N 4,43; Cl 6,04.

P R I m e R 38. (3R-(1(2S*,4R*),3,4 ))-1,3,4,5-tetrahydro-3-hydroxy-1-((4-hydroc - C-2-pyrrolidinyl) methyl)-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

A suspension of 1.9 g (3.5 mmole) of the compound indicated in the heading of example 37, 25 ml of acetic acid is treated with 0.5 g of catalyst 10% palladium on coal and hydronaut at atmospheric pressure for 24 hours According to TLC (eluent 20% methanol in acetic acid) the reaction was completed approximately 6%. Add 0.2 g of catalyst and continuing the hydrogenation another 48 hours the catalyst is Filtered off and washed it with ethanol. The filtrate was concentrated in vacuo at 40aboutWith, the residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. This leads to the formation of a solid product which is insoluble in both phases. 1.3 g of this material was dissolved in 7 ml of hot ethanol and filtered through paper "hyflo (N 50). The solvent is evaporated, the residue is treated with acetonitrile with the formation of 0.77 g of colorless solid, so pl. 212-214aboutC []D= +74,1about(the m ethereal HCl solution. The solvent is evaporated, the residue is treated with acetonitrile to obtain and 0.61 g of colorless solid, so pl. 217-218aboutC []D= =+75,2about(C = 1.0 mol/l in methanol).

Calculated,%: C 55,21; H 5,54; N The Ceiling Of 5.60; Cl 7,09; F Is 11.39.

C23H25F3N2O4HCl 0,75 H2O.

Found,%: C 55,24; H 5,50; N 5,62; Cl 7,29; F 11,37.

P R I m e R 39. (3R-(1(2S*,4S*),3 ,4 ))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxy - phenyl)-1-((4-phenylmethoxy-2-pyrrolidinyl) methyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it, monohydrochloride.

A) (2S, 4S)-4-hydroxy-1-(tert-butoxycarbonyl)-2-pyrrolidinecarbonyl acid.

A solution of N-butoxycarbonyl-4-TRANS-hydroxy-Z-Proline (11,55 g, 0.05 mol) and triphenylphosphine (14.4 g, 55 mmol) in 450 ml of dry tetrahydrofuran in an argon atmosphere at 20aboutWith treated dropwise with a solution of diisopropylcarbodiimide (10.9 ml, by 0.055 mol) in 50 ml of tetrahydrofuran for 30 min, then stirred an additional 2 hours the Reaction mixture was concentrated in vacuo to a volume of 100 ml, then treated with 100 ml odnopolyarnogo of sodium hydroxide solution. After stirring for 15 minutes, the tetrahydrofuran is removed, and the remaining aqueous solution washed with ethyl acetate (pour). Water with ethyl acetate. The organic fraction was washed with brine, dried with magnesium sulfate and concentrated in vacuo, obtaining 13 g of viscous oil. When grinding with hot diisopropyl ether and cooling to obtain 10.2 g of the compound indicated in the heading A. T. pl. 147-148,5aboutC.

[ ]D= -47,1about(C = 0,92 mol/l in ethanol).

C) (2S,4S)-4-(phenylmethoxy)-1-(tert-butoxycarbonyl)-2 - pyrrolidinecarbonyl acid.

A solution of the compound indicated in the heading And (10,1 g that 43.8 mmol) and benzyl chloride (5,55 g that 43.8 mmol) in 60 ml of dried DMF (dimethylformamide) in an argon atmosphere cooled to -78aboutWith and treated immediately with sodium hydride (3.50 g, 87 mmol) (60% in oil). Remove the cooling bath, the reaction mixture is allowed to warm to room temperature and stirred her during the night. The mixture was poured on ice and washed 2 times with ethyl acetate. The basic aqueous solution is acidified to pH 2.0 sistermanns hydrochloric acid, saturated with sodium chloride and extracted 2 times with ethyl acetate. The organic fraction was washed with brine, combined and dried with magnesium sulfate. Concentrated in vacuo, getting to 18.6 g of oil. Method flash chromatography on 1700 ml of silica gel El-p-s-1 during the elution with a mixture of 200:1 ethyl acetate:acetic sour propilovogo ether gives of 7.75 g of this compound, with temperatures 110-111aboutC []D= -28,8about(C = 0,96, ethanol).

C) (2S-4S)-4-(phenylmethoxy)-1-(tert-butoxycarbonyl)-2 - pyrrolidineethanol.

A solution of compound from part b (of 7.75 g, 24 mmol) in ethylchloride in 150 ml of dry tetrahydrofuran in an argon atmosphere at 15-20aboutWith treated dropwise with a solution of triethylamine (2,44 g, 24 mmol) in 10 ml of tetrahydrofuran within 10-15 minutes After stirring for 2 h, the solids filtered and washed with fresh tetrahydrofuran. The combined filtrate and washings are cooled in a water bath at 15aboutC and treated dropwise with a solution of sodium borohydride (1,36 g, 36 mmol) in 10 ml of water. After stirring at room temperature for 4 h volatiles removed in vacuum and the residue dissolved in ethyl acetate, washed with 1 N. hydrochloric acid, water. 1 N. a sodium hydroxide solution, water and brine. Dried with magnesium sulfate the organic portion was concentrated in vacuo, obtaining 7.2 g of crude product. Method flash chromatography on 1 l of silica gel El-p-s-1, while elution with a mixture of 4 g of ethyl acetate:hexane (3:7) and 2 l of a mixture of ethyl acetate: hexane (1:1) get x 6.15 g of compound indicated in the heading, in the form of oil, []D= is 18.5aboutmethyl)pyrrolidin.

A solution of the compound indicated in heading (3.0 g, 9.6 mmol) in 15 ml of pyridine is treated with toluensulfonate (2,05 g of 10.7 mmol) and stirred under argon at room temperature over night. The reaction mixture was diluted with ethyl acetate and washed with 1 N. hydrochloric acid until the aqueous wash will not become acidic (3.4 times), then with water, sodium bicarbonate and brine. Dried with magnesium sulfate the organic portion was concentrated in vacuo, getting 4,55 g of oil. Method flash chromatography on 800 ml of silica gel El-p-s-1, while elution with a mixture of 1:4 ethyl acetate:hexane, gain of 3.9 g of compound header D.

[]D= -8,01about(C = 1,76, in chloroform).

(E) (3R-(1(2S*,4S),3, 4))-1-(1-(tert-butoxycarbonyl)-4-(phenylmethoxy)-2-pyrrole-dinyl) -methyl)-3-hydroxy-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1-benzazepin-2-it.

A solution of (3R-CIS))-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-he (2.35 g, 6.7 mmol) and the compound of the title (D) (3.50 g, 7.6 mmol) in 25 ml drained of dimethylformamide under argon is treated with cesium carbonate (3,26 g, 10.05 mmol), then heated at 50aboutWith during the night. The original benzazepin remains, although toilet consumed, and the mixture was stirred at 60aboutSee magnesium and concentrated in vacuo, getting to 4.87 g of oil. Method flash chromatography on 1000 ml of silica gel El-p-s-1, while elution with a mixture of 5:1 toluene:ethyl acetate, get to 3.36 g of compound indicated in the heading E, []D= +of 113.2about(C = 0.87 mol/l, chloroform).

F) (3R-(1(2S*,4S*),3 , 4 ))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-1-((4 - phenylmethoxy-2-pyrrolidinyl)methyl)-6- (trifluoromethyl)-2H-1 - benzazepin-2-it, monohydrochloride.

The compound from part E) (3.1 g, 4,84 mmol) dissolved in 10 ml dichloromethane and treated with 7.5 ml (0.1 mol) triperoxonane acid. The mixture is heated at the temperature of the beginning of the boil for 1 hour Volatile matter is distilled off in vacuo, the residue dissolved in ethyl acetate, washed with sodium hydrogen carbonate solution, water and brine. The organic portion is dried with magnesium sulfate, concentrated in vacuo, to obtain 2.5 g of oil, flash chromatography on 800 ml of silica gel El-p-s-1 during the elution with a mixture of ethyl acetate:methanol (93:7), gives 2,08 g specified in the connection header in the form of butter.

[]D= +141,1about(C = 0.88 mol/l, chloroform).

The above free base (700 mg, 1.3 mmol) dissolved in 15 ml of acetonitrile and treated with excess ethereal HCl solution. Volatile matter is distilled off in vacuum, the mod is.

[ ]D= +78,6about(C = 0.90 mol/l in methanol).

Calculated,%: C 62,03; H 5,63; N 4,82; Cl 6,10; F 9,81.

C30H31F2N2O4HCl 0,2 H2O.

Found,%: C 61,93; H 5,77; N 4,92; Cl 6,01; F 9,79.

P R I m e R 40. (3R-(1(2S*,4S*),3 ,4 ))-1,3,4,5-tetrahydro-3-hydroxy-1-((4-hydroc - C-2-pyrrolidinyl) methyl)-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

A solution of 1.25 g (2,31 mmol) of the compound indicated in the heading of example 39, in 15 ml of methanol containing 400 mg of the catalyst 10% palladium on coal, treated with 0.73 g (11.6 mmol) of ammonium formate, and the mixture is refluxed over night. According to TLC, the reaction was not completed. Additionally, add 0.2 g of catalyst and 0.3 g of ammonium formate and continue boiling for the night. The catalyst is filtered off through Celite, and the solvent is distilled off in vacuum. The residue is dissolved in ethyl acetate and washed with 1 N. a sodium hydroxide solution, water and brine. The organic portion is dried with magnesium sulfate, concentrated in vacuo; obtain 0.75 g of oil. Flash chromatography on 200 ml of silica gel El-p-s-1 (pre-treated with a mixture of 100: 1 methylene chloride:triethylamine), while elution with a mixture of ethyl acetate: methanol (95:5), tx2">

The above free base (480 mg, 1.06 mmol) dissolved in 10 ml of acetonitrile and treated with excess ethereal HCl solution, resulting in precipitation of the salt. This salt is collected, washed with acetonitrile and ether, dried in vacuum over phosphorus pentoxide at 100aboutWith getting 436 mg of the product so pl. 252-255aboutC. []D= +84,8about(=Of 0.56 mol/l in methanol).

Calculated,%: C 56,73; H 5,38; N 5,75; Cl 7,28; F 11,71.

C23H25F3N2O4HCl 0.5 H2O.

Found,%: C 56,55; H 5,26; N 5,70; Cl Of 7.48; F 11,74.

P R I m e R 41. (3R-(1(3S*,5S*),3 ,4 ))-1,3,4,5-tetrahydro-3-hydroxy-1-((5-(hydro-ximity)-3 - pyrrolidinyl)-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it, monopolar.

A) (2S,4R)-4-hydroxy-2-pyrrolidinecarbonyl acid, methyl ester.

To 70 ml of methanol is added slowly acetyl chloride (7,6 ml, 107 mmol). This reaction is exothermic. Add 10 g of (2S,4R)-4-hydroxy-2-pyrrolidinecarbonyl-howl acid (76,2 mmol) and the mixture is refluxed 4 hours After that add another portion of acetyl chloride (3 ml) in 30 ml of methanol. The mixture is boiled for another 3 hours, the Reaction mixture was cooled to room temperature and add 750 ml of diethyl ether. Formed bests,4R)-4-hydroxy-1-(phenylmethyl)-2-pyrrolidinylcarbonyl acid, methyl ether.

A mixture of compound from part a (11.85 g, to 65.2 mmol), triethylamine (18,55 ml, 130,04 mmol) and 15 ml of chloride gasoline (130,04 mmol) is refluxed in 60 ml dichloromethane within 7 hours the Formed suspension is partitioned between chloroform and 1 N. a solution of sodium hydroxide. The organic layer was washed with 1 N. sodium hydroxide, then with brine. The organic layer is then dried with sodium sulfate and concentrated. The crude residue is subjected to flash chromatography on a column of silica gel (h cm), which elute according to the following scheme: 1) 2 l dichloromethane; 2) 4 l of a mixture of 3% methanol in dichloromethane and 4 l of a mixture of 5% methanol in dichloromethane. Pure fractions are concentrated, receiving and 15.3 g of compound indicated in the title, in the form of a colorless oil.

C) (2S,4R)-4-hydroxy-1-(phenylmethyl)-2-pyrrolidineethanol.

Suspension of sociallyengaged (5 g, 126 mmol) in 250 ml of diethyl ether cooled to 0aboutC. are added dropwise the connection specified in the header, (9.88 g, 42 mmol), in solution in 150 ml of diethyl ether. After stirring 1 h at 0aboutC, the reaction gently stew by adding 5 ml water, 5 ml of 15% sodium hydroxide solution and 15 ml of water. After stirring 1 h poltrot concentrated and evaporated with toluene (2 times 100 ml), to get of 7.97 g of compound indicated in the heading, in the form of a colorless oil.

D) (2S,4R)-4-hydroxy-1-(phenylmethyl)-2-(tert-butyldiphenylsilyl) pyrrolidin.

tert-Butylchloroformate (11,05 ml, 42,5 mmol) are added dropwise to a solution of the compound indicated in the heading, (of 7.97 g of 38.5 mmol) in 20 ml of pyridine at 0aboutC. After stirring for 1 h the reaction mixture was partitioned between ether and water. The organic layer is washed 2 times with water (50 ml), dried with magnesium sulfate and concentrate. The crude residue is subjected to flash chromatography on a column (2,5x40) with silica gel, which elute first 2 l of methylene chloride and then with a mixture of 5% methanol in methylene chloride (2 l). Pure fractions are combined and mixed fractions again chromatographic in column (h cm) with silica gel, which elute with a mixture of 2% methanol in dichloromethane. All pure fractions are concentrated, receiving 9.88 g is specified in the header (D) connection.

E) (2S-4R)-4-((4-methylphenylsulfonyl)methyl)-1-(phenylmethyl)-2- (tert-butyldiphenylsilyl)pyrrolidin.

Para-toluensulfonate (3.1 g, 16.3 mmol) are added to a solution of compound from part D) (4,56 g, 10.9 mmol) in 12 ml of pyridine at 0aboutWith. POM solution of sodium bicarbonate and ether. The organic layer is dried with magnesium sulfate and evaporated. According to TLC significant number of connections from the header D) has not responded. The residue is again dissolved in 12 ml of pyridine and add 2 g of para-toluensulfonate (11 mmol). The reaction mixture is additionally stirred for 18 hours After the above processing receive crude residue (5.8 g) which is purified by the method of flash chromatography on silikagelevye column h cm (eluent is a mixture of 1:4 ethyl acetate and hexane). Pure fractions concentrated to obtain 4.44 g of the substance specified in the header of the E in the form of a light yellow oil.

F) (3R-(1(3S*, 5S*),3 ,4 ))-1-(5-(tert-butyldiphenylsilyl)-1-(penile - Tyl)-3 - pyrrolidinyl)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1-benzazepin-2-it.

A mixture of the compound indicated in heading (E), (3.0 g, 5 mmol), (3R-CIS)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1-benzazepin-2-it (1,58 g, 4.5 mmol) and cesium carbonate (7,34 g of 22.5 mmol) in 45 ml of distilled methyl ethyl ketone is refluxed for 18 hours, the Reaction mixture was cooled to room temperature, add 50 ml of ethyl ether and the suspension filtered through Celite. The cake on the filter well premiatii on silikagelevye column h cm, which elute with a mixture of 15% ethyl acetate in hexane. Pure fractions are concentrated, receiving 2.4 g specified in the header F) compound as a colourless foam.

G), (3R-(1(3S*, 5S*), 3 ,4 ))-1-(5-(hydroxymethyl)-1-(phenylmethyl)-3-pyrrolidinyl) -1,3,4,5 - tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it.

A solution of tetrabutylammonium fluoride (2.9 g, 9,18 mmole) in 15 ml of tetrahydrofuran is added to stirred solution of compound from part F (3,19 g of 4.17 mmol) in 35 ml of tetrahydrofuran. After stirring for 2 h the reaction mixture was diluted with 100 ml of ethyl ether, and the ether layer washed with 50 ml water and 50 ml brine. The organic layer is dried with magnesium sulfate and concentrate. The residue is purified by the method of flash chromatography on silikagelevye column 5x30 cm using a mixture of 5% methanol in dichloromethane as eluent. Pure fractions are combined and mixed fractions chromatographic again silikagelevye column 5x30 cm, using the following elution scheme: 1 l of dichloromethane, 1 l of a mixture of 1% methanol in dichloromethane, 1 l of 2% methanol in dichloromethane, 0.5 l of 3% methanol in dichloromethane and 0.5 l of a mixture of 5% methanol in dichloromethane. Pure fractions are concentrated, receiving 1,788 g specified in the header of the G-connect is l)-4-(4-methoxyphenyl)-6-(tri-vermeil)-2H-1 - benzazepin-2-it, monopolar.

The solution of the substance from part G (1.55 g, 2,87 mmol) in 30 ml of ethyl acetate hydronaut over the catalyst of 20% palladium hydroxide on coal 175 mg) for 24 h, using a balloon device. After that, according to TLC remained significant amount of starting material. Add another 175 mg of catalyst and continuing the hydrogenation period of 48 hours the Reaction is still not complete, so the reaction mixture was filtered through Celite and the cake on the filter, well washed with methanol (150 ml). The filtrate is concentrated to a dark residue is re-dissolved in 30 ml of methanol (fresh bottle). Added 370 mg of the catalyst and the mixture hydronaut, as indicated for 8 hours then the reaction mixture was filtered, and the filtrate concentrated. The residue is purified by chromatography on silikagelevye column h cm, using the following elution scheme: 2 l of a mixture of dichloromethane:methanol: triethylamine, 94: 5: 1, 1 l of a mixture of dichloromethane:methanol:triethylamine, 89:10:1. Pure fractions concentrated to a solid gray color, which when combined evaporation from a mixture of toluene:methanol = 1:1 (50 ml) and ethyl acetate: methanol = 1:1 (2 times 50 ml) to give 1.04 g specified in the connection header.

This free base (972 mignola. The solution is concentrated to a foam, which was dissolved in a mixture of methanol, isopropanol and ethanol and filtered through Celite. The filtrate is concentrated to a yellow crystalline substance, which is triturated with hot isopropanol, getting to 1.15 g is specified in the header of substance: white crystals with so pl. 212-214aboutC (decomposition), 168aboutWith (softening), 185about(Darkening).

TLC: Rf = 0,19 (eluent-dichloromethane:methanol:ammonium hydroxide = 95:4:1), free base

[]D= + 66,8about(C=1.0 mol/l in methanol).

Calculated,%: C 57,38; H 5,58; N Of 4.67; F Of 9.55.

C23H25F3N2O4C4H4O40.5 C3H8O.

Found,%: C 57,33; H 5,59; N 4,73; F 9,41.

P R I m e R 42. (3R-(1(3R*,5S*),3,4 ))-1,3,4,5-tetrahydro-3-hydroxy-1-((5-hydroc - simetal)-3 - pyrrolidin-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin - 2-it, monopolar.

F) (2S, 4S)-4-(phenylcarbamoyloxy)-1-(phenylmethyl)-2-(tert - butyldiphenylsilyl)pyrrolidin.

Diethylazodicarboxylate (2,80 ml, 16.3 mmol) added dropwise over 5 min to a stirred solution of compound from part D of example 41 (5 g, and 11.2 mmol), triphenylphosphine (to 4.41 g, a 16.8 mmol) and benzoic acid (3,14 g, 28 mmol) in 110 ml of tetrahydrofuran is of recarbonate sodium and ether. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrate. The remainder of the double cleanse method flash chromatography on silikagelevye column h cm (eluent is a mixture of 5:95 ethyl acetate and hexane). The most pure fractions concentrated to obtain of 3.97 g of the substance specified in the header And in the form of a light yellow oil.

C) (2S,4S)-4-hydroxy-1-(phenylmethyl)-2-(tert - butyldiphenylsilyl)pyrrolidin.

A mixture of compound indicated in the heading And (3,95 g, 7.2 mmol), 1 n sodium hydroxide solution (72 ml, 72 mmol), 72 ml of tetrahydrofuran and 72 ml of methanol is refluxed for 1 h, the Reaction mixture was distributed between ethyl acetate and brine. The organic layer was washed with brine, dried with magnesium sulfate and concentrate. The residue is subjected to flash chromatography on a column (5 × 20 cm) with silica gel, which elute with a mixture of ethyl acetate:hexane (1:3). Pure fractions are concentrated, receiving 1.85 g is specified in the header) connection in the form of a colorless oil.

C) (2S, 4S)-4-((4-methylphenylsulfonyl)methyl)-1-(phenylmethyl)-2- (tert-butyldiphenylsilyl)pyrrolidin.

The mixture of steam-toluensulfonate (1.2 g, of 6.25 mmol) and the compound from part b) (1.85 g is sasenum solution of sodium bicarbonate and ethyl ether. The organic layer was washed with brine, dried with magnesium sulfate and evaporated. The residue is purified by the method of flash chromatography on silikagelevye column h cm (eluent is a mixture of 1:9 ethyl acetate and hexane). Pure fractions concentrated to obtain 2.3 g of the substance specified in the header, in the form of a colorless oil.

D) (3R-(1(3E*, 5S*), 3 , 4 ))-1-(5-(tert-butyldiphenylsilyl)-1-(penile - Tyl)-3 - pyrrolidinyl)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)- 6-(trifluoromethyl)-2H-1-benzazepin-2-it.

The mixture of compounds specified in the header), (2.0 g, to 3.33 mmol), (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-she (1.2 g, of 3.33 mmol), cesium carbonate (5.4 g, and 16.7 mmol) and 30 ml of methyl ethyl ketone is refluxed for 20 hours, the Reaction mixture was cooled to room temperature and add 50 ml of ethyl ether. The resulting thick suspension was filtered through Celite, and the filtrate concentrated to dryness. The residue is purified by the method of flash chromatography on silikagelevye column h cm, which elute the mixture of ethyl acetate and hexane (1:4). Pure fractions are concentrated, getting 980 mg specified in the title D compound. The concentration of mixed fractions give 800 mg of impure material, which popcorn is, 1 l of 25% ethyl acetate in hexane. Pure fractions combined with those of the first column and obtain 1.45 g specified in the title compounds as colorless oils.

(E) (3R-(1(3R*,5S*),3 , 4 ))-1-(5-(hydroxymethyl)-1-(phenyl-methyl)-3-pyrrolidinyl)- 1,3,4,5 - tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it.

Odnokorennye fluoride solution of Tetra-n-butylamine (the 3.65 ml, 3.65 mmol) are added to a solution of compound from part D (1,395 g and 1.83 mmol) in 20 ml of tetrahydrofuran at room temperature. After stirring for 1 h the reaction mixture was diluted with 50 ml of ethyl ether and the ether layer washed with 50 ml of water. After washing with brine and drying with magnesium sulfate, the filtrate concentrated to a yellow foam. The residue is purified by the method of flash chromatography on silikagelevye column 5x30 cm using a mixture of ethyl acetate: hexane = 3:1 as eluent. Pure fractions are concentrated, getting 0.85 grams specified in the title E compound, as a white foam.

F) (3R-(1(3R*, 5S*), 3 , 4 ))-1,3,4,5-tetrahydro-3-hydroxy-1-((5-hydroxymethyl)-3 - pyrrolidinyl)-4-(4-methoxyphenyl)-6-(tri-vermeil)-2H-1-benzazepin - 2-it, monopolar.

A mixture of substances from part E (0,80 g, 1.48 mmol) and catalyst (20% palladium hydroxide Navo. The catalyst was removed by filtration through Celite, and the cake on the filter is washed with acetic acid (20 ml). When removing the acetic acid in vacuo receive the oil which is partitioned between saturated sodium carbonate solution and ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated to a white foam. This foam is cleaned by the method of flash chromatography on silikagelevye column (5 × 20 cm, using the following elution scheme: 1 l of a mixture of 5% methanol in dichloromethane, 1 l of 10% methanol in dichloromethane, 2 l, 15% methanol in dichloromethane and 0.5 l of a mixture of 1:1 methanol:dichloromethane. Pure fractions are concentrated, getting 595 mg specified in the title compound, as a white foam.

This free base (405 mg, 0.9 mmol) dissolved in 3 ml of methanol and add a solution of 104 mg (0.9 mmol) of fumaric acid in hot methanol (2 ml). The resulting solution was concentrated to a solid which is triturated in ether and dried at 50aboutC and a pressure of 0.5 mm RT.art., getting 532 mg specified in the header of a substance is a white powder with so pl. 121-130aboutC (decomposes).

[ ]D= +68,0about(C = 0.54 mol/l in methanol).

Calculated,%: C 54,78; H 5,42; N 4,72; F 9,63.

C28

A) 2-Chloromethylthiazole.

To a chilled solution of the hydrochloride of 2-chloromethylketone (3 g, and 19.4 mmol) (preparation described in the journal Halh.Chim. Acta v. 27, 1773, 1944) in 5 ml of water, add about 75 ml of anhydrous ethyl ether. To this solution is added an excess of solid potassium carbonate and the resulting mixture is stirred for 10 minutes the Ether layer is decanted and the remaining suspension is washed 4 times in about 75 ml of anhydrous ethyl ether. The ether layers are combined and dried over anhydrous magnesium sulfate. Distillation of the solvent in vacuo gives 1,89 g of compound indicated in the heading And in the form of a white foam with so pl. 63-64aboutC.

B) (3R-CIS)-1-((4,5-dihydro-1H-imidazol-2-yl)methyl-1,3,4,5-tetrahydro - 3-hydroxy-4-(4-methoxyphenyl)-6-trifluoromethyl)-2H-1-benzazepin-2-it.

A solution of (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it (4.44 g, 12.6 mmol) and 0.62 g (of 15.5 mmol) of a 60% dispersion of sodium hydride in mineral oil in 70 ml of dry dimethylformamide (dried over sieves 4A) is heated at 70aboutWith 30 minutes Then add 2-chloromethylthiazole (1.08 g, 9,1 th water. The organic layers are combined, dried over anhydrous magnesium sulfate and then evaporated in vacuum, obtaining a yellowish residue. This residue is dissolved in ethyl acetate and subjected to flash chromatographicaliy (800 ml of silica gel pre-treated with a solution of 10:1:1 ethyl acetate:methanol-triethylamine). Elution with a mixture of 10:1:0.1 ethyl acetate /methanol/triethylamine gives to 2.55 g of compound indicated in the title, []D= +116,5about(C = 1.07, and methanol).

(C) (3R-CIS)-1-((4,5-dihydro-1H-imidazol-2-yl)methyl)-1,3,4,5 - tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6-trifluoromethyl)-2H-1 - benzazepin-2-it, monohydrochloride.

A solution of compound from part b (1,02 g, 2.5 mmol) in 30 ml of acetonitrile is treated with excess ethereal HCl solution. The solvents are removed by evaporation in vacuo and the residue triturated with anhydrous ethyl ether, receiving specified in the header of the connection (of 1.03 g). This compound (0.96 g, 2.04 mmol) is recrystallized from dichloromethane and diisopropyl ether, receiving 0,86 g specified in the connection header with so pl. 128-130aboutC. []D= +90,6about(C = 0,98, methanol).

Calculated,%: C 53,77; H To 5.21; N 8,55; Cl 7,21; F 11,60.

C22H22F3N3O3HCl 1,2 H2O.

Found, the XI-7-(methoxyethoxy)-4-(4-methoxyphenyl)-2H-1-benzazepin - 2-it, monopolar.

Specified in the title compound is prepared using the procedure described in example 43, but at the stage In this example, replace (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-trifluoromethyl)-2H-1 - benzazepine-2, CIS-3-hydroxy-7-methoxyethoxy-4-(4-methoxide - nil)-2H-1 - benzazepine-2, So pl. 200-210aboutC (decomposes).

Calculated,%: C 58,28; H 5,91; N 7,55.

C23H27N3O5C4H4O40,83 H2O.

Found,%: C 58,46; H 5,73; N 7,37.

P R I m e R 45. (3R-CIS)-1,3,4,5-tetrahydro-3-hydroxy-1-((1H-imidazol-2-yl)methyl)- 4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it, monohydrochloride.

A) (3R-CIS)-1-((1H-3-phenylmethyl-imidazol-2-yl)methyl)-1,3,4,5 - tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6-trifluoromethyl)-2H-1 - benzazepin-2-it.

A solution of (3R-CIS(-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it (2,02 g, 5,74 mmol), 1-phenylmethyl-2-chloromethyl-imidazole hydrochloride (1,67 g, 6,87 mmol) (preparation described in the journal of the IACS, volume 71, C. 383, 1949) and 60% dispersion of sodium hydride in mineral oil (0,59 g of 14.8 mmol) leave much to be mixed during the night.

The reaction stew by adding 1 N. hydrochloric acid and then neutralized with 50% hydroxide solution is to see twice (50 ml), saturated solution of sodium bicarbonate, then 2 times (50 ml) and brine. The solvent is removed in vacuum, obtaining a reddish-brown oil. Flash chromatography on 800 ml of silica gel El-p-s-1, using a 20: 1 mixture of ethyl acetate and methanol gives 1,11 g of compound indicated in the title And in the form of a solid white foam, []D= +105,0about(C = a 1.01, methanol).

B) (3R-CIS)-1-((1H-imidazol-2-yl)methyl)-1,3,4,5-tetrahydro-3-hydroxy - 4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzene-pin-2-it.

A solution of the compound of the title (1,09 g of 1.95 mmol) in 0.24 g of catalyst (10% palladium on coal in 5 ml of 96% alcohol hydronaut at atmospheric pressure during the night.

The reaction mixture was filtered, and the solvents removed in vacuo. The residue is dissolved in ethyl acetate and washed with a solution of 1 N. a solution of sodium hydroxide. The aqueous phase is extracted three times with ethyl acetate. The combined organic layers dried with magnesium sulfate and concentrated in vacuo to obtain 666 mg of the compound of the title In the form of a solid white foam.

(C) (3R-CIS)-1,3,4,5-tetrahydro-3-hydroxy-1-((1H-imidazol-2-yl)methyl)- 4-(methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzene-pin 2-he, monohydrochloride.

A solution of the compound of the title (0.52 g, to 1.21 mmol) in acetonitrile is treated istwo. His triturated with isopropyl ether and dried in vacuum over phosphorus pentoxide at 100aboutTo receive 0.45 g specified in the connection header.

So pl. 188-191aboutC.

[ ]D= +101,0about(=Of 1.02, methanol).

Calculated,%: C 56,03; H 4,58; N 8,91; Cl 7,52; F 12,09.

C22H20F3N3O3HCl 0,2 H2O.

Found,%: C 56,20; H 4,35; N 8,92; Cl 7,15; F 11,71.

P R I m e R 46. (2R-(2a,3a,5(R*)))-3-(atomic charges)-2,3-dihydro-2-(4-methoxyphenyl)- 5-(2-pyrrolidinyl)-1,5-benzothiazepin-4(5H)-he, monohydrochloride.

A) S-1-(tert-butoxycarbonyl)-2-((4-methylphenylsulfonyl)methyl) pyrrolidone.

To S-1-(tert-butoxycarbonyl)-2-pyrrolidineethanol (20.6 g, is 102.4 mmol) in 100 ml of pyridine at room temperature in the argon added under stirring para-toluensulfonate (23,4 g, 122,8 mmol). After 5 h add more of 9.8 g (a 51.2 mmol) para-toluensulfonate. After a total stirring for 23 h, the reaction mixture was diluted with ethyl acetate and washed her with a saturated solution of copper sulphate in water (3 times). The organic layer is dried with magnesium sulfate, filtered and concentrated. Yellow liquid chromatographic on a column of silica gel, which elute 10-30% ethyl acetate in

C) (2S-(2 ,3 ,5(R*)))-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-(1-(tert - butoxycarbonyl)-2-pyrrolidinyl)methyl)-1,5-Ben zodiazepine-5-(5H)-he.

(2S-CIS)-2,3-dihydro-3-hydroxy-2-(4 - methoxyphenyl)-1,5 - benzothiazepin-4(5H)-on (of 3.56 g, 11,81 mmol), cesium carbonate (5,77 g, 17,72 mmol) and the compound indicated in the heading And (6,30 g, 17,72 mmol) in 40 ml of dimethylformamide is heated to 50aboutC. After 16 h, the reaction mixture was cooled to room temperature, diluted with water and extracted with ether (3 times). The combined extracts are washed 3 times with 10% aqueous lithium chloride, dried with magnesium sulfate, filtered and concentrated. Yellow foam chromatographic on a column of silica gel. Elution 10-25% ethyl acetate in hexane gives 4,51 g of compound indicated in the title, in the form of a yellow foam.

C) (2S-(2 , 3 , 5(R*)))-2, 3-dihydro-3-(atomic charges)-2-(4-methoxyphenyl)-5-(1-(tert - butoxycarbonyl)-2-pyrrolidinyl)methyl)-1,5 - benzothiazepin-4-(5H)-he.

The connection specified in the header (1.0 g, to 2.06 mmol) 4-dimethylaminopyridine (0.50 g, 4,13 mmol) and acetic anhydride (1,05 ml of 10.3 mmol) in 20 ml of dichloromethane is stirred at room temperature under argon for 15 hours, the Reaction solution was absorbed on silica gel (60-200 mesh) and chromatographic on Colangelo.

D) (2S-(2 , 3 ,5(R*)))-3-(atomic charges)-2,3-dihydro-2-(4-methoxyphenyl)-5-(2 - pyrrolidinyl)-1,5-benzothiazepin-4-(5H)-he, monohydrochloride.

The connection specified in the header (0.84 g, to 1.60 mmol) in 5 ml triperoxonane acid and 5 ml of dichloromethane is stirred under argon at room temperature for 1 h, the Reaction solution is concentrated under reduced pressure, then diluted with an aqueous solution of potassium bicarbonate and extracted 3 times with ethyl acetate. The combined extracts are dried with magnesium sulfate, filtered and concentrated. The yellow foam was dissolved in ethyl acetate and added an excess of ethereal HCl solution. Concentration, followed by rubbing in 50 ml of ether gives 0.75 g specified in the title compound as a white foam with so pl. 132-135aboutC []D= +66,06about(C = 1 methanol).

Calculated,%: C 58,01; H 6,03; N 5,88; Cl 7,44; 6.73 X.

C23H26N2O45 HCl 0,73 H2O

Found,%: C 58,00; H The 6.06; N Of 5.89; Cl 7,18; 6,48.

P R I m e R 47. (2S-(2 , 3 ,5(R*)))-3-atomic charges)-2,3-dihydro-8-methoxy-2-(4-labels - Setenil)- 5-(2-pyrrolidinyl)-1,5-benzothiazepin-4(5H)-he, monohydrochloride.

The connection specified in the header, prepared using the method of example 46, but replacing in part b of this example (2-Cys)e - toxi-1,5 - benzothiazepin-4(5H)-he so pl. 147-154aboutC [ ]D= +50,0about(C = 1, methanol).

Calculated,%: C 56,63; H 6,09; N 5,51; Cl 6,97; S 6,30.

C24H28N2O5S HCl 0,89 H2O.

Found,%: C 56,72; H 5,94; N 5,42; Cl 7,15; S 6,30.

P R I m e R 48. (2S-(2 ,3 ,5(R*)))-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-(2 - pyrrolidinyl)-1,5-benzothiazepin - 4(5H)-he, monohydrochloride.

A) (2S-(2 ,3 ,5(R*)))-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-(1- (benzyloxycarbonyl)-2-pyrrolidinyl)methyl)-1,6-Ben zodiazepine - 4*5H)-he.

(25-CIS)-2,3-Dihydro-3-hydroxy-2-(4 - methoxyphenyl)-1,5 - benzothiazepin-4(5H)-he (1,25 g, 4,15 mmole), cesium carbonate (2,03 g, from 6.22 mmol) and 5-1(benzyloxycarbonyl)-2-((4-methylphenylsulfonyl)-methyl) pyrrolidin (2,02 g, 5,19 mmole) in 20 ml of dimethylformamide is heated to 50aboutC. After 23 h, the reaction mixture was cooled to room temperature, diluted with water and extracted 3 times with ether. The combined extract is washed with 3 times 10% solution of lithium chloride in water, dried with magnesium sulfate, filtered and concentrated. Viscous yellow oil chromatographic on a column of silica gel, which elute 15-30% ethyl acetate in hexane, receiving a substance specified in the header And (1,74 g), in the form of a white solid.

C) (2S-(2A, 3A,5(R*)))-2,3-dihydr inania, specified in the header And (1.2 g, 2,31 mmol), 1.2 g of catalyst (10% palladium on coal (100 wt%) and ammonium formate (1.2 g, 19.0 mmol) in 40 ml of methanol is heated to boiling. After 5 h add another 0.6 g of catalyst and continue stirring for another 19 hours the Reaction mixture is cooled to room temperature before filtering add anhydrous magnesium sulfate. Solids are well washed with methanol. The filtrate is concentrated, and the residue was diluted with saturated aqueous potassium bicarbonate and extracted 3 times with ethyl acetate. The combined extract is dried with magnesium sulfate, filtered and concentrated to obtain a pale yellow foam, which dissolve accelerate in dichloromethane. To the solution is added an excess dissolved in ether HC l. Removal of volatile compounds under reduced pressure, followed by rubbing the solid residue in a mixture of 2:1 ether:dichloromethane, gives specified in the title compound (0.35 g) - amorphous solid white. So pl. above 240aboutC (decomposes).

[]D= +to 91.6about(C = 1, methanol).

Calculated,%: C 58,26; H The 6.06; N 6,47; Cl 9,01; S 7,41.

C21H24N2O3S 1,1 HCl 0,46 H2O.

Found,%: C 58,45; H 5,76; N 6,28; Cl 9,35; S 7,41.

P R I m e R 49. (2S-hidrochloride.

A) (2S-(2,3 ,5(R*)))-2,3-dihydro-3-(2-methyl-1-oxopropoxy))-2-(4-methoxyphenyl)- 5-(1-(tert-butoxycarbonyl)-2-pyrrolidinyl) methyl)-1,5-benzothiazepin - 4(5H)-he.

A solution of (2S-(2A,3A,5(R*)))-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-(1- (tert-butoxycarbonyl)-2-(pyrrolidinyl)methyl)-1,5-benzothiazepin - 4(5H)-it (847 mg, about 1.75 mmol), N,N-dimethylaminopyridine (427 mg, 3.5 mmol) and the anhydride somaclonal acid (600 mg, 3.6 mmole) in dichloromethane (25 ml) stirred at room temperature for 3 hours, the Reaction mixture was concentrated under reduced pressure and the residual oil chromatographic on a column of silica gel. When the elution of 10-20% ethyl acetate in hexane obtain 870 mg of the compound indicated in the heading And in the form of a white foam.

C) (2S-(2a, 3a,5 (R*)))-2,3-dihydro-2-(4-methoxyphenyl)-3-(2-methyl - 1-oxopropoxy)-5-(2-pyrrolidinyl)-1,5-benzothiazepin - 4(5H)-he, monohydrochloride.

The connection header (1,02 g of 1.84 mmol) in 5 ml dichloromethane and 5 ml triperoxonane acid is stirred at room temperature for 15 minutes Then the reaction mixture was concentrated under reduced pressure and the resulting residue is dissolved in ethyl acetate and washed with saturated aqueous potassium bicarbonate. The aqueous layer was extracted 3 times with ethyl acetate and objectiveview on a column of silica gel (pretreated with 1% of triethylamine) and elute with a mixture of 7% methanol in dichloromethane. The free amine was dissolved in ether and converted into hydrochloric salt by adding an excess of ethereal solution of hydrogen chloride. When the concentration get a pale yellow foam which is triturated thoroughly with ether and filtered. The output specified in the connection header is 0.70 g of a yellow solid substance with so pl. 197-199aboutC (decomposes).

[ ]D= +34,86about(C = 1, methanol).

Calculated,%: C 60,47; H 6.42 Per; N 5,64; Cl 7,14; S 6,46.

C25H30N2O4S HCl 0,3 H2O.

Found,%: C 60,32; H 6,38; N 5,76; Cl 6,80; S 6,55.

P R I m e R 50. (2S-(2A,3A,5(R*)))-2,3-dihydro-2-(4-methoxyphenyl)-3-((methyl-amino) carbonyl)oxy-5-(2-pyrrolidinyl)- 1,5-benzothiazepin-4(5H)-he, monohydrochloride.

A) 2S-(2a, 3a, 5(R*)))-2,3-dihydro-3-(((methylamino)carbonyl)-oxy)-2- (4-methoxyphenyl)-5-(1-(1-(tert-butyloxycarbonyl)-2-PIR rollitini) methyl)-1,5-benzothiazepin-4(5H)-he.

To a solution of (2S-(2A,3A,5(R*)))-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-(1- (tert-butoxycarbonyl)-2-pyrrolidinyl)-methyl)-1,5-benzothiazepin - 4(5H)-she (1.0 g, to 2.06 mmole) in 15 ml of anhydrous dichloromethane at 0aboutWith added under stirring 116 ml (about 0.82 mmole) and to 0.19 g of methyl isocyanate (3,30 mmole). The reaction mixture is allowed to warm to room school for 5 hours Add water, the aqueous mixture is extracted 3 times with ethyl acetate. The combined organic extracts are dried with magnesium sulfate, filtered and concentrated. The crude white foam chromatographic on a column of silica gel and elute with a mixture of 10-20% ethyl acetate in hexane, to obtain 0,89 g of compound indicated in the heading And in the form of a white foam.

C) (2S-(2a, 3a,5(R*)))-2,3-dihydro-2-(4-methoxyphenyl)-3-(((methylamino) carbonyl)oxy)-5-(2-pyrrolidinyl)-1.5-benzothia - zipin-4(5H)-he, monohydrochloride.

Specified in the header And the connection (0,89 g of 1.64 mmol) in 5 ml dichloromethane and 5 ml triperoxonane acid is stirred at room temperature for 30 minutes, the Reaction mixture was concentrated and the resulting residue is dissolved in ethyl acetate and washed with saturated aqueous potassium bicarbonate. The organic layer is separated and the aqueous layer was extracted 2 times with ethyl acetate. The combined organic layers dried with magnesium sulfate, filtered and concentrated. The free base is dissolved in ether with minimal addition of ethyl acetate to provide a homogeneous solution. Add an excess of ethereal HCl and the volatiles removed under reduced pressure to obtain 0.66 g is specified in the header of the LASS="ptx2">

Calculated,%: C 55,70; H 6,10; N Of 8.47; Cl 7,15; S 6,46.

C23H27N3O4S HCl 1,0 H2O.

Found,%: C 65,79; H Of 5.81; N 8,49; Cl 7,03; S 6,50.

P R I m e R 51. (3R-(1(S),3 ,4 ))-3-(the atomic charges)-1,3,4,5-tetrahydro-7-methoxy-4- (4-methoxide - nil)- 1-(2-pyrrolidinyl)-2H-1-benzazepin-2-it, monohydrochloride. Specified in the title compound is prepared using the method of example 13, using CIS-3-hydroxy-7-methoxy-4-(4-methoxyphenyl)-2H-1-Ben-Zacepin-2-it, so pl. above 250aboutC.

[ ]D= +92,17about(C = 1.0 mol/l in methanol).

Calculated,%: C 62,74; H Is 6.61; N 5,86; Cl 7,41.

C25H30N2O5HCl 0,2 H2O.

Found,%: C 62,88; H 6,70; N 6,04; Cl 7,26.

P R I m e R 52. (2S-(2 ,3 ))-2,3-dihydro-5-(4,5-dihydro-1H-imidazol-2-yl)methyl)-3 - hydroxy - 2-(4-metoxyphenyl)-1,5-benzothiazepin-4(5H)-he, monohydrochloride.

Specified in the title compound is prepared using the method of example 43, using (2R-CIS)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5 - benzothiazepin-4(5H)-he. The product crystallizes from ethanol. So pl. 252about(Razlog.).

[ ]D= +94,0about(C = 1.0 mol/l in methanol).

0,28 (eluent - 18:1:1 dichloromethane:methanol:acetic acid).

Calculated,%: C 55,53; H the 5.45; N 9,71; Cl 8,20; S 7 CLASS="ptx2">

P R I m e R 53. (2S-(2 ,3 ))-3-the atomic charges)-2,3-dihydro-2-(4-methoxyphenyl)-5-(2 - pyridinylmethyl)-1,5-benzothiazepin-4 (5H)-he, monohydrochloride.

Specified in the title compound is prepared by heating the compound indicated in the title of example 23, with acetic anhydride, 3 hours at 110-115aboutC. the Colorless product is crystallized from acetonitrile, so pl. 200-202about(Razlog.).

[ ]D= +137,0about(C = 1.0 mol/l in methanol).

Calculated,%: C 57,88; H 5,26; N 5,63; Cl 7,12; S 6,44.

C24H22N2O4S HCl for 1.5 H2O.

Found,%: C 59,09; H 5,20; N 5,62; Cl Of 7.48; S 6,52.

P R I m e R 54. (3R-CIS)-3-(atomic charges)-1-((4,5-dihydro-1H-imidazol-2-yl)methyl)- 1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1 - benzazepin-2-it, monohydrochloride.

A) (3R-CIS)-1-((4,5-dihydro-1-(tert-butoxycarbonyl)-imidazol-2-yl) methyl)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)- 6- (trifluoromethyl)-2H-1-benzazepin-2-it.

A solution of the compound indicated in the heading of example 43, (a 3.83 g, 8,84 mmol) in 30 ml of dried methylene chloride is treated with tert-butoxycarbonylamino (2,77 g, 12.7 mmole) (1.4 EQ.) and dimethylaminopyridine (0.11 g, 0.9 mmole). The solution is stirred over night. The reaction mixture was concentrated to a volume of about is the quality of the driving phase mixture 2:1 hexane and ethyl acetate. When removing solvents in vacuo obtain 1.51 g of the compound indicated in the heading And in the form of a white solid foam, so pl. 114-116aboutC.

B) (3R-CIS)-3-(atomic charges)-1-((4,5-dihydro-1-(tert-butoxycarbonyl)- imidazol-2-yl)methyl)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1-benzazepin-2-it.

A solution of the compound indicated in the heading And (1.50 g, 2.8 mmole) in 30 ml of dried dichloromethane is treated with acetic anhydride (1.66 g, 16.2 mmol, 5.8 EQ) and dimethylaminopyridine (0.68 g, 5.7 mmol, 2 EQ.). The solution is stirred over night. The reaction mixture absorb approximately 30 ml of Celite and chromatographic 350 ml silica gel l-p-s-1-eluent is a mixture of 1.5:1:0,1 - hexane:ethyl acetate:methanol). When removing solvents under vacuum remains 0.96 g of the compound indicated in the title, in the form of a white foam with so pl. 105-108aboutC.

(C) (3R-CIS)-3-(atomic charges)-1-((4,5-dihydro-1H-imidazol-2-yl)methyl)- 1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6-trifluoromethyl)-2H-1 - benzazepin-2-it, monohydrochloride.

A solution of the compound indicated in heading (0.87 g, 1.5 mmole) in 10 ml of dried dichloromethane is treated with 10 ml triperoxonane acid. The reaction mixture was stirred 2 h at room temperature. The solvents are removed in vacuo the potassium carbonate and then brine. The organic layer is dried over magnesium sulfate and the solvents removed in vacuum, obtaining of 0.77 g of white foam with so pl. 109-111aboutC. the Solution is specified free base (0.74 g, 1.6 mmole) in ethyl acetate is treated with excess HCl in ether. The resulting solid is collected and washed 4 times with ethyl acetate. The solid is dissolved on the filter with acetonitrile and the solvent removed in vacuum, obtaining 0,42 g (51%) indicated in the title compounds as white solids with so pl. 260-261aboutC.

[]D= +84,6about(=1,11, in methanol).

Calculated,%: C 53,72; H 5,04; N 7,83; Cl To 10.62; F 6,61.

C24H24F3N3O4HCl 1,43 H2O.

Found,%: C 53,87; H 5,14; N 7,68; Cl 10,70; F 6,79.

P R I m e R 55. (3R-CIS)-1-((4,5-dihydro-1H-imidazol-2-yl)methyl)-1,3,4,5 - tetrahydro-3-hydroxy-7-methoxy-4-(4-methoxide - nil)-2H-1 - benzazepin-2-it, monohydrochloride.

A) (3R-(3A, 4A, 3S*))-3-(2-benzyloxycarbonylamino)-propionyl 1,3,4,5-tetrahydro-7-methoxy-4-(4-methoxyphenyl)-2H-1 - benzazepin-2 - it (7,24 g, 23.1 mmole) in 70 ml of tetrahydrofuran is treated 2S-N-carboninternational.com (at 8.60 g, 28,88 mmole) and then a water-soluble carbodiimide (8,82 g and 46.2 mmole). After 1 h, add N,N-dimethyl mesh add 250 ml of ether and filtered. The filtrate is washed (250 ml - portions): odnomomentnym aqueous solution of hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The remainder chromatographic on a column of silica gel, which elute with a mixture of 50 to 75% ethyl acetate and hexane, then ethyl acetate to obtain 10.5 g of a white foam. This foam is additionally chromatographic and elute with 50% ethyl acetate in hexane, obtaining 4.4 g diastereomer (3S-CIS)-product and 4.6 g of 3R-CIS-isomer connection header A.

B) (3R-CIS)-1,3,4,5-tetrahydro-3-hydroxy-7-methoxy-4-(4 - methoxyphenyl)-2H-1-benzazepin-2-it.

Stir a suspension of the compound indicated in the heading And (4.6 g, 7,73 mmol) in 85 ml of methanol is treated with a 25% solution of sodium methoxide in methanol (5,52 ml, 23,19 mmole). Within 5-10 min all solids into solution. After 30 min the mixture was poured into 250 ml of normal acid solution and extracted 3 times with ethyl acetate. An ethyl acetate extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue is ground to powder in a mixture (1:1) of ethyl acetate and hexane, the solid precipitate is filtered off, dried in vacuum, obtaining 1.73 g connection, MC is the ROI elute with a mixture of 50-75% ethyl acetate in hexane, in order to additionally obtain 350 mg of the product specified in the header, in the form of a white solid with so pl. 171-173aboutC []D= =187about(C = 0.55 mol/l in methanol).

(C) (3R-CIS)-1-((4,5-dihydro-1H-imidazol-2-yl)methyl)-1,3,4,5 - tetrahydro-3-hydroxy-7-methoxy-4-(4-methoxyphenyl)-2H-benzo - zipin - 2-it, monohydrochloride.

Sodium hydride (100 mg, 4,14 mmole) is added with stirring to a solution of the compound indicated in the heading, (1.08 g, 3.45 mmole) in 15 ml of dry dimethylformamide. After 30 minutes add 490 mg (4,14 mmole) of 2-chloromethylketone. The mixture is stirred at room temperature for 1.5 h and then cooled rapidly by the addition of water. The mixture is extracted 3 times with ethyl acetate. An ethyl acetate extracts are combined and washed 3 times with 10% aqueous solution of lithium chloride. Then an ethyl acetate extract is washed with diluted hydrochloric acid and water. Water extracts combined alkalinized solid potassium bicarbonate and extracted 5 times with methylene chloride. Chlormethiazole extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated, obtaining of 1.32 g of the free base of the compound indicated in heading (white solid). The solution of this free basis is hydrogen. Precipitated white precipitate is filtered off, washed twice with ethyl acetate and twice with ether, dried in vacuum, to obtain 1.64 g specified in the connection header, so pl. 183-188aboutC.

[ ]D= +155,5about(C = 1 mol/l in methanol).

Calculated,%: C 59,78; H 5,98; N 9,51; Cl 8,02.

C22H25N3O5HCl 0,62 H2O.

Found,%: C 59,36; H 6,14; N 9,43; Cl 7,92.

P R I m e R 56. (3R-CIS)-3-(atomic charges)-1-((4,5-dihydro-1H-imidazol-2-yl)-methyl)- 1,3,4,5-tetrahydro-7-methoxy-4-(4-methoxy - phenyl)-2H-1-benzazepin-2-he hydrochloride.

Specified in the title compound is prepared from (3R-CIS)-1-((4,5-dihydro-1H-imidazol-2-yl)methyl)-1,3,4,5 - tetrahydro-3-hydroxy-7-methoxy-4-(4-methoxyphenyl)-2H-benzazepin - 2-it, according to the method described in example 54, so pl. above 270aboutC.

[]D= +95,0about(C = 1 mol/l in methanol).

Calculated,%: C 59,19; H 6,09; N 8,63; Cl 7,28.

C24H27N3O5HCl 0,72 H2O.

Found,%: C 59,36; H Of 5.75; N 8,46; Cl 7,05.

P R I m e R 57. (3R-(1(S*),3 ,4 ))-1,3,4,5-tetrahydro-3-(hydroxy)-7-methoxy-4-(4-IU-toxigenic)- 1-(2-pyrrolidinyl)-2H-1-benzazepin-2-it, monohydrochloride.

A) (3R-(1(S*),3 , 4 ))-1,3,4,5-tetrahydro-3-(hydroxy)-7-methoxy-4-(4-metaxis (CIS)-1,3,4,5-tetrahydro-3-hydroxy-7-methoxy-4-(4-methoxyphenyl)- 2H-1-benzazepin-2-it (part E, example 55), according to the method described in the preparation of the compound indicated in the heading of part a of example 38.

B) (3R-(1(S*),3 , 4 ))-1,3,4,5-tetrahydro-3-(hydroxy)-7-methoxy-4-(methoxyphenyl)-1- (2-pyrrolidinyl)-2H-1-benzazepin-2-it, monohydrochloride.

This compound is prepared from (3R-(1(S*),3 , 4))-1,3,4,5-tetrahydro-3-(hydroxy)-7 - methoxy-4-(4-methoxyphenyl)-1- ((N-benzyloxycarbonyl)pyrrolidin-2-yl)methyl)-2H-1-benzazepin-2 the procedure described in the preparation of the compounds specified in the header of example 16, so pl. 179-181aboutC.

[ ]D= +109,4about(C = 1.0 mol/l in methanol).

Calculated,%: C 62,55; H Of 5.84; N 6.35mm; Cl 8,03.

C24H28N2O3HCl of 0.48 H2O.

Found,%: C 62,86; H 6,88; N 6,04; Cl 8,23.

P R I m e R 58. (2S-(2 ,3 ,3(R*)))-2,3-dihydro-3-hydroxy-8-methoxy-2-(4-methoxy-phenyl)-5- (2-pyrrolidinyl)-1,5-benzothiazepin-4-(5H)-he, monohydrochloride.

A) (2S-(2,3,3(R*)))-2,3-dihydro-3-(2-benzyloxycarbonylamino-3-phenyl) propionyl 8-methoxy-2-(4-methoxyphenyl)-1,5-Ben zodiazepine-4-(5H)-he.

(2-S)-Carbonintensity - NIN (6,88 g, 22,99 mmole) is added at room temperature and stirring for CIS-2,3-dihydro-3-hydroxy-8-methoxy-2-(4 - methoxyphenyl)-1,5 - benzothiazepin-4(5H)-ONU (6,09 GA) and then after 1 h dimethylaminopyridine (0.45 g, 3.7 mmole). Stirring is continued for 75 min, the mixture was diluted with 280 ml of ether, washed with 1 N. hydrochloric acid, saturated sodium bicarbonate solution, saturated brine, dried over magnesium sulfate and concentrated in vacuo. The mixture is purified chromatographically, then obetovannoi ghvd, receiving the connection specified in the header And (1.30 grams).

C) (2S-CIS)-2,3-dihydro-3-hydroxy-8-methoxy-2-(4-methoxyphenyl)-1,5 - benzothiazepin-4-(5H)-he.

The connection specified in the header And, (1,30 g, 2.12 mmole) in 21 ml of methanol and 0.2 ml of water in the atmosphere of argon is treated with a 25% solution of sodium methoxide in methanol (1.0 ml, 4.3 mmole). Stirring is continued for 90 min, the mixture is diluted with 100 ml of water and stirred for an additional 30 minutes Colorless product is collected by filtration, so pl. 180-183about(Razlog.).

[]D= +85,4about(S = 0,79 mol/l, in dimethylformamide).

C) (2S-(2 , 3 ,3(R*)))-2,3-dihydro-3-hydroxy-8-methoxy-2-(4-methoxyphenyl)-5- (2-pyrrolidinyl)-1,5-benzothiazepin-4-(5H)-he, monohydrochloride.

Specified in the title compound is prepared using the method of example 64, parts b and D of (2R-CIS)-2,3-dihydro-3-hydroxy-3-methoxy-2-(4-methoxyphenyl)- 1,5-benzothiazepin-4(5H)-it.

So pl. 121-124aboutWith (4; S 6,55.

C22H26N2O4S HCl 2,14 H2O.

Found,%: C 53,99; H Of 6.02; N 5,71; Cl EUR 7.57; S Of 6.65.

P R I m e R 59. (2S-CIS)-5-(4,5-dihydro-1H-imidazol-2-yl)methyl-2,3-dihydro-3 - hydroxy-8-methoxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4-(5H)-he, monohydrochloride.

Specified in the title compound is prepared from (2S-CIS)-2,3-dihydro-3-hydroxy-8-methoxy-2-(4-methoxyphenyl)-1,5 - benzothiazepin-4-(5H)-she, as described in example 43, so pl. 192-199aboutC.

[ ]D= +62,9about(C = 1.0 mol/l in methanol).

Calculated,%: C 54,30; H And 5.30; N 9,05; Cl 8,40; S 6,90.

C21H22NO4S HCl 0,66 H2O.

Found,%: C, 54.16 Per; H 5,52; N 9,19; Cl 8,04; S 6,92.

P R I m e R 60. (25-CIS)-3-atomic charges - 5-(4,5-dihydro-1H-imidazol-2-yl)methyl)-2,3 - dihydro-8-methoxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4-(5H)-he, monohydrochloride.

Specified in the title compound is obtained from (25-CIS)-5-(4,5-dihydro-1-imidazol-2-yl)methyl)-2,3-dihydro-3 - hydroxy-8-methoxy-2-(4-methoxyphenyl)-1,5 - benzothiazepin-4(5H)-it (the connection from the header of example 59 (according to the methods described in example 54, so pl. 275aboutC.

[ ]D= +65,19about(=1,0).

Calculated,%: C 54,29; H 5,52; N Compared To 8.26; Cl 6,97; S 6,30.

C23H25N3ClSOl-2-yl)methyl)-1,3,4,5-tetrahydro - 3-hydroxy-7-methylthio-4-(4-methoxyphenyl)-2H-1-benzazepin-2-it, monohydrochloride.

Specified in the title compound was prepared from (CIS)-1,3,4,5-tetrahydro-3-hydroxy-7-methylthio-4-(4-methoxyphenyl)- 2H-1-benzazepin-2 the procedure described in example 43, so pl. 195-198aboutC.

Calculated,%: C 57,50; H 5,98; N 9,15; Cl 7,72; S 6,98.

C22H25N3O3S HCl 0,64 H2O.

Found,%: C 57,60; H Is 6.19; N 9,05; Cl 7,63; S 6,84.

P R I m e R 62. (CIS-1-((4,5-Dihydro-1H-imidazol-2-yl)methyl)-1,3,4,5-tetrahydro - 3-hydroxy-7-methylsulphonyl-4-(4-methoxyphenyl)-2H-1-benzazepin-2-it, monohydrochloride.

A) (CIS)-1,3,4,5-tetrahydro-3-hydroxy-7-methylsulphonyl-4-(4 - methoxyphenyl)-2H-1-benzazepin-2-it.

A solution of (CIS)-1,3,4,5-tetrahydro-3-hydroxy-7-methylthio-4-(4-methoxyphenyl)-2H-1-benzo sepin-2-she (1.0 g, 3.04 from mmol) in 30 ml of dried methylene chloride in 5aboutWith the process metallocarboxypeptidase acid (of 0.615 g, 3.04 from mmole). After 30 min the reaction is terminated and the reaction mixture is diluted with ethyl acetate, washed have a saturated solution of sodium bicarbonate, water and brine. Organic layer was filtered and concentrated in vacuo, obtaining of 1.02 g of the solid residue. After trituration in hot ethyl acetate, cooling and filtering receive 600 mg of the product so pl. 214-216th methylene/methanol). Fraction of the product are combined and concentrated in vacuo, and the residue is crystallized from ethyl acetate to obtain an additional 200 mg of product.

In) (CIS)-1-((4,5-dihydro-1H-imidazol-2-yl)methyl)-1,3,4,5-tetrahydro-3 - hydroxy-7-methylsulfinyl-4-(4-methoxyphenyl)-2H-1-benzazepin-2-it, monohydrochloride.

The connection of the header, made from substances specified in the title And using the techniques described in example 43, so pl. 195-205aboutC.

Calculated,%: C 54,21; H 5,91; N 8,62; S 6,58; Cl 7.23 Percent.

C22H26ClN3O4S1,3 H2O.

Found,%: C 54,48; H 5,77; N 8,35; S 6,33; Cl 7,62.

P R I m e R 63. (3R-(1-(S*),3 ,4 )-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-1-(2 - azetidinone)-6-(trifluoromethyl)-2H-1-benzazepin-2-he, salt fumaric acid (1:1).

A) S-1-((1,1-dimethylmethoxy)carbonyl)azetidin-2-carboxylic acid.

Di-tert-BUTYLCARBAMATE (2,18 g, 9.9 mmol) is added at once to a stirred mixture of (Z)-azetidin-2-carboxylic acid (1.0 g, to 9.9 mmole), triethylamine (2,12 ml, 15.0 mmol), 10 ml of acetone and 10 ml of water. The resulting reaction mixture is stirred for 4 h at room temperature, after which the mixture is partitioned between 100 ml ethyl acetate and 100 ml of water. The aqueous layer was acidified to pH 3 joint organic extracts are dried with magnesium sulfate and concentrate, to obtain 2.0 g of the compound indicated in the title, in the form of a colorless oil.

C) Methyl ester of S-1-((1,1-dimethylmethoxy)carbonyl)-azetidin-2-carboxylic acid.

A mixture of (S)-1-((1,1-dimethylmethoxy)carbonyl)-azetidin-2-carboxylic acid (2.0 g, 9.9 mmol), potassium carbonate (6.9 g, 50.0 mmol) and under the conditions (6.25 ml, 100 mmol) in 20 ml of dimethylformamide is stirred under argon at room temperature for days. Excess under the conditions pumped into a trap cooled with dry ice, and the remaining mixture was poured into water and extracted with 300 ml of ethyl ether. The organic extract is washed 2 times with 150 ml of brine, dried with magnesium sulfate and concentrated, obtaining 1.85 g of the substance specified in the header (In), in the form of a colourless liquid. []D= -114,8about(C = 2.5 mol/l, chloroform).

C) R, S-1-((1,1-dimethylmethoxy)carbonyl)azetidin-2-carboxylic acid, 1,1-dimethylethylene ether.

To a solution of S-1-((1,1-dimethylmethoxy)carbonyl)-azetidin-2-carboxylic acid, methyl ether (1,83 g, 8.5 mmole) in 38 ml of tertbutanol at room temperature add 18,8 g odnopolyarnogo solution tertbutoxide potassium in tetrahydrofuran. The reaction mixture was stirred for 5 h, after which it was diluted with ethyl EFI acid, a saturated solution of sodium bicarbonate and brine. The organic extracts are dried with magnesium sulfate and concentrated, obtaining 1.63 g of the compound indicated in heading (C), in the form of a colourless liquid.

D) R,S-1-((1,1-dimethylmethoxy)carbonyl)-azetidin-2-methanol.

Borohydride lithium (0,23 g, 10.5 mmol) is added at once to a solution of (R, S)-1-((1,1-dimethylmethoxy)carbonyl)-azetidin-2-carboxylic acid, 1,1-dimethyl ester (1,59 g, to 6.19 mmole) in 20 ml of tetrahydrofuran at 0aboutC. the Reaction mixture is allowed to warm up to room temperature, then stirred for 18 h and then partitioned between brine and ethyl acetate. The organic extracts are washed odnomomentnoe hydrochloric acid and brine, dried with magnesium sulfate and concentrating, getting to 0.92 g of compound indicated in heading (D), in the form of a colorless oil.

[]D= 0about.

E) R,S-1-((1,1-dimethylmethoxy)carbonyl)azetidin-2-methyl-(4-methylbenzoyl) sulfonate.

A mixture of R, S-1-((1,1-dimethylmethoxy)carbonyl)-azetidin-2-methanol (0.9 g, 4.9 mmole) and p-toluensulfonate (1,87 g, 9.8 mmole) in 10 ml of pyridine is stirred for 60 h at room temperature and at this point, add another 0.5 g (2.6 mmol) of p-toluensulfonate sodium and the mixture is stirred for 30 min, after which it was partitioned between 100 ml ethyl acetate and 100 ml of saturated solution of sodium bicarbonate. The organic layer is washed 2 times with 70 ml odnomomentnoe hydrochloric acid, 50 ml of a saturated solution of sodium bicarbonate and 50 ml of brine, dried with magnesium sulfate and concentrate. The crude residue purified by the method of flash chromatography (column 5x12 cm, eluent - 4:1 hexane: ethyl acetate), obtaining of 1.43 g of compound indicated in heading (E), in the form of a yellow oil.

F) (3R-(1(S*), 3 ,4 ))-1,3,4,5-tetrahed - ro-3-hydroxy-4-(4-methoxyphenyl)-1-(1-((1,1- dimethylmethoxy)carbonyl)-azetidine-2-me - Teal)-6-(trifluoromethyl)- 2H-1-benzazepin-2-he (3R-((1,1-dimethylmethoxy)carbonyl)azetidin - Neil-2-methyl(-6-trifluoromethyl)-2N-1-benzazepin-2-it.

A mixture of R, S-1-((1,1-dimethylmethoxy)-carbonyl)-azetidin-2-methyl-(4 - methylbenzoyl)sulfonate (0,492 g of 1.46 mmol), (3R-CIS)-1,3,4,5-tetrahydro-3-hydroxy-4-(4 - methoxyphenyl)-2H-1 - benzazepin-2-she (and 0.46 g, 1.3 mmol) and cesium carbonate (0,977 g, 30.0 mmol) in 4 ml of dimethylformamide is stirred for 18 h at 60aboutC, then the reaction mixture was partitioned between 100 ml ethyl acetate and 100 ml of water. The organic extracts washed with water (2 times 50 ml) and brine (50 ml) and then dried with magnesium sulfate and concentrate. The crude light yellow estato is a mixture of 1 liter of 1: 1 hexane: ethyl acetate), receiving 0.2 g (30%) (3R-(1(S*),3,4 ))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)- 1-(1-((1,1- dimethylmethoxy)carbonyl)azetidine-2-methyl)-6-trifluoromethyl)-2H-1 - benzazepin-2-it is in the form of a white foam, along with 0,232 g (34%) (3R-(1(R*),3 ,4 ))-1,3,4,5-tetrahydro-3-hydroxy-4-(4 - methoxyphenyl) -1-(1-((1,1- dimethylmethoxy)carbonyl)azetidine-2-methyl)-6- (trifluoromethyl)- 2H-1-benzazepin-2-it, also in the form of a white foam, and 0.15 g of mixed fractions.

G), (3R-((S*), 3, 4 ))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-1-(2 - azetidinone)-(6-(trifluoromethyl)-2H-1-benzo - zipin-2-he, salt fumaric acid (1:1).

A mixture of (3R-(1(S*),3 , 4 ))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-1-(1- ((1,1- dimethylmethoxy)carbonyl)azetidine-2-methyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it (0.55 g, of 1.06 mmole) and 3.3 ml three - forexpros acid in 3.3 ml of methyl chloride is stirred for 2 h at room temperature. The reaction mixture was concentrated under reduced pressure. Add toluene and the mixture is again concentrated under reduced pressure, obtaining a yellow oil, which was distributed between ethyl acetate and odnomomentnym solution of sodium hydroxide. The organic extracts washed with brine, dried with magnesium sulfate and concentrated, obtaining 0,424 g of crude free base, which cleanse method is>The
(C = 0.50 mol/l, in methanol).

Calculated,%:C 57,26; H 5,17; N 5,14; F 10,45.

C22H23N2F3O3C4H4O40,49 H2O.

Found,%: C 57,24; H Of 5.05; N 5,16; F 10,61.

P R I m e R 64. (3R-(1(R*),3 ,4 ))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)- 1-(2 - azetidinone)-6-(trifluoromethyl)-2H-1-benzazepin-2-he, salt fumaric acid (1:1).

Specified in the title compound is prepared from (3R-(1(R*),3A,4A))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)- 1-(1-((1,1-dimethylmethoxy)carbonyl)attide - Neil-2-methyl)-6- (trifluoromethyl)-2H-1-benzazepin-2-it is described in part F of example 63, using the techniques described in part G of example 63. So pl. 112aboutWith (softened), 140-146aboutC (decomposes).

[ ]D= +90,2about(C = 0.55 mol/l in methanol).

Calculated,%: C 56,33; H 5,27; N Of 5.05; F 10,28.

C22H23N2F3O3C4H4O40,99 H2O.

Found,%: C 56,21; H 5,22; N 5,17; F 10,55.

P R I m e R 65. (3R-CIS)-1-((methyl-4,5-dihydroimidazole-2-yl)methyl)-3-hydroxy-4- (4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it.

A) (3R-CIS)-1-(cyanomethyl)-3-hydroxy-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1-benzazepin-2-it.

To a solution of 0.60 g Geri ethoxyphenyl)-6 - trifluoromethyl-2H-1 - benzazepin-2-it. The solution is stirred teenie 15 min, cooled at 0aboutC and added dropwise thereto a solution of 1.03 ml iodoacetonitrile (of 14.2 mmol) in 10 ml dry tetrahydrofuran. The solution is allowed to warm to room temperature over 2 h, then partitioned between water and ether. The aqueous layer was washed with ether and the combined ether extracts washed with brine and dried with magnesium sulfate. The solution is evaporated to about 20 ml, add 10 ml of hexane, and the solution is quickly frozen, getting 0.74 g of (3R-CIS)-1-(cyanomethyl)-3-hydroxy-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1-benzazepin-2-it is in the form of a light yellow crystalline substance. The mother liquor gives additional 2,04 g of the product.

B) (3R-CIS)-1-((1-methyl-4,5-dihydroimidazole-2-yl)methyl)-3-hydroxy - 4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it.

Through the suspension of 1.95 g of (3R-CIS)-1-cyanomethyl)-3-hydroxy-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1-benzazepin-2-it (5 mmol) in 20 ml of ether containing at 0.31 ml of absolute ethanol (5,24 mmole) at 0aboutWith propulsive gaseous hydrogen chloride, until dissolved solid. This solution was sealed and stored at 5aboutC for 4 days and at -20aboutWith 6 days. The ether is decanted from the research is emesto. The ether is decanted and the white solid washed with ether. This solid is dissolved in 25 ml of dimethylformamide and added dropwise 12.5 ml of this solution to a solution of 0.33 ml of N-methylethylenediamine (3.75 mmol) in 5 ml of dried DMF (dimethylformamide) at 0aboutC. the Solution was stirred at room temperature for 90 min, add aqueous potassium carbonate and the solution is extracted twice with ether. The combined ether extracts are washed 2 times with water, once with brine, dried with potassium carbonate and evaporated, receiving of 0.77 g of solid white. This substance is dissolved in ether and add to it the ether saturated with hydrogen chloride, getting a white solid. It is filtered off, washed 2 times with ether and dissolved in a homogeneous mixture of water, potassium carbonate, ether and dioxane. Add ether to the phases were separated, the aqueous layer washed with additional ether and the combined organic extracts washed with brine, su - shat potassium carbonate and evaporated, getting 0.66 g of a white solid. This substance was purified chromatography with elution with a mixture of 5% methanol in dichloromethane for three preparative plates for thin-layer chromatography, which were previously the sue 10% methanol in dichloromethane and the combined solution is evaporated, getting 0.27 g of light-yellow foamy substance. This solid is dissolved in ethyl acetate and adding ether saturated with hydrogen chloride to obtain a waxy solid. The solution is evaporated and dissipate ether. The solid is dissolved in a mixture of 1:1 methanol:isopropyl ether and add 150 ml of isopropyl ether. The solid is filtered off and dried in the air, getting 235 mg of (3R-CIS)-1-((1-methyl-4,5-dihydroimidazole-2-yl)methyl)-3-hydroxy - 4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it is in the form of a light brown solid with so pl. above 240aboutC.

[ ]D= +level 98.2 (C = 1 mol/l in methanol).

Calculated,%: C 53,68; H 5,56; N 8,16; F 11,07; Cl 6,689.

C23H25N3F3Cl 1,7 H2O.

Found,%: C 54,08; H 5,46; N Of 7.90; F Is 10.68; Cl 6,90.

P R I m e R 66. (3R-CIS)-1-((4,5-dihydro-1H-imidazol-2-yl)methyl)-1,3,4,5 - tetrahydro-3-hydroxy-6-chloro-4-(4-methoxyphenyl)-2H-1 - benzazepin-2-it, monohydrochloride. A) (CIS)-1,3,4,5-Tetrahydro-3-((2-carboxyphenyl)-carboxyl)-6-chloro - 4-(4-methoxyphenyl)-2H-1-benzazepin-2-it.

Stir a suspension of CIS-1,3,4,5-tetrahydro-3-hydroxy-6-chloro-4-(4-methoxyphenyl)-2H-1 - benzazepin-2-it is obtained by the method of example 61, 100 ml of dichloromethane mmol) of phthalic anhydride. Solids are quickly dissolved and the resulting solution stirred for 2 h at room temperature. The mixture on the parts of the process odnomomentnoe hydrochloric acid (83 ml), receiving heavy rainfall. After stirring and cooling for 30 min, the product was filtered, washed with 25 ml of water (five times) and dried, obtaining specified in the header And the product (22,58 g) so pl. 165-167aboutC. After recrystallization from acetonitrile, the sample of this material melts at 220-222aboutC.

B) (3R-CIS)-1,3,4,5-tetrahydro-3-((2-carboxyphenyl)carboxy)-6 - chloro-4-(4-methoxyphenyl)-2H-1-benzazepin-2-he, Sol S- -methylbenzylamino.

Heat the mixed suspension (CIS)-1,3,4,5-tetrahydro-3-((2 - carboxyphenyl)carboxy)-6-chloro-4- (4-methoxyphenyl)-2H-1-benzazepin-2-it (22,17 g, and 47.5 mmol) in 250 ml of methanol and treated with a solution of S-alpha-methylbenzylamine (5,80 g, and 47.5 mmole) in 50 ml of methanol. The mixture is heated to boiling (under reflux) to give a solution, which then begins to crystallize. After maturation over night at room temperature, the crystalline product is filtered off, washed with methanol (3 times 20 ml) and dried, obtaining specified in the title In the product (a 12.03 g) so pl. 160aboutC.

[ ]D who yl)- 2H-1-benzazepin-2-it.

To a stirred solution of hydrate of lithium hydroxide (3.4 g, 81 mmol) in water (113 ml) add substance specified in the header (11.85 g, 20,5 mmole). The resulting solution was treated with 11 ml of methanol and heated to boiling under reflux. Separate heavy precipitate. This suspension is heated at 60-70aboutC for 1 h, diluted with 100 ml of water, cooled and stirred for 2 hours, the Solid is filtered off, washed with water and dried, obtaining mentioned in the title substance as a colorless solid (USD 5.76 g), so pl. 191-193aboutC.

THE METHOD OF OBTAINING NITROGEN-CONTAINING HETEROCYCLIC COMPOUNDS OR THEIR PHARMACEUTICALLY ACCEPTABLE SALTS.

The method of obtaining nitrogen-containing heterocyclic compounds of General formula

< / BR>
where R1is hydroxy, lower alkanoyloxy, OCONY1Y2where Y1, Y2is hydrogen, lower alkyl, X is CH2, R2group of the formula

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where n' = 0,1,2,3, n = 2,1,0, where Y3, Y4is hydrogen, lower alkyl, Y5- phenyl, lower alkoxy, hydrogen, lower alkoxy; and when X Is S, R2group of the formula

< / BR>
< / BR>
< / BR>
where Y3, Y5have the specified values;

R3- n is oxyl,

or their pharmaceutically acceptable salts,

characterized in that the compound of General formula

< / BR>
where X, R3, R4, R1have the specified values,

is treated with a base in an inert organic solvent followed by treatment of the compound of formula R2Y, where R2has the specified values, Y - tsepliaeva group, with selection of the target product in free form or in the form of a pharmaceutically-acceptable salt.

Priority signs

20.06.88 when X - CH2,

< / BR>
< / BR>
< / BR>
< / BR>
n'= 0,1;

22.05.89 when X Is S, R2group

< / BR>
< / BR>


 

Same patents:

FIELD: organic chemistry, medicine, hormones, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that act as agonists of peptide hormone vasopressin. Invention describes the compound of the general formula (1) or its pharmaceutically acceptable salt wherein V represents a covalent bond or NH; X is taken among CH2, oxygen atom (O) and N-alkyl; Z represents sulfur atom (S) or -CH=CH-; R1 and R2 are taken independently among hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom and alkyl; R3 is taken among hydroxyl group (OH), O-alkyl and NR4R5 wherein each R4 and R5 represents independently hydrogen atom (H) or alkyl, or both represent -(CH2)q-; p = 0, 1, 2, 3 or 4; q = 4 or 5. Also, invention describes a pharmaceutical composition eliciting agonistic activity with respect to V2-receptors, a method for treatment of enuresis, nicturia and diabetes insipidus, method for control of enuresis and a method for treatment of enuresis and a method for treatment of diseases associated with damage in blood coagulability. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 31 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): wherein R1 means hydrogen atom (H) or (C1-C8)-alkyl; R2 means (C1-C8)-alkyl, -CH2-O-(C1-C8)-alkyl, -OH or -CH2OH; R2a means H; or R2 and R2a for in common -CH2-CH2-; R3 means halogen atom, perhalogenalkyl, -CN, -SR5, -NHR5, -N(R5)2, aryl or heteroaryl wherein indicated aryl can comprise optionally up to two substitutes chosen from (C1-C8)-alkyl, halogen atom, perhalogenalkyl and alkoxy-group, and indicated heteroaryl can comprise optionally up to two substitutes chosen from halogen atom and (C1-C8)-alkyl; R4 means H, halogen atom, perhalogenalkyl, -CN, -OR5, -SR5, -NHR5, -N(R5)2, -OH, aryl or heteroaryl wherein indicated aryl can comprise optionally up to two substitutes chosen from (C1-C8)-alkyl, halogen atom, perhalogenalkyl and alkoxy-group, and indicated heteroaryl can comprise optionally up to two substitutes chosen from halogen atom and (C1-C8)-alkyl; or R3 and R in common with atoms to which they are added can form 5- or 6-membered heterocyclic ring comprising one oxygen atom (O); each R5 means independently (C1-C8)-alkyl, (C2-C8)-alkenyl, aryl, heteroaryl, arylalkyl, alheteroarylalkyl, perhalogenalkyl or allyl; R6 means H or (C1-C8)-alkyl, or their pharmaceutically acceptable salts, solvates or hydrates under condition that if R6 differs from H then R4 can't mean H; if R1 and R2 mean methyl and R4 means H then R3 can't -NHR5 or -N(R5)2; if R1 and R2 mean methyl and R4 means H then R3 can't imidazole, substituted imidazole or imidazole derivative. Also, invention relates to a pharmaceutical composition used for modulation of 5-HT2C receptors, a method for modulation of 5-HT2C receptors, a method for prophylaxis or treatment of disorders of the central nervous system and obesity, a method for reducing food consumption in mammals, a method for inducing the satisfying sense in mammals and to a method for preparing the composition. Invention provides synthesis of novel compounds possessing useful biological properties and preparing pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

70 cl, 1 tbl, 57 ex

FIELD: chemistry.

SUBSTANCE: 4,4-diphtor-1,2,3,4-tetrahydro-5H-1-benzazepine derivative of the formula (I) or its pharmaceutically acceptable salt are described , the signs of the formula stand for the following R1: amines, which can be substituted, -OH or O-low alkyl; R2: CF3 or halogen, R3: H or halogen, a, b: each of them has ordinary link or olefinic link, notably that one has ordinary link and the other - olefinic link, X-: (1) -CH=CH-, Y; (1) CH or N, in the case when a has ordinary link and b - olefinic link, -A-: -O-, -S-, -NH or N (low alkyl), and B: low alkyl, low alkenyl, low alkynyl, cycloakyl or aryl, each of them can be substituted. The pharmaceutical composition of agonist V2 receptor arginine-vasopressin, which includes the compound of the formula I as an active ingredient is described.

EFFECT: new compound has effective, biological properties.

36 tbl

Compounds // 2327690

FIELD: chemistry.

SUBSTANCE: description is given of compounds with formula (I) in which A and B represent -(CH2)m- and -(CH2)n- groups respectively; R1 represents hydrogen or C1-6 alkyl; R2 represents hydrogen, C1-6alkyl, C1-6alkoxy, -S-C1-6alkyl, -(CH2)pNR5R6 optionally substituted aryl, heteroaryl or optionally substituted heterocyclyl; R3 represents optionally substituted aryl or optionally substituted heteroaryl; R4 represents hydrogen, C1-6alkyl or halogen; R5 and R6 each independently represents hydrogen or C1-6akyl; Z represents -(CH2)rX-, in which the -(CH2)r- group is bonded to R3 radical, or -X(CH2)r-, in which X is bonded to R3 radical; X represents oxygen, -NR7 group or -CH2- group; R7 represents hydrogen or C1-6alkyl; m and n independently represent an integer, chosen from 1 and 2; p represents 0; r independently represents an integer, chosen from 0 and 1. The invention also relates to use of the given compounds in therapy, in particular, as antipsychotic agents. The result is achieved when using serotonin receptors 5-HT2c, 5-HT2A and 5-HT6.

EFFECT: given compounds have antagonist affinity to serotonin receptors.

12 cl, 9 tbl, 265 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula I, in which R1 represents hydrogen or a group, which forms a biologically labile ester, R2 represents hydrogen, C1-C4-alkyl or C1-C4-hydroxyalkyl, and R3 represents C1-C4-alkyl; C1-C4-alkoxy-C1-C4-alkyl; C1-C4-hydroxyalkyl, which is optionally substituted with a second hydroxy group and all hydroxy groups of which are optionally esterified with C2-C4-alkanoyl or amino-acid residue; (C0-C4-alkyl)2amino-C1-C6-alkyl; C3-C7-cycloalkyl; C3-C7-cycloalkyl-C1-C4-alkyl; phenyl-C1-C4-alkyl, the phenyl group of which is optionally substituted 1-2 times with C1-C4-alkyl, C1-C4-alkoxy group and/or halogen; naphthyl-C1-C4-alkyl; C3-C6-oxoalkyl; phenylcarbonylmethyl, the phenyl group of which is optionally substituted 1-2 times with C1-C4-alkyl, C1-C4-alkoxy group and/or halogen, or 2-oxoazepanyl, or R2 and R3 together represent C4-C7-alkylene, methylene groups of which are optionally substituted 1-2 times with carbonyl, nitrogen, oxygen and/or sulphur and/or optionally substituted once with a hydroxy group, which is optionally esterified with C2-C4-alkanoyl or amino-acid residue; C1-C4-alkyl; C1-C4-hydroxyalkyl, the hydroxy group of which is optionally esterified with C2-C4-alkanoyl or amino-acid residue; phenyl or benzyl, and R4 represents hydrogen or a group, which forms a biologically labile ester, where R1 and R4 groups are independently chosen from C1-C4-alkyl; C1-C4-alkoxy-C1-C4-alkoxy-C1-C4-alkyl; C3-C7-cycloalkyl; C3-C7-cycloalkyl-C1-C4-alkyl; N,N-di-(C0-C4-alkyl)amino-C1-C6-alkyl; phenyl or phenyl-C1-C4-alkyl, optionally substituted 1 or 2 times in the phenyl ring with halogen, C1-C4-alkyl or C1-C4-alkoxy group or C1-C4-alkylene chain, bonded with two neighbouring carbon atoms; dioxolanylmethyl, optionally substituted in the dioxolane ring with C1-C4-alkyl; C1-C6-alkanoyloxy-C1-C4-alkyl, optionally substituted in the oxy-C1-C4-alkyl group with C1-C4-alkyl; 1-[[(C1-C4-alkyl)carbonyl]oxy]C1-C4-alkyl esters; 1-[[(C4-C7 cycloalkyloxy)carbonyl]oxy]C1-C4-alkyl esters, 2-oxo-1,3-dioxolan-4-yl-C1-C4-alkyl esters, which optionally contain a double bond in the dioxolane ring; 2-oxo-1,3-dioxolan-4-ylmethyl; and to physiologically compatible salts of acids with formula I and/or to physiologically compatible acid-additive salts of formula I compounds. The invention also relates to a pharmaceutical composition, to use of formula I compounds in paragraph 1, to a method of obtaining formula I compounds, as well as to compounds with general formula II.

EFFECT: obtaining new biologically active compounds, with inhibitory activity towards neutral endopeptidase, endothelin converting enzyme and soluble human endopeptidase.

20 cl, 80 ex, 9 tbl

FIELD: pharmacology.

SUBSTANCE: invention concerns novel compounds of formula (1a), formula (1b), formula (1c) and formula (1d), as well as pharmaceutical composition based on them and their application in medicine obtainment. R1-R4, G, W, X, X1, U, V, a, b are defined in the invention claim.

EFFECT: compound with antagonistic effect on vasopressin V1A receptor.

73 cl, 133 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound which represents 6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methylnicotine amide , or to its pharmaceutically acceptable salt. This compound and its pharmaceutically acceptable salts exhibits affinity to a histamine H3 receptor and are antagonists and/or inverse agonists of said receptor.

EFFECT: development of an effective method of producing the benzazepin derivative, the pharmaceutical compositions containing it, and application of the benzazepin derivative for treating neurological and psychiatric disturbances.

18 cl, 6 ex, 1 tbl

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention provides 1,5-benzothiazepines of general formula I (formulae presented below), in which Rv and Rw are independently selected from hydrogen and C1-C5-alkyl; one of Rx and Ry represents hydrogen or C1-C6-alkyl and the other hydroxy or C1-C6-alkoxy; Rz is selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1 of invention; v is a number from 0 to 5; one of R4 and R5 represents group of general formula IA; R3 and R6 and the second from R4 and R5 are independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1; R3 and R6 and the second from R4 and R5 being optionally substituted by one or several R16 groups at their carbon atoms; D represents -O-, -N(Ra)-, -S(O)b- or -CH(Ra)-, wherein Ra is hydrogen or C1-C6-alkyl; and b=0-2; ring A represents aryl or heteroaryl and is optionally substituted by one or several substituents selected from R17; R7 represents hydrogen, C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R18; R8 represents hydrogen or C1-C4-alkyl; R9 represents hydrogen or C1-C4-alkyl; R10 represents hydrogen or C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R19; R11 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORc)(ORd), -P(O)(OH)(ORc), -P(O)(OH)(Rd), or -(O)(ORc)(Rd), wherein Rc and Rd are independently selected from C1-C6-alkyl; or R11 represents group of general formula IB, in which X is -N(Rq)-, N(Rq)C(O)-, -O-, or -S(O)a, wherein a=0-2; and Rq is hydrogen or C1-C4-alkyl; R12 represents hydrogen or C1-C4-alkyl; R13 and R14 are independently selected from hydrogen, C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23 can be optionally independently substituted by one or several substituents selected from R20; R15 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Re), or -P(O)(ORe)(Rf), wherein Re and Rf are independently selected from C1-C6-alkyl; or R15 represents group of general formula IC, in which R24 is selected from hydrogen and C1-C4-alkyl; R24 is selected from hydrogen, C1-C4-alkyl carbocyclyl, heterocyclyl, and R27, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R27 can be optionally independently substituted by one or several substituents selected from R28; R26 is selected from carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORg)(ORh), -P(O)(OH)(ORg), -P(O)(OH)(Rg), or -P(O)(ORg)(Rh), wherein Rg and Rg are independently selected from C1-C6-alkyl; p=1-3; wherein meanings for R13 can be the same or different; q=0-1; r=0-3; wherein meanings for R14 can be the same or different; m=0-2; wherein meanings for R10 can be the same or different; n=1-3; wherein meanings for R7 can be the same or different; z=0-3; wherein meanings for R25 can be the same or different; R16, R17, and R18 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N,N-(di-C1-C4-alkyl)amino, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, and N,N-(di-C1-C4-alkyl)sulfamoyl; wherein R16, R17, and R18 can be optionally independently substituted by one or several of R21 at their carbon atoms; R19, R20, R23, R27, and R28 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N.N-(di-C1-C4-alkyl)amino, C1-C4-alkanoylamino, N-(C1-C4-alkyl)carbamoyl, N,N-(di-C1-C4-alkyl)carbamoyl, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, N,N-(di-C1-C4-alkyl)sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfino, amidino, phosphono, -P(O)(ORa)(ORb), -P(O)(OH)(ORa), -P(O)(OH)(Ra), or -P(O)(ORa)(Rb), wherein Ra and Rb are independently selected from C1-C6-alkyl and wherein R19, R20, R23, R27, and R28 can be optionally independently substituted by one or several of R22 at their carbon atoms; R21 and R22 are independently selected from halogen, hydroxy, cyano, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl; or pharmaceutically acceptable salt thereof, solvate, or salt solvate. Described are also method for preparing compounds of formula I, pharmaceutical compositions based on compounds I, and a method for achieving inhibiting effect relative to interscapular brown adipose tissue (IBAT), and intermediates. (I), (IA), (IB), (IC).

EFFECT: expanded synthetic possibilities in the 1,5-benzothiazepine series.

36 cl, 121 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new oxoazepanylacetamide and oxoazepanylphenoxyacetamide derivatives, or to their stereoisomers or pharmaceutically acceptable salts described by general formula I where Q means O, S or N(R25); R25 means H; R80 is C6arylC1-4alkyl substituted by one or two substituted independently chosen from R3 groups; each R3 is independently chosen from a group including C1-4alkyl, C1-4alkoxy group, C2-6alkenyloxy group, halogen, C6aryloxy group, N(R20)(R21), R50, heteroaryl chosen from pyridine and thiazol where each alkoxy group and heteroaryl has optionally up to three substitutes independently chosen from R61 groups; and alkyl has optionally three substitutes independently chosen from R60 groups; or two R3 groups when they are present on carbon neighbours, together can form a fragment of formula -(O)a-(CH2)b-(O)c-(CH2)d-(O)e- where a, c and e independently mean 0 or 1, and both b and d independently mean 0, 1, 2 or 3; provided the fragment does not contain two oxygen neighbors and summed a, b, c, d and e are equal to 3 at least; R1 is chosen from a group including H, C1-4alkyl, C6arylC1-4alkyl; each R60 independently is chosen from a group including C1-C6a alkoxy group, NR12R13, halogen, heterocycloalkyl, such as piperidine; each R61 independently is chosen from a group including R60 and C1-C6alkyl; X means a group of formula -(CH2)n- where n means 2 or 3; or a group of formula II where Y means CH2, S; R75 and R76 means H; Z means C6aryl or heteroaryl, such as pyridine; each of which has optionally one substitutes chosen from R2 groups; R2 is chosen from a group including H, C1-4alkyl, halogen, heterocycloalkylC1-4alkyl, C6arylC1-4alkylaminoC1-4alkyl and a group of formula -(CH2)fN(R11)-(R10); where each heterocycloalkyl, arylalkylaminoalkyl has oprtionally one substitute chosen from R61 groups; f means 1; R11 means H; R10 means C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, aryl, C6arylC1-4alkyl, heteroarylC1-4alkyl where aryl has optionally one substitute chosen from R61 groups; each R12 and R13 independently mean C1-4alkyl; each R20 and R21 independently mean C1-4alkyl where alkyl has optionally one substitute chosen from R60 groups; and provided that the compound does not represent N-(4-ethoxybenzyl)-N-(2-oxoazepane-2-yl)-2-phenoxyacetamide or N-[(2-fluorophenyl)methyl]-N-(2- oxoazepane-3-yl)-2,2-diphenylacetamide. Also, the invention refers to a pharmaceutical composition of the compound of formula I, to methods of treating HCV viral infection and methods of relieving the symptoms of HCV viral infection with using the compound of formula I.

EFFECT: there are produced new oxoazepanylacetamide and oxoazepanylphenoxyacetamide derivatives showing HCV replication inhibiting activity.

1 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to use of compounds of formula II for treating and/or preventing liver disease mediated IBAT selected from Alajil syndrome (ALGS), progressive family inside liver cholestasis (PFIC), primary billiar cirrhosis (PBC), primary sclerosing cholangitis (PSC), non-alcoholic liver steatohepatitis (NASH) and itching caused by cholestatic liver disease, as well as to based pharmaceutical composition and method of treating said diseases. In general formula II M denotes CH2 or NH; R1 denotes H or hydroxy; R2 represents H, CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2OH, -CH2OCH3, -CH(OH)CH3, -CH2SCH3 or -CH2CH2SCH3.

EFFECT: treating and preventing hepatic disorders.

11 cl, 1 tbl, 20 ex

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