Derivatives benzazepine or benzodiazepine

 

(57) Abstract:

Usage: in medicine, because it has vasodilator activity. The inventive product is derived benzazepine and benzodiazepine formula

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or their pharmaceutically acceptable salts, where R1- lower alkoxy, OH, lower alkanoyloxy, OCOHY8Y9X - CH2or S, provided that if X is CH2, R2means and others, if X Is S, R2means and the other R3- lower alkoxy, etc., R4- lower alkoxy and the other Reagent 1: compound of formula I, where R2means H. the Reagent 2: base. Reaction conditions: in an inert solvent followed by treatment of the compound of formula R2-L, where L is tsepliaeva group. 36 C.p. f-crystals.

The invention relates to compounds which have the formula I

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and their pharmaceutically acceptable salts possess useful vasodilator activity. In the formula I, throughout the description, the symbols have the following values:

X is-CH2- or-S-; R1this is a group-CH(Y1)Y2or OY3; when X represents a group-CH2- R2it

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when X represents-S-, R2is

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R3and R4each nezakonnuju, cyano-, hydroxy-, alkanoyloxy-, -O-CO-NY8Y9, the fluoro-substituted alkoxygroup fluoro-substituted alkyl (cycloalkyl)alkoxy-, nitro-, -NY10Y11, -S(O)malkyl-S(O)maryl, -CO-Y12or-O-CO-Y13; n or n' is independently 0, 1, or 3; m is 0, 1 or 2;

Y1and Y2independently is hydrogen or alkyl, Y1is hydrogen and Y2alkenyl, quinil, aryl, heteroaryl or cycloalkyl, or Y1and Y2together with the carbon atom to which they are attached represent cycloalkyl.

Y3is a hydrogen atom, alkyl, alkanoyl, alkenyl, arylcarbamoyl, heteroarylboronic or a group-CO-NY8Y9.

Y4and Y5each independently represents a hydrogen atom, alkyl, aryl or aralkyl, provided that, when both are present, they both are not hydrogen atoms, and, in addition, provided that when they are both attached to the same carbon atom, any one of them is not hydrogen.

Y6and Y7each independently is a hydrogen atom, alkyl, cycloalkyl or arylalkyl, or Y6and Y7together with the nitrogen atom to which they are attached, is what isimo is a hydrogen atom, the alkyl, aryl or heteroaryl, or Y8and Y9together with the nitrogen atom to which they are attached, are, pyrrolidinium, piperidinium or morpholinium.

Y10and Y11each independently is a hydrogen atom, alkyl, alkanoyl, arylcarbamoyl, heteroarylboronic or a group-CO-NY8Y9;

Y12is a hydroxy-, alkoxy-, aryloxy-, amino-, alkylamino or dialkylamino;

Y13this is alkyl, alkoxy or aryloxy-; and

Y14is hydrogen, hydroxy-, alkoxy-, aryloxy or Allakaket.

Listed below are definitions of various terms used to describe benzazepines of this invention.

These definitions apply to terms used throughout the description (unless limited otherwise in special cases) either individually or as part of a larger group.

The terms "alkyl" and "alkoxy" refer to non-branched, and branched chain groups. Preferred are groups having from 1 to 10 carbon atoms.

The term "alkenyl" refers to non-branched, and branched chain groups. Preferred yavlenie. Examples of the groups substituted phenyl is phenyl group substituted by 1, 2 or 3 amino groups, alkylamino-, dialkyl-, amino-, nitro groups, halogen, hydroxyl, trifluoromethyl, alkyl (having 1 to 4 carbon atoms), alkoxy (1-4 carbon atoms), alkanoyloxy-, carbonyl or carboxyl groups.

The term "alkanoyl" refers to groups having the formula alkyl are Preferred those alcoholnye group which has 2 to 11 carbon atoms.

The term "heteroaryl" refers to an aromatic heterocyclic group having at least one heteroatom in the ring. The preferred groups are pyridinyl, pyrrolyl, imidazolyl, furyl, thienyl, oxazolyl or thiazolyl.

The term "cycloalkyl" refers to groups having 3,4,5,6 or 7 carbon atoms.

The term "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "fluoro-substituted alkyl and fluoro-substituted alkoxy" refer to alkyl and CNS groups (as described above), in which one or more hydrogen atoms substituted by fluorine atoms. Examples of groups are trifluoromethyl, 2,2,2-triptorelin, pentafluoroethyl, formatosi, deformedarse etc.

Substances formulabuy useful compounds for selection of products from reaction mixtures by formation of salts in the environment, in which the salt is insoluble. Then the free base can be obtained by neutralizing such basis as hydroxy sodium. Can then be obtained any other salt of the free base and the corresponding inorganic and organic acids. Examples are hydrogenogenic, especially the hydrochloride and hydrobromide, sulfate, nitrate, phosphate, borate, acetate, maleate, citrate, succinate, benzonate, ascorbate, salicylate, methanesulfonate, bansilalpet, toluensulfonate etc.

The carbon atoms in positions -3 and -4 benzazepine ring and the carbon atoms at positions -2 and -3 benzodiazepinovogo rings for compounds of the formula I represents an asymmetric atoms. Therefore, the substances of the formula I exist in enantiomeric and diastereomeric forms, and as their racemic mixtures. They are all in the scope of this invention. Suppose that the substances of the formula I, which have isconfigurable have the most power and are therefore preferred

Detailed description of the invention.

Substances of the formula I and their pharmaceutically acceptable salts are cardiovascular agents. They act as a vasodilator agents that block the entry of calc the position, containing one (or a combination) the substance of this invention, the patient decreases blood pressure in a hypertensive mammal (e.g. human). For lowering blood pressure is suitable single dose or daily dose divided into two or four portions, providing a dosage of from about 0 1 to 100 mg per 1 kg of body weight per day, preferably about 1 to 50 mg per 1 kg per day. Preferably, the substances are prescribed pills, however, can also be used parenteral methods of purposes, such as subcutaneous, intramuscular, or intravenous.

In the activity block the entry of calcium compounds of the formula I and their pharmaceutically acceptable salts, they are protivogipertonicheskoe agents are also useful as antiarrhythmic agents, antianginal agents, antifibrillatory agents, anti-asthma agents, anti-ischemic agents, as agents to increase the ratio of HDL-cholesterol to total serum cholesterol in the blood, and in limiting myocardial infarction.

Additionally, the substance of this invention are useful as therapeutic agents for congestive heart failure for the treatment of diseases of the peripheral soudanese hypertrophy (e.g., hypertrophic cardiomyopathy), for the treatment of pulmonary hypertension, as an additive to cardioplegia solutions for cardiopulmonary bypass and as an adjunct to thrombolytic therapy.

In addition, it is assumed that the substances of the invention will be useful in the treatment of vascular disorders of the Central nervous system, for example, as anticatholicism agents, agents against migraine in therapy of Central ischemia and therapy subroutines hemorrhoids and also in the treatment of behavioral disorders of the Central nervous system, for example, in the treatment of psychiatric conditions, including depression, mania, anxiety and schizophrenia, or in the treatment of epilepsy, or to improve cognitive abilities.

Moreover, it is assumed that substances of this invention can be used as antidiarrhea agents in the treatment of dysmenorrhea, in the treatment of tinnitus and other hearing and vestibular apparatus, to facilitate various forms of tumors, to cancel the resistance to adriamycin, regulation of cell growth, for the treatment of glaucoma, kidney disease, hepatotoxicity (eg, cirrhosis), various hypersecretory endocrine, isichei dystrophy and cancer.

Substances of this invention can also be formulated in combination with a beta-adrenergic agent, or anti-arrhythmic agent, a diuretic, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichlormethiazide, polythiazide or benzthiazide, as well as ethacrynic acid, technofan, chlorthalidone, furosemide, muzolimine bumetanide, triamterene, amiloride and spironolactone and salts of such compounds, inhibitors of the enzyme that turns angiotesin, such as captopril, zofenopril, fosinopril enalapril, delapril, pentopril, inapril, ramipril, lisinopril, and salts of such compounds, thrombolytic agents, such as plasminogen activator tissue (Pat), recombinant Pat streptokinase, urokinase, proqinase and Antilibanus complex plasminogen streptokinase activator (APSAC, Eminase, Beecham of Labratories). In such products combinations, if they are made as a fixed dose, the substance of this invention are within the above described range of doses, and the other pharmaceutically active agent within the approved doses.

The substances of formula I can be used in the formulation moralnego purpose or in sterile solutions or suspensions for parenteral purposes. Substances of the formula I can also be administered via a transdermal patch or nasal inhalation solutions. Approximately 10-500 mg of the substance formula 1 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 substances of formula I can be prepared from corresponding compounds having the formula II

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Preparation of racemic and narramissic forms of the compounds of the formula II, when X is a group-CH2is described in U.S. patent 4752 645, issued June 21, 1988, for those substances in which R1is a group-CH(Y1)Y2and in U.S. patent 4748 239 dated may 31, 1988 for substances in which R1is a group-OY3and Y3is a hydrogen atom. Substances of the formula II in which X represents a sulfur atom, and R1group OY3prepared as described in U.S. patent 3562 257, issued February 9, 1971

Substances of the formula II in Sentabrya 1987 Substances of the formula II in which R1is a group-O-Y3and Y3is different from a hydrogen atom, can be obtained by alkylation or acylation (using traditional methods) of the corresponding compounds of formula II in which R1is a hydroxyl group.

Substances of the formula II in which R1is a group-OH, can be prepared in prizemistoj form through the interaction of racemic compounds of formula II, where R1is a group-OH with prizemistoj acid or amino acid

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where Z and Z1are different, using traditional metodiki acylation, such as a carbodiimide and a catalyst such as dimethylaminopyridine to get the mixture of diastereomeric compounds of the formula II in which R1is a group

This mixture diastereoisomeric compounds can be separated by experts in the field of chemistry, using chromatographic methods or crystallization. Nerezisca the compounds of formula II in which R1is a group-OH is obtained from purified diastereoisomers by hydrolysis with base, such as hydroxy sodium or sodium methoxide.

When printing handling is(for example, dimethylformamide or dimethylsulfoxide) with subsequent interaction with the compound of the formula III: R2-Z

where Z is tsepliaeva group, such as halogen or tolyloxy-receive the corresponding product of formula I.

Alternate, compound formula I can be obtained by reacting the compounds of formula II with the compound of the formula III under conditions of phase transfer in a mixture of water and dichloromethane or toluene in the presence of an appropriate base (for example, barium hydroxide or sodium hydroxide) and catalyst (e.g., designed chloride or hydrosulfate Tetra-n-butylamine).

Alternatively, the products of formula I in which R1is a group of-OH may be proaccelerin or proanimirovany (using traditional methods) to obtain the products of formula I in which R1this group-O-Y3and Y3different from the hydrogen atom.

An additional method of obtaining compounds of the formula I, in which R2is the group:

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enables handling of the compounds of formula II alkali metal hydride (e.g. sodium hydride) in an inert solvent ( for example dimethylformamide or dimethyl sulfoxide) with p the e the formula V

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When recovering the substances of the formula V using, for example, catalytic hydrogenation (for example, rhodium on aluminum oxide) receive the corresponding product of formula I, having formula VI

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During the restoration aminating substances of the formula VI to the corresponding aldehyde or ketone using a chemical reducing agent (e.g., cyanoborohydride sodium) receive the corresponding product of formula 1, having the formula VII

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in which at least one of the substituents Y6and Y7different from hydrogen.

Alternatively, the substances of the formula I, in which R2is:

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can be first prepared by treating compound of formula II with alkali metal hydride (e.g. sodium hydride) in an inert organic solvent (e.g. dimethylformamide or dimethyl sulfoxide) and subsequent interaction with a suitable compound having the formula VIII, Ra-L, in which the group Rarepresents a

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The resulting compound has the formula IX

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and can interact with ozone in an inert solvent (for example, geroizirovanny hydrocarbon) followed in order to teach proper connection those having the formula: X

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in which R6represents a

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The substance of formula X can be treated with the appropriate amine, having the formula XI H NY6Y7in the presence of a reducing agent (e.g. hydrogen, using a catalyst such as palladium on carbon, or chemical reducing agent, such as cyanoborohydride sodium), to obtain the corresponding product of formula I.

In addition, you may receive an intermediate product of the formula X, in which R6is a or

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through interaction of the compounds of formula II with the compound of the formula XIIa, XIIb

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Substances of the formula I, in which R2is a group

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can be synthesized by reaction of compounds of formula II with an alkylating agent such as chloroacetonitrile to get a substance of the formula I, in which R2is a group-CH2CH. The formed substance of the formula I, in which R2this is a group CH2CH, can interact with alcohol, such as ethanol, in the presence of a catalyst, such as hydrochloric acid or ethoxide sodium to obtain a substance of the formula I, in cat2N-(CH)2)nNHY6get the substances of the formula I, in which R2is a group.

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Preferred agents of this invention are those in which R3is located in position -6 or -7 benzazepine rings or position -8 or -9 benzodiazepinovogo kernel and represents a halogen atom, trifluoromethyl or methoxy group; and R4is located at position -4 of the phenyl ring to which it is linked and is alkoxygroup. Most preferred are compounds where R3are 6-trifluoromethyl-or 7-methoxy group at benzazepine core, or 8-methoxy group in benzodiazepinovom the nucleus, and R4is a methoxy group.

The following examples represent specific embodiments of this invention.

Example 1.

[1-(TRANS-3,4-1-[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 willamina)cyclohexane in 12 ml of dry dimethylformamide for 15 minutes This solution was stirred at room temperature for 20 min and then heated to 75oC for 70 minutes Add 0.15 g of sodium hydride and 0.8 g of (TRANS)-1-iodine-2-(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 silicagel with 1% triethylamine: a 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 specified in the title compound with a melting point above 250oC.

Analysis calculated for C27H34ClF3N2CIS)-1-[2-(Dimethylamino)propyl]-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-3-methyl-6-(trifluoromethyl)-2H-1-benzazepin-2-it, isomer monohydrochloride.

Mix a solution of 3.0 g (8.69 mmol) of (CIS)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-3-methyl-6-(trifluoromethyl)-2H-1-benzazepin-2-it in 90 ml of 2-butanol is treated with 1.7 g (of 10.75 mmol), 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-methoxy-phenyl)-3-methyl-6- (trifluoromethyl)-2-1-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 Resolume, dried with magnesium sulfate and evaporated. The residue is dissolved in diethyl ether, repeat the evaporation, and the residue Susan with a pump, receiving 3,86 g solids. After two crystallization from diisopropyl ether gain of 1.05 g of solid substance with a melting point of 154 157oC. Thin-layer chromatograph is torontofunny product Rf 0,17 (30:70 acetogenin).

The above 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 as a colourless solid with a melting point 159 161oC.

Analysis calculated for C24H29F3N2O2C 66,34; H OF 6.73; N 6,45.

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

The residue from the second crystallization from diisopropyl ether fraction from the above 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) and 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 hydrochloric salt with a melting point 101 104oC (foaming), sinters at 88oC. Thin layer chromatography: Rf 0.40 in (eluent 40:60 acetone-hexane) Rf 0.25 in (eluent 8:1:1 dichloromethane-methanol-acetic acid)

Analysis: calculated for C24H29F3N2O2HCl0,5H

Royal solutions in diisopropyl ether after crystallization of the free base of the isomer A of example 2 is evaporated to obtain 2.4 g of waxy precipitate. According to thin-layer chromatography (eluent 40:60 acetone-hexane) this material is approximately 40:60 mixture of isomer A and isomer B.

This mixture chromatographic 40 g Balcerowski silica gel, elute with a mixture of 40:60 acetone-hexane to obtain and 0.46 g of isomer B-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 of 83

86oC (foaming), sinters at 76oC. Thin layer chromatography: Rf 0,22 (eluent 40:60 acetone-hexane).

Analysis calculated for C24H29F3N2O2HCl0,5 H2O, C 60,05; H 6,51; N Of 5.84; Cl 7,39.

Found, C 60,0; H 7,00; N 5,62; Cl 7,17.

Example 4. (CIS)-1-[2-Amino-1-methylethyl]-1,3 4-5-tetrahydro-4-(4-methoxyphenyl)-3-biphenyl) a3-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 of a 60% dispersion in oil) in 15 ml of dry dimethylformamide added 1.50 g (4,29 mmol) of (CIS)-3-methyl-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it. The solution is stirred for 15 min at room temperature, cooled to 0oC and then add exactly at 0.42 ml (5 37 mmol) of 2-chloropropionitrile. The solution was stirred at 0oC 15 min, warmed to room temperature for 15 min and heated to 45oC for 90 min Add 50 mg of sodium hydride and 0.15 ml of chloropropionitrile and the solution stirred at 45oC 20 minutes

The reaction is interrupted by the addition of 1 molar solution of ammonium chloride, and dimethylformamide is removed under high vacuum with gentle heating. The residue is partitioned between ether and 1 molar solution of ammonium chloride, and the 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 (Boby get 0,90 g of pure BPI in the form of a white solid. When chromatography also obtain 0.34 g of almost pure less rolling isomer (DIF), which is soluble in hot hexane containing 5% diisopropyl ether. When cooled receive 0,29 g of pure RAC in the form of hexagonal prisms with a melting point 166-168oC. When chromatographicaliy mixed fractions receive an additional of 0.44 g of pure BPI (the total weight of 1.34 g) and 0.31 g DIF (total weight of 0.60 g).

B). (CIS)-2-(2-Amino-1-methylethyl)-1,3 4 5-tetrahydro-4-(methoxyphenyl)-3-methyl-6-(trifluoromethyl)-2H-1-benzazepin-2 he, isomer B, monohydrochloride.

A solution of 0.87 g of the more mobile isomer (CIS)-1 3 4,5-tetrahydro-4-(4-methoxyphenyl) a 3-dimethyl-2-oxo-6-(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, and the 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 the Nola 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 the connection header in the form of a white solid with a melting point 157-162oC (foams).

Analysis calculated for C22H26ClF3N2O2O21H2O, C 59,15; H 5,96; N 6,27; Cl 7,93; F 12,78.

Found, C 59,15; H 6,10; N 6,04; Cl 7,84; F 12,78.

Example 5. (CIS)-1-(2-(Dimethylamino)-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 0.62 g of (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 (of 1.52 mmol, see example 4) and 1.3 ml of 37% aqueous formaldehyde in 10 ml of acetonitrile is added at once with stirring to 0.31 g of cyanoborohydride sodium and then added 0.16 ml of acetic acid. This solution is stirred for 30 minutes Add ether and 5% potassium carbonate, the mixture separates into layers. The organic layer was washed with brine, dried with magnesium sulfate and evaporated, getting 0.84 g of thick oil. When chromatographicaliy on silica gel with a mixture of 2% methanol: 1% triethylamine: dichloromethane gain of 0.30 g of pure free base specified in the Uspenskiy is evaporated, and the residue is twice dissolved in methanol and evaporated.

To a glassy solid substance add hot diisopropyl ether and added dropwise hot methanol until the solid has dissolved. The solution is filtered, add hot Isopropylamine ether until a stable turbidity, and the solution is cooled and stored in the refrigerator, getting 220 mg specified in the header of a white solid, with a melting point above 220oC.

Analysis calculated for C24H30ClF3N2O20,60 H2O, C 59,84; H-6-53; N-5,81; Cl Was 7.36; F11,83.

Found, C-59,84; H-6,52; N-5,76; Cl-7,27; F-11-93.

Example 6. (CIS)-1-(2-(Dimethylamino)-1-methylethyl)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-3-methyl-6-(trifluoromethyl)-2H-1-benzazepin-2 he, isomer a, monohydrochloride.

A) (CIS)-1-(2-amino-1-methyl)-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)-a, 3-dimethyl-2-oxo-6-(trifluoromethyl)- 1H-1-benzazepin-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 in technoriver. 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.

B)(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 solution of 0.56 g of the crude (CIS)-1-(2-amino-1-methylethyl)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-3-methyl-6- (trifluoromethyl)-2H-1-benzazepin-2-it (1.38 mmol) in 10 ml of acetonitrile containing 1.2 ml of 37% formaldehyde added under 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% potassium carbonate solution, and 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 in the form of a foamy solid white. This material solution is emesto dissolved in methanol, and the solvent is evaporated. The solid is again dissolved in methanol, and the solution is filtered through Celite and evaporated. The solid is dissolved in 2 ml of thermal methanol and add hot diisopropyl ether until then, until you start blushing. The solution is cooled, and the solid is collected by filtration, getting 0.27 g specified in the connection header in the form of a crystalline solid with a melting point above 220oC.

Analysis calculated for C24H30ClF3H2O2. HCl, C-61,20; H, 6.42 Per; N-5,95; Cl-7,53; F12,10.

Found, C-61,15; H-6,52; N-5,88; Cl-7,71; F-11,78.

Example 7. (3R-(1-(R*)3,4)-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 0oC is treated dropwise with a solution of di-tert-BUTYLCARBAMATE (1 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 to shift the CSOs viscous oil (13 g). This crude material was used in subsequent reactions without further purification.

B) R-N-Methyl-2-pyrrolidineethanol.

Sociallyengaged (7.6 g, 200 mmol) is added in small portions to dry tetrahydrofuran (200 ml), cooled to 0 5oC. and Then added dropwise a solution of R-N-(tert-butoxycarbonyl)-2-pyrrolidineethanol (13 g untreated, 50 mol) in 100 ml dry tetrahydrofuran under thorough stirring for 45 minutes After 30 min at 0oC room temperature the reaction mixture is heated to boiling (under reflux) for 16 hours Then the reaction mixture was cooled to 0oC, and 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, hydochloric.

To a solution of R-N-Il (0.74 g, to 52.1 mmol). The reaction mixture is heated to boiling for 2 h and then cooled to room temperature and concentrate 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*)-3,4))-1-((1-methyl-2-pyrrolidinyl)methyl)-3-(hydroxy)-1,3,4,5-tetrahydro-4(4-methoxyphenyl) -6-(trifluoromethyl)-2H-1-benzazepin-2-it.

Sodium hydride (0,19 g, 8.1 mmol) are added to a solution of (3R - 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) and the mixture heated to 80oC 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 to 3% methanol in dichloromethane to poluchi,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-(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-dimethylaminopyridine (0.07 g, 1.07 mmol) in dry dichloromethane (6 ml) stirred at room temperature for 60 hours, the Reaction mixture is then absorbed by the silica gel (60 to 200 mesh), poured into a column of silica gel and elute the mixture of 1 to 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 ether 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) with a melting point of 158 162oC.

()D+ to 126.8 deg. (C 1.0 mmol/l in methanol).

Analysis calculated for C26H30ClF3N21,0 H2O, C-57,31; H-Of 5.92; N-5,14; Cl-6,51; F-10,46.

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

Example 8. (3R-(1(S*),3,4))-3-(the atomic charges)-1-(2-(dimethylamino)-3-phenylpropyl)-1, 3, 4, 5-tetrahydro-4-(4-methoxyphenyl)-6-trifluoromethyl)-amino-3-phenyl-1-propanol (6.0 g, 4.0 mmol) and 37% aqueous formaldehyde (20ml) 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 2n. potassium hydroxide solution (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, obtaining mentioned in the title compound as a viscous oil (6,48 g).

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

K S-2-(Dimethylamino)-3-phenyl-1-propanol (3.0 g of 16.7 mmol) in 20 ml of chloroform at 0oC 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 PKE connection in the form of not-quite-white solid (2.38 g) with a melting point 167,5-168,5oC.

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-(hydroxy)-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it (of 1.05 g, 3.0 mmol) in 30 ml of dry dimethylformamide. This mixture was stirred at room temperature for 1 h, after which add 0,89 g (4.5 mmol) of the hydrochloride of (S)-1-chloro-2-(dimethylamino)-3-phenylpropane and the mixture is heated to 85oC for 2 h, the Reaction mixture is cooled terminate the reaction by adding water and extracted three times with etiracetam. 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-(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-dimethyl)amino)-3-phenylpropyl)-1 3, 4, 5-tetrahydro what eliminatedin (0.55 g, a 4.53 mmol) in dry dichloromethane (25 ml) was stirred at room temperature for 16 hours

The reaction mixture absorb silica gel (60-200 mesh), poured into a column of silica gel and elute with a mixture of 5-25% ethyl acetate in hexane, getting mentioned in the title compound as free base (white foam). This free base is dissolved in ether and adding an excess of ethereal solution of hydrogen chloride, to obtain specified in the title compound as a white solid (0.96 g) with a melting point 144-147oC.

()D+52,40 deg.C 1.0 mol/l in methanol).

Analysis calculated for C31H34ClF3N2O40,76 H2O, C-61,56; H-of 5.92; N-4,63; Cl-5,86; F-9,42

Found, C-61,60; H-6,00; N-4,59; Cl-5,93; F-9,23.

Example 9. (3R-(1(R*),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) 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 m (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 2n. potassium hydroxide solution (250 ml). The mixture extragere with ethyl acetate three times and the combined extracts washed with 1N. potassium hydroxide solution and extracted three times with 1H. a solution of 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).

B) 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 0oC 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) with temperature PL is ro-4-(4 - methoxyphenyl)-6-(trifluoromethyl)-2H-I-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 at room temperature for 1 h, after which add 0,60 g (3.0 mmol) of the hydrochloride of (R)-1-chloro-2- (dimethylamino)-3-phenylpropane, and the mixture is heated to 80oC for 2.5 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 and brine. Filtered, dried over anhydrous magnesium sulfate and concentrated. The crude product chromatografic on a column of silica gel and elute the mixture of 20 to 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-(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-(1R*), 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, of 1.95 mmol), acetic anhydride (1.0 g, 9.8 mmol) and 4-dimethylaminopyridine (0,48 g, 3.90 mmol) in dry dichloromethane (20 Liveout on a column of silica gel and elute with a mixture of 5 to 25% ethyl acetate in hexane, getting 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 title compound as a white solid (0,61 g) with a melting point of 146 150oC.

()D+137,3 deg. (C=1.0 mol/l in methanol).

Analysis calculated for C31H34ClF3N2O40,56 H2O, C-61,93; H-Of 5.89; N-4,66; Cl-5,90; F-9,48.

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

Example 10. (3R-CIS)-1-(2-(Dimethylamino)-1-methylpropyl)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

The following preparation is carried out in the atmosphere. Mix a solution of (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-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-methylpropan (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 78oC for 1.25 h

After cooling, the weight of dimethylformamide at the and 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, This number combined with 0.64 g of the product from previous experience, dissolved in ether, filtered to transparency and evaporated. 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. Salt is separated and the organic layer extracted with 40 ml of water. The combined aqueous phase is washed (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), the combined layers washed with an ethyl acetate 20 ml Resolume, dried with magnesium sulfate and finally evaporated at a pressure of 0.2 mm receiving 3,66 g of solid substance.

During the subsequent crystallization from 25 ml of hot isopropanol get colorless material (free base of the compound indicated in the title) weight of 2.36 g with a melting point of 157 159oC (sinters at 155oC).

Analysis calculated for C24H29F3N2O3C-63,98; H-of 6.49; N-6,2 1,2 ml of 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 getting after drying when the pump pumping 2.67 g specified in the title compound as a colourless solid with a melting point 90-93oC (foaming), sinters at 82oC. ()D+114 deg. (C=1.00 mol/l, methanol).

Analysis calculated for C24H29F3N2O3HCl0,5H2O, C-58,12; H-6,30; N-5,64; Cl-7,15.

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

Example 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, and 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-(peremeshivayte 1 h at room temperature, heated to 70oC, and the 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 mmol) is stirred in 5 ml of dimethylformamide for 2 min and added to the reaction mixture alkylation. The resulting solution was stirred at 70oC for 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) to give 1.90 g of pure more rolling isomer (BPI is t 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 of diisopropyl ether by heating, and the solution is filtered from a small amount of insoluble material.

The filtrate is 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 a melting point 136-142oC.

()D+146,2 degrees (C=1 mol/l, methanol).

Analysis: calculated for C28H30ClF3N2O30.52 mol H2O, C-61,77; H-5,75; N-5,14; Cl-6,51; F-10,47.

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

Example 12. (3R-CIS)-1-(2-(Dimethylamino)-1-phenylethyl)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6-(tryptomer)-2H-1-benzazepin-2-it, isomer B, monohydrochloride.

When chromatography 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 A, there was no fractions containing the less mobile isomer (DIF). The fractions containing DIF (contaminated Brucite 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-(trifluoromethyl)-2H-1-benzazepin-2-it.

This material chromatographic on six plates for thin-layer preparative chromatography (eluent of 5% methanol/dichloromethane) baseband 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 of the compound indicated in the title. This material is dissolved in ether, filtered through Celite to remove the haze and add ether saturated with hydrogen chloride. The resulting solid white filtered, washed 2 times with ether, and dried in air receiving 0,42 g is specified in the header of a substance in the form of a white solid with a melting point 165-171oC. ()D+221,8 deg. (C 1 mol/l, methanol).

Analysis calculated for C28H30N2O3ClF30,49 H2O, C-61,84; H-5,74; N-5,15; Cl-6,51; F-10,48.

Found, C-61,84; H-5,851; N Is 5.07; Cl-6,12; F-10,-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

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

Powdered anhydrous carbernet potassium (41 g, 297 mmol) is added under stirring to a solution of 5-2-pyrrolidineethanol (6g, 59,32 mmol) in 120 ml of acetone. The mixture is cooled to 0oC and added dropwise to benzylchloride (16,94 ml, 118,6oC mmol). After 40 min the reaction mixture was diluted with atidaryta and water. The organic layer is separated and the aqueous layer was extracted with ethyl acetate. The organic extracts combine 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 is specified in the header of the substance in the form of a light yellow oil.

B) 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 concentrate the filtrate and purify chromatographies (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-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-he (0.8 g, 2.3 mmol). After 1 h at room temperature added 0.97 g (3.4 mmol) of (S)-1-(benzyloxycarbonyl)-2-(methyl bromide)-pyrrolidine.

The reaction mixture is heated at 65oC for 2.5 h, and 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 65oC the mixture is cooled, and 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 the 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)methyl)-1,3,4,5-tetrahydro-4- (4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it.

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

The ammonium formate (0,23 g of 2.64 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 header of the connection in view of the rad. (C 1.0 mol/l in methanol).

Analysis calculated for C25H27F3N2O4HClO0,29H2O, C-58,06; H Lower Than The 5.37; N-5,42; Cl-6,86; F-11,02.

Found, C-58,37; H Lower Than The 5.37; N Is 5.54; Cl-7,05; F-Of 10.58.

Example 14. (3R-(1(S*),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) S-N-(tert-Butoxycarbonyl)-2 pyrrolidineethanol.

A solution of S-2-pyrrolidineethanol (10 g, 100 mmol) in dry dichloromethane (250 ml) is treated at 0, 5oC is 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.

B) 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 5oC to a suspension of sociallyengaged (11.4 g, 300 mmol). The mixture is refluxed for 16 hours Then cooled in a bath of ice water, and the excess hydride is destroyed by adding dropwise a saturated solution of sodium sulfate is Ino washed 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 97oC/500 mm RT.article.

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

Chloride thionin (3.28 ml, 45 mmol) is added dropwise to a solution of S-N-methyl-2-pyrrolidineethanol (1.73 g, 15 mmol) in 15 ml of chloroform at 0 - 5oC. 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-tetrahydro-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 0oC and add hydrochloric salt (S)-2-(chloromethyl)-2-1-methylpyrrolidine (0.52 g, 3 mmol). After stirring at room temperature for 1 h, add additional sodium hydride (0, what tatom. 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 g) as a white foam.

E) (3R-(1(S*), 3,4)-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.

N, N-Dimethylaminopyridine (0,41 g, to 3.34 mmol) are added to a solution of (3R-(I(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, 1,67 mmol) and acetic anhydride (0,79 ml, 8.4 mmol) in dichloromethane (18ml). 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 23% 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 you the treatment in the form of a white solid (0,536 g), with a melting point 151-154oC.

()D+ 80,0 deg. (C 1 0 mol/l in methanol).

Analysis calculated for C26H29F3N2O4HCl0,63H2O, C-58,00; H-5,85; N-5,20; Cl-6,59; F-10,59.

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

Example 15. (3R-(I(R*), 3,4)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-1-(2-pyrrolidinyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

A) R-N-(Benzyloxycarbonyl)-2 - pyrrolidineethanol.

Benzyl ether of Harborview acid (6 ml of 39.5 mmol) added dropwise at 0oC to a suspension of powdered anhydrous potassium carbonate (13,7 g, 99 mmol) and (R)-2-pyrrolidineethanol (2G, 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).

B) R-1-(Benzyloxycarbonyl)-2-(methyl bromide)pyrrolidin.

A solution of R-N-(Benzyloxycarbonyl)-2-pyrrolidineethanol (4,55 g, anatoy temperature during the night. 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)-3-hydroxy-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6-(tryptomer)-2H-1-benzazepin-2-it.

To a suspension of sodium hydride (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 80oC the 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 receiving specified in the header connection (4,32 g) contaminated with unreacted (3R-CIS)-3-(hydroxy)-4-(4-methoxyphenyl)-6 - trifluoromethyl)-2H-1-benzo is-6- (trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

The ammonium formate (1.8 g, 28.3 mmol) is added at once to suspene catalyst 10% palladium on coal (1G) and (3R-(1(R*),3,4))-1-((1-benzyloxycarbonyl-2-pyrrolidinyl)methyl)-3-hydroxy-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-she (3.5 g, to 5.66 mmol) in 60 ml of methanol. The 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 under reduced pressure and finally under vacuum get mentioned in the title compound in the form of not-quite-white solid (0.21 g), melting point 147-151oC.

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

Analysis calculated for C23H25F3N2O3HCl1,0H2O, C-56,50; H Is 5.77; N-5,73; Cl-7,25; F-11,66.

Found, C-56,76; H-5,74; N-5,50; Cl-7,12; F-11,36.

Example 16. (3R-(1(S*)3,4)-1, 3, 4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl(-biloxicasino-2-pyrrolidinyl)methyl)-3-hydroxy-1,3,4,5-tetrahydro-4-(4-methoxyphenyl) -6-(trifluoromethyl)-2H-1-benzazepin-2-he

To a suspension of sodium hydride (0,19 g, 4.8 mmol) in dimethylformamide (40 ml) was added (3R-CIS)-3-(hydroxy)-4-(4-methoxyphenyl) -6-(trifluoromethyl)-2H-1-benzazepin-2-he (1,41 g, 4 mmol). After 1 h, add 1.7 g (6 mmol) (S) 1-(benzyloxycarbonyl)-2- (methyl bromide)pyrrolidine and the mixture is heated to 80oC 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-(trifluoromethyl)-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(S*), 3,4))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-1-(2-pyrrolidinyl)-6- (tryptomer)-2H-1-benzazepin-2-it, monohydrochloride.

The ammonium formate (0,57 g, 9.1 mmol) are added to a suspension of the catalyst is 10% palladium on coal (0.34 g) and (3R-(1(S*),3,4)-1-((1-benzyloxycarbonyl-2-pyrrolidinyl)-methyl)-3-Gidroagregat to boil for 30 min, cooled and filtered through anhydrous magnesium sulfate.

The remainder of the solids washed with ethyl acetate. The combined filtrate is concentrated and then chromatografic on a column of silica gel. Elute 2.5% methanol in ethyl acetate and then 10% methanol in dichloromethane, receiving specified in the header of the 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 70oC to get listed in the title compound (0.64 g), melting point 159-163oC.

()D+71,3 deg. (C 1.0 mol/l in methanol).

Analysis calculated for C23H25F3N2O3HCl,0,5 H2O,

C-57,56; H-5,67; N Of 5.84; Cl-7,39; F-11,88

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

Example 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), is heated in 50 ml of acetic anhydride, heated to 110-124oC (bath temperature) in an oil bath. Acetylation of the society (analysis thin-layer chromatography). In parallel, gradually in the course of heating the formed by-product with a high value of Rf. After cooling, the mass of acetic anhydride is removed on a rotary evaporator at a pressure of 0.2 mm RT.article 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) and dried in vacuum. When a solid substance contains no solvent, it loses hydroscopicity and can be exposed to the atmosphere. The weight of 1.23 g, melting point 88-91oC (bubbles) is sintered at 81oC.

()D+104 deg. (C=1.0 mol/l in methanol).

Analysis calculated for C26H31N2O4HClH2O, C-57,09; H-6,26; N-5,12; Cl-6,48.

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

Example 18. (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, Manager the

To a mixed solution of 10 g of (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it (28.5 mmol) and 4,85 mmol of imidazole (71,2 mmol) in 10 ml of dry dimethylformamide at 35oC add 5.10 g of tert-butyldimethylsilyloxy. The solution is stirred overnight at 35oC, 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 title compound as an amorphous solid with a melting point 114-116oC.

B) (3R-CIS)-3-(tert-butyldimethylsilyloxy)-1-(1-cyano) -propyl)-4-(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-butultimately-silyloxy)-4- (4-methoxyphenyl)-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, and the solution is heated to 75oC for 1 h

Add an additional 0.15 g of sodium hydride and 0.3 g 2 chlorobutyronitrile, and the solution is heated to 75oC in techine careful heating. The residue is partitioned between ether and odnomernym solution of ammonium chloride, the organic phase is washed with water and brine, dried with magnesium sulfate and evaporated, getting 4.68 g of a brown resin. By thin-layer chromatography (eluent 50% ether in hexane) shows that 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 a melting point 54-57oC.

C)(3R-CIS)-1-1((amino)methyl)propyl)-3-(tert-butyldimethylsilyloxy)-1-(1-cyano)propyl)-4 (4-methoxyphenyl)-6- (trifluoromethyl)-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 - Benahavis-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 with 2 restoratio 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-butyldimethylsilyloxy)-4-(4-methoxyphenyl )-6-(trifluoromethyl)-2H-1 - benzazepin-2-it.

To 0.26 g of solid cyanoborohydride sodium (4.2 mmol) at 0oC added with stirring in small portions a solution to 0.70 g of (3R - CIS)-1-(1-((amino)methyl propyl)-3-(tert-butyldimethylsilyloxy)-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 receiving 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)-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-butyldimethylsilyl is 0.55 g of three-hydrate tetrabutylammonium fluoride (1,74 mmol) at one time, in the form of solids. The solution is stirred for 20 min, partitioned between ether and water, and the organic layer washed with 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 suspension 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 144-148oC ()D+89,60 deg. (C=1 mol/l in methanol).

Analysis calculated for C24H30ClF3N2O31,06 H2O,

C-56,96; H-6,38; N Is The 5.45; Cl-7,24; F-11.11 IS

Found, C-56,96; H-6,40; N Is 5.54; Cl-7,00; F-Of 11.26.

Example 19. (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.

A) (3R-CIS)-3-(tert-butyldimethylsilyloxy)-1-(1-cyano)-propyl) -4-(4-lot isomer (DIF) PI chromatographicaliy nitrile mixture, described for (3R-CIS)-1- (1-Dimethylamino)methyl)propyl)-1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride (see example 18). The fractions containing DIF, are combined and evaporated, getting 1,91 g of solid substance.

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 - benzazepin-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-benzazepin-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, which is 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-(tertBUTYLPEROXY)-4-)4 methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2-it.

To 0,46 g hard cyanoborohydride soda is l)propyl)-3-(tert-butyldimethylsilyloxy)-4- (4-methoxyphenyl)-6-trifluoromethyl)-2H-1-benzazepin-2-she of 2.27 mmol) and 2.1 ml of 37% aqueous formaldehyde in 20 ml of acetonitrile, then add pure acetic acid.

Remove the ice bath, the solution is stirred for 2 h, add 0.15 ml of acetic acid and 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 Rf0,52 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-2He, isomer a, monohydrochloride.

To a solution of 0.44 g of (3R-CIS)-3-(tert-butyldimethylsilyloxy)-1- (1-(dimethylamino)methyl)propyl)-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-tetrabutylammonium (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 compound as a white solid with a melting point of 126 131oC.

()D+106,8 deg (C 1 mol/l in methanol).

Analysis calculated for C24H30ClF3N2O30,78 H2O, C-57,54; H 6,35; N-5,59; Cl-7,08; F-11,38.

Found, C-57,54; H-6,39; N-5,64; Cl-Of 6.96; F-11,09.

Example 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-it, isomer B, monohydrochloride.

A) (3R-CIS)-3-(tert-butyldimethylsilyloxy)-(3R-CIS)-3- (tert-butultimately-silyloxy)-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzo-zipin-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 50oC 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 50oC for 3 hours the Solution is cooled to room temperature, concentrated in vacuo to remove the 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 with 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 - benzazepin-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 - benzazepin-2-she (1.5 mmol) in 100 ml of methanol, saturated with ammonia at 0oC for 5 min and add 0.2 g of a catalyst of 5% rhodium oxide of al is 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 is 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-methoxyphenyl) is 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 50oC for 1 h Add an additional 0.02 g of sodium hydride and 0.07 ml 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, to which ylamine 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-benzazepin-2-it, isomer B, monohydrochloride.

To a solution of (3R-CIS)-1-(1-((methylamino)methyl)ethyl)-3 -(tertBUTYLPEROXY)-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 0,320 g (C=1 mol/g, in ethanol).

Analysis calculated for C22H25F3N2N2HCl 0,98 H2O, C-55,45; H-5,90; N-5,73; Cl-7,94; F-Of 11.61.

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

Example 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-5-he.

Add 1.0 g (2,86 mmol) of (CIS)-1,3,4,5-tetrahydro-4- (4-methoxyphenyl)-3-meteo-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 45oC for 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 mg of hexane and cooling during the night recip is 4,5 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 A and 146 mg of the catalyst 10% palladium on coal in 50 ml 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 nuclei1H and C13the 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 and are collected by filtration, washed 2 times with ether and dried in vacuum at 75oC for several days to get listed in the title compound (0,58 g, 79%) as white solid powder with a melting point of 165 170oC.

Analysis calculated for C25H23F3N2O20,9HCl0,19H2O, C-63,00; H-5,13; N-5,88; Cl-6,69; F-11,96.

Found, C-63,00; H-4,87; N-6,03; Cl-6,55; F-To 11.79.

Example 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. the-2-he.

To a solution of 2.0 g (5,69 mmol) (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it in 10 ml of dry dimethylformamide added 230 mg of sodium hydride (5,69 mmol of a 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 to make from the solution is filtered and washed with cold ethyl acetate. Obtain 1.68 g (63%) specified in the header of A 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 (0,44-metom and water. The aqueous phase is extracted with ethyl acetate (3 times 50 ml). The combined organic phases are washed with water, odnomomentnym solution of sodium bicarbonate and brine and dried over magnesium sulfate. The solvent is removed in vacuum, obtaining of 0.85 g (46%) indicated in the title B compound as a yellow solid.

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

To a solution of 0.85 g (of 1.65 mmol) substances specified in the header B 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%) indicated in the title C compound.

D) (3R-CIS)-1-(2-dimethylaminophenyl)-1, 3, 4, 5-tetrahydro-4-(4-methoxyphenyl)-3-atomic charges-6 (trifluoromethyl)-2H-I - benzazepin-2-it, monohydrochloride.

Hard cyanoborohydride sodium (62 mg, 0.98 mmol) is added a solution of 120 mg (0.25 mmol) of the compound of the title C and 0.6 ml of 37% aqueous 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 is of carbonate potassium. The organic phase is washed with aqueous potassium carbonate solution, water and brine, dried over magnesium sulfate and evaporated. The residue is dissolved in ether, and after adding an ethereal solution 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-hydroaxe-6-(trifluoromethyl)-2H-1-benzazepin-2-it, 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 is 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 ethylacetate 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 chloride Woogo in the header of the substance with a melting point of 217 to 220oC.

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

Analysis calculated for C26H25F3N2O3HCl 0,72 H2O,

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

Found, C-60,07; H At 5.27; N-5,18; Cl-6,89; F-To 10.62.

Example 23. (3R-CIS)-1, 3, 4, 5-tetrahydro-4-(4-methoxyphenyl)-3-hydroxy-1-(2-pyridinylmethyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

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) 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, the solids filtered off, washed with butanolom, 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 Resolume, dried with magnesium sulfate and finally the solvent is evaporated at a pressure of 0.2 mm RT. senior Get of 7.3 g of a light yellow foamy residue. The residue after curing for Saturday and Sunday rastvoryayutsya, getting to 6.9 g of light yellow brittle foam. According to thin-layer chromatography (TLC) Rf=0,65 (eluent a mixture of 95:5 methylene chloride:methanol).

Above the base in 50 ml of methanol is treated with 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 T melting point 184-186oC (foaming).

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

Analysis calculated for C24H21F2N2O3HCl 0,75 H2O, C-58,54; H-To 4.81; N-5,69; Cl7,20.

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

Example 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 completely severe is more, getting 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%) of isomer And with a melting point 177-180oC.

Isomer And dissolved in 20 ml of hot isopropanol. Filtered through a mesh filter (to remove traces of catalyst), cooled overnight and filtered, getting to 0.72 g of nearly colorless solid, ()D+112 degrees (C= 1 mol/l in methanol). After recrystallization from 18 ml of hot isopropanol product weight equal to 0.63 g (21%), melting point 177-180oC ()D+113 degrees (C=1 mol/l in methanol). (TLC)Rf=0,59 (eluent mixture of 80:20 methylene chloride:methanol).

Analysis calculated for C24H27F3N2O3HCl0,25H2O, C-58,89; H-By 5.87; N-5,72; Cl-7,24.

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

(3R-CIS)-1, 3, 4, 5-tetrahydro-4-(4-methoxyphenyl)-3-hydroxy-1-(2 piperidinylmethyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride, isomer B/

Upon evaporation of the filtrate obtained in the first crystallization of the isomer A, gain of 1.46 g of the crude isomer B. After converting a free base, followed by chromatographytandem on to which the material is 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. When removing the solvent in vacuo get solid, which is triturated with ether, receiving of 0.54 g of product with a melting point 130 140oC ()D+66 degrees (C=1 mol/g), in methanol).

Analysis calculated for C24H27F3N2O3HCl1,25 H2O, C-56,80; H-6,05; N-5,52; Cl-6,98.

Found, C-56,77; H Is 5.77; N-5,39; Cl-6,93.

Example 25. (3R-(1-(R*), 3,4))-1,3,4,5-tetrahydro-3-hydroxy-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-tetrahydro-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-tetrahydro-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it.

Sodium hydride (1.44 g, of 5.99 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 0oC and add one of 7.36 g (30 mmol) of (S)-1-(benzyl-2-(chloromethyl)pyrrolidine. The mixture is heated to room is stragiht three times with ethyl acetate. United an ethyl acetate extracts are washed with 10% aqueous solution of sodium chloride, dried with magnesium sulfate, filtered and concentrated. Solid orange dissolved in a minimum amount of 0.5 N. hydrochloric acid and extracted 3 times with ether to remove unreacted (3R-CIS)-3-(hydroxy)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-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-tetrahydro-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 betw the C 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 3 times with ethyl acetate. The combined extracts washed with water, dried with magnesium sulfate, filtered and concentrated. Get a mixture of compounds C and D specified 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 sulfate and elute 15 to 30% ethyl acetate in hexane, to get the connection specified in the header of the E (7,89 g 85%) Rfof 0.38 (silica gel, 50% ethyl acetate in hexane) and the connection specified in the header of F(0.87 g, 9.4 per cent); Rfof 0.50 (silica gel, 50% ethyl acetate in hexane).

G), (3R-(1(R*), 3,4-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-1-(3-piperidinyl)-6-trifluoromethyl)-2H-1 - benzazepin-2-it, 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). Then after 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 is HCl. The solution is concentrated under reduced pressure and finally vacuum to obtain specified in the title compound (450 mg, 68%) as a white solid with a melting point of 183 188oC ()D+102,6 (C 1 mol/l in methanol).

Analysis calculated for C23H25F3N2O3HCl H2O, C-56,51; H Is 5.77; N-5,73; Cl-7,25.

Found, C-56,58; H-5,75; N-Of 5.53; Cl-7,02.

Example 26. (3R-(1(R*), 3,4-3 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-(benzyloxy-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 μl of acetyl chloride. The reaction mixture is heated at 70oC 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 UP>*), 3,4-3 atomic charges)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1-(3-piperidine)-6- (trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

To a solution of the compound indicated in the title of A (920 mg, 1.53 mmol) in 25 ml of ethyl acetate and 1 ml triperoxonane acid was added with stirring to 200 mg of the catalyst of Pearlman, MD hydroxide, palladium 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 hidrocarbonetos potassium. 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 mg of the free base as a white foam. This free amine pressure, getting 420 mg specified in the title compound (65%) as a white solid with T melting 177-180oC.

()D+107,9 degrees (C=1, methanol)

Analysis calculated for C25H27F3N2O4HCl0,81 H2O, C-56,91; H-5,66; N-5,31; Cl-6,72; F-10,80.

Found, C-56,84; H-5,67; N-5,38; Cl-6,41; F-10,79.

Example 27. (3R-(1(S*), 4,3 6-Chloro-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-1-(2-pyrrolidinyl)-2H-1-benzazepin-2-it.

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

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

B) S-N-tert-butoxycarbonyl-2-(methyl bromide)pyrrolidin.

Specified in the header of A connection (29,8 g, 148,3 mmol) and chetyrehhloristy carbon (99 g, 297 mmol) triphenylphosphine (77,8 g, 297 mmol) in 1000 ml of ether is stirred at room temperature for 18 hours Solid precipitate is removed by filtration, and the solids are well washed with hexane. When the concentration of the filtrate receives a yellow liquid, which after rzanovo header B (45%), in the form of a colourless liquid.

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

(CIS)-6-Chloro-4-(4-methoxyphenyl)-3-hydroxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-he (3.0 g, 9,44 mmol) are added to a suspension of sodium hydride (0.27 g, 11,33 mmol) in 95 ml dimethylformamide (sustained over molecular sieve 4A) and stirred for 1 hour Add the connection specified in the header of B (3.0 g, 11,33 mmol), and the mixture is heated 3 hours at 80oC. Add an additional 0.11 g (4,58 mmol) of sodium hydride and the connection of the header B (1.25 g, 4,72 mmol). Editorial mixture is heated for 2 h at 80oC, cooled 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 C (0.65 g, 13.7 percent). ()D+to 135.2 degrees (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)-2H-1-benzazepin-the l of methylene chloride was stirred at room temperature for 6 hours Add saturated aqueous solution of potassium bicarbonate to podselect the reaction mixture which is then diluted with water and extracted 3 times with ethyl acetate. Combined extract is dried with magnesium sulfate, filtered and concentrated, obtaining 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 T melting 80-84oC. ()D+148,0 degrees (C=1 mol/l in methanol).

Analysis calculated for C22H25ClN2O3,4-3 (atomic charges)-6-chloro-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1-(2-pyrrolidinyl)-2H-1-benzazepin-2-he

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 the compound of the title (C) from example 27 (0,72 g), 1.44 mmol) and acetic anhydride (0.68 g, 7.2 mmol) in 20 mmol 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 header is)-1-(2-pyrrolidinyl)-2H-1-benzazepin-2-it.

A solution of the compound indicated in the heading A, (0.65 g, 1.20 mmol) and triperoxonane 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 and then water before you extracted it with ethyl acetate (3 times). Dried over magnesium sulfate, filtered and concentrated, obtaining specified in the header of the connection (of 0.53 g, 100%) as a white foam, with T melting 74-78oC: ()D+130,0 deg. (C 1, methanol).

Analysis calculated for C24H27CIN2O40,29 H2O,C-64,33; H-6,20; N-6,25; CI TO $ 7.91.

Found, C-64,61; H-6,03; N-5,96; CI-7,51.

Example 29. (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.

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

To a suspension of 20 g IS,2R-karatekin-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 the free base is billaut 42 ml of 37% aqueous formaldehyde solution. With periodic cooling in a bath of ice added to 10.5 g cyanoborohydride sodium (167 mmol) in solid form. Again with periodic cooling, added dropwise glacial acetic acid until then, until the pH is reduced to 8. The solution was stirred at room temperature for 30 min and evaporated. The residue is extracted three times from 2n. the sodium hydroxide solution with ether and the combined ether extracts are washed with 0.5 g of 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%) indicated in the title A compound as a white crystalline substance.

B) IR-2R-(N-dimethylamino)-1-phenyl-1-chloropropane.

To a solution of compound from A header (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 0oC is not allocated a solid product. Distilled methylene chloride and the remaining ravago solids, which is collected by filtration, washed 3 times with hexane and air-dried. When recrystallization from 150 ml of acetone and 5 ml of methanol receive 0,98 g of compound indicated in the heading B (isomer A) as a pale brown prisms.

()D-110,9°. C 1 mol/l in methanol).

C) (3R-(1(2R*), 3,4-1-(2-dimethylamino)-1 - phenylpropyl)-3-(tert-butyldimethylsiloxy)-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-(trifluoromethyl)-2H-1-benzazepin-2-she (to 1.61 mmol).

The solution is stirred for 10 min, heated to 70oC and add a solution of 0.87 g (3,22 mmol) of the compound from header B 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 title B 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 remainder distributed IU the mandate, getting 1.51 g light yellow oil. Flash chromatography on silica gel (eluent of 40% ethyl acetate in hexane) gives of 0.58 g of compound indicated in heading (C) in the form of a white solid pans, contaminated with 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 C 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 salts 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 value of Rfof 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 0,37 g free on the Fira, 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, obtaining 205 mg specified in the title compound as a white solid foam with a melting point above 220oC ()D+180 deg (C 1 mol/l in methanol).

Analysis calculated for C29H31F3N2O3HCl 1,26 H2O, C 60,92; H 6,09; N 4,90; Cl 6,20; F Becomes 9.97.

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

Example 30. (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, monohydrochloride, isomer B.

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

To a suspension of 1.08 g of sodium hydride, (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-dimethylamine)-1-phenyl-1-avaudioplayer (13 mmol, see example 29) in the solid is recarbonate sodium, the dimethylformamide is removed in a high vacuum careful when heating, and the residue partitioned between ether and aqueous potassium carbonate solution. The organic layer was washed with brine, dried with magnesium sulfate and evaporated getting 6,18 g of a thick brown oil by the Method of 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 Rf0,41 g in 50% ethyl acetate in hexane) contaminated with a small amount of more 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.

C) 3R-(1(2R*), 3,4 )-1-(2-dimethylamino) -1-phenylpropyl)-1,3,4,5-tetranitro-3-hydroxy-5-(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 sweat four preparative plates for thin-layer chromatography (eluent-75% ethyl acetate in hexane. The band corresponding to the value of Rf0,19 (75% ethyl acetate in hexane), extracted with a mixture of 5% methanol in methylene chloride, and the solution is filtered and evaporated to obtain 0.50 g of the free base specified in the title compound, as a white solid foam. This free base is dissolved in ether, the filtrate 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 a melting point 191 - 192oC.

()D+242,6 deg (C 1.05 mol/l in methanol).

Analysis calculated for C29H31F3N2O3HCl 0,22 H2O, C 62,98; H 5,91; N 5,06; Cl 6,41; F 10,30.

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

Example 31. (3R-(1(2S), 3,4)-1-(2-(Dimethylamino)-1-phenylpropyl)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxide OpenAL.

To a stirred solution of 1R, 2S-norephedrine (25 g, 0,165 mol) and 50 ml of formaldehyde (37% solution in water) in 150 ml of acetonitrile at 0oC added 16.3 g cyanoborohydride sodium (0.26 mol) in several portions. Within 20 min 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 with natalitetom magnesium 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.

B) (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 taanila (122 mmol) in 15 ml of chloroform, the Reaction mixture is 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 get to 2.29 g (80%) of the compound indicated in the heading B in the form of a yellow solid, containing 15% 1S, 2S-isomer.

iffany)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, isomer B.

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 dry dimethylformamide added sodium hydride as a 60% dispersion in oil (0.39 g, 9,67 mmol). The reaction mixture was stirred for 1 h in argon atmosphere at room temperature. Add 0,76 g (3,22 mmol) undiluted substances from header B, and the reaction mixture is stirred at 50oC 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 heading C.

D) (3R-(1(2S*),3,4))-1-(2-Dimethylamino) -1-phenyl-propyl)-1, 3, 4, 5 tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride, isomer B.

To a stirred solution of 1.18 g of the compound of the title C (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 iolence 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, receiving of 0.47 g of pure indicated in the title compound with a melting point 148-151oC.

()D+167,6 deg (C=0.75 mol/l, in methanol).

Analysis calculated for C29H31F3N2O3HCl1,87H2O, C-59,77; H-6,18; N-4,80; Cl-Between 6.08; F-9,78.

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

Example 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 (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, monohydrochloride, isomer A.

A mixture of compound indicated in the heading And (0.4 g 1,72 mmol), the compound from part a of example 18 (0.8 g, of 1.42 mmol) and cesium carbonate (16, 5, 16 mmol) in 10 ml of dry dimethylformamide is heated at 55oC 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 B.

C) (3R-(1(S*), 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.

To a stirred solution of 0.7 g of compound header B (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 distributed between ethyl acetate and water. The organization is calling the 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 scatter methanol, getting a white solid (0,38 g) specified in the header.

Melting point 233-235oC,

Analysis calculated for C29H31F3N2O3HCl,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 paratoluenesulfonyl (1.6 g, 8.4 mmol) stirring in 10 ml of pyridine for 4 hours. The reaction mixture is 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 and 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 e, the colourless oil.

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

A mixture of compound indicated in the heading And (0.9 g, of 2.72 mmol), (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-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 hours 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 liter of the mixture 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 a melting point 147-149 C.

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

A mixture of substances from part (865 mg, 1.7 mmol), fossa acid for 4 hours. After that impose additional 220 mg of ammonium formate (3.5 mmol) and 120 mg of palladium (10%) on coal. This mixture is boiled for 30 minutes, and then the catalyst is filtered off through Celite. The cake on the filter, well washed with methanol, and the filtrate was concentrated in vacuo. The residue is partitioned between a solution of sodium carbonate and ethyl acetate.

The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue is purified methods 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 - benzazepin-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 a mixture of methane is tion with a melting point 228-231oC.

()D+57,86 deg (C=1.0 mol)l acetic acid.

Analysis calculated for C22H23F3N2O3C4H4O4C-58,20; H IS 5.07; N-5,22; F-TO 10.62;

Found, C-58,09; H-To 4.81; N-5,27; F-10,45.

Example 34. (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) 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 hours, the tetrahydrofuran is removed in vacuo, and the residue partitioned between 1N. hydrochloric acid and ethyl acetate.

The organic layer is again extracted with 1N. 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 the Ute, to obtain 3.3 g (yield 59%) specified in the header And connections, in the form of a colorless oil.

B) 3S-1-benzyl-3-hydroxypyrrolidine.

Add a homogeneous solution of sodium hydroxide (25 ml, 25 mmol) to a solution of the compound indicated in the title of A (3,15 g, and 11.2 mmol) in 100 ml of methanol. The reaction mixture immediately becomes cloudy and is manifested after 30 minutes. After stirring for 30 minutes, 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 removed in vacuo to obtain 1.5 g (yield 77%) of the compound indicated in the heading B in the form of a colorless oil.

C) 3 S-benzyl-3(pair-toluensulfonate)pyrrolidin.

A mixture of 3R-1-benzyl-3-hydroxypyrrolidine (1.45 g, 8.2 mmol) and paratoluenesulfonyl (2.35 g, 12.3 mmol) is stirred in 16 ml of pyridine for 20 hours. After that, the reaction mixture is partitioned between aqueous sodium hydrogen carbonate solution and ethyl ether. The organic layer is washed with a solution hydrocarbonate sodium, water then brine. After drying with sodium sulfate the organic layer is evaporated first with shallow vacuum and okoles-chromatography on silikagelevye column 5 x 25 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 C compound, as a pale yellow oil.

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

A mixture of compounds that is specified in the header C (2.2 g, only 6.64 mmol), (3R-CIS)-3-hydroxy-4-4(4-methoxyphenyl)-6- (trifluoromethyl)-2H-2-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 is 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 5 x 25 cm using a mixture of 3:1 ethyl acetate in hexane as eluent. This column is only achieved partial purification. Therefore, the concentrated fraction (2.35 g, 88% purity) chromatographic again silikagelevye column 5 x 25 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(S*), 3,4 )- 1,3,4,5-tetrahydro-3-hydroxy-4-(4-met the substance of 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 is filtered off and the cake on the filter is washed with glacial acetic acid (15 ml). The filtrate is diluted with 150 ml of water, and the acidic mixture is alkalinized solid carbonator sodium. 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 5 x 25 cm, which is pretreated with a mixture of dichloromethane, methanol and triethylamine, 94:1:1. 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 until white is jut 925 mg (yield 68%) indicated in the title compound as a white crystalline substance with a melting point 228-231C.

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

Analysis calculated for C22H23F3N2O3C4H4O40.1 C3H80(isopropanol),

C-58,22; X-5,17; N-5,16; F-10,51.

Found, C-58,07; X-5,11; N-5,26; F-10,44.

Example 35 (this primer dedicated to the connection specified in the header of example 16, but differs in the method of preparing compounds of part A of example 16).

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

A) S-1-(Benzyloxycarbonyl)-2- ((paratoluenesulfonyl)methyl) pyrrolidin.

To S-1-(Benzyloxycarbonyl)-2-pyrrolidineethanol (105,7 g, 449 mmol) in 400 ml of pyridine at 0oC slowly add paratoluenesulfonyl (102,8 g, 539 mmol). The reaction mixture is allowed to warm to room temperature and stirred for 20 hours. 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 teploe in the header of A connection, in the form of a light purple solid.

B) (3R-(1(S*), 3,4 ))-1-((1-benzyloxycarbonyl-2-pyrrolidino)methyl)-1,3,4,5-tetrahydro-3-gidroksi-4-(4 - methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it.

The connection specified in the procurement of A (34,6 g, 89,0 mmol), (3R-CIS)-1,3,4,5-tetrahydroxy-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 50oC. After 8 hours, add another connection header A (2.8 g, 7.2 mmol) and continue stirring for another 12 hours. The reaction mixture is 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 minutes before adding 100 ml of hexane and stirred for further 30 minutes. Filtering gives 34,5 g specified in the title B compound as a pale yellow powder.

C) (3R-(1(S*), 3,4 ))1,3,4,5-tetrahydro-3 - hydroxy-4-(4-methoxyphenyl)-1-(3-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 abaut when the 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 by ennola. The filtrate is concentrated and the residue was diluted with a saturated solution of potassium bicarbonate and extracted 3 times 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 (61,61 mmol) fumarol 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). UB>25F3N2O3HCl0,73H2O, C-57,07; H-5,72; N-5,79; F-11,78; Cl-7,32.

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

Example 36. (3R-(1(S*), 3,4 ))-3-(the atomic charges)-1,3,4,5-tetrahydro-7-methoxyethoxy-4-(4-methoxyphenyl)-1-(2-pyrrolidinyl)-2H-1-benzazepin-2-he-monopolar.

A) (3R-(1(S*), 3,4 ))-1-((N-benzyloxycarbonyl-2-pyrrolidino)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-benzazepin-2-she (1.5 g, 4,37 mmol), anhydrous cesium carbonate (2,84 g is 8.75 mmol) and the connection specified in A header of example 35 (2.55 g, 6,56 mmol) in 50 ml of dimethylformamide is heated to 58oC for 28 hours. The reaction mixture is 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 columns 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 obtainD+161,31 deg (C=1,0, methanol)), less mobile isomer (0.8 g, Rf of 0.55, eluent 50% ether in methylene chloride, ()D-81,81 deg (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 an additional amount of more rolling isomer (0.33 g). The total yield BPI was 0.77,

B) (3R-((S*), 3,4 ))-1-((1-benzyloxycarbonyl-2-pyrrolidinyl)methyl)-3-(atomic charges)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl) -7-(methoxyethoxy)2-H-1-benzazepin-2-it.

The connection specified in the header of A (0,70 g, 1.25 mmol), 4-dimethylaminopyridine (0.31 g, 2.5 mmol) and acetic anhydride (0.64 g, 6,24 mmol) was stirred at room temperature in an argon atmosphere for 14 hours. The reaction solution absorbs silica gel (60-200 mesh) and chromatographic on a column of silica gel. When the elution of 20-40% ethyl acetate in hexane to obtain 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, salt fumaric acid (1:1).

To a solution of the compound indicated in heading (0.64 g, 1.06 mmol) in 10 ml utilizatorii vessel is connected with the cylinder, filled with hydrogen. The vacuum vessel under reduced pressure and filled with hydrogen. Then the mixture is intensively stirred at room temperature for 6 hours to remove hydrogen and add anhydrous magnesium sulfate. Solids are removed by suction and filtration and well washed with ethyl acetate. The filtrate is concentrated under reduced pressure, and the residue is dissolved 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 a melting point 126-130oC ()D89,7 deg. (C=1 mol/l in methanol).

Analysis calculated for C26H32N2O6C4H4O40,6 H2O C-OF 60.50; H-6,30; N-4,71.

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

Example 37. (3R-(1(S*), 3,4 ))-1,3,4,5-tetrahydro-3-hydroid.

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

A suspension of 20.0 g (0.125 mol) of TRANS-4-hydroxy-L-Proline and 38.0 g (0,174 mol) di-tert-BUTYLCARBAMATE in 250 ml of dioxane is slowly treated with 350 ml odnopolyarnogo solution of sodium hydroxide, and then stirred at room temperature for 24 hours. The mixture was concentrated in vacuo to a volume of approximately 200 ml, and then diluted with 150 ml of water. After washing with ethyl acetate, the aqueous layer was acidified with 6 N. 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 a melting point 104-106oC.

Analysis calculated for C10H17NO5C-51,94; H-7,40; N-6,05.

Found: C-51,31; H-At 7.55; N-5,67.

B) (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 (bath temperature of 78oC) process of 0.38 g (0,009 mol) of a 60% dispersion hydride intothree dilaut it to pH 2, using 6 N. 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

Analysis calculated for C17H32NO5C-63,53; H-7,21; N-4,35.

Found, C-63,08; H-7,38; N-43,06.

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

Solution and 4.40 g (13 mmol) of the compound of the title In 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 mmol) of triethylamine in 10 ml of tetrahydrofuran. After stirring for 1 hour 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 hour the solvent is evaporated, and the residue in ethyl acetate solution is washed with 1 N. hydrochloric acid, water, 1N. the sodium hydroxide solution, water and brine. The dried solution is evaporated, getting 3,23 g butter.

Method flash chromatography using the eluent mixture of ethyl acetate and hexane 1:2 2.76 g of the compound indicated in the heading C, / ()D/=-28,3 deg (C=1,86, htor 2.7 g (8,7 mmol) of the compound of the title C 5.8 g a (17.4 mmol) chetyrehpostovye carbon and 4.5 g of a (17.4 mmol) 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 combine with ethereal hcl, and the solvent is evaporated to obtain a semi-solid material, which is extracted 2 times with boiling hexane. Oily residue after evaporation of the hexane dissolved in ethyl acetate and treated balcerowski silica gel (60 to 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 the ethyl acetate hexane gives 2.3 g of target compound indicated in the heading ON,

/()D/ -37,9 deg (C 2,59, in chloroform).

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

Mix a solution of 0.93 g (2.6 mmol) of (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it in 10 ml of dimethylformamide is treated with 0.13 mg (3.3 mmol) of potassium hydride (of 0.39 ml of a 35% suspension in oil is Ostapenko added to the reaction mixture, then heated (oil bath temperature 60oC) 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 crude product is dissolved in 5 ml of toluene, freeze for 1 hour, then filtered, obtaining 0.28 g of the starting material. Method flash chromatography of the remaining solution in 400 ml of silica gel using as eluent 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+116,9 deg (C 1,95, in chloroform).

F) (3R-(1(S*), 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 (0.95 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. a sodium hydroxide solution, water and SUB>D+137,0 deg (C 1.0 mol/l in chloroform.

Analysis calculated for C30H31F3H2O4C 66,65; H 5,77; N 5,18.

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

Above is dissolved in 15 ml of ether and treated with 1 equivalent of ethereal HCl solution to obtain 0,42 g of colorless product with a melting point 184 186oC.

()D+50,4 deg (C 1.15 mol/l in methanol).

Analysis calculated for C30H31F3N2O4HCl, C 60,55; H To 5.93; N 4,70; Cl 5,95.

Found, C 60,79; H 5,59; N 4,43; Cl 6,05.

Example 38. (3R-(1(S*), 3,4 ))-1,3,4,5-tetrahydro-3-hydroxy-1-((4-hydroxy-2-pyrrolidinyl)methyl)-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

A suspension of 1.9 g (3.5 mmol) 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 TCX (eluent 20% methanol in acetic acid) the reaction was completed about 60% of the 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 40oC, the residue is dissolved in utilizatorilor 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, and the residue is treated with acetonitrile with the formation of 0.77 g of colorless solid, melting point 212 - 214 C, ()D+74,1 deg. (C 0,72 mol/l in methanol).

The above product is dissolved in 3 ml of methanol and treated with 1 equivalent of ethereal HCl solution. The solvent is evaporated, and the residue is treated with acetonitrile to obtain and 0.61 g of colorless solid, melting point 217 218oC ()D+75.2 deg. (C 1.0 mol/l in methanol).

Analysis calculated for C23H25F3N2O4HCl0,75 H2O, C 55,21; H 5,54; N The Ceiling Of 5.60; F Is 11.39; Cl - 7,09.

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

Example 39. (3R-(1((1S*), 3,4))-1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl)--1-((4-phenylmethoxy-2-pyrrolidinyl)methyl)-6- (trifluoromethyl)-2H-1-benzazepin--2-he, monohydrochloride.

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

A solution of N-butoxycarbonyl-4-TRANS-hydroxy-L-Proline (11.5g) )0.05 mol) and triphenylphosphine (14.4 g, 55 mmol) in 450 ml of dry tetrahydrofuran in an argon atmosphere at 20 ° C dropwise process amerivault 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, the remaining aqueous solution washed with ethyl acetate (pour). The aqueous layer was acidified to pH 1.5 to sistermanns hydrochloric acid, saturated sodium chloride and extracted 2 times 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 gain of 10.2 g of compound indicated in the heading A. melting point 147 148,5oC

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

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

The solution of the connection specified in the header of A (10,01 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 -78oC and treated immediately with sodium hydride (3.50 g, 87 mmol) (60% in oil). Remove the cooling bath and the reaction mixture is allowed to warm to room temperature and stirred her during the night. The mixture was poured on ice and washing the th 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 acid receive a 9.35 g of compound indicated in the heading B in the form of a crude solid. Crystallization from isopropyl ether gives of 7.75 g of this compound with a temperature of 110 111oC ()D=-28,8 deg (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) and ethylchloride in 150 ml of dry tetrahydrofuran in an argon atmosphere for 15 of the 20oC is treated dropwise with a solution of triethylamine (2,44 g, 24 mmol) in 10 ml of tetrahydrofuran for 10 to 15 minutes. After stirring for 2 hours, the solids filtered and washed with fresh tetrahydrofuran. The combined filtrate and washings are cooled in a water bath at 15oC 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 hours, volatiles are removed in vacuo, and the residue dissolved in EUW 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 l 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 C, in the form of oil. ()Dis 18.5 degrees (C=1.5, chloroform).

D) (2S, 4S)-4-(phenylmethoxy)-1-(tert-butoxycarbonyl)-2-(4-methylphenylsulfonyl)methyl)pyrrolidin

A solution of the compound indicated in the heading C (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 (34 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, when the elution mixture, while elution with a mixture of 1:4 ethyl acetate: hexane, gain of 3.9 g of compound header D.

()D-8,01 deg (C=1,76, in chloroform).

E) (3R-(1(2S*4S*) 3,4)-1- ((-1(tert-butoxycarbonyl)-4-(phenylmethoxy)-2-pyrrolidinyl)-methyl) -3-hydroxy-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6-(driftor is n-2-n (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 50oC during the night. The original benzazepin remains, although toilet consumed, and the mixture was stirred at 60oC for 2 days.

The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried with magnesium sulfate and concentrated in vacuo, getting to 4.87 g of oil. Method flash chromatography on 100 ml of silica gel El-Pai-es-1 at the elution with a mixture of 5:1 toluene:ethyl acetate get to 3.36 g of compound indicated in the heading of the E ()D+of 113.2 degrees (C=0.84 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 mmol) 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, and the residue dissolved in ethyl acetate, washed with sodium hydrogen carbonate solution, water and brine. The organic portion is dried sulfate is implement a mixture of ethyl acetate: methanol (93,7) gives 2,08 g specified in the connection header in the form of butter.

()D+141,4 deg(C=0.88 mmol/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 vacuo, and the residue triturated with diisopropyl ether to obtain 0.73 g of salt in the form of a white powder with a melting point of 120 - 140oC. ()D+78,6 deg(C=0.90 mol/l, chloroform).

Analysis calculated for C30H31F3N2O4HCl0,2 H2O, C-62,03; H-5,63; N-4,82; Cl-6,10; F-9,81.

Found, C-61,93; H Is 5.77; N-4,92; Cl-6,01; F-9,79.

Example 40. (3R-(1(2S*, 4S*) 3,4 )-1,3,4,5-tetrahydro-3-hydroxy-1-((4-hydroxy-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 during the night. The catalyst is filtered off through Celite, and the solvent is distilled off in vacuum. The remainder of rostellata magnesium, 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) at summirovanii a mixture of ethyl acetate: methanol (95: 5) to give 0.50 g specified in the connection header in the form of foam.

()D+148,9 deg (C=0.85 mol/l, chloroform).

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 100oC, getting 436 mg of product with a melting point 252-255oC.

()D+84,8 deg(C=0,56 mol/l in methanol).

Analysis calculated for C23H25F3N2O4HCl0,5H2O, C-56,73; H Is 5.38; N-5,75; Cl-7,28; F-11,71.

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

Example 41. (3R-(1(3S*, 5S*) 3,4 ))-1,3,4,5-tetrahydro-3-hydroxy-1-((5-(hydroxymethyl)-3-pyrrolidyl)-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monferrat.

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

To 70 ml of methanol is added slowly acetyl chloride (7,6 ml, 107 mmol). This reaction em refrigerator 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 is cooled to room temperature and add 750 ml of diethyl ether. The resulting colorless crystals are filtered and dried, obtaining 11,89 g of compound indicated in the heading A.

B) (2S, 4S)-4-hydroxy-1-(phenylmethyl)-2-pyrrolidinecarbonyl acid, methyl ester.

The mixture of compounds on part a (11.85 g, to 65.2 mmol), triethylamine (18,55 ml) (130,04 mmol) and 15 ml of benzyl chloride (130,0 mmol) is refluxed in 60 ml dichloromethane within 7 hours. The resulting suspension is partitioned between chloroform and 1N. the sodium hydroxide solution. The organic layer was washed with 1N. 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,4S)-4-hydroxy-1-(phenylmethyl)-2-pyrrolidinone what about the drops add connection specified in the header B (9.88 g, 42 mmol), in solution in 150 ml of diethyl ether. After stirring 1 hour at 0oC, 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 at room temperature the suspension is filtered through Celite, and the cake on the filter is washed thoroughly with ether. The filtrate is concentrated and evaporated with toluene (2 times 100 ml), to obtain of 7.97 g of compound indicated in the heading C, in the form of a colorless oil.

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

tert-Butylchloroformate (11,05 ml, 42,5 mmol) are added dropwise to a solution of the compound indicated in the heading C (of 7.97 g of 38.5 mmol) in 20 ml of pyridine at 0oC. After stirring for 1 hour the reaction mixture is 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 cm) 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 on kawut, getting 9.88 g specified in the title D compound.

E) (2S, 4S)-4-(4-methylphenylsulfonyl)methyl)-1- (phenylmethyl)-2-(tert-butyldiphenylsilyl)pyrrolidine.

para-Toluensulfonate (3.1 g, 16.3 mmol) is added to a solution of compound from part D (4,56 g, 10.9 mmol) in 12 ml of pyridine at 0oC. After stirring 1 hour at 0oC and 4 hours at room temperature, the reaction mixture was partitioned between aqueous sodium hydrogen carbonate solution and ether. The organic layer is dried with magnesium sulfate and evaporated. According to TLC significant number of connections from the title 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 stirred for additional 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-(phenylmethyl)-3-pyrrolidinyl)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6-(triptolide-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 metallicity refluxed for 18 hours. The reaction mixture is cooled to room temperature, add 50 ml of ethyl ether, and the suspension filtered through Celite. The cake on the filter, well washed with ether, and the filtrate concentrated to a dark orange oil. The crude product is purified by the method of flash chromatography 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 title F compound, as a colourless foam.

G), (3R-(1(3S*, 5S*) 3,4 )-1-1(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 mmol) in 15 ml of tetrahydrofuran is added to mixed solution of connection on the part of F (3,19 g of 4.17 mmol) in 35 ml of tetrahydrofuran. After stirring for 2 hours the reaction mixture is diluted with 100 ml of ethyl ether, and the ether layer washed with 50 ml water and 50 ml Resolume. 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, COI is matographic 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% in dichloromethane. Pure fractions are concentrated, receiving 1,788 g specified in the title G compound, as a white foam.

H) (3R-(1(3S*, 5S*) 3,4 )-1,3,4,5-tetrahydro-3-hydroxy-1-((5-(hydroxymethyl)-3-pyrrolidinyl)-4-(4-methoxyphenyl)-6-(trifluoromethyl)-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) within 24 hours, 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 within 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 stated above, within 8 hours. After that the reaction mixture is filtered, and the filtrate concentrated. The residue is purified by the method of chromate is: triethylamine, 94:5:1; 1 l 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 mg, 2,158 mmol) is dissolved in methanol and added 250 mg (2,158 mmol) of fumaric acid in solution in hot methanol. 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 a melting point 212-214oC (decomposition), 168oC (softening), 185oC (darkening).

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

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

Analysis calculated for C23H25F3N2O40.5 C3H8O, C-57,38; H-5,58,

N-4,67; F-OF 9.55.

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

Example 42. (3R-(1(3S*,5S*) 3,4 ))-1,3,4,5-tetrahydro-3-hydroxy-1-((5-(hydroxymethyl)-3-Biloxi)-1-(phenylmethyl)-2-(tert-butyldiphenylsilyl)pyrrolidin.

Diethylazodicarboxylate (2,80 ml of 16.8 mmol) added dropwise over 5 minutes 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 at room temperature. After stirring 2 hours, the reaction mixture was partitioned between aqueous sodium hydrogen carbonate solution 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 of A, in the form of a light yellow oil.

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

A mixture of compounds that is specified in the header of A ( 3,95 g, 7.2 mmol), 1H. of sodium hydroxide solution (72 ml, 72 mmol), 72 ml of tetrahydrofuran and 72 ml of methanol is refluxed for 1 hour. The reaction mixture is 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 chromatographie in column (5 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.

A mixture of paratoluenesulfonyl (1.2 g, of 6.25 mmol) and the compound from part B (1.85 g, 4,15 mmol) in 5 ml of pyridine is stirred for 18 hours at room temperature. The reaction mixture was partitioned between saturated sodium hydrogen carbonate solution 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 a 2.13 g of the substance specified in the title compound C as a colorless oil.

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

A mixture of compounds that is specified in the header of C (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 is cooled to room temperature and add 50 ml of ethyl ether. is Odom flash chromatography on silikagelevye column h cm (eluent a 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 again chromatographic on column h cm, using the following elution scheme: 3 l of a mixture of 15% ethyl acetate in hexane, 1 l of 25% ethyl acetate in hexane. Pure fractions combined with a clock of the first column and obtain 1.45 g specified in the billet D compound as a colourless oil.

E) (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.

Odnokorennye fluoride solution of Tetra-n-butylamine (the 3.65 ml, 3.65 mmol) are added to a solution of the compound in part D (1,395 g and 1.83 mmol) in 20 ml of tetrahydrofuran at room temperature. After stirring for 1 hour the reaction mixture is 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 silicagel column 5x30 cm using a mixture of ethyl acetate:hexane 3: 1 as eluent. Pure fractions concentrated to obtain 0.85 grams specified in the header is leinil)-4-(4-methoxyphenyl)-6-trifluoromethyl)-2H-1-benzazepin-2-it, monopolar.

A mixture of substances from part E (0,80 g, 1.48 mmol) and catalyst 20% palladium hydroxide on coal in 20 ml of acetic acid hydronaut for 18 hours at room temperature, using a balloon device. 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 liter 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 concentrated to obtain 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 50oC and a pressure of C (decomposes).

()D+ 68,0 hail (0.54 mol/l, chloroform).

Analysis calculated for C28H29F3H2O81,41 H2O, C 54,78; H-5,42; N-4,72; F-9,63.

Found, C-55,16; H At 5.27; N-4,79; F-9,24.

Example 43. (3R-CIS)-1-((4,5-Dihydro-1-H-imidazol-2-yl)methyl)-1,3,4,5-tetrahydro-3-hydroxy-4-(methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

A) 2-chloromethylthiazole.

To a chilled solution of the hydrochloride of 2-chloromethylketone (3 g, and 19.4 mmol) (preparation described in the journal Helv. 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 A, in the form of a white foam with so pl. 63 64oC.

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

A solution of (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-she (4,Yes (dried over sieves 4A) is heated at 70oC, 30 minutes. Then add 2-chloromethylthiazole (1.08 g, 9.1 mmol). The mixture is left to mix for 16 hours at 70oC. the Reaction mixture was washed 2 times with ice 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 (080 ml of silica gel pre-treated with a solution of 10:1:1 ethyl acetate methanol triethylamine). Elution with a mixture of 10:1:1 ethylacetate/methanol/triethylamine gives to 2.55 g of compound indicated in the blank B, ()D+ 116,5 deg (C 1.07, 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, 23.5 mmol) in 30 ml of acetonitrile 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 130oC ()>O, C-53,77; H-To 5.21; N-8,55; Cl-7,21; F-11,60.

Found, C-53,77; H-4,961; N-8,88; Cl-7,14; F-11,38

Example 44. CIS-1-((4,5-Dihydro-1H-imidazol-2-yl)methyl)-1,3,4,5-tetrahydro-3-hydroxy-7-(methoxyethoxy)-4-(4 - methoxyphenyl)-2-H-1-benzazepin-2-it, monopolar.

Specified in the title compound is prepared using the procedure described in example 43, but at the stage B of example replace (3R - CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1 - benzazepin-2 is CIS-2-hydroxy-7-methoxyethoxy-4-(4-methoxyphenyl)-2H-1-benzazepin-2. So pl. 200-210oC (decomposes).

Analysis calculated for C23H27H3O5C4H4O40,83 H2O, C-58,28; H-5,91; N-7,55.

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

Example 45. (3R-CIS)-1,3,4,5-tetrahydro-3-hydroxy-1-((1H-imidazol-2-yl)methyl)-4-(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-chloromethylthiazole-hydrochloride (1,67 g, 6,87 mmol) (preparation described in JACS journal volume 721, C. 383, 1949) and 60% dispersion hydride is t add 1 to N. hydrochloric acid and then neutralized with 50% sodium hydroxide solution to a pH of about 11. The reaction mixture was extracted 2 times with ethyl acetate. Organic salts are combined and washed twice (50 ml), saturated sodium hydrogen carbonate solution, 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 of A, in the form of a solid white foam, ()D+105,0 deg (C 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 - benzazepin-2-it.

A solution of the compound of the title A (1,09 g of 1.95 mmol) and 0.24 g of catalyst 10% palladium on coal in 5 ml of 95% 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 B as a solid white foam.

A solution of the compound of the title B (0.52 g, to 1.21 mmol) in acetonitrile is treated with excess hydrogen chloride in ether solution. Volatiles are removed in vacuo, getting a white solid. His triturated with isopropyl ether and dried in vacuum over phosphorus pentoxide at 100oC. Obtain 0.45 g specified in the connection header. So pl. 188 191oC.

()D+101,0 deg (C of 1.02, methanol).

Analysis calculated for C22H20F3N3O3HCl0,2H2O, C-56,03; H-4,58; H-8,91; Cl-7,52; F-12,09.

Found, C-56,20; H Is 4.35; N-8,92; Cl-7,15; F-11,71.

Example 46. (2S-( 2,3 ), 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-pyrrolidineethanol (20.6 g, is 102.4 mmol) in 100 ml of pyridine at room temperature under argon was added when mixing paratoluenesulfonyl (23,4 g, 122,8 mmol). After 5 hours, add a couple of 9.8 g (a 51.2 mmol) para-toluensulfonate. After a total stirring for 23 hours, 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, filtration is the Etat in hexane, to get 32,1 g of compound indicated in the title of A, in the form of a colorless viscous liquid.

B) (2S-( 2,3 5(R*)))-2,3-dihydro-3-hydroxy-2-4-methoxyphenyl)-5-(1-(tert-butoxycarbonyl)-2-pyrrolidino)methyl)- 1,5-benzothiazepin-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 connection specified in the header of A (6,30 g, 17,72 mmol) in 40 ml of dimethylformamide is heated to 50oC. After 16 hours the reaction scheme is 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 to 25% ethyl acetate in hexane gives 4,51 g of compound indicated in the heading B 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 B (1.0 g, 2,063 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 in argon in Teeniemovies 5 to 20% ethyl acetate in hexane gives compound C header (0,94 g) protein solid.

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

The connection specified in the header C (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 hour.

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 to give 0.75 g specified in the title compound as a white foam with so pl. 132-135 C ()D=+66,06 degrees (C=1, methanol).

Analysis calculated for C23H26N204HCl073H20, C-58,01; H-6,03; N-5,88; Cl-7,44; F-6.73 X.

Found, C-58,00; H-The 6.06; N-Of 5.89; Cl-7,18; F6,48.

Example 47. (2S-(2,3,5(R*)))-3(atomic charges)-2,3-dihydro-8-methoxy-2-(4-methoxyphenyl)-5-(-2-pyrrolidinyl)-1,5 - benzothiazepin-4-(5H)-he, monohydrochloride.

The connection specified in the header is prepared using the method of example 46, but replacing in part B of this example (2-8-methoxy-1,5 - benzothiazepin-4(5H)-he. T. pl. 147-154 C. ()D+50.0 deg (C=1, methanol).

Analysis calculated for C24H28N2O5S HCl0,89H2O, C-56,63; H-6,09; N-5,51; Cl-6,97; S-6,30.

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

Example 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)-1,5-benzothiazepin-4(5H)-he.

(2S-CIS)-2,3-dihydro-3-hydroxy)-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-he (1,25 g, 4,15 mmol), cesium carbonate (2,03 g, from 6.22 mmol) and 5-1(benzyloxycarbonyl)-2-((4-methylphenylsulfonyl) -methyl)pyrrolidin (2,02 g, 5,19 mmol) in 20 ml of dimethylformamide is heated to 50 C. After 23 hours, 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) as a white solid.

B) (2S-(2,3, 5(R*)))-2,3-dihydro-3-hydroxy-the TES in the header And (1.2 g, 2,31 mmol), 1.2 g of the 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 hours, add 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 was dissolved in dichloromethane. To the solution is added an excess of dissolved HCl in ether. 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 240 C (decomposes).

()D=+to 91.6 degrees (C=1, methanol).

Analysis calculated for C21H24N2O3S1,1HCl0,46H2O, C-58,26; H-The 6.06; N-6,47; Cl-9,01; S-7,41.

Found, C-58,45; H-USD 5.76; N-6,28; Cl-9,35; S-7,41.

Example 49. (2S-(2,3, 5(R*)))-2,3-dihydro-2-(4-methoxyphenyl) -3-(2-m)))-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-(2,3, 5(R*)))- 2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-(1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-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 mmol) in dichloromethane (25 ml) was 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.

B) (2-S(2,3, 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 A (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 solution of hydrocarbonate potassium. The aqueous layer was extracted 3 times with ethyl acetate, and the combined is alance 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 solid substance with So pl. 197 199oC (decomposes).

()D+34,86 deg (C 1, methanol).

Analysis calculated for C25H30N2O45 HCl0,3H2O, C-60,47; H, 6.42 Per; N-5,64; Cl-7,14; S-6,46.

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

Example 50.

(2S-( 2,3 ) 5(R*)))-2,3-dihydro-2-(4-methoxyphenyl)-3(((methylamino)carbonyl)oxy)-5-(2-pyrrolidinyl)-1,5-benzothiazepin-4(5H)-he, monohydrochloride.

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

To a solution of (2S-(2a, 2a, 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 mmol) in 15 ml of anhydrous dichloromethane at 0oC add with stirring 116 ml (0.82 mmol) and 0,19 g of methyl isocyanate (3,30 mmol).

The reaction mixture is allowed to warm DNIe continue for another 5 hours. Add water, and the aqueous mixture 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 to 20% ethyl acetate in hexane, to obtain 0,89 g of compound indicated in the heading A, in the form of a white foam.

B) (2S-( 2,3, 5(R*)))-2,3-dihydro-2-(4-methoxyphenyl) -3(((methylamino)carbonyl)oxy)-5-(2-pyrrolidinyl)-1,5-benzothiazepin -4(5H)-he, monohydrochloride.

Specified in the header of A 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 specified in sagola the ethanol).

Analysis calculated for C23H27N3O4S HCl1,0H2O, C-55,70; H-69,10; N-Of 8.47; Cl-7,16; S-6,46.

Found, C-55,79; H-Of 5.81; N-8,49; Cl-7,03; S-6,50.

Example 51. (3R-(1(S) 3,4 )-3-(atomic charges)-1,3,4,5-tetrahydro-7-4-(4-methoxyphenyl)-1-(2-pyrrolidinyl)-2H-1-Betaseron-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-benzazepin-2-it. Melting point above 250oC. ()D+92,17 deg (C 1.0 mmol/l in methanol).

Analysis calculated for C25H3ON2O5HCl0,2H2O, C-62,74; H-6,61; N-5,86; Cl-7,41.

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

Example 52. (2S-(2,3))-2,3-dihydro-5-(4,5-dihydro-1H-imidazol-2-yl)methyl)-3-hydroxy-2(4-methoxyphenyl)-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. Melting point 252oC (decomposes).

()D+94,0 deg (C 1.0 mol/l in methanol), Rf0,28 (eluent - 18:1:1 dichloromethane methanol acetic acid).

Analysis calculated for C20H21N<3. (2S-(2,3)-3-(atomic charges)-2,3-dihydro-2-(4-methoxyphenyl)-2-(2-pyrrolidinyl)-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 110-115oC. the Colorless product is crystallized from acetonitrile. Melting point 200-202oC (decomposes).

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

Analysis calculated for C24H22N2O4S HCl1,5H2O, C-57,88; H-5,26; N-5,63; Cl-7,12; S-6,44

Found, C-58,09; H-5,20; N-5,62; Cl-Of 7.48; S-6,52.

Example 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)-H-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 mmol) (1.4 EQ.) and dimethylaminopyridine (0.11 g, 0.9 mmol).

The solution is stirred over night. The reaction mixture was concentrated to a volume of about TBE 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 A, in the form of a white solid foam, T melting point 114-116oC.

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

The solution of the connection specified in the header of A (1.50 g, 2.8 mmol) 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-e-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 heading B in the form of a white foam with T. Lawley 105-108oC.

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 the heading B (0.87 g, 1.5 mmol) in 10 ml of dried dichloromethane is treated with 10 ml triperoxonane acid. The reaction mixture is stirred for 2 hours at room temperature. The solvents are removed in vforum 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 a melting point 109-111oC. Solution of the above free base (of 0.741 g, 1.6 mmol) 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 compound as a white solid with a melting point 260-261oC.

()D+84,6 deg (C=1,11, in methanol).

Analysis calculated for C24H24F3H3O4HCl1,43H2O, C-53,72; H-5,04; N-7,83; Cl-To 10.62; F-6,61.

Found, C-53,87; H-5,14; N-7,68; Cl-10,0; F-6,79.

Example 55. (3R-CIS)-1-((4,5-dihydro-1H-imidazol-2-yl)methyl)-1,3,4,5-tetrahydro-3-hydroxy-7-methoxy-4-(4-methoxyphenyl)-2H-1-benzazepin-2-it, monohydrochloride.

A) (3R-( 3,4 3S))-3-(2-benzyloxycarbonylamino-3-phenyl) -propionyl 1,3,4,5-tetrahydro-7-methoxy-4-(4-methoxyphenyl)-2H-1-benzazepin-2-it.

Suspension (CIS)-1,3,4,5-tetrahydro-3-hydroxy-7-methoxy-4-(4-methoxyphenyl)-2H-1-benzazepin-2-it (of 7.24 g of 23.1 mmol) in 70 ml of tetrahydrofuran is treated 2S-N-carbobenzoxy the Ute N,N-dimethylaminopyridine (566 mg), and the homogeneous solution was stirred at room temperature for 1.5 hours. The reaction mixture was added 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 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 suspensio the connection specified in the header of A (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 mmol). Within 5-10 minutes of all solids into solution. After 30 minutes the mixture was poured into 250 ml of 1 n acid solution and extracted 3 times with ethyl acetate.

An ethyl acetate extracts are combined, dried over anhydrous sodium sulfate, filter and concentrate the IU getting 1.73 g of the compound indicated in the title. The mother liquor is concentrated and then chromatografic on a column of silica gel, which elute with a mixture of 50-75% ethyl acetate in hexane, to obtain additional 350 mg of the product specified in the header B, in the form of a solid substance with a melting point 171-173oC ()D187 deg (C 0.55 mol/l in methanol).

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

Sodium hydride (100 mg, 4.14 mmol) was added when peremeshivanii to a solution of the compound indicated in the heading B (1.08 g, of 3.45 mmol) in 15 ml of dry dimethylformamide. After 30 minutes, add 490 mg (4.14 mmol) of 2-chloromethylketone. The mixture is stirred at room temperature for 1.5 hours 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 asanoha in the header (white solid). The solution of this free base (1.8 g) in a mixture of chloride methyltetrazol treated dropwise with excess ethereal solution of hydrogen chloride. 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. Melting point 183-188oC.

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

Analysis calculated for C22H25N3O5HCl0,62 H2O, C-59,78; H Is 5.98; N-9,51; Cl-8,02.

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

Example 56. (3R-CIS)-3-(atomic charges)-1-((4,5-dihydro-1H-imidazol-2-yl)methyl-1,3,4,5-tetrahydro-7-methoxy-4-(4-methoxyphenyl)-2H-1-benzazepin-2-he hydrochloride.

Specified in the title compound is prepared from (R-CIS)-1-((4,5-dinitro-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. Melting point above 270oC ()D+95,0 deg (C 1 mol/l in methanol).

Analysis calculated for C24H27N3O5HCl0,72 H2O, C-59,19; H-6,09; N-8,63; Cl-7,28.

Found, C-59,36; H-5,75; N-8,46; Cl-7,05.

Example 57. (3R-(1(S*3,4 )-1,3,4,5-tetrahydro-3-hydroxy-7-methoxy-4-(4-Megiddo-3-hydroxy-7-methoxy-4-(4-methoxyphenyl)-1-(N-benzyloxycarbonyl)pyrrolidin-2-yl)methyl)-2H-1-Benahavis-2-it.

This compound is prepared from (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 title of part A of example 38.

B) (3R-(1(S*3,4 ))-1,3,4,5-tetrahydro-3 - hydroxy-7-methoxy-4-(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. Melting point 179-181oC.

()D+109,4 deg (C 1.0 mol/l in methanol).

Analysis calculated for C24H28N2O4HCl0,48H2O, C-62,55; H-6,84; N-6.35mm; Cl-8,03;

C-62,86; H-6,88; N-6,04; Cl-8,23;

Example 58. (2S-( 2,3 3(R*))-2,3-dihydro-3-hydroxy-8-methoxy-2-(4-methoxyphenyl)-5-(2-pyrrolidinyl)-1,5 - benzazepin-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-benzothiazepin-4-(5H)-he.

(2S)-carbonemissionsalok (6,88 g, 22,99 mmol) is added at room g), 18.4 mmol) in dry dimethylformamide (55 ml) in an argon atmosphere. Add soluble carbodiimide (7,05 grams of 36.7 mmol) and then, after 1 hour, dimethylaminopyridine (0.45 g, 3.7 mmol). Stirring is continued for 75 minutes, the mixture was diluted with 280 ml of ether, washed with 1N. hydrochloric acid, saturated sodium bicarbonate solution, saturated brine, dried over magnesium sulfate and concentrated in vacuo. The mixture is purified chromatographically and then obetovannoi ghvd, receiving the connection specified in the header And (1.30 grams).

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

The connection specified in the header And (1.30 grams), 2,12 mmol) 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 mmol). Stirring is continued for 90 minutes, the mixture is diluted with 100 ml of water and stirred for an additional 30 minutes. The colorless product is collected by filtration. Melting point 180-183oC (decomposes).

()D+85,4 deg (C 0,79 mol/l, in dimethylformamide).

C) (25-(2,3, 5(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 is methoxyphenyl)-1,5-benzothiazepin-4 (5H)-it.

Melting point 121 124oC (decomposes).

()D+62,9 deg (C 1,08 mol/l in methanol).

Analysis calculated for C22H26N2O4S HCl2,14H2O, C 53,98; H 6,44; N 5,72; Cl 7,24; S 6,55

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

Example 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. Melting point 192 199oC. ()D+62,9 deg (C 1.0 mol/l in methanol).

Analysis calculated for C21H22NO4S HCl0,66H2O, C 54,30; H And 5.30; N 9,05; Cl 8,40; S 6,90.

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

Example 60. (2S-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 (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)-it (the connection from the header of example 59) according to the methods described in example 54. So pl. 275oC. ()D2O, C 54,29; H 5,52; N compared to 8.26; Cl 6,27; S - 6,30

Found, C 54,68; H 5,32; N 7,72; Cl 7,42; S 5,95.

Example 61. (CIS)-1-(4,5-dihydro-1H-imidazol-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-it according to the methods described in example 43. So pl. 195 198oC.

Analysis calculated for C22H25N3O3S HCl0,64H2O, C 57,50; H 5,98; N 9,15; Cl 7,72; S 6,98.

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

Example 62. (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.

A) (CIS)-1,3,4,5-tetrahydro-3-hydroxy-7-methylsulfinyl-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-benzazepin-2-she (1.0 g, 3.04 from mmol) in 30 ml of dried methylene chloride in 5oC handle meta-chloroperoxybenzoic acid (of 0.615 g, 3.04 from mmol). After 30 minutes the reaction is terminated, and the reaction mixture is diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, water and Russolo is hot ethyl acetate, cooling and filtering receive 600 mg So pl. 214 216oC. the mother solution was concentrated in vacuo and chromatographic on silica gel "e-p-s-1 (ethylene-methylene chloride/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-methylsulphonyl-4-(4-methoxyphenyl)-2H-1-benzazepin-2-it, monohydrochloride.

The connection of the header is made from substances specified in the title And using the techniques described in example 43; T. pl. 195 205oC.

Analysis calculated for C22H26N3O4S 1,3 H2O, C 54,21; H 5,91, N 8,62; S 6,58; Cl 7,27

Found, C 54,48; H 5,77; N 8,35; Cl 7.62mm; S 6,33.

Example 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)-2-carboxylic acid.

Di-tert-BUTYLCARBAMATE (2,18 g, 9.9 mmol) is added at once to a stirred mixture of (L)-azetidin-2-carboxylic acid (1.0 g, 9.9 mmol), triethylamine (2,12 ml, 15.0 mmol), 10 ml of acetone and 10 ml of water. OBRAZOVATEL ethyl acetate and 100 ml of water. The aqueous layer was acidified to pH 3 10% citric acid solution. The resulting acidic mixture is extracted with 2 times 200 ml of ethyl acetate, and the combined 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.

B) Methyl ester of S-1-((1,1-dimethylethoxysilane)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 8 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 Resolume, dried with magnesium sulfate and concentrated, obtaining 1.85 g of the substance specified in the header B, in the form of a colourless liquid.

()D-114,8 deg (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 IDA potassium in tetrahydrofuran. The reaction mixture is stirred for 5 hours, after which it was diluted with ethyl ether (200 ml). The resulting mixture was successively washed with 100 ml brine, odnomomentnoe hydrochloric acid, saturated sodium hydrogen carbonate solution and brine. The organic extracts are dried with magnesium sulfate and concentrated, obtaining 1.63 g of the compound indicated in the 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 mmol) in 20 ml of tetrahydrofuran at 0oC. the Reaction mixture is allowed to warm up to room temperature, then stirred for 18 hours and then partitioned between brine and ethyl acetate. The organic extracts are washed with 1 N. hydrochloric acid and brine, dried with magnesium sulfate and concentrating, getting to 0.92 g of compound indicated in the heading of D, in the form of a colorless oil.

()D0 hail.

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

A mixture of R,S-1-((1,1-dimethylmethoxy)carbonylation-2-m the owls at room temperature, and at this point, add another 0.5 g (2.6 mmol) of paratoluenesulfonyl, and the reaction mixture is stirred an additional 2 hours. Then add 10 ml of saturated solution of hydrocarbonate sodium, and the mixture is stirred for 30 minutes, 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 of 1 N. hydrochloric acid, 50 ml of a saturated solution of sodium bicarbonate and 50 ml Resolume, dried with magnesium sulfate and concentrate. The crude residue purified by the method of flash chromatography (column 5x12 cm, eluent 4:1 hexane in ethyl acetate), obtaining of 1.43 g of compound indicated in the heading of the E, in the form of a yellow oil.

F) (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-he (3R-((1,1-dimethylamine)carbonyl)azetidine-2 - methyl)-6-(trifluoromethyl)-2H-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 hours at 60oC, then p is Aza 50 ml) and brine (50 ml) and then dried with magnesium sulfate and concentrate. The crude light yellow residue purified and the isomers separated by the method of flash chromatography (column 5x12 cm, 5 liters of a mixture of 3:1 hexane:ethyl acetate and 1 l of a mixture of 1:1 hexane: ethyl acetate) to give 0.2 g (30%) of ((3R-(1(S*)3,4))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl) -1-(1-((1,1-dimethylmethoxy)carbonyl)azetidin-2 - methyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it is in the form of a white foam, along with 0,232 g (34%) of ((3R -(1(S*)3,4))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)--1- (1-((1,1-dimethylmethoxy)carbonyl)azetidin-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 - benzazepin-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)azetidin-2 - methyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it (0.55 g, 1.06 mmol) and 3.3 ml triperoxonane acid in 3.3 ml of methyl chloride is stirred for 2 hours 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 hydroxyurea free base, which is cleaned by the method of flash-chromatography; melting point 155oC (softened) 162-170oC (decomposes).

()D+62,8 deg (C=0.50 mol/l, in methanol).

Analysis calculated for C22H23N2F3O3C4H4O4H2O, C-57,26; H-5,17; N-5,14;

F-10,45.

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

Example 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*)3,4))-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)--1- (1-(1,1-dimethylmethoxy)carbonyl)azetidin-2-methyl)-6-(trifluoromethyl-2H-1-benzazepin-2-she described part F of example 63, using the techniques described in part G of example 63. Temperature melting 112oC (softened), 140-146 C (decomposes). ()D+90,2 deg (C=0.55 mol/l in methanol).

Analysis calculated for C22H23N2F3O3C4H4O40,99 H2O, C-56,33; H-5,27;

N-OF 5.05; F-10,28.

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

Example 65. (3R-CIS)-1-((1-methyl-4,5-dihydro-imidazol-2-yl)methyl)-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-it.

A) sodium hydride (14.9 mmol, 60% dispersion in oil) in 150 ml dry tetrahydrofuran added 5.0 g of (3R-CIS)-3-hydroxy-4-(4-methoxyphenyl)-6-trifluoromethyl-2H-1 - benzazepin-2-it. The solution is stirred for 15 minutes, cooled at 0oC, 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 hours, and 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-dihydro-imidazol-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-hydroaxe-4-(methoxyphenyl)-6-trifluoromethyl-2H-1-benzazepin-2-she (5.0 mmol) in 20 ml of ether containing at 0.31 ml of absolute ethanol (5,24 mmol) at 0oC propulsive gaseous hydrogen chloride, until not re days. The ether is decanted from the thick oily residue, which was defended, and add to the residue with dry ether to obtain white solid. 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 0oC. the Solution was stirred at room temperature for 90 minutes, 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, dried with potassium carbonate and evaporated, getting 0.66 g of a white solid. This substance cleanse khromatograficheskii, previously suirvey a mixture of 5% triethylamine in dichloromethane. The main strip is removed and extracted twice with a mixture of 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-dihydro-imidazol-2-yl)methyl)-3-hydroxy-4-(4-methoxyphenyl)-6-trifluoromethyl-2H-1-benzazepin-2-it is in the form svetlo brown solid with a melting point above 240oC.

()D+of 98.2 degrees (C=1 mol/l in methanol).

Analysis calculated for C23H25N3F3Cl 1,70 H2O, C-53,68; H-5,56; N-8,16; F-11,07; Cl-6,89.

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

Example 66. (3R-CIS)-1-((1-methyl-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-carboxyamide-3-hydroxy-6-chloro-4-(4-methoxyphenyl)-2H-1-benzazepin-2-it, obtained by the method of example 61, 100 ml of dichloromethane is treated with a solution of 5.55 g (55 mmol) of triethylamine in 50 ml of dichloromethane, and then 1.0 g of dimethylaminopyridine and 8.2 g (55 mmol) of phthalic anhydride. Solids are quickly dissolved, and the resulting solution is stirred for 2 hours 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 minutes, 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) with a melting point of 165 167oC. After recrystallization from acetonitrile, the sample of this material melts at 220 222oC.

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

Heat the mixed suspension (CIS)-1,3,4,5-tetrahydro-3-((2-carboxyphenyl)carbonyl)-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 mmol) in 50 ml of methanol. The mixture is heated to boiling (under reflux) to give a solution, which then begins to crystallize. After Wystawiennicze 20 ml) and dried, getting listed in the title In the product (a 12.03 g) with a melting point of 160oC.

()D-15,5 deg (C 1,0, acetic acid).

C) (3R-CIS)-1,3,4,5-tetrahydro-3-hydroxy-6-chloro-4-(4-methoxyphenyl)-2H-1-benzazepin-2-it.

To a stirred solution of hydrate of lithium hydroxide (3,40 g, 81 mmol) in water (113 ml) add substance specified in the header B (11.85 g, of 20.5 mmol). 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 70oC for 1 hour, diluted with 100 ml of water, cooled and stirred for 2 hours. The solid is filtered off, washed with water and dried, obtaining specified in the header C substance in the form of a colorless solid material (5,76 g), melting point 191 193oC.

()D+of 83.4 deg (C 1,0, acetic acid).

D) (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.

The connection specified in the header D, prepared from the compounds specified in the header C, following the procedure described in example 43, melting point 196 200oC.

()D+80,4 deg C (1,0, m is ahydro-4-(4-methoxyphenyl)-1-(2-pyrrolidinyl)-6-trifluoromethyl)-2H-1-benzazepin-2-it, monohydrochloride.

Specified in the title compound is prepared from R-1-(tert-butoxycarbonyl)-2-((4-methylphenylsulfonyl)methyl)-pyrrolidine and (3 R-CIS)-1,3,4,5-tetrahydro-3 - hydroxy-4-(4-methoxyphenyl)-6-trifluoromethyl-2H-1-benzazepin-2, as described in methods of example 46, melting point 153 157oC.

()D-104,8 deg (C of 1.0, methanol).

Analysis calculated for C25H27N2O4F30,32 H2O, C 57,88; H To 5.57; N 5,40; F 10,99; Cl 6,83.

Found, C 57,78; H Of 5.89; N 5,50; F 10,61; Cl 6,88.2

1. Derivatives benzazepine or benzodiazepine General formula

< / BR>
where R1hydroxy, lower alkoxy, lower alkanoyloxy, OCONY8Y9where Y8and Y9hydrogen, lower alkyl; X is CH2or S,

thus, when X is CH2, R2the group of formulas

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
when X S, R2the group of formulas

< / BR>
< / BR>
< / BR>
n10, 1, 2, 3;

n 0, 1, 2;

Y6, Y7hydrogen, lower alkyl;

Y14-phenyl-lower alkoxy, hydrogen, lower alkoxy;

R3lower alkoxy, lower alkyl, hydrogen, halogen, trifluoromethyl, lower alkylsulfonyl;

R4lower alkoxy,

or their pharmaceutically priemlemye. Connection on p. 1, where R2-

< / BR>
5. Connection on p. 1, where R3methoxy or trifluoromethyl; R4located in the 4-position of the phenyl ring to which it is attached, and is lower alkoxy.

6. Connection on p. 1, where R44-methoxy.

7. Connection on p. 1, where R3methoxy or trifluoromethyl.

8. Connection on p. 1, which is (3R)1S*(3,4)-3-(acetoxy)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1-(2 - pyrrolidinyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-one or its acceptable from a pharmaceutical point of view of salt.

9. Connection on p. 1, which is (3R-)1S*(3,4)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-1-(2-pyrrolidinyl)- 6-(trifluoromethyl)-2H-1-benzazepin-2-one or its acceptable from a pharmaceutical point of view of salt.

10. Connection on p. 1, which is (3R)1S*(3,4)(6-chloro-1,3,4,5-tetrahydro-3-hydroxy-4-(4 - methoxyphenyl)-1-(2-pyrrolidinyl-methyl)-2H-1-benzazepin-2-one.

11. Connection on p. 1, which is (3R)1S*(3,4)(3 atomic charges)-6-chloro-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1-(2 - pyrrolidinyl)-2H-1-benzazepin-2-one.

12. Connection on p. 1, which monochlorohydrin isomer (2-dimethylamino)-1-phenylpropyl/-1,3,4,5-tetrahydro-3-hydroxy-4-(4 - methoxyphenyl(3R)-CIS/1-/2- /dimethylamine/1-phenylethyl/1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6 - trifluoromethyl)-2H-1-benzazepin-2-it.

14. Connection on p. 1, which monochlorohydrin isomer And /3R/-1/2S*/3,4/ /-1-/2-dimethylamino-/1-phenylpropyl/-1.3,4,5-tetrahydro-3-hydroxy-4-(4 - methoxyphenyl)-6-trifluoromethyl/-2N-1-benzazepin-2-it.

15. Connection on p. 1, which fumaric (1:1) salt /3R/1/R*/3,4//- 1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-1-/3-pyrrolidinyl/-6- /tripometer/-2N-1-benzazepin-2-it.

16. Connection on p. 1, which monochlorohydrin /3R-/1/ 25, 4P, 3, 4, //1,3,4,5-tetrahydro-3-hydroxy-4/4-methoxyphenyl-//4-/phenylmethoxy/2 - pyrrolidinyl/methyl/-6-trifluoromethyl/2N-1-benzazepin-2-it.

17.Connection on p. 1, which monochlorohydrin /3R-/ 1/2S*,4R*/,3,4/ /1,3,4,5-tetrahydro-3-hydroxy-1-//4/hydroxy-2-pyrrolidinyl/-4/4-methoxyphenyl/- 6-/trifluoromethyl/-2N-1-benzazepin-2-it.

18. Connection on p. 1, which monochlorohydrin /3R-/1/- 2S*,4R*/,3,4//1,3,4,5-tetrahydro-3-hydroxy-1-//4-hydroxy-2-pyrrolidinyl/methyl/4-/4 - methoxyphenyl/-6-/trifluoromethyl/-2N-1-benzazepin-it.

19. Connection on p. 1, which monochlorohydrin /3R-CIS/1- //4,5-dihydro-1H-imidazol-yl/methyl/-1,3,4,5-tetrahydro-3-hydroxy-4-/4 - methoxyphenyl/-6-/trifluoromethyl/2N-1-benzazepin-2-it.

20. Connection on p. 1, which monochlorohydrin /2S-/2,3,5/R*///-3 - atomic charges/2,3-dihydro-8 is seesa monochlorohydrin /2S-/2,3,5/R*///- 2,3-dihydro-2-/4-methoxyphenyl/3-/2-methyl-1 - oxopropoxy/-5-/2-pyrrolidinyloxyl/-1,5-benzothiazepin-4/5H/she

22. Connection on p. 1, which monochlorohydrin /3R-/1/ S*/3,4//-3-/atomic charges/-1,3,4,5-tetrahydro-7-methoxy-4-/methoxyphenyl-/1-/2 - pyridinylmethyl/-2N-1-benzazepin-2-it.

23. Connection on p. 1, which monochlorohydrin /3R-CIS-3-/atomic charges-/1-/4,5-dihydro-1H - imidazol-2-yl/methyl/-1,3,4,5-tetrahydro-/4-methoxyphenyl/-6-/trifluoromethyl/ -2N-1-benzazepin-2-it.

24. Connection on p. 1, which monochlorohydrin /3R-CIS/-1-/4,5-dihydro-1H-imidazol-2-yl/methyl/-1, 3,4,5-tetrahydro-3-hydroxy-7-methoxy-4-/4-methoxyphenyl/2N-1-benzazepin-2-it.

25. Connection on p. 1, which monochlorohydrin /3R-CIS-3- /atomic charges/-1-//4,5-dihydro-1H-imidazol-2-yl//methyl/-1,3,4,5-tetrahydro - methoxy-4-/4-methoxyphenyl/-2N-1-benzazepin-2-it.

26. Connection on p. 1, which monochlorohydrin /3R-/1/2S*,4R*/,3,4///- 1,3,4,5-tetrahydro-3-hydroxy-7-methoxy-4-/4-methoxyphenyl/-1-/2 - pyrrolidinyloxyl/-2N-1-benzazepin-2-it.

27. Connection on p. 1, which monochlorohydrin /3S-2,3,5/R*///-2,3-dihydro-3-hydroxy-8-methoxy-2-/4 - methoxyphenyl/-5-/2-pyrrolidinyloxyl/-1,5-benzothiazepin-4-/5H/she is.

28. Connection on p. 1, which is diazepin-4-/5H/she is.

29. Connection on p. 1, which monochlorohydrin /2S-CIS/3-atomic charges-5-/4,5-dihydro-1H - imidazol-yl/methyl/-2,3-dihydro-8-methoxy-2-/4-methoxyphenyl/-1,5 - benzothiazepin-4-/5H/she is.

30. Connection on p. 1, which monochlorohydrin /CIS/-1-//4,5 - dihydro-1H-imidazol-2-yl/methyl/-1,3,4,5-tetrahydro-3-hydroxy-7-methyl-4-/- 4-methoxyphenyl/-2N-1-benzazepin-2-it.

31. Connection on p. 1, which monochlorohydrin /CIS/-1-//4,5-dihydro-1H-imidazol-2 - yl/methyl/-1,3,4,5-tetrahydro-3-hydroxy-7-methylsulfanyl-4-/4-methoxyphenyl/- 2N-1-benzazepin-2-it.

32. Connection on p. 1, which fumaric (1:1) salt /3R-/1/S*/,3,4//1,3,4,5-tetrahydro-3-hydroxy-4-/4-methoxyphenyl/-1-/2 - azetidinone/6-/trifluoromethyl/-2N-1-benzazepin-2-it.

33. Connection on p. 1, which fumaric (1:1) salt /3R-/1/R*/,3,4// 1,3,4,5-tetrahydro-3-hydroxy-4-/4-methoxyphenyl/-1-/2-azetidinone/-6- /trifluoromethyl/-2N-1-benzazepin-2-it.

34. Connection on p. 1, which is the /3/ /R/-CIS-1-//1-methyl-4,5-dihydro-imidazol-2-yl/-methyl/-3 - hydroxy-4-/4-methoxyphenyl/-6-/trifluoromethyl/-2N-1-benzazepin-2-it.

35. Connection on p. 1, which monochlorohydrin /3R-CIS/-1//4,5-dihydro - 1H-imidazol-2-yl/-methyl/-1,3,4,5-tetrahydro-3-hydroxy-6-chloro-4-/4 - methoxyphenyl/-2N-1-benzazepin-2-it.

36. With the-pyridinylmethyl-6- /trifluoromethyl/-2N-1-benzazepin-2-it.

37. Connection on p. 1, where R1HE, lower alkoxy, lower alkanoyloxy, OVOP8Y9; R2a group of the formula

< / BR>
< / BR>
< / BR>
Priority signs:

20.06.88 when X CH2, R2-

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
n 0,1.

22.05.89 if X S; R2-

< / BR>
< / BR>
5

 

Same patents:

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

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

ororor< / BR>
ororwhere 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

CHY5ororwhere Y3, Y5have the specified values;

R3lowest alkoxyl, lower alkyl, hydrogen, halogen, trifluoromethyl, lower alkylsulfonyl, R

The invention relates to 6-oxo-asiminoaei compounds, namely to new derivatives of 6-oxo-3,4,5,6-tetrahydro-1H-azepino [5,4,3-cd] indole with, if necessary, in the 3rd or 4th position of the skeleton of the ring substituted aminoalkyl balance, and their acid salts of accession, and to pharmaceutical preparations containing these compounds, process for the preparation of these compounds and intermediates for their production

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

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

ororor< / BR>
ororwhere 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

CHY5ororwhere Y3, Y5have the specified values;

R3lowest alkoxyl, lower alkyl, hydrogen, halogen, trifluoromethyl, lower alkylsulfonyl, R

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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