Derivatives benzoxazine, methods for their preparation, pharmaceutical drug

 

(57) Abstract:

Derivatives benzoxazine in the form of optically pure isomer or mixture of optical isomers of formula 1, where the Y - pipe, fluorine, chlorine, methyl or methoxy; R1is phenyl, substituted by fluorine, stands, methoxy, trifluoromethyl or phenyl, or Tien-2-ilen group; R2is methyl; R3- alkyl, phenylalkyl, possibly substituted 2-3 metaxalone, or 2-(pyridin-2-yl)ethyl, or R2and R3form together with the nitrogen atom 4-phenyl(piperidine-1-yl), 4-phenylmethyl-(piperidine-1-yl), 1,2,3,4-tetrahydroisoquinoline-2-yl, 6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-yl, 5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-yl, 6,7 - dimethoxy-1,2,3,4 - tetrahydroisoquinoline-2-yl, 2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl, 7,8-dimethoxy - 2,3,4,5-tetrahydro-1H-3-encasedin-3-yl, X is carbonyl or sulfonyl; or their salts in vitro demonstrate the properties of the calcium-neural antagonists, a in vivo neuroprotective and anti-ischemic properties. 3 S. and 2 C.p. f-crystals, 1 PL.

The object of the present invention are derivatives of benzoxazine, their preparation and use in therapy.

Derivatives benzoxazine according to the invention correspond to General formula (I):

< / BR>
where Y is hydrogen atom, fluorine and chlorine, or methyl is etileno, methoxy-, triptorelin and phenyl groups, or Tien-2-ilen group,

R2is a methyl group,

R3or (C1-C4)-alkyl group, or phenyl-(C1-C2)-alkyl group, which ring is optionally substituted 2-3 methoxypropane, or 2-(pyridin-2 - yl)-ethyl group, or R2and R3form together with the nitrogen, or 4-phenyl-(piperidine-1-ilen) group, or 4-phenylmethyl-(piperidine-1-ilen) group or 1,2,3,4-tetrahydroisoquinoline-2-ilen group, or 6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-ilen group or 5,8 - dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-ilen group, or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-ilen group, either 2,3,4,5-tetrahydro-1H-3 - benzazepin-3-ilen group, or 7,8-dimethoxy-2,3,4,5-tetrahydro - 1H-3-benzazepin-3-ilen group, and X is either a carbonyl group, or sulfonylurea group.

Preferred derivatives corresponding to General formula (I),

where R1is a phenyl group substituted 3-(triptorelin) group

R2and R3form together with the nitrogen 6,7 - dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-ilen group, and

X is a carbonyl group.

Because the molecule represented by the General formula (I), the content is a mixture of enantiomers. Finally, the compounds of the invention can be presented in the form of free bases or salts of joining pharmaceutically acceptable acids. These different forms are included in the scope of the invention.

In accordance with the invention, it is possible to obtain compounds where X is a carbonyl group (scheme 1 is given in the end of the description).

Spend the reaction of 2-aminophenol of the General formula (II), where Y is defined above, with triperoxonane anhydride of the formula (III) in the presence of a base, such as pyridine, in a solvent such as ether. Get amide of General formula (IV), the reaction with ethyl-4-bromont-2-anatom formula (V) is carried out in the presence of a base, such as sodium methylate, in a solvent such as ethanol, at a temperature of about 80oC. Then the function of ester derivative of 3,4-dihydro-2H-1,4-benzoxazin-3-acetic acid ethyl ester of General formula (VI) restore using a reducing agent such as alumalite lithium, to obtain a derivative of 3,4 - dihydro - 2H-1,4-benzoxazin-3-ethanol General formula (VII), the reaction with the acid chloride of the acid of General formula (VIII), where R1is as defined above, is carried out in a solvent such as dichloromethane, to obtain the alcohol of General formula (IX), which experience is an amine of General formula (XI), where R2and R3is as defined above, to obtain compounds of formula (I bis), which corresponds to General formula (I), where X is a carbonyl group.

If X - sulfonylurea group, it is possible to obtain compounds of General formula (I) according to scheme 2, shown at the end of the description.

Spend the reaction of 2-aminophenol of the General formula (II), where Y is as defined above, with a chloride of the General formula (III') in the presence of a base, such as pyridine. Get the compound of General formula (IV'), the reaction with ethyl-4 - bromont-2-anatom formula (V) is carried out in the presence of a base, such as sodium methylate, in a solvent such as ethanol, at a temperature of 80oC. Then restore the function of ester compounds of General formula (VI') with a reducing agent, such as alumalite lithium, to obtain compounds of General formula (VII'), reaction with thionyl chloride is carried out in a solvent such as chloroform, to obtain compounds of General formula (X'), which is then condensed with an amine of General formula (XI), where R2and R3is as defined above.

Original products are commercially available or described in the literature or can be synthesized as described or known work, and, to obtain optically pure compound of General formula (I), you can use the alcohol of General formula (IX) or (VII'), which are isolated, for example, enzymatic method.

The basic principle of the enzymatic method is the separation of optically pure alcohol and the corresponding acetate opposite configuration, for example, by chromatography on a column of silica gel.

In the first embodiment, the racemate of the alcohol of formula (IX) or (VII') is subjected to chemical acylation, for example, using acetic anhydride, one of the two enantiomers of racemic acetate is subjected to stereospecific hydrolysis in the presence of the enzyme and separated not subjected to hydrolysis of the acetate. Obtain optically pure alcohol and optically pure acetate opposite configuration, which if desired may also be subjected to chemical or enzymatic hydrolysis to obtain secondary enantiomer alcohol.

In accordance with a second embodiment, recent alcohol of formula (IX) or (VII') is subjected to stereospecific the acylation in the presence of an enzyme as a catalyst for the esterification of salts of enantiomers, for example, using vinyl acetate. As described above, are optically clean the chickpeas chemical or enzymatic hydrolysis to obtain secondary enantiomer of the alcohol.

These two methods can be obtained, depending on the enzyme, such as or clockwise rotating enantiomer of the alcohol (IX) or (VII') and its acetate opposite configuration. Using such enzymes, such as lipase Mucor Miehei, Penicillium cyclopim or sprouts of cereals.

Intermediate compounds are new and also form the subject of the invention. They meet the General formula (XII)

< / BR>
where Y is as defined above, and R is either a hydrogen atom, and R' is 2-hydroxyethylene group, or R-COR1group, where R1is a phenyl group substituted by a fluorine atom or a methyl, methoxy-, triptorelin and phenyl group, or Tien-2-ilen group, a R' - 2-hydroxyethylene group or 2-chloraniline group, or R-SO2R1group, where R1is a phenyl group substituted by a fluorine atom or a methyl, methoxy-, triptorelin and phenyl group, or Tien - 2-ilen group, and R' is 2-hydroxyethylene or 2 - chloraniline or ethoxycarbonylmethylene group.

The following examples illustrate in detail the receipt of some derivatives according to the invention. Elemental analysis, infrared spectrum and the spectrum of nuclear magnetic resonance confirmed the structure of the obtained page table.

Example 1 (Compound No. 28).

() 3-[2-(7,8-dimethoxy-2,3,4,5-tetrahydro-1-H-3-benzazepin-3 - yl)ethyl] -4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazin, fumarate.

1.1. N-(2-hydroxyphenyl)triptorelin.

In a 4-liter reactor, under stirring with a magnetic stirrer, is introduced into the suspension in 1.5 liters of ether 104 g of (0.95 mole) of 2-aminophenol, to which add 77 ml of pyridine. The reaction medium is cooled with a mixture of ice and ethanol. Pin for 1 hour, 200 g of (0.95 mole) triperoxonane anhydride. Leave until the temperature rises to room, then continue to mix for 1 hour. Add to the reaction medium ice water, lighten, the organic phase is washed successively in 1 l of 1N hydrochloric acid, water, saturated sodium bicarbonate solution, then with saturated solution of sodium chloride. Dried over magnesium sulfate and evaporated to dryness.

Obtain 170 g of product, which is used in the next step.

1.2. ()-3,4-hydro-2H-1,4-benzoxazin-3-acetic acid ethyl ester.

In a 4-liter reactor, under stirring with a magnetic stirrer, enter 165 g (0,8 mol) of the compound obtained as described above, in a solution of 2 liters of ethanol. Add sequentially 151 ml of 5.3 N solution m is CA, again enter into 500 ml of water and 200 ml of 1N sodium hydroxide, then extracted with ether. The organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated to dryness. Allocate 153 g of the product, which is purified by chromatography on a column of silica gel, elwira dichloromethane.

Get 55 g of the product.

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

A 2-liter reactor is injected 300 ml of tetrahydrofuran and cooled with a mixture of ice and salt. Under a stream of argon is added 15 g of lithium aluminum hydride, and then added dropwise 55 g (0.25 mol) of the compound obtained as described above, in solution in 300 ml of tetrahydrofuran. Stirred for 2 hours. The reactor is cooled with a mixture of dry ice and acetone, and then added dropwise 50 ml of water and 20 ml of 1N sodium hydroxide solution. Stirred for 2 hours and leave at night alone. The precipitate is filtered on kieselguhr, washed successively with tetrahydrofuran and ethyl acetate, concentrated to dryness. Allocate 40 g of the crude product, which was purified by chromatography on a column of silica gel elwira a mixture of hexane/ethyl acetate (50/50).

Get 35 g of the product.

1.4. ()-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazin is in p. 1.3, 7.6 g (by 0.055 mole) of potassium carbonate and added dropwise to 8.3 ml (0.005 mole) of 3- (trifluoromethyl)benzoyl chloride in solution in 25 ml of dichloromethane. Leave at room temperature under stirring with a magnetic stirrer for 2 hours. The organic phase is allocated, washed follower of 1N sodium hydroxide solution, water, then saturated sodium chloride solution. It is dried over magnesium sulfate and concentrated to dryness. The resulting oil purified by chromatography on a column of silica gel, elwira a mixture of hexane/ethyl acetate (50/50). Allocate 11 g of a yellow oil which crystallizes after a night of rest. Clean 2 g of this oil by chromatography on a column of silica gel, elwira a mixture of hexane/ethylacetat (3/2).

Obtain 1.3 g of product.

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

To 3.51 g (0,01 mol) of the compound obtained under item 1.4, in solution in 50 ml of dichloromethane, added to 2.9 ml of thionyl chloride and left stirring at room temperature for 3 hours. Again added to 2.9 ml of thionyl chloride and left stirring at room temperature for 2 hours. Concentrate to dryness, extracted with toluene and again concentrated to dryness.

Obtain 3.2 g of product.

1.7. N-(2,2-dimethoxymethyl)-3,4-dimethoxybenzoate.

In the solution 52,7 ml of 0.48 mol) of 2,2-dimethoxyethane cooled to 10oC and containing of 67.5 ml of triethylamine in 500 ml of dichloromethane, was added dropwise 104 g (of 0.48 mol) of the compound obtained under item 1.6, in solution in 250 ml of dichloromethane. After mixing, leave to restore to room temperature and left stirring for 1 hour. Add 500 ml of ice water and the organic phase is lighten. Exhale, washed with a saturated solution of magnesium sulfate and concentrated to dryness.

Obtain 128 g of the product as a viscous oil.

1.8. 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-it.

Leave stirring for 8 hours at room temperature to 128 g (of 0.45 mol) of the compound obtained under item 1.7, dissolved in a mixture of 640 ml of concentrated hydrochloric acid and 640 ml of acetic acid. Leave, stirring, for 3 days at room temperature. Add 2 kg of ice, and the product precipitated in the sediment, otfiltrovat, washed with a mixture of water/methanol and wysu the>/P>1.9. 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-it.

Hydrogenation obtained under item 1.8 of the connections carried out for 3 hours at a pressure of 0.42 MPa and a temperature of 50oC in the presence of 1 g of 10% palladium on coal. Canceryou dry, filtered on diatomaceous earth and washed with acetic acid. The residue is extracted with dichloromethane and washed sequentially with a saturated solution of magnesium bicarbonate and canceryou dry.

Gain of 13.2 g of the product.

Melting point: 186 to 190oC.

1.10. 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine, hydrochloride.

To a suspension of 2.2 g (0,01 mol) of the compound obtained in p. 1.9, in solution in 25 ml of dry tetrahydrofuran in an argon atmosphere, was added dropwise at room temperature, 20 ml of a 1N solution of DIBORANE in tetrahydrofuran. Heated under reflux for 2 hours. Cooled with a mixture of ice and alcohol and added dropwise 30 ml of 6N hydrochloric acid. Heated for 1 hour at 80oC. Alkalinized 4N sodium hydroxide solution and extracted with ethyl acetate. The organic phase is collected, washed with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness. The residue is again introduced into 100 ml of 1N hydrochloric acid propan-2-allowdeny: 236oC.

1.11. ()-3-[2-(7,8-dimethoxy-2,3,4,5-tetrahydro-IH-3 - benzazepin-3-yl)ethyl] -4-[3-(trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4-benzoxazin, fumarate.

Mix 3 g (0,015 mol) of the compound obtained under item 1.5, of 3.56 g (0,0096 mol) of the compound obtained under item 1.10, 2.66 g of potassium carbonate, 100 mg of potassium iodide and 50 ml of dimethylformamide. The mixture is heated to 80oC for 4 hours, then poured onto a mixture of ice and water. Extracted with ether, the organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness. The remaining oil is purified by chromatography on a column of silica gel, elwira a mixture of dichloromethane/methanol (99/1), then a mixture of dichloromethane/methanol (98/2). Obtain 1.8 g of the base. Get fumarate, adding the equivalent of fumaric acid. It is isolated and will recrystallized in propan-2-OLE.

Melting point: 182-184oC.

Example 2 (Compound 16).

()-3-[2-(6,7-dimethoxy-1,2,3,4-tetrahydroxy-nolin-2-yl)ethyl] -4-[(4-were)sulfonyl]-3,4-dihydro-2H-1,4 - benzoxazin, oxalate.

2.1. N-(2-hydroxyphenyl)-4-methylbenzenesulfonamide.

20 g (0,18 mol) of 2-aminophenol add 35 g (0,18 mol) of Teilhard and 60 ml of pyridine. Leave stirring,their phases are washed successively with water, 1N hydrochloric acid and again 2 times with water. Dried over magnesium sulfate and concentrated to dryness.

Obtain 44 g of the product.

2.2. ()-4-[(4-were)sulfonyl] -3,4-dihydro-2H-1,4 - benzoxazin-3-acetic acid ethyl ester.

5.3 g (0,02 mol) of the compound obtained under item 2.1, added to 5.1 g (0,03 mole) ethyl-4-bromont-2-enoate, and 3.8 ml of 5.3 N solution of sodium methylate and 25 ml of ethanol. The mixture is heated under reflux during the night. Is evaporated to dryness, the residue is extracted sequentially with ethyl acetate, water and, finally, 1N sodium hydroxide solution. The organic phase is collected, extracted and washed with water, then saturated sodium chloride solution. Dried over magnesium sulfate, then evaporated to dryness.

Get 8 g of the product, which is used in this form at a later stage.

2.3. ()-4-[(4-were)sulfonyl] -3,4-dihydro-2H-1,4 - benzoxazin-3-ethanol. Dissolved in an argon atmosphere to 0.23 g (0,006 mole) of lithium aluminum hydride in 20 ml of tetrahydrofuran. Added dropwise to 1.5 g (0,004 mol) of the compound obtained under item 2.2, in solution in 5 ml of tetrahydrofuran. Upon completion of the reaction consistently add 0.7 g of water, 0.3 g of 1N sodium hydroxide solution and again with 0.7 g of water. The mixture is filtered over kieselguhr, washed terapia dry.

Obtain 1.4 g of product.

2.4. ()-3-(2-chloroethyl)4-[(4-were)sulfonyl]-3,4-dihydro-2H-1,4-benzoxazin.

Dissolve 2 g (0,006 mole) of the alcohol obtained under item 2.3, in 15 ml of chloroform. Was added dropwise 2.2 g (0,018 mole) of thionyl chloride and a drop of dimethylformamide. Heated under reflux for 5 hours. Is evaporated to dryness, the residue extracted a minimal amount of toluene and again evaporated to dryness.

Obtain 2.1 g of product.

2.5. ()-3-[2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-yl)ethyl]-4-[(4-were)sulfonyl]-3,4-dihydro-2H-1,4-benzoxazin, oxalate.

1.2 g (0,0034 mol) of the compound obtained in paragraph 2.4, added 0.65 g (0,0034 mole) of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 6 ml of 3-methylbutanol. The mixture is heated at 80oC overnight and evaporated to dryness. The residue is again injected into the dilute ammonia and extracted twice with ether. The organic phase is washed with water, dried over magnesium sulfate and evaporated to dryness. The resulting product was then purified by chromatography on a column of silica gel, elwira a mixture of dichloromethane/methanol 1%.

Obtain 0.8 g of product.

Oxalate receive, adding the equivalent of oxalic acid. Will recrystallize it in a mixture of ethyl acetate/ethanol is N18).

()-3-[2-(6,7-dimethoxy-1,2,3,4 - tetrahydroisoquinoline-2-yl)ethyl]-4-[3-(trifluoromethyl)benzoyl]- 3,4-di-hydro-2H-1,4-benzoxazin, oxalate.

3.1. ()-3-[2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-yl)ethyl]-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazin, oxalate.

To a solution of 2.0 g (0,005 mol) of the compound obtained under item 1.5 in 10 ml of dimethylformamide, at room temperature, stirring in argon atmosphere, added 1.24 g (0,005 mol) of the hydrochloride of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 4 g of potassium carbonate and 0.9 g of potassium iodide. The mixture is heated at 80oC for 4 hours. Cool and add 40 ml of water and 100 ml of ether. The phases are separated, and the aqueous phase is extracted with twice 100 ml of ether. The combined organic phases are washed with 100 ml saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness. Get 3 g of the product as a brown oil, which was purified by chromatography on a column of silica gel, elwira a mixture of methanol/dichloromethane (1/9).

Get 1,89 g base in the form of a yellow oil.

Oxalate receive, adding the equivalent of oxalic acid. Allocate and recrystallized in the form of white crystals in a mixture of isopropanol/isopropyl ether.

T is withinlee-2-yl)ethyl]-4-[3- (trifluoromethyl)benzoyl]-3,4-di-hydro-2H-1,4-benzoxazin, oxalate.

4.1. ()-4-[3-(trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4 - benzoxazin-3-ethanol.

Introducing a suspension of 8.7 g (0,025 mol) of racemic alcohol obtained under item 1.4, 1.09 liters of hexane. Add to 7.7 ml (0,082 mole) of vinyl acetate and 4.35 g of lipase Mucor Miehei. Leave for 15 hours at room temperature, the mixture is filtered under vacuum. Obtain 10.7 g of a yellow oil, which contains a mixture of clockwise rotating alcohol such as acetate. Separated by chromatography on a column of silica gel, elwira a mixture of ethyl acetate/cyclohexane (1/1).

Get 3,62 g of chemically pure clockwise rotating alcohol.

The rotational ability: []2D0= +620 (C = 0,99; dichloromethane).

The excess of enantiomers: = 99,7% (chiral CLHP).

4.2. ()-3-(2-chloroethyl)-4-[3-(trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4-benzoxazin.

To a solution of 4 g (to 0.011 mole) of the alcohol obtained under item 4.1, in 20 ml of dichloromethane, at room temperature, stirring in argon atmosphere, add 3 ml level (0.041 mole) of thionyl chloride. Continue to stir at room temperature for 18 hours. Is evaporated to dryness, and the resulting product is used in this form in the next step.

Get to 4.46 g of the product.

In a solution of 4.46 g (0,012 mol) of the compound obtained under item 4.2, in 40 ml of dimethylformamide, at room temperature, stirring in argon atmosphere, add 2,31 g (0,012 mol) of the hydrochloride of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, and 3.31 g (0,024 mole) of potassium carbonate. The mixture is heated at 80oC for 4 hours, then cooled. Add successively with 40 ml of water and 100 ml of ether, the phases separated and the aqueous phase is extracted with twice 100 ml of ether. The combined organic phases are washed with 100 ml of saturated solution of sodium chloride. Dried over magnesium sulfate, filtered and evaporated to dryness.

Obtain 7 g of the product, which is purified by chromatography on a column of silica gel, elwira a mixture of methanol/dichloromethane (1/9). Get 1,17 g of the base oil.

Oxalate receive, adding the equivalent of oxalic acid. Allocate and recrystallized in the form of white crystals in a mixture of ethyl acetate, isopropyl ether and acetone.

The rotational ability: []2D0= +690 (C = 0,976; methanol).

Example 5 (Compound N 18b).

(-)-3-[2-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-yl)ethyl] -4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazin, oxalate.

Get 6,14 g such as acetate (=70%) in the form of oil, which is ground to powder in 200 ml of hexane. Get a residue corresponding to the racemic acetate, which is filtered. The filtrate is evaporated to dryness.

Obtain 3.94 g of chemically pure such as acetate.

The rotational ability: []2D0= -530 (C =1,2; dichloromethane)

The excess of enantiomers: = 99,5% (chiral CLHP) 3.94 g such as acetate are dissolved in 40 ml of toluene. Add 200 ml of 0.01 M phosphate buffer solution (KH PO/Na PO) at pH 7.2 and 1.2 g of lipase Mucor Miehei. The mixture is stirred over night at room temperature, maintaining a constant pH by adding 0.5 M aqueous solution of sodium hydroxide using a pH meter. Add 100 ml of ethyl ether, the organic phase is separated, and vadouvan sodium chloride. Dried over magnesium sulfate, filtered and evaporated to dryness. Obtain 2.8 g of chemically pure such as alcohol.

The rotational ability: []2D0= -59,80 (=1,32; dichloromethane)

The excess of enantiomers: = 99,5% (chiral CLHP).

5.2. (-)-3-(2-chloroethyl)-4-[3-(trifloromethyl)benzoyl] -3,4-dihydro-2H-1,4-benzoxazin.

To a solution of 2.8 g (0,080 mole) of the alcohol obtained under item 5.1, in 20 ml of dichloromethane, at room temperature, stirring in argon atmosphere, add 3 ml level (0.041 mole) of thionyl chloride. Continue to stir at room temperature for 18 hours. Is evaporated to dryness, and the resulting product is used in this form in the next step.

Get totaling 3.04 g of the product.

5.3. (-)-3-[2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-yl)ethyl]-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4 - benzoxazin, oxalate.

In a solution of 3.04 from (0,008 mol) of the compound obtained under item 5.2, in 40 ml of dimethylformamide, at room temperature, stirring in argon atmosphere, add 3,17 g (to 0.016 mole) of the hydrochloride of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline of 2.26 g (to 0.016 mole) of potassium carbonate. The mixture is heated at 80oC for 4 hours, then cooled. Add successively with 40 ml of water Kuwayt in 100 ml of a saturated solution of sodium chloride. Dried over magnesium sulfate, filtered and evaporated to dryness. Get 5 g of the product, which is purified by chromatography on a column of silica gel, elwira a mixture of methanol/dichloromethane (1/9).

Gain of 1.30 g of the base oil.

Oxalate receive, adding the equivalent of oxalic acid. Allocate and recrystallized in the form of white crystals in a mixture of propan-2-ol, diisopropyl ether and acetone.

Melting point: 129-130oC.

The rotational ability: []2D0= -710 (=1,03 methanol).

Example 6 (Compound N 38).

()-3-[2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-yl)ethyl] -6-methyl-4-[3- (trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazin, oxalate.

6.1. N-(2-hydroxy-5-were) triptorelin.

In liter reactor, under stirring with a magnetic stirrer, to prepare a suspension of 350 ml of diethyl ether and 25 g (0.2 mol) 2-amino-4-METHYLPHENOL add to 20.5 ml of pyridine, the reaction medium is cooled with a mixture of ice and ethanol and added dropwise within 1 hour and 28 ml (0.2 mole) triperoxonane anhydride. Leave the mixture to rise to room temperature and continue to stir for 1 hour. Add ice water, the organic is sodium, then a saturated solution of sodium chloride, dried over magnesium sulfate and the solvent is evaporated. Get 37,07 g of product, which is used in the next step.

6.2. ()-6-methyl-3,4-dihydro-2H-1,4-benzoxazin-3-acetic acid ethyl ester.

A 3-liter reactor, cooled to 0oC, is introduced, under stirring with a magnetic stirrer, 760 ml of ethanol and slowly, in small pieces, add 5,79 g (0,252 mole) of sodium is then added dropwise 37,45 (to 0.17 mole) of N-(2-hydroxy-5-methyl-phenyl) trifurcated and 43.7 g (to 0.17 mol) of 75% pure ethyl-4-bromont-2-enoate, the mixture is heated at 110oC for 2 hours. The solvent is evaporated to dryness, again introduced into 100 ml of water and 40 ml of 1N sodium hydroxide, and extracted with diethyl ether. The organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate and the solvent is evaporated. Get 28,58 g of product, which is purified by chromatography on a column of silica gel, elwira with a mixture of cyclohexane/isopropyl ether (50/50).

Get 23,48 g of the product.

6.3. ()-6-methyl-3,4-dihydro-2H-1,4-benzoxazin-3-ethanol

In liter reactor introduced 150 ml of tetrahydrofuran, cooled with a mixture of ice and salt, and, in argon atmosphere, add 6 g (0,158 mole) of aluminum hydride Agitatory and stirred for 1.5 hours. The reactor is cooled with a mixture of dry ice and acetone, and then added dropwise 40 ml of water and 20 ml of 1N sodium hydroxide solution and stirred for 0.5 hour.

The precipitate is filtered on kieselguhr, washed successively with tetrahydrofuran, then with ethyl acetate and evaporated the solvent. Allocate 20,29 g of the crude product, which was purified by chromatography on a column of silica gel, elwira with a mixture of cyclohexane/ethyl acetate (50/50).

Get 22,94 g of the product.

6.4. ()-6-methyl-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazin-3-ethanol.

In liter flask was placed 200 ml of dichloromethane, 22,87 g (amount of 0.118 mol) ()-6-methyl-3,4-dihydro-2H-1,4-benzoxazin-3-ethanol, 17,53 g (a 0.125 mole) of potassium carbonate was added dropwise and 26,19 ml (0,125 mole) of 3-(trifluoromethyl) benzoyl chloride in solution in 200 ml of dichloromethane and continue stirring at room temperature for 3 hours. Add 120 ml of 1N sodium hydroxide, the organic phase is separated, washed with water, then saturated sodium chloride solution, dried over magnesium sulfate and 46,25 g of the obtained oil is purified by chromatography on a column of silica gel, elwira with a mixture of cyclohexane/ethyl acetate (6/4).

Get 19,66 g of the product.

6.5. ()-3-(2-chloroethyl)-6-methyl-4-[3-(riptiger-2H-1,4 - benzoxazin-3-ethanol solution in 230 ml of dichloromethane, add 19,6 ml of 0.27 mole) of thionyl chloride, and the mixture is stirred at room temperature for 3 hours.

The solvent is evaporated and the excess thionyl chloride, the residue is extracted with toluene and evaporated, the residue is purified by chromatography on a column of silica gel, elwira with a mixture of cyclohexane/isopropyl ether (2/1).

Get 13,83 g of the product.

6.6. ()-3-[2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-yl)ethyl] -6-methyl-4-[3-(trifluoromethyl)benzoyl]-3,4 - dihydro-2H-1,4-benzoxazin, oxalate

To a solution of 2 g (0,005 mol) of ()-3-(2-chloroethyl)-6-methyl-4-[3-(trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4-benzoxazine in 20 ml of N,N-dimethylformamide, at room temperature, under stirring with a magnetic stirrer, an argon atmosphere, added 1.19 g (0,005 mol) of the hydrochloride of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 1.78 g (0,013 mol) of potassium carbonate and 0.82 g (0,005 mol) of potassium iodide and the mixture is heated at 150oC for 1 hour. Cool it, add 55 ml of water and 50 ml of diethyl ether, the phases are separated, and the aqueous phase is extracted with twice 50 ml of diethyl ether, the combined organic phases are washed with 100 ml saturated sodium chloride solution, dried over magnesium sulfate, filtered and the solvent evaporated.

Dichlormethane/methanol (95/5). Get 0,450 g of pure reason in the form of a yellow oil.

Oxalate receive, adding the equivalent of oxalic acid, highlight it and recrystallized in the form of white crystals in a propane-2-Ola. Get 0,180 g oxolane (ratio of acid:base = 0,8:1).

Melting point: 164-166oC.

Example 7 (Compound N35).

() 6 - chloro-3-[2-(2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)ethyl]-4-[3-(trifluoromethyl) benzoyl]-3,4-dihydro-2H-1,4-benzoxazin, oxalate.

7.1. N-(5-chloro-2-hydroxyphenyl)triptorelin.

In liter reactor, under stirring with a magnetic stirrer, is placed in suspension in 320 ml of diethyl ether, 25 g (0,174 mole) 2-amino-4-chlorophenol, add 18 ml of pyridine, the reaction medium is cooled with a mixture of ice and ethanol and added dropwise within 1 hour of 24.6 ml (0,174 mole) triperoxonane anhydride, the mixture is left to rise to room temperature and continue to stir for 1 hour.

Add ice water, lighten, the organic phase is washed successively 320 ml of 1N hydrochloric acid, water, saturated sodium bicarbonate solution, then with saturated sodium chloride solution, dried over magnesium sulfate and the solvent is evaporated. Get of 40.3 g of the product of the LASS="ptx2">

A 3-liter reactor, cooled to 0oC, is introduced, under stirring with a magnetic stirrer, 430 ml of ethanol and slowly, in small pieces, add 3.8 g( 0,166 mole) of sodium is then added dropwise to 40 g (0,166 mole) of N-(5-chloro-2-hydroxy-phenyl)trifurcated and 40 g (0,155 mol) of 75% pure 4-bromont-2-Atalanta, the mixture is heated at 85oC for 2 hours. The solvent is evaporated, again introduced into 100 ml of water and 40 ml of 1N sodium hydroxide, and extracted with diethyl ether.

The organic phase is separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated.

Get 28,58 g of product, which is purified by chromatography on a column of silica gel, elwira with a mixture of cyclohexane/isopropyl ether (50/50).

Get 23,72 g of the product.

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

In liter reactor introduced 150 ml of tetrahydrofuran, cooled with a mixture of ice and salt, and, in argon atmosphere, type of 5.92 g (0,156 mole) of lithium aluminum hydride, and then added dropwise 23,52 g (9,0973 mol)

() 6-chloro-3,4-dihydro-2H-1,4-benzoxazin-3-ethyl-acetate in solution in 150 ml of tetrahydrofuran and the mixture is stirred for 1.5 hours. The reactor is cooled with a mixture of dry ice is filtered on kieselguhr, washed with tetrahydrofuran, then with ethyl acetate and the solvent is evaporated. Allocate 27.5 g of the crude product, which was purified by chromatography on a column of silica gel, elwira with a mixture of cyclohexane/ethyl acetate (50/50).

Get 19,67 g of the product.

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

In liter flask was placed 100 ml of dichloromethane, 19,17 g (of 0.09 mole) ()6-chloro-3,4-dihydro-2H-1,4-benzoxazin-3 - ethanol, 13.3 g (0,096 mole) of potassium carbonate and added dropwise 20 g (0,096 mole) of 3-(trifluoromethyl)benzoyl chloride in solution in 100 ml of dichloromethane and the mixture continued to stir at room temperature for 3 hours.

Add 90 ml of 1N sodium hydroxide, the organic phase is separated, washed with water, then saturated sodium chloride solution, dried over magnesium sulfate and the solvent is evaporated. Obtain 36 g of oily product, which was purified by chromatographie on a column of silica gel, elwira with a mixture of cyclohexane/ethyl acetate (2/1).

Get 24,21 g of the product.

7.5. ()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 solution in 260 ml of Diacov.

The solvent is evaporated and the residue is extracted with toluene and evaporated. 25,21 g of the obtained oil is purified by chromatography on a column of silica gel, elwira with a mixture of cyclohexane/isopropyl ether (50/50).

Get 23,73 g of the product.

7.6. () 6-chloro-3-[2-(2,3,4,5-tetrahydro-1H-3 - benzazepin-3-yl)ethyl]-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H - 1,4-benzoxazin, oxalate.

To a solution of 2 g (0,005 mol) ()6-chloro-3-(2-chloroethyl)-4-[3-(trifluoromethyl)benzoyl] -3,4-dihydro-2H-1,4-benzoxazine in 20 ml of N,N-dimethylformamide, at room temperature, under stirring in an argon atmosphere, added 0.9 g (0,005 mol) of the hydrochloride 2,3,4,5-tetrahydro-1H-3-benzazepine, 1.7 g (0,0124 mole) of potassium carbonate and 0.82 g (0,005 mol) of potassium iodide and the mixture is heated at 110oC for 1 hour. Cool it, add 55 ml of water and 50 ml of diethyl ether, the phases are separated, and the aqueous phase is separated and extracted twice with 50 ml diethyl ether. The combined organic phases are washed with 100 ml saturated sodium chloride solution, dried over magnesium sulfate, filtered and the solvent evaporated. Get to 2.55 g of the product in the form of oil, which is purified by chromatography on a column of silica gel, elwira a mixture of dichloromethane/methanol (98/2). Obtain 1.84 g of pure onlysee in ethanol.

Melting point: 192-194oC.

The table at the end of the description illustrates the chemical structure and physical properties of some compounds according to the invention.

The legend on the table.

In column "R" "n-A-C6H4"is a phenyl group substituted at position n ring group A.

In the column "Sel" (salt): "-" denotes a compound in the form of the base, "ox." means oxalate, "fum." means fumarate; if the molar ratio of acid: base different from 1:1, it is indicated in parentheses.

In column "F" (oC) (melting point) "dec" means "melting with decomposition"

Compounds according to the invention underwent pharmacological tests which showed their useful properties for use in therapy as active substances.

Inhibition of entry of calcium induced by KCl in slices of cerebral cortex of immature rats.

Used rat Sprague-Dawley, males or females, aged 8 days. After displacement of the cervical vertebrae cut out the brain and prepare the slices parietal areas of the cerebral cortex.

Intracellular calcium concentration ([Ca2+]i) is measured according to the technology described in J. Pharm. Exp. Ther. (1992) 261 324-330.on O2/CO2(95%/5%) and containing Fura-2 AM at a concentration of 7 μm, after incubation, the slices are washed several times with the same buffer solution and leave in the same buffer solution prior to use.

To measure ([Ca2+]i) slices placed at 30oC cube spectrofluorometer that perfusion buffer solution Krebs using a pump. Depolarization slices exercise, perfusia for 3 minutes buffer Krebs solution containing 50 mm KCl. In the perfusion fluid is injected test the connection after 7 minutes after the first depolarization and carry out a second depolarization after 7 minutes after administration of the tested compounds. See fluorescence with two excitation wavelengths, 340 nm (form associated with calcium) and 380 nm (free form), and the wavelength of emission -510 nm. ([Ca2+]i) are calculated according to the method described in J. Biol. Chem. (1985) 260 3440-3450. The inhibitory activity of test compounds is calculated as the ratio of increase ([Ca2+]i), inhibited 50 mm KCl, taken as 100%.

Factor inhibiting input of Ca2+induced by the compounds according to the invention, is dose-dependent and ranges from 10 to 65% for concentric the project to complete cerebral ischemia mouse. Ischemia was caused by cardiac arrest, induced by rapid intravenous injection of magnesium chloride.

When this test was measured "survival time", i.e. the interval between the moment of introduction of magnesium chloride and the last marked respiratory movement of the mouse. This last move is seen as a decisive sign of the functioning of the Central nervous system.

Stop breathing comes in approximately 19 seconds after administration of magnesium chloride.

Male mice (SWISS OF1IFFA CREDO) were studied in groups of 10. Before the experiments, they were fed and watered ad libitum. "Survival time" was measured 10 minutes after the intraperitoneal administration of the compounds of the invention. The results are given as the difference between the "survival time", measured in a group of 10 mice, which was introduced by the connection, and "survival time", measured in a group of 10 mice, which was introduced by the carrier fluid. Correlation between survival time and the dose of the compounds were recorded graphically on a semi-log curve.

This curve shows the effective 3-second dose (DE3"calcium, i.e., the dose (in mg/kg), which causes an increase in "survival time" for 3 seconds compared to odnovremenno statistically significant and repeatable.

Dose DE3"for compounds of the invention is from 0.2 to 60 mg/kg, intraperitoneally.

Study of the potential-dependent (voltage-dependent) barium chloride flow technology patch-clamp.

Measurement of barium chloride flows through potential-dependent calcium channels was carried out on the cells of the cortex of newborn rats (Sprague-Dawley) in culture (6-10 days)

The measuring chamber with a volume of 800 µl containing cells of the cortex of the rat, placed on the plate inverted microscope (Olympus IMT-2TMand see with magnification of 400 times. Cameras are continuous perfusion (4-6 ml/min) using a dispenser solutions, allowing 9 entries (fatal amount of < 50 μl), only the output of which is in the form of a plastic tube with a hole 5 μm is less than 3 mm from the studied cells. The advantage of this device is that it provides a rapid exchange of fluid at the level of the studied cells. The method used patch-clapm described in Pfluegers Archives (1981) 391 85-100. The amplifier Axopatch-1DTMtogether with the computer AT 386-33 MHz software PCLAMPTM"Axon InstrumentsTM" used to stimulate cells, data collection and analysis results. To register barium chloride flows, pipettes and the>/P>The tip of the pipette is filled ethanol extracellular solution having the following composition (in mm): CsCl (140), CaCl2(1), Na2-ATP, AGTC (11, pCa=8), Hepes (10), Tris-OH (pH = 7,2).

Upon receipt of the full cell configuration it is subjected to perfusion with a solution of tea-barium, having the following composition: tea-C1 (144), BaCl2(5). MgCl2(2), CsCl (3), glucose (10), Hepes (10), Tris-OH (pH = 7,4).

This solution allows to measure calcium flux (equivalent to the barium flow passing through the potential-dependent calcium channels), not taking into account the sodium and potassium flows.

The total potential-dependent barium flux obtained by depolarizing voltage generated with a duration of 250 msec when the membrane potential from -80 mV to -16 mV. The stimulation frequency of 0.25 Hz.

Compounds according to the invention are introduced into the solution in the environment of the tea-barium with stable amplitude barium flow. After obtaining a stable inhibitory effect cell again perpusilla control tea-bereavem solution for monitoring reversion effect.

The effect compared with the effect of 1 μm solution of cadmium. Blocking effect on voltage-dependent calcium channels varies depending on the doses of rassm and a concentration of 1 μm.

The test results of the compounds of the invention show that in vitro, they have properties of calcium-neural antagonists, a in vivo neuroprotective and anti-ischemic properties.

In accordance with these results, the compounds may be used for the treatment and prevention of cerebral disorders, for example, caused by an attack of cerebral, cardiac or respiratory, thrombosis or embolism of cerebral vessels, to treat aging brain, dementia due to multiple heart attacks, dementia, such as Alzheimer's disease or sickness Maximum, for the treatment of olive-cerebellopontine atrophy and other diseases associated with degeneration of nerve cells, such as chorea Huntington, amyotrophic lateral sclerosis, for the treatment of cranial and spinal injuries, to prevent nerve lesions result in convulsions, to treat certain types of cancer, neurological changes in AIDS and diabetic retinopathy.

To do this, they can be provided in any pharmaceutically acceptable form for enteral and parenteral introduction, together with an appropriate diluent, for example, in the form of tablets, coated tablets, gel capsules, capsules, suppositories, the reamers of farmcampsite.

Solution for injection:

Active substance 5 mg

Glucose is 250 mg

Water for injection in vials of 5 ml to 5 ml

Gelatin capsules:

The active 100 mg

Talc - 24 mg

Gel silicon dioxide capsule 125 mg - 1 mg

Tablet:

The active principle is 400 mg

Gel silicon dioxide 10 mg

Stearic acid - 20 mg

Starch grains on the tablet 475 mg - 45 mg

Syrup:

Active early - 5 g

4-hydroxymethylbenzene 150 mg

Saccharose - 50 grams

Distilled water to the bottle of capacity of 100 ml to 100 YPD

1. Derivatives benzoxazine in the form of optically pure isomer or mixture of optical isomers, responsible of General formula I

< / BR>
where Y is hydrogen atom, fluorine or chlorine, or a methyl or methoxy group;

R1or phenyl group substituted by a fluorine atom or a group selected from methyl, methoxy-, triptorelin and phenyl groups, or Tien-2-ilen group;

R2is a methyl group;

R3or (C1-C4) alkyl group or phenyl (C1-C2)alkyl group in which ring optionally substituted 2-3 methoxy groups, or 2-(pyridin-2-yl) ethyl group;

Eridan-1-ilen) group, or 1,2,3,4-tetrahydroisoquinoline-2-ilen group, or 6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-ilen group or 5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-ilen group, or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-ilen group, or 2,3,4,5-tetrahydro-1H-3-benzazepin-3-ilen group, or 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-3-ilen group;

X - or carbonyl group, or sulfonylurea group,

or their salts attaching a pharmaceutically acceptable acids.

2. Derivatives under item 1 of the formula I, in which R1-3-(trifluoromethyl)phenyl group; R2and R3form together with the nitrogen 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-ilen group, and X is a carbonyl group.

3. The method of obtaining derivatives of benzoxazine under item 1, characterized in that if X is a carbonyl group, carried out the reaction of 2-aminophenol of the General formula II

< / BR>
where Y is as defined in paragraph 1,

with triperoxonane anhydride to obtain the amide of General formula IV

< / BR>
which enter into reaction with ethyl-4-bromont-2-ENATOM, then restore the function of ester 3,4-dihydro-2H-1,4-benzoxazin-3-acetate of General formula VI

< / BR>
obtaining 3,4-dihydro-2H-1,4-benzoxazin-3-ethanol total is

where R1- as defined in paragraph 1,

to obtain the alcohol of General formula IX

< / BR>
which is subjected to reaction with thionyl chloride to obtain compounds of General formula X

< / BR>
and, finally, conduct the reaction of the latter with an amine of General formula XI

< / BR>
where R2and R3- as defined in paragraph 1 or if X - sulfonylurea group,

spend the reaction of 2-aminophenol of the General formula II

< / BR>
where Y is as defined in paragraph 1, with chloride of the General formula III'

R1-SO2-Cl

to obtain compounds of General formula IV'

< / BR>
which is subjected to reaction with ethyl-4-bromont-2-ENATOM with obtaining the compounds of formula (VI'), then restore the function of ester compounds of General formula VI'

obtaining the compounds of formula VII'

< / BR>
which is subjected to reaction with thionyl chloride to obtain compounds of General formula X'

< / BR>
which is then condensed with an amine of General formula XI

< / BR>
where R2and R3- as defined in paragraph 1.

4. The method according to p. 3, characterized in that programalso and levogyrate enantiomers of alcohols of the General formula IX, VII' allocate enzymatic way, then continue the synthesis.

5. Pharmaceutical what beviteli.

 

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