Derivatives of 3-(2-amino-ethyl)-4-[3-(trifluoromethyl)benzoyl]-3,4 - dihydro-2h-1,4 - benzoxazine, a method of receiving and containing pharmaceutical composition

 

(57) Abstract:

Describes new derivatives of 3-(2-amino-ethyl)-4-[3-(trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4-benzoxazine in the form of a pure optical isomer or mixture of optical isomers, corresponding to the General formula I, in which R1represents a hydrogen atom, fluorine or chlorine or methyl, C1-C3-alkoxy - or nitro-group; R3individually denotes a hydrogen atom or a C1-C3is an alkyl group; R4separately corresponds 2,3-dihydro-1H-inden-2-ilen group, 2,3-dihydro-1H-inden-1-ilen group or 1,2,3,4-tetrahydronaphthalen-1-ilen group or in the alternative, if R3and R4together with the nitrogen atom to which they are attached, form a 1,2,3,4-tetrahydro-N-pyrido[3,4-b]indole-2-ilen group, 1,2,3,4-tetrahydro-N-pyrido[4,3-b] indole-3-ilen group, 4,5,6,7-tetrahydrothieno[2,6 -] pyrid-6-ilen group, 4,5,6,7-tetrahydrothieno[3,2-C]pyrid-6-ilen group or a 2,3-dihydro-1H-isoindole-2-strong group of formula a, b, c, d, e in the form of bases or of salts obtained by addition of acids. The compounds of formula I can be used as therapeutic agents. Also described is a method of obtaining the above-mentioned compounds of the electronic calcium homeostasis. 3 S. p. and 1 C.p. f-crystals, 2 tab.

The present invention relates to derivatives of 3-(2-amino-ethyl)- 4-[3-(trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4-benzoxazine, their reception, and their therapeutic use.

Provided by the present invention compounds correspond to the General formula I

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in which R1represents a hydrogen atom, fluorine or chlorine or methyl, C1-C3-alkoxy - or nitro-group;

R3individually denotes a hydrogen atom or a C1-C3is an alkyl group;

R4separately corresponds 2,3-dihydro-1H-inden-2-ilen group, 2,3-dihydro-1H-inden-1-ilen group or 1,2,3,4-tetrahydronaphthalen-1-ilen group or in the alternative case

R3and R4together with the nitrogen atom to which they are attached, form a 1,2,3,4-tetrahydro-N-pyrido[3,4-b] indole-2-ilen group, 1,2,3,4-tetrahydro-N-pyrido[4,3-b] indole-3-ilen group, 4,5,6,7-tetrahydrothieno[2,3-c] pyrid-6-ilen group, 4,5,6,7-tetrahydrothieno[3,2-C]pyrid-6-ilen group or a 2,3-dihydro-1H-isoindole-2-ilen group, the corresponding formulas are given below:< / BR>
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The preferred compounds are those in the formula of which radicals is hydrogen or C1-C3is an alkyl group, a R4corresponds 2,3-dihydro-1H-inden-2-ilen group, 2,3-dihydro-1H-inden-1-ilen group or 1,2,3,4-tetrahydronaphthalen-1-ilen group.

Because the molecule is described by the General formula I contain an asymmetric carbon atom (position 3 system benzoxazinone ring), provided by the present invention compounds can exist in the form of pure enantiomers or mixtures of enantiomers. In addition, if the radical R4represents a 2,3-dihydro-1H-inden-1-ilen group or 1,2,3,4-tetrahydronaphthalen-1-ilen group, this molecule contains a second asymmetric center.

Thus provided by the present invention, the compound may exist in the form of a pure optical isomer or mixture of such isomers.

Finally, provided by the present invention compounds may be presented in the form of free bases or salts formed by the addition of acids.

In accordance with the present invention, the compounds described by General formula I, can be obtained using the method presented in the schematic on the next page.

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2-Amino is the formula III, in the presence of a base, such as pyridine, in a solvent such as ether.

The obtained amide responsible of General formula IV, result in interaction with ethyl-4-bromo-2-butenoate corresponding to the formula V in the presence of a base, such as ethoxide sodium in a solvent such as ethanol, at a temperature of approximately 80oC. the ester group derived ethyl-3,4-dihydro-2H-1,4-benzoxazin-3-acetate described General formula VI, or restore (in General) using a reducing agent such as sociallyengaged, or (if the radical R1is a nitro-group) using sodium borohydride (1.1-dimethylethanol [Synth. Commun. (1982),12(6),463] to obtain a derivative of 3,4-dihydro-2H-1,4-benzoxazin-3-ethanol that meets the General formula VII, which lead into an interaction with 3-(trifluoromethyl)benzoyl chloride corresponding to the formula VIII in a solvent such as dichloromethane, to obtain the alcohol corresponding to General formula IX, which result in interaction with thionyl chloride to obtain the compound described by the General formula X. Finally, the last connection lead in the interaction with the amine that meet the General formula HNR3

In particular, aminophenol, responsible of General formula II, in which the radical R1represents a methoxy group, described in [J. Am. Chem.Soc. (1949), 71, 1265].

Amines corresponding to General formula HNR3R4in which the radical R4represents 2,3-dihydro-1H-inden-2-ilen group, described in [J. Med.Chem. (1980), 23, 745].

Amines described General formula HNR3R4in which the radical R4represents 2,3-dihydro-1H-inden-1-ilen group, described in [J. Am.Chem.Soc. (1966), 88, 2233].

Amines that meet the General formula HNR3R4in which the radical R4indicates 1,2,3,4-tetrahydronaphthalen-1-ilen group, described in [J. Am. Chem. Soc. (I960), 82, 459; C. R. Hebd. Seances Acad.Sci. Ser.C (1969), 268, 2225; J. Med. Chem. (1969), 9, 830].

1,2,3,4-Tetrahydro-N-pyrido[3,4-b] indole is described in [Organic Synthesis(1971), 51, 136].

1,2,3,4-Tetrahydro-N-pyrido[4,3-b] indole is described in [J. Chem. Soc. (C) (1968), 1235].

4,5,6,7-Tetrahydrothieno[3,2-c] pyridine and 4,5,6,7-tetrahydrothieno[2,3-C] pyridine described in [Arkiv Kemi(1970), 13(19), 217].

4,5,6,7-Tetrahydrothieno[3,2-c]pyridine described in [EP-A-0342118].

2,3-Dihydro-1H-isoindole described in [Organic Synthesis coll. (1973), 5, 406 and 1069].

If you wish to obtain optically pure soloy IX, which can be obtained, for example, using enzymatic method.

The basic principle of the specified enzymatic method consists in the separation of the optically pure alcohol and the corresponding acetate, characterized by the opposite configuration, for example, using chromatography on silicagel column.

In accordance with the first variant of the method racemic alcohol corresponding to the formula IX is subjected to chemical acylation, for example, with acetic anhydride, stereospetsifichno hydrolyzing one of the two enantiomers specified racemic acetate in the presence of the enzyme and separated acetate, which have not undergone hydrolysis. Thus obtained optically pure alcohol, as well as optically pure acetate, characterized by the opposite configuration, which, if desired, can be in turn obtained by chemical or enzymatic effects to obtain a second enantiomer of the specified alcohol.

In accordance with a second embodiment of the method of the racemic alcohol corresponding to the formula (IX) is subjected to stereospecific the acylation in the presence of an enzyme that catalyzes the reaction of esterification of only one of the above e the Cesky pure alcohol, and optically pure acetate, characterized by the opposite configuration, which, if desired, can be in turn obtained by chemical or enzymatic effects to obtain a second enantiomer of the specified alcohol.

Depending on what type of enzyme used, levogyrate or programalso enantiomer of the alcohol and its acetate, which is characterized by the opposite configuration can be obtained in these two ways.

Usable enzymes can be, for example, lipase from Mucor miehei, Penicillum cyclopium or wheat germ.

In addition, if the radical R4represents a 2,3-dihydro-1H-inden-1-ilen group or 1,2,3,4-tetrahydronaphthalen-1-ilen group, these compounds contain in its molecule a second asymmetric center and therefore exist in the form of diastereoisomers. The use of chiral amines [J. Am. Chem.Soc. (1966), 88, 2233; C. R. Hebd. Seances Acad.Sci. Ser.C (1969), 268, 2225] allows the synthesis of optically pure compounds.

The following examples illustrate in detail the production of several compounds provided by the present invention.

Elemental Mick the brackets in the names examples correspond to the numbers in the table below.

Example 1 (compound No. 1).

()-3-[2-(1,2,3,4-Tetrahydro-N-pyrido[3,4-b] indol-2-yl)ethyl] -4- [(3-trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4-benzoxazine (E)-2-butenedioate (1: 1).

1.1. N-(2-Hydroxyphenyl)triptorelin.

In equipped with a magnetic stirrer reactor with a capacity of 4 l receive a suspension of 1.5 liters of diethyl ether and 104 g (0,95 M 2-aminophenol, then add 77 ml of pyridine. Cool the reaction medium a mixture of ice and ethanol within one hour added dropwise to 200 g of (0.95 M) triperoxonane anhydride obtained mixture was allowed to warm to room temperature and continue stirring for 1 h

Add ice water and the organic phase is separated, sequentially washed with 1 n hydrochloric acid, water, saturated solution of acid sodium carbonate and a saturated solution of sodium chloride. Dried the organic phase over magnesium sulfate and the solvent is evaporated.

Obtain 170 g of product, which is used in accordance with the description of the next stage.

1.2. Ethyl ()-3,4-dihydro-2H-1,4-benzoxazin-3-acetate.

650 ml of ethanol injected into equipped with a magnetic stirrer reactor emkosti added dropwise 53 g (0,259 M) N-(2-hydroxyphenyl)trifurcated and 50 g (0,259 M) ethyl - 4-bromo-2-butenoate 75% purity and incubated the mixture at a temperature of 80oC for 1.5 h

The solvent is evaporated and taken the remainder in 160 ml of water and 65 ml of 1 n sodium hydroxide, then extracted with diethyl ether. The organic phase is washed with a saturated solution of sodium chloride and dried over magnesium sulfate, then the solvent is evaporated. Get 38,22 g of product, which is purified by chromatography on silicagel column, elute with a mixture of cyclohexane and isopropyl ether in the ratio 1:1. Get 28,02 g of the product.

1.3. ()-3,4-Dihydro-2H-1,4-benzoxazin-3-ethanol.

190 ml of tetrahydrofuran is introduced into a reactor with a capacity of 1 l, is cooled with a mixture of ice and salt, in an atmosphere of argon added to 7.7 g (0,202 M) sociallyengaged, and then added dropwise 28,02 g (to 0.127 M) ethyl ()-3,4-dihydro-2H-1,4-benzoxazin-3-acetate, dissolved in 190 ml of tetrahydrofuran, and the resulting mixture was stirred for 3 h

Cooled reactor with a mixture of dry ice and acetone, are added dropwise 60 ml of water and 30 ml of 1 n sodium hydroxide solution and continue stirring for 0.5 hours

The formed precipitate is removed by filtration through kieselgel, sequentially rinsed his tetrahydrofuran and ethyl acetate, evaporated codenameeagle column, elute with a mixture of cyclohexane and ethyl acetate in the ratio of 1:1. Obtain 15.5 g of product.

1.4. ()-4-[3-(Trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4 - benzoxazin-3-ethanol.

77 ml of dichloromethane, 15,93 g (0,072 M) ()-3,4-dihydro-2H-1,4-benzoxazin-C-ethanol and 10,67 g (0,077 M) of potassium carbonate is introduced into a round bottom flask with a capacity of 500 ml, added dropwise of 16.05 g (0,077 M) 3-(trifluoromethyl)benzoyl chloride dissolved in 77 ml of dichloromethane, and the resulting mixture was stirred at room temperature for 3.5 h

Add 72 ml of 1N sodium hydroxide, the organic phase is separated and washed with water and then a saturated solution of sodium chloride, dried over magnesium sulfate and the solvent is evaporated. Get 33,48 g of oily product, which was purified using chromatography on silicagel column, elute with a mixture of cyclohexane and ethyl acetate in the ratio of 1:1. Get 21,93 g of the product.

1.5. ()-3-(2-Chloroethyl)-4-[3-(trifluoromethyl)benzoyl] -3,4 - dihydro-2H-1,4-benzoxazin.

To 21,93 g ()-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4 - benzoxazin-C-ethanol, dissolved in 280 ml of dichloromethane, add 18 ml (0,248 M) of thionyl chloride and the resulting mixture was stirred at room temperature for 6 hours

is using chromatography on silicagel column, elute with a mixture of cyclohexane and isopropyl ether in the ratio 1:1. Get to 21.74 g of the product.

1.6. ()-3-[2-(1,2,3,4-Tetrahydro-N-pyrido[3,4-b]indol-2-yl)ethyl]-4-[3-(trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4-benzoxazine (E)-2-butenedioate (1:1).

To a solution of 2.5 g (0,007 M) ()-3-(2-chloroethyl)-4-[3-(trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4 - benzoxazine in 20 ml of N,N-dimethylformamide, stir on a magnetic stirrer at room temperature in an argon atmosphere added 1.20 g (0,007 M) 1,2,3,4-tetrahydro-N-pyrido[3,4-b] indole, 1.45 g (0,0105 M) of potassium carbonate and of 1.16 g (0,007 M) of potassium iodide and incubated the mixture at a temperature of 160oC for 1 h this mixture is cooled, add 80 ml of water and 80 ml of ethyl acetate, separate the phases and twice the aqueous phase is extracted with 80 ml of ethyl acetate. Combine the organic phases are washed with 100 ml saturated sodium chloride solution, dried over magnesium sulfate, filtered and the solvent evaporated. Get 4 g of oily product, which was purified using chromatography on silicagel column, elute with a mixture of cyclohexane and ethyl acetate in the ratio of 7:3. Get 3.5 g of pure reason in the form of a yellow oil.

The fumarate of the specified radix is obtained by d is RME white crystals.

As a result, there 1,71 g fumarata. The melting point 211-212oC.

Example 2 (compound No. 12).

()-6-Fluoro-3-[2-(4,5,6,7-tetrahydrothieno[2,3-c] pyrid-6-yl)ethyl] -4- [(3-trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4-benzoxazine (E)-2-otential (1:1).

2.1. 2-Amino-4-terfenol.

To a solution of 50 g (0,318 M) 4-fluoro-2-NITROPHENOL in 1.5 liters of water, stir with a magnetic stirrer, add 120 g (0,689 M) hydrosulfite sodium, heated the mixture to reflux distilled, add 120 g (0,689 M) hydrosulfite sodium and maintain the condition of reflux distilled in a period of 0.75 hours

Cool the mixture, portions add sour sodium carbonate to until the pH becomes basic, add 1 l of diethyl ether, the separated phase and the aqueous phase is extracted with 1 l of diethyl ether. Combine the organic phases are washed with 1 l of water and 1 l of a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and the solvent evaporated. Obtain 21.1 g of product, which is used in accordance with the description of the next stage.

2.2. N-(5-fluoro-2-hydroxyphenyl)triptorelin.

In equipped with a magnetic stirrer reactor with a capacity of 1 l receive a suspension new environment with a mixture of ice and ethanol. Within 1 hour added dropwise 23.3 g (0,165 M) triperoxonane anhydride, allow the mixture to warm to room temperature and continue stirring for 3 hours

Add ice water and the organic phase is separated, sequentially washed with 170 ml of 1 n hydrochloric acid, water, saturated solution of acid sodium carbonate and a saturated solution of sodium chloride. Dried the organic phase over magnesium sulfate and the solvent is evaporated.

Get to 32.7 g of product, which is used in accordance with the description of the next stage.

2.3. Ethyl ()-6-Fluoro-3,4-dihydro-2H-1,4-benzoxazin-3-acetate.

370 ml of ethanol injected into equipped with a magnetic stirrer reactor with a capacity of 1 l, cooled to 0oC and slowly, in small portions, add 3.5 g (0,146 M) of sodium, and then successively added dropwise 32,54 g (0,146 M) N-(5-fluoro-2-hydroxyphenyl)trifurcated and opposed to 28.18 per g (0,146 M) ethyl-4-bromo-2-butenoate 75% purity and incubated the mixture at a temperature of 80oC for 3 h

The solvent is evaporated and taken the remainder in 90 ml of water and 37 ml of 1 n sodium hydroxide, then extracted with diethyl ether. The organic phase promill. Get 38,74 g of product, which is purified by chromatography on silicagel column, elute with a mixture of cyclohexane and isopropyl ether in the ratio 1:1. Get 23,22 g of the product.

2.4. ()-6-Fluoro-3,4-dihydro-2H-1,4-benzoxazin-3-ethanol.

145 ml of tetrahydrofuran is introduced into a reactor with a capacity of 1 l, is cooled with a mixture of ice and salt, in an atmosphere of argon gas added 5.9 g (0,153 M) sociallyengaged, and then added dropwise 23,22 g (0,097 M) ethyl ()-6-fluoro-3,4-dihydro-2H-1,4-benzoxazin-3-acetate, dissolved in 145 ml of tetrahydrofuran, and the resulting mixture was stirred for 2.5 hours Cooled reactor with a mixture of dry ice and acetone, added dropwise in 45 ml of water and 23 ml of 1N sodium hydroxide solution and continue stirring for 0.5 hours

The formed precipitate is removed by filtration through kieselgel, sequentially rinsed his tetrahydrofuran and ethyl acetate, evaporated contained in the filtrate solvents and get 18,07 r gross product, which is purified by chromatography on silicagel column, elute with a mixture of cyclohexane and ethyl acetate in the ratio of 1:1. Get a 13.9 g of the product.

2.5. ()-6-Fluoro-4-[3-(trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4 - benzoxazin-3-ethanol.

out in a round bottom flask with a capacity of 500 ml, added dropwise 15,44 g (0,074 M) 3-(trifluoromethyl)benzoyl chloride dissolved in 70 ml of dichloromethane, and the resulting mixture was stirred at room temperature for 5 hours

Add 70 ml of 1 n sodium hydroxide, the organic phase is separated and washed with water and then a saturated solution of sodium chloride, dried over magnesium sulfate and the solvent is evaporated. Get 27,53 g of oily product, which was purified using chromatography on silicagel column, elute with a mixture of cyclohexane and ethyl acetate in the ratio of 1:1. Get 11,27 g of the product.

2.6. ()-3-(2-Chloroethyl)-6-fluoro-4-[3-(trifluoromethyl)benzoyl] - 3,4-dihydro-2H-1,4-benzoxazin.

To 11,27 g (0,031 M) ()-6-fluoro-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazin-3 - ethanol, dissolved in 140 ml of dichloromethane, add 9 ml (0,124 M) of thionyl chloride and the resulting mixture was stirred at room temperature for 5 hours

The solvent is evaporated and the residual in toluene, which is evaporated and the resulting oil purified by chromatography on silicagel column, elute with a mixture of cyclohexane and isopropyl ether in the ratio 1:1. Get 10,33 g of the product.

2.7. ()-6-Fluoro-3-[2-(4,5,6,7-tetrahydrate is the target of 1.11 g (0,003 M) ()-3-(2-chloroethyl)-6-fluoro-4- [3-(trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4-benzoxazine in 15 ml of N,N-dimethylformamide, stir on a magnetic stirrer at room temperature in an argon atmosphere added 0.66 g (0,003 M) 4,5,6,7-tetrahydrothieno[2,3-C] pyridylacetate, 1.19 g (0,0086 M) of potassium carbonate and 0.5 g (0,003 M) of potassium iodide and incubated the mixture at a temperature of 160oC for 1 h this mixture cool, add 50 ml of water and 50 ml of diethyl ether, separating the phases and twice the aqueous phase is extracted with 50 ml diethyl ether. Combine the organic phases are washed with 50 ml saturated sodium chloride solution, dried over magnesium sulfate, filtered and the solvent evaporated. Obtain 1.56 g of oily product, which was purified using chromatography on silicagel column, elution with a mixture of cyclohexane and ethyl acetate in the ratio of 7:3. Get 0,80 g base in the form of a yellow oil.

The fumarate of the specified radix is obtained by adding an equivalent amount of fumaric acid, allocate it and recrystallized from 2-propanol in the form of white crystals.

As a result, there 0,77 g fumarata. The melting point 181-182oC.

Example 3 (compound # 24).

()-3-[2-[(2, C-Dihydro-1H-inden-2-yl)methylamino] ethyl] -6-methoxy-[ 4-(3-trifluoromethyl)benzoyl]-3,4-dihyd radovanom magnetic stirrer reactor with a capacity of 2 l receive a suspension of 1 l of diethyl ether and 75,33 g (0.54 M) 2-amino-4-methoxyphenol, then add 56 ml of pyridine. Cool the reaction medium a mixture of ice and ethanol within one hour added dropwise to 131.4 g (of 0.625 M) triperoxonane anhydride obtained mixture was allowed to warm to room temperature and continue stirring for 2 h

Add ice water and the organic phase is separated, sequentially washed with 500 ml of 1 n hydrochloric acid, water, saturated solution of acid sodium carbonate and a saturated solution of sodium chloride. Dried the organic phase over magnesium sulfate and the solvent is evaporated.

Get to 41.6 g of product, which is used in accordance with the description of the next stage.

3.2. Ethyl ()-6-methoxy-3,4-dihydro-2H-1,4-benzoxazin-3-acetate.

450 ml of ethanol injected into equipped with a magnetic stirrer reactor with a capacity of 1 l, cooled to 0oC, slowly, in small portions, add 7 g (0,32 M) of sodium, and then successively added dropwise 37,94 g (0.16 M) of N-(2-hydroxy-5-methoxyphenyl)trifurcated and 41.2 g (0.16 M) ethyl-4-bromo-2-butenoate 75% purity and incubated the mixture at a temperature of 80oC for 2 h

The solvent is evaporated and taken the obtained residue in 100 ml of water and 40 ml of 1 thief of sodium chloride and dried over magnesium sulfate, then the solvent is evaporated. Get 38,46 g of product, which is purified by chromatography on silicagel column, elute with a mixture of cyclohexane and isopropyl ether in the ratio 1:1. Get 21,22 g of the product.

3.3. ()-6-methoxy-3,4-dihydro-2H-1,4-benzoxazin-3-ethanol.

130 ml of tetrahydrofuran is introduced into a reactor with a capacity of 1 l, is cooled with a mixture of ice and salt in the atmosphere of argon add 5 g (0,132 M) sociallyengaged, and then added dropwise 20,73 g (0,0825 M) ethyl ()-6-methoxy-3,4-dihydro-2H-1,4-benzoxazin-3-acetate, dissolved in 130 ml of tetrahydrofuran, and the resulting mixture was stirred for 1.5 h

Cooled reactor with a mixture of dry ice and acetone, are added dropwise 40 ml of water and 20 ml of 1 n sodium hydroxide solution and continue stirring for 0.5 hours

The formed precipitate is removed by filtration through kieselgel, sequentially rinsed his tetrahydrofuran and ethyl acetate, evaporated contained in the filtrate solvents and get to 25.15 g of a coarse product, which is purified by chromatography on silicagel column, elution with a mixture of cyclohexane and ethyl acetate in the ratio of 1:1. Get 10,53 g of the product.

3.4. ()-6-Methoxy-4-[3-(cryptomate-2H-1,4-benzoxazin-3-ethanol and 7.4 g (0,0535 M) of potassium carbonate is introduced into a round bottom flask with a capacity of 500 ml, added dropwise 11,16 g (0,0535 M) 3-(trifluoromethyl)benzoyl chloride, dissolved in 80 ml of dichloromethane, and the resulting mixture was stirred at room temperature for 2 h

Add 50 ml of 1N sodium hydroxide, the organic phase is separated and washed with water and then a saturated solution of sodium chloride, dried over magnesium sulfate and the solvent is evaporated. Get 22,25 g of oily product, which was purified using chromatography on silicagel column, elute with a mixture of cyclohexane and ethyl acetate in the ratio of 2:1. Get 14,74 g of the product.

3.5. ()-3-(2-Chloroethyl)-6-methoxy-4-[3-(trifluoromethyl) benzoyl]-3,4-dihydro-2H-1,4-benzoxazin.

To 14,74 g (0,039 M) ()-6-methoxy-4-[3-(trifluoromethyl)benzyl]-3,4-dihydro-2H-1,4-benzoxazin-3-ethanol, dissolved in 165 ml of dichloromethane, add 14 ml (0,19 M) of thionyl chloride and the resulting mixture was stirred at room temperature for 5 hours

The solvent is evaporated and the residual in toluene, which is evaporated to obtain dry matter and the resulting oil purified by chromatography on silicagel column, elute with a mixture of cyclohexane and isopropyl ether in the ratio 1:1. Gain of 14.7 g of the product.

the Zina of tandikat (1:1).

To a solution of 1.6 g (0,004 M) ()-3-(2-chloroethyl)-6-methoxy-4-[3-(trifluoromethyl)benzoyl] - 3,4-dihydro-2H-1,4-benzoxazine in 18 ml of N,N-dimethylformamide, stir on a magnetic stirrer at room temperature in an argon atmosphere added 0.73 g (0,004 M) N-methyl-2,3-dihydro-1H - inden-2-amine hydrochloride, to 1.38 g (0.01 M) potassium carbonate and 1.66 g (0,004 M) of potassium iodide and incubated the mixture at a temperature of 150oC for 1 h

This mixture is cooled, add 38 ml of water and 70 ml of diethyl ether, separating the phases and twice the aqueous phase is extracted with 70 ml of diethyl ether. Combine the organic phase is washed with 70 ml of saturated solution of sodium chloride, dried over magnesium sulfate, fillout and the solvent is evaporated. Get 1,91 g of oily product, which was purified using chromatography on silicagel column, elute with a mixture of dichloromethane and methanol in the ratio of 85:15. Get 0,940 g of pure reason in the form of a yellow oil.

The oxalate of the specified radix is obtained by adding an equivalent amount of oxalic acid, allocate it and recrystallized from ethyl acetate in the form of white crystals.

As a result, there 0,370 g of the oxalate. The point has been melted down the[(3-trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazine (E)-2-butenedioate (1:1), a mixture of ()-diastereomers in the ratio of 65: 35.

4.1. N-(5-Chloro-2-hydroxyphenyl)triptorelin.

In equipped with a magnetic stirrer reactor with a capacity of 1 l 25 g (0,174 M) 2-amino-4-chlorophenol suspension in 320 ml of diethyl ether, then add 18 ml of pyridine. Cool environment with a mixture of ice and ethanol within one hour added dropwise to 24.6 ml (0,174 M) triperoxonane anhydride obtained mixture was allowed to warm to room temperature and continue stirring for 1 h

Add ice water, divided phase after will delamination, the organic phase is successively washed with 320 ml of 1 n hydrochloric acid, water, saturated solution of acid sodium carbonate and saturated sodium chloride solution, dried over magnesium sulfate and the solvent is evaporated. Get of 40.3 g of the product, which is used in accordance with the description of the next stage.

4.2. Ethyl ()-6-chloro-3,4-dihydro-2H-1,4-benzoxazin-3-acetate.

420 ml of ethanol injected into equipped with a magnetic stirrer reactor with a capacity of 3 l, cooled to 0oC, slowly, in small portions, add 3.8 g (0,166 M) of sodium, and then successively added dropwise to 40 g (0,166 M) N-(5-chlorine is mesh at a temperature of 85oC for 2 h the solvent is Evaporated and taken the obtained residue in 100 ml of water and 40 ml of 1N sodium hydroxide, and then extracted with diethyl ether. Separate the organic phase, washed her with a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated. Get 28,58 g of product, which is purified by chromatography on silicagel column, elute with a mixture of cyclohexane and isopropyl ether in the ratio 1:1. Get 23,72 g of the product.

4.3. ()-6-Chloro-3,4-dihydro-2H-1,4-benzoxazin-3-ethanol.

150 ml of tetrahydrofuran is introduced into a reactor with a capacity of 1 l, cooled with a mixture of ice and salt, in an argon atmosphere type of 5.92 g (0,156 M) sociallyengaged, and then added dropwise 23,52 g (0,0973 M) ethyl ()-6-chloro-3,4-dihydro-2H-1,4-benzoxazin-3-acetate, dissolved in 150 ml of tetrahydrofuran, and the resulting mixture was stirred for 1.5 hours Cooled reactor with a mixture of dry ice and acetone, added dropwise 40 ml of water and 20 ml of 1 n sodium hydroxide solution and continue stirring for 0.5 hours the precipitate is removed by filtration through kieselgel, then rinsed with tetrahydrofuran and then with ethyl acetate and the solvent is evaporated. Allot of 27.5 g of a coarse product, which ocenie 1:1. Get 19,67 g of the product.

4.4. ()-6-Chloro-4-[3-(trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4 - benzoxazin-3-ethanol.

100 ml of dichloromethane. 19,17 g (0,09 M) ()-6-chloro-3,4-dihydro-2H-1,4-benzoxazin-3-ethanol and 13.3 g (0,096 M) of potassium carbonate is introduced into a round bottom flask with a capacity of 1 l was added dropwise 20 g (0,096 M) 3-(trifluoromethyl)benzoyl chloride, dissolved in 100 ml of dichloromethane, and the resulting mixture was stirred at room temperature for 3 hours

Add 90 ml of 1 n sodium hydroxide, the organic phase is separated and washed with water and then a saturated solution of sodium chloride, dried over magnesium sulfate and the solvent is evaporated. Obtain 36 g of oily product, which was purified using chromatography on silicagel column, elute with a mixture of cyclohexane and ethyl acetate in the ratio of 2:1. Get 24,21 g of the product.

4.5. ()-6-Chloro-3-(2-chloroethyl)-4-[3-(trifluoromethyl)benzoyl] - 3,4-dihydro-2H-1,4-benzoxazin.

To 24,21 g ()-6-chloro-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazin-3-ethanol, dissolved in 260 ml of dichloromethane, add 18 ml (0.25 M) of thionyl chloride and the resulting mixture was stirred at room temperature for 6 hours

The solvent is evaporated, the residue taken but with a mixture of cyclohexane and isopropyl ether in the ratio 1:1.

Get 23,73 g of the product.

4.6. ()-6-Chloro-3-[2-[(1,2,3,4-tetrahydronaphthalen-1-yl) methylamino]ethyl] -4-[3-(trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4-benzoxazine (E)-2-butenedioate (1:1).

To a solution of 1.8 g (0,0044 M) ()-6-chloro-3-(2-chloroethyl)-4-[3- (trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4-benzoxazine in 13 ml of N,N-dimethylformamide, stir on a magnetic stirrer at room temperature in an argon atmosphere added 0.88 g (0,0044 M) N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride, 1,23 g (0,009 M) of potassium carbonate and 0.74 g (0,0044 M) of potassium iodide and incubated the mixture at a temperature of 120oC for 1 h 30 min

This mixture cool, add 50 ml of water to obtain a sticky product, which is washed with water and dissolved in 50 ml of ethyl acetate, dry the solution over magnesium sulfate, filtered and the solvent is evaporated under reduced pressure. Get 2,39 g of oily product, which was purified using chromatography on silicagel column, elute with a mixture of cyclohexane and ethyl acetate in the ratio 8:2. Gain of 1.62 g of the base.

To obtain fumarata 0.35 g (0,003 M) fumaric acid is added to 15 ml of 2-propanol, heat this mixture to reflux distilled, evaporated dissolve lizovyvatj from 2-propanol. Finally, after drying under the conditions of heating in the presence of phosphorus pentoxide obtain 0.3 g fumarata. The melting point of 145-146oC.

Example 5 (compound N 38). (+)-6-Chloro-3-[2-[(2,3-dihydro-1H-inden-2-yl)methylamino] ethyl] -4- [(3-trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4-benzoxazine (E)-2-butenedioate (1:2).

5.1. (-)-6-Chloro-4-[3-(trifluoromethyl)benzoyl] -3,4-dihydro-2H - 1,4-benzoxazin-3-ethanol.

5.7 g (0,0148 M) ()-6-chloro-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazin-3 - ethanol are dissolved in 60 ml of ethyl acetate, added 570 mg of lipase from Mucor miehei in a concentration of 10% in the resin (Lipozyme IM60TM, NovoTM) and 1.36 ml of vinyl acetate, the resulting mixture was stirred at room temperature, monitor the reaction using high-performance liquid chromatography on a chiral column, elute with a mixture of hexane and 2-propanol in a ratio of 95:5.

After the reaction is carried out for 3 days, the degree of conversion reaches 52%, and the prevalence of its enantiomers of the alcohol - more than 98%. The resulting mixture was filtered through kieselgel, rinse the solid with 10 ml of ethyl acetate, concentrating the filtrate under reduced pressure and separate the mixture of ether and levogyrate alcohol using pulse chromatogr who have this mixture in the ratio of 4:6 for elution of alcohol.

Get 2.5 g levogyrate alcohol and 3.0 g of ether.

Alcohol: []2D5= -48o(c=0.5; CHCl3), ee = 98,3%.

Aired: ee = 91%.

5.2. (+)-6-Chloro-3-[2-[(2,3-dihydro-1H-inden-2-yl)methylamino] ethyl] -4- [3-(trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4-benzoxazine (E)-2-butenedioate (1:2).

The process is carried out under the same conditions described in the above examples, processing thionyl chloride (-)-6-chloro-4-[3-(trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4-benzoxazin-3-ethanol to obtain 6-chloro-3-(2-chloroethyl)-4-[3-(trifluoromethyl)benzoyl] -3,4-dihydro-2H-1, 4-benzoxazin (optical rotation of which is not defined), then the join result in interaction with N-methyl-2,3-dihydro-1H-inden-2-amine, and then processed the basis of fumaric acid.

The melting point of 168-169oC []2D0+16,2o(C=1; CH3OH).

Example 6 (compound No. 39). (-)-6-Chloro-3-[2-[(2,C-dihydro-1H-inden-2-yl)methylamino] ethyl] -4- [(Z-trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4-benzoxazine (E)-2-butenedioate (1:2).

6.1. (+)-6-Chloro-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H - 1,4-benzoxazin-3-ethanol.

3.0 g of the ester obtained in example 5.1, dissolved in 14 ml of toluene, add the e to the formation of the emulsion, then add 300 mg free lipase from Mucor miehei (BiocatalystTMand monitor the reaction using high-performance liquid chromatography on a chiral column as described in example 5.1.

After the reaction is carried out for 67 h, the degree of conversion reaches 28%, and a pH equal to 6.95, using 4n sodium hydroxide bring the pH of the reaction medium to 7.5, the mixture is heated to 35oC and continue mixing.

After the reaction is carried out for a further 48 h, the conversion rate is 67%; the pH is again adjusted to 7.5, add 300 mg of the indicated enzyme and continue mixing. After the reaction is carried out for 32 h, the degree of conversion reaches 82%, and the prevalence of alcohol enantiomers 98,1%. The resulting mixture is diluted with 100 ml diethyl ether and filtered through kieselgel, the aqueous phase is extracted four times with 100 ml of diethyl ether, the organic phase is dried over magnesium sulfate, the solvent is evaporated under reduced pressure and the resulting residue purified using chromatography as described in example 5.1.

Obtain 2.15 g programalso alcohol and 0.49 g of the ether.

Alcohol: []2D5= +51

The process is carried out under the same conditions described in the above examples, processing thionyl chloride (+)-6-chloro-4-[3-(trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4-benzoxazin-3 - ethanol to obtain 6-chloro-3-(2-chloroethyl)-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4 - benzoxazin (optical rotation of which is not defined), then the join result in interaction with N-methyl-2,3-dihydro-1H-inden-2-amine, and then processed the basis of fumaric acid.

The melting point of 169 - 170oC []2D0= -16,9o(c=1; CH3IT).

Example 7 (compound N 36). ()-3-[2-[(2,3-Dihydro-1H-inden-2-yl)amino] ethyl] -6-nitro-4- [(3-trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazine (E)-2-butenedioate (1:1).

7.1. N-(2-Hydroxy-5-nitrophenyl)triptorelin.

Prepare a suspension of 18 g (0,116 M) 2-amino-4-NITROPHENOL in 210 ml of diethyl ether, add 16 ml of pyridine, cooled the mixture in a bath with ice and ethanol, are added dropwise 24.5 g (0,116 M) triperoxonane anhydride.

The obtained mixture was allowed to warm to room temperature and continue stirring over night.

The resulting mixture was poured into 200 ml of water with Leon acidic sodium carbonate and a saturated solution of sodium chloride. After drying over magnesium sulfate receive 22,29 g of yellow solid, which is used in accordance with the description of the next stage.

7.2. Ethyl ()-6-nitro-3,4-dihydro-2H-1,4-benzoxazin-3-acetate.

220 ml of ethanol injected into equipped with a magnetic stirrer, three-neck flask with a capacity of 1 l), cooled to 0oC, slowly, in small portions, add 3 g (of 0.133 M) of sodium, and then successively added dropwise 22,29 g (0,088 M) N-(2-hydroxy-5-nitrophenyl)trifurcated and 22,65 g (0,088 M) ethyl-4-bromo-2-butenoate 75% clean and maintain the mixture in a state of reflux distilled for 3 h

The solvent is evaporated and taken the remainder in 53 ml of water and 21 ml of 1 n sodium hydroxide, then extracted with diethyl ether. The organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated. Get an orange-red oil, which was purified using chromatography on silicagel column, elute with a mixture of cyclohexane and ethyl acetate in the ratio of 85:15. Get a 9.25 g of the product.

7.3. ()-6-Nitro-3,4-dihydro-2H-1,4-benzoxazin-3-ethanol.

A mixture of 8.4 g (0,0317 M) ethyl ()-6-nitro-3,4-dihydro-2H-1,4-benzoxazin-3-acetate, 3 g (0 is plam add to 26.6 ml of methanol and incubated the mixture in a state of reflux distilled for 30 minutes

The resulting mixture was cooled in an ice bath, add 60 ml of water, evaporated methanol and 1,1-dimethylethanol and thrice extracted with an aqueous mixture of 120 ml of ethyl acetate. The organic phase is washed twice with 80 ml of saturated solution of sodium chloride, dried over magnesium sulfate and filtered, and the solvent is evaporated under reduced pressure. Obtain 27.5 g of oily product, which was purified using chromatography on silicagel column, elute with a mixture of cyclohexane and ethyl acetate in the ratio of 60:40.

Gain of 5.2 g of the product, which crystallized in cold conditions and used in accordance with the description of the next stage.

7.4. ()-6-Nitro-4-[3-(trifluoromethyl)benzoyl] -3,4-dihydro - 2H-1,4-benzoxazin-3-ethanol.

40 ml of dichloromethane, 5,16 g (0,023 M) ()-6-nitro-3,4-dihydro-2H-1,4-benzoxazin-3-ethanol and 3.5 g (0.025 M) of potassium carbonate is introduced into a round bottom flask with a capacity of 500 ml, added dropwise with 5.2 g (0.025 M) of 3-(trifluoromethyl)benzoyl chloride dissolved in 40 ml of dichloromethane, and the resulting mixture was stirred at room temperature for 3.5 h

Add 22 ml of 1 n sodium hydroxide, is evaporated with dichloromethane and extracted with aqueous residue with ethyl acetate. After washing and drying organographia on silicagel column, elute with a mixture of cyclohexane and ethyl acetate in a ratio of from 7:3 to 5:5. Gain of 5.4 g of pure product.

7.5. ()-3-(2-Chloroethyl)-6-nitro-4-[3-(trifluoromethyl) benzyl]-3,4-dihydro-2H-1,4-benzoxazin.

To lower than the 5.37 g (0,0135 M) ()-6-nitro-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazin-3-ethanol, dissolved in 80 ml of dichloromethane, add 4,85 ml (0,0675 M) of thionyl chloride and the resulting mixture was stirred, heated to a warm state in a bath of hot water for 5 h 30 min

The solvent is evaporated, the residue taken in toluene, which is evaporated, and the residue was washed with diisopropyl ether to obtain 21,74 g of product, which is used in accordance with the description of the next stage.

7.6. ()-3-[2-[(2, C-Dihydro-1,4-inden-2-yl) amino]ethyl]-6-nitro-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4 - benzoxazine (E)-2-butenedioate (1: 2).

To the solution was 1.58 g (0,0038 M) ()-3-(2-chloroethyl)-6-nitro-4-[3-(trifluoromethyl)benzoyl] -3,4 - dihydro-2H-1,4-benzoxazine in 15 ml of N,N-dimethylformamide, stir on a magnetic stirrer at room temperature in an argon atmosphere add to 0.69 g (0,0038 M) N-methyl-2,3-dihydro-1H - inden-2-amine hydrochloride, 1,32 g (0,0095 M) potassium carbonate and 0.63 g (0,0038 M) of potassium iodide and incubated the mixture Ave is etilovogo ether, separate the phases, the aqueous phase is twice extracted with 50 ml diethyl ether. Combine the organic phase, washed twice with 50 ml of saturated solution of sodium chloride, dried over magnesium sulfate, filtered and the solvent evaporated. Obtain 2.5 g of oily product, which was purified using chromatography on silicagel column, elution with a mixture of dichloromethane and methanol in a ratio of 98: 2. Gain of 1.36 g of pure reason in the form of a yellow oil. Fumarate receive, adding an equivalent amount of fumaric acid to the specified base, dissolved in hot 2-propanol, highlight the desired fumarate and recrystallized from methanol.

The result of 0.90 g fumarata. The melting point 176-178oC.

Table 1 below illustrates the chemical structures and physical properties of several compounds provided by the present invention. In the column "Salt" the sign "-" denotes a compound in the form of a Foundation, "the oaks." denotes the oxalate or tandikat and "FUM." indicates fumarate or (E)-2-butenedioate; round brackets are the ratio shows the molar ratio between the acid and the base.

Provided by the present invented the s compounds as therapeutic agents.

Thus, these compounds were involved in the test is complete cerebral ischemia in mice. This ischemia occurs due to suppression of cardiac activity-induced rapid intravenous injection of magnesium chloride. In this test measure the "survival time", i.e. the time interval between the moment of introduction of magnesium chloride and the last marked respiratory movement of each mouse. The specified movement is seen as the latest evidence of the functioning of the Central nervous system.

Suppression of respiratory activity occurs in approximately 19 seconds after the injection of magnesium chloride.

Male mice (line Swiss OF1 IFFA CREDO) study in groups of 10 individuals. Before experiments, animals get food and drink without restrictions. Survival time is measured after 10 min after intraperitoneal administration of the compounds provided by the present invention. The results obtained are in the form of the difference between the survival time measured in a group of 10 mice that received provided by the present invention compounds, and survival time, measured in a group of 10 mice received carrier fluid. The correlation between the changes of time survival is epicheskoi curve.

The specified curve allows the calculation of the "3-second effective dose" (ED3), i.e. the dose (in mg/kg), causing an increase in survival time compared to control group of 10 untreated mice for 3 seconds.

The increase in survival time of 3 seconds is on the one hand statistically significant, with the other repeatable.

For provided by the present invention compounds of the value of the ED3is in the range from 0.1 to 30 mg/kg intraperitoneal injection.

Provided by the present invention compounds were also involved in the study of the potential-dependent (dependent on voltage) current barium using the so-called patch-clamp methods.

The barium currents moving through potential-dependent calcium channels, measured on the drug culture cortesnyc cells (cultured for 6-10 days) newborn rats (line Sprague-Dawley); if these cells are mixed currents, involving L-, N - and P-channels [Soc.Neurosci.Abstr. (1989), 15, 823].

The measuring chamber with a capacity of 800 µl containing cortexone cells, placed on a tripod inverted microscope Olympus ITM-2TMand examine the cells at 400x magnification. These cemerty volume < 50 µl), only the output of which represents a polyethylene tube with a diameter of 500 μm, is less than 3 mm from the investigated cells. The specified device is convenient because it allows you to quickly change the solution in the cells under study.

Used the patch-clamp method described in [Plueger Archives (1981), 391, 85-100] . For cell stimulation, data acquisition and analysis of the results obtained using the Axopatch amplifier-IDTMconnected to the computer AT 386-33 MHz using software PCLAMPTMfrom Axon InstrumentsTM. In order to register the barium currents, to cells with the help of hydraulic Narashige micromanipulator WRTMfail borosilicate glass pipette. The tip of these pipettes filled reference intracellular solution having the following composition (in mm): CsCl (140), CaCl2(1), Na2ATP (4), EGTA (11; pCa=8), Hepes (10), Tris-OH (pH=7,2).

After find the so-called "whole cell" configuration, the specified cell is washed by the so-called solution of TEA-Barium, having the following composition (in mm): TEA-Cl (144), BaCl2(5), MgCl2(2), CsCl (3), glucose (10), Hepes (10), Tris-OH (pH=7,4).

This solution allows you to measure calcium currents (moving on akov sodium and potassium.

Full potential-dependent current of barium determined using phase depolarization potential duration of 250 MS, in which the magnitude of the membrane potential change from -80 mV to 0 mV. The specified frequency stimulation is 0.25 Hz.

Provided by the present invention compounds are dissolved in an environment TEA-Barium and use at the time of amplitude stabilization of barium current. After the discovery of stable inhibitory effect of the investigated cell again washed control solutions TEA-Barium to identify the address of the specified effect.

The efficiency of the observed effect is compared with the efficiency of a 100 μm solution of cadmium. The inhibition potential-dependent barium current varies depending on the doses of the compounds under study and, in the case of the most active compounds, reaches the level of 40% at a concentration of 1 μm and 90% at a concentration of 10 ám.

The results of the experiments are presented in table 2.

The results of experiments conducted with the use provided by the present invention compounds, indicate that in vitro, these compounds exhibit features of neural calcium antagonists, a in vivo they have not is, what these compounds may be used for treatment or prevention of brain diseases, such as, for example, the following: ischemic attack, suppression of cardiac or respiratory activity, embolism or thrombosis of the brain, for the treatment of cerebral aging, dementia, following the multiple heart attacks, dementia, such as Alzheimer's disease or sickness Maximum, to ensure olivopontocerebellar atrophy and other neurodegenerative diseases, such as Huntington's chorea and amyotrophic lateral sclerosis, for the treatment of cranial and spinal cord injury to prevent nervous diseases accompanied by convulsive States, for the treatment of certain forms of cancer, for the treatment of neurological diseases caused by AIDS, as well as for the prevention and treatment of diabetic retinopathy, macular degeneration of the optic nerve and associated with glaucoma retinopathy, and, in General, for the treatment of any pathology associated with dysfunction of neuronal calcium homeostasis.

For this purpose, these compounds may be represented in all the pharmaceutical forms intended for enteral or parenteral application, capsul, allatoona capsules, suppositories or solutions or suspensions used for drinking or injections that are assigned based to provide day use from 1 to 1000 mg of active agent.

Examples of pharmaceutical compositions.

Below, the pharmaceutical compositions obtained well-known in this field ways by mixing ingredients.

The solution for injection.

The active substance 5 mg

Glucose is 250 mg

Water for injection as needed up to 5 ml

one ampoule of 5 ml

Gelatin capsule.

The active substance 100 mg

Talc - 24 mg

Silica gel - 1 mg

one capsule 125 mg

Tablet.

The active substance - 400 mg

Silica gel 10 mg

Stearic acid - 20 mg

Corn starch - 45 mg

on one tablet 475 mg

The syrup.

The active substance is 5 grams

Methyl ester of 4-hydroxybenzoic acid - 150 mg

Saccharose - 50 grams

Distilled water as required up to 100 ml

one bottle of 100 ml,

1. Derivatives of 3-(2-amino-ethyl)-4-[3-(trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4-benzoxazine in the form of pure optionstable a hydrogen atom, fluorine or chlorine, or methyl, WITH1- C3-alkoxy - or nitro-group;

R3individually denotes a hydrogen atom or a C1- C3is an alkyl group;

R4separately corresponds 2,3-dihydro-1H-inden-2-ilen group, 2,3-dihydro-1H-inden-1-ilen group or 1,2,3,4-tetrahydronaphthalen-1-ilen group, or in the alternative case

R3and R4together with the nitrogen atom to which they are attached, form a 1,2,3,4-tetrahydro-N-pyrido[3,4-b] indole-2-ilen group, 1,2,3,4-tetrahydro-N-pyrido[3,4-b]indole-3-ilen group, 4,5,6,7-tetrahydrothieno [2,3-c] pyrid-6-ilen group, 4,5,6,7-tetrahydrothieno[3,2-c]pyrid-6-ilen group or a 2,3-dihydro-1H-isoindole-2-ilen group, the corresponding formulas are given below

in the form of bases or of salts obtained by addition of acids.

2. Connection on p. 1, characterized in that the radical R1represents a fluorine atom or chlorine, or a methyl or methoxy group, R3denotes a hydrogen atom or a C1- C3is an alkyl group, and R4corresponds 2,3-dihydro-1H-inden-2-ilen group, 2,3-dihydro-1H-inden-1-ilen group or 1,2,3,4-tetrahydronaphthalen-1-ilen group.

3. The method of obtaining compounds on everyany anhydride to obtain amide, responsible of General formula IV

< / BR>
which lead into interaction with ethyl 4-bromo-2-butenoate, and then with a reducing agent to restore the ether group of the thus obtained derivative of ethyl 3,4-dihydro-2H-1,4-benzoxazin-3-acetate described General formula VI

< / BR>
to obtain a derivative of 3,4-dihydro-2H-1,4-benzoxazin-3-ethanol that meets the General formula VII

< / BR>
which lead into interaction with 3-(trifluoromethyl)benzoyl chloride to obtain the alcohol corresponding to General formula IX

< / BR>
which lead into interaction with thionyl chloride to obtain the compound described by the General formula X

< / BR>
and, finally, the join result in interaction with the amine that meet the General formula HNR3R4.

4. The pharmaceutical composition intended for the treatment of diseases associated with dysfunction of neuronal calcium homeostasis, characterized in that it contains a connection on p. 1 in combination with excipients.

 

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< / BR>
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< / BR>
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