Derivatives of oxazolidinone, receiving and containing the medicine and pharmaceutical composition

 

(57) Abstract:

Describes new derivatives of oxazolidinone General formula I

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where the values of R1- R5specified in paragraph 1 of the formula. The compounds exhibit selective inhibitory ability against Mao-a or inhibitory ability in relation to both MAO-A and MAO-Century Describes how they are received. Also describes drugs that may find application in the treatment of depression, panic attacks, phobias, anxiety, migraine, age-related mental disorders, or dementia, as well as in the prevention or treatment of neurodegenerative diseases. 4 C. and 8 C.p. f-crystals, 3 ill., table 1.

The invention relates to derivatives of 3,3 and 4,5-Tetra-hydro-1H-oxazolo[3,4-a] quinoline-1-it, their reception, and therapeutic use.

Known (EP 0322263) derivatives and 3,3,4,5-tetrahydro-1H-oxazolo[3,4-a] quinoline-1-it is suitable for use as antidepressants.

Provided by the present invention compounds are responsible of General formula I

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in which n is 0 or 1;

R1represents a hydrogen atom or atenilol, methyl, ethyl, penello or cyano,

R3corresponds to a hydrogen atom, or hydroxyl or benzyloxy, and

R4and R5are hydrogen atoms;

or R2and R4together form a group -(CH2)4-,

R3represents a hydroxyl group, and

R5denotes a hydrogen atom;

or R2and R5together form a group-O-(CH2)3- and

R3and R4are hydrogen atoms;

or R2and R5together form a group -(CH5)4-,

R3corresponds to the hydroxyl group, and

R4represents a hydrogen atom.

Provided by the present invention compounds can be in the form of various isomers, including in the form of enantiomers and diastereoisomers. The present invention encompasses these various forms, as well as mixtures thereof, including racemic mixtures.

Compounds corresponding to the formula (I) can be obtained in accordance with the method given in Appendix 1, and this method assumes that the connection is described by formula II

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in which R1represents a hydrogen atom or atenilol, methyl, phenyl, hydroxymet which X denotes a halogen atom, or labile group, such as mesilate or tailorshop,

obtaining compounds corresponding to the formula I, in which R1corresponds to the above signs, then restore the specified compound described by formula I in which R1is atenolol group, to obtain compounds corresponding to the formula I, in which R1represents an ethyl group. Compounds under formula II, in which R1represents a hydrogen atom, atenolol, methyl or phenyl group, can be obtained from ethyl 2-formyl-6-methoxy-1,2,3,4-tetrahydroquinolin-1-carboxylate, known compounds, which are described in EP 0322263.

In that case, if R1denotes a hydrogen atom, specified the method is that:

- ethyl 2-formyl-6-methoxy-1,2,3,4-tetrahydroquinolin-1-carboxylate is treated regenerating agent such as borohydride sodium or borohydride potassium,

- ciclitira formed in this connection by bringing it in contact with the base, such as sodium methoxide, and, finally,

is subjected to demethylation of 7-methoxy-3,3 and 4,5-tetrahydro-1H - oxazolo[3,4-a]quinoline-1-he corresponding to the formula IV


- ethyl 2-formyl-6-methoxy-1,2,3,4-tetrahydroquinolin-1-carboxylate is treated organomagnesium compound described by the formula R1MgX, where R1represents atenilol, methyl or phenyl group, and X denotes a halogen atom,

- ciclitira formed in this connection by bringing it in contact with the base, such as sodium methoxide, and, finally,

is subjected to demethylation of 7-methoxy-3,3 and 4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline-1-he corresponding to the formula V

< / BR>
in which R1corresponds to the above notation. Compounds under formula II, in which R1represents hydroxymethylene or methoxymethyl group can be obtained from 3-ethynyl-7-hydroxy-3,3 a, 4,5-tetrahydro-1H-oxazolo[3,4-a] quinoline-1-it, compounds corresponding to the formula II in which R1is atenolol group, as follows:

- protects the corresponding hydroxyl group, resulting in a compound described by formula VI

< / BR>
where Pr denotes a protective group such as benzyl group;

- handle the connection specified by the ozone, and then regenerating agent such as broger the receiving connection, under the formula II, where R1is hydroxymethylene group, or treated with dimethyl sulfate to form compounds corresponding to the formula Vlll

< / BR>
which then remove the protective group to obtain the compounds corresponding to formula II, where R1represents methoxymethyl group.

Compounds corresponding to the formula I, in which R1means atenilol, methyl, ethyl, hydroxymethylene or methoxymethyl group can exist in the form of CIS - and TRANS-isomers,

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which, in turn, derived from CIS - and TRANS-isomers of the corresponding compounds under formula II, and the latter is obtained as described above after separation by chromatography of CIS - and TRANS-isomers of the specified derivative, provided by formula V.

< / BR>
Compounds corresponding to the formula I, in which

R1represents atenolol group, and

R3- benzyloxy;

or in the alternative case

R1is hydroxymethylene or methoxymethyl group, and

R3is hydroxyl or benzyloxycarbonyl; and

the radicals R4and R5mean is what this method involves, that

- 3-ethynyl-7-hydroxy-3,3 a, 4,5-tetrahydro-1H - oxazolo[3,4-a]quinoline-1-he, the compound corresponding to the formula II in which R1is atenolol group, is treated with a compound described by the formula R2CH(OH)-(CH2)-(CH2)nX, where X represents a halogen atom or a labile group such as tosyloxy or methyloxime,

- process the thus obtained compound corresponding to the formula IX

< / BR>
benzyl-halide,

- lead the resulting compound described by the formula X

< / BR>
in the interaction with ozone and then with a regenerating agent, such as borohydride sodium, obtaining the derivative corresponding to the formula XI, which is then

< / BR>
or deprive the protective groups with formation of the corresponding compounds under formula (I), where R1means hydroxymethylene group, and R3- hydroxyl group,

any process of dimethyl sulfate to obtain the compounds described by formula Xll

< / BR>
- from which further removes the protective group with formation of the corresponding compounds under formula I, in which R1represents methoxymethyl groups is th, corresponding to the formula I, derived from the enantiomers and diastereoisomers compounds described by formula II, and/or enantiomers of the compounds of the formula III.

In turn, these enantiomers and diastereoisomers compounds under formula II, obtained from the enantiomers and diastereoisomers compounds corresponding to the formula IV or V, allocated from racemic ethyl 6-methoxy-2-methoxy-carbonyl-1,2,3,4-tetrahydroquinolin-1-carboxylate according to the method presented in Annex 3.

This method involves the separation using enzymatic hydrolysis of the enantiomers of ethyl 6-methoxy-2-methoxycarbonyl-1,2,3,4-tetrahydroquinolin-1-carboxylate, which

- the above racemic compound, located in a buffer solution such as a mixture of one-deputizing phosphate and potassium disubstituted phosphate, or in a two phase medium, such as a mixture of toluene and buffer solution, treated with enzyme extract, such as esterase pig liver, acetone powders liver horse, pig, ox or rabbit, and, in particular, acetone powder liver sheep (manufactured by Sigma), and

using the extraction is separated ethyl S-(-)-6-methoxy-2-one method is oxalate.

In that case, if ethyl R-(+)-2-carboxy-6-methoxy-1,2,3,4-tetrahydroquinolin-1-carboxylate handle thionyl chloride in a solvent such as toluene, and then with methanol, to obtain ethyl R-(+)-6-methoxy-2 - methoxycarbonyl-1,2,3,4-tetrahydroquinolin-1-carboxylate.

In that case, if ethyl R-(+)- and S-(-)-6-methoxy-2-methoxycarbonyl-1,2,3,4-tetrahydroquinolin-1 - carboxylate is treated with lithium borohydride, get, respectively, R-(-)- and S-(+)-enantiomers of 7-methoxy-3,3 and 4,5-tetrahydro-1H-oxazolo-[3,4-a]- quinoline-1-she (IV).

In that case, if ethyl R-(+)- and S-(-)-6-methoxy-2-methoxycarbonyl-1,2,3,4-tetrahydroquinolin-1 - carboxylate is treated with a hydride diisobutylaluminum in a solvent such as toluene, get, respectively, ethyl R-(+)- and S-(-)-2-formyl-6-methoxy-1,2,3,4-tetrahydroquinolin-1 - carboxylate, which was to bring him into interaction with organomagnesium compound corresponding to the formula R1MgX, in which

R1represents atenilol, methyl or phenyl group, and

X is a hydrogen atom, in a solvent such as tetrahydrofuran, and then bring in the interaction with sodium methoxide in a solvent such as toluene, and then subjected to chromatographic separation (S),3a(R)], on the other hand, the corresponding (+) diastereoisomer in configuration [3(S), 3a(S)] [3(R),3a(S)].

In order to get used as the starting material racemic ethyl 6-methoxy-2-methoxycarbonyl-1,2,3,4-tetrahydroquinolin-1-carboxylate:

- 6-methoxyquinoline lead in interaction with potassium cyanide or cyanide of trimethylsilyl, as well as with benzoyl chloride in the presence of a solvent, such as dichloromethane,

- formed with 1-benzoyl-2-cyano-6-methoxy-1,2-dihydroquinoline lead in the interaction with Hydrobromic acid in acetic acid, then with aqueous ammonia and finally with acetic acid,

is thus obtained 2-carboxy-6-methoxyquinoline process thionyl chloride in a solvent such as toluene and then methanol with the formation of 6-methoxy-2-methoxycarbonyl - quinoline,

- the specified connection restored in an atmosphere of hydrogen in the presence of platinum oxide and hydrochloric alcohol in methanol to obtain 6-methoxy-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline,

- the specified connection handle ethyl-chloroformate in a solvent such as dichloromethane, in the presence of potassium carbonate.

Prevederilor-3-hydroxybutane] -3,3 and,4,5-tetrahydro-1 H-oxazolo[3,4-a] quinoline-1-he

1.1. CIS - and TRANS-()-3-ethynyl-7-methoxy-3,3 and 4,5 - tetrahydro-1H-oxazolo[3,4-a] quinoline-1-he

To mix the solution 116,3 g (0,442 M) ethyl 2-formyl-6-methoxy-1,2,3,4-tetrahydroquinolin-1-carboxylate in 800 ml of tetrahydrofuran, cooled to a temperature of -30oC, in an atmosphere of argon for 30 min add 486 ml (0,486 M) 1 M bromide vinylmania. The specified reaction medium continue to stir for 2 h, then add cold saturated aqueous solution of ammonium chloride. The resulting mixture was twice extracted with ethyl acetate, the relevant extracts are washed with water, dried over sodium sulfate, then the solvent is evaporated under reduced pressure. The resulting oil is again dissolved in 340 ml of toluene and kept at the temperature of reflux distilled to remove traces of water. Then when the 90oC add 1 ml of 10% aqueous solution of sodium methoxide in methanol and again incubated this mixture at the temperature of reflux distilled away the formed ethanol. The resulting mixture is evaporated to the dry state, the selected residue is taken in ethyl acetate and washed with water, an appropriate organic phase is dried over sodium sulfate, then the solvent is evaporated under reduced l of acetate in the ratio of 4:1, with the release of 32.9 g of TRANS-named derived compounds (i.e pl.: 100oC) and 13.4 g of the corresponding CIS-derivative (i.e. square: 134oC).

1.2. TRANS-()-3-ethynyl-7-hydroxy-3,3 a, 4,5-tetrahydro-1H - oxazolo[3,4-a]quinoline-1-he

To a solution of 24.6 g (0.1 M) of TRANS-()-3-ethynyl-7-methoxy-3,3 and 4,5-tetrahydro-1H - oxazolo[3,4-a]quinoline-1-she's in 280 ml of dichloromethane are added dropwise 19 ml (0.20 M) tribromide boron at a temperature of 0oC, and then, after 1 HR, saturated sodium bicarbonate solution until neutral pH. Filter this mixture and the filtrate is extracted with dichloromethane containing 10% methanol. The organic phase is washed with water and dried over sodium sulfate, and then under reduced pressure, the solvent is evaporated. The resulting solid residue is triturated in a mixture of dichloromethane and methanol in the ratio of 1:1. Filter the mixture and dry it with the final output is 21.4 g of the product.

So pl.: 216oC.

Using as the starting material CIS-()-3-ethynyl-7-methoxy-3,3 a, 4,5 - tetrahydro-1H-oxazolo[3,4-a] quinoline-1-he will receive CIS-()-3 - ethynyl-7-hydroxy-3,3 and 4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline-1-it.

So pl.: 250oC

1.3. [3,3 a,7(R)] 3-Ethynyl-7-[4,4,4-trnl-7-hyroxy - and 3,3,4,5-tetrahydro-1H-oxazolo[3,4-a] quinoline-1-she's in 150 ml of acetonitrile in an argon atmosphere at room temperature add 25.4 g (0,183 M) of potassium carbonate, and then 34,9 g (was 0.138 M) 1-iodine-3(R)-hydroxy-4,4,4-triptorelin. After 4 h, this mixture was diluted with dichloromethane and washed with water. Appropriate organic phase is dried over sodium sulfate and under reduced pressure, the solvent is evaporated. The resulting oil purified by chromatography on silicagel column, elution with chloroform containing 0-3% methanol. After crystallization from a mixture of acetone and diisopropyl ether get 30 g of the product.

So pl.: br135.8oC.

Example 2.

[3,3 a,7(R)] -3-Hydroxymethyl-7-[4.4.4-Cryptor-3-benzyloxybenzyl] -3,3 and,4,5 - tetrahydro-1H-oxazolo[3,4-a]quinoline-1-he

2.1. [3,3 a,7(R)] -3-Ethynyl-7-[4,4,4-Cryptor-3-benzyloxybenzyl]-3,3 and, 4,5-tetrahydro - 1H-oxazolo[3,4-a]quinoline-1-he

To a solution of 30.0 g (840 mm) [3,3 a,7(R)] -3-ethynyl-7-[4,4,4-Cryptor-3-hydroxybutane] -3,3 and,4,5-tetrahydro-1H - oxazolo[3,4-a]quinoline-1-she's in 300 ml of toluene, add a solution of 13.4 g of sodium hydroxide in 13.4 ml of water, 2.7 g (8.4 mm) of tetrabutylammonium bromide, and then to 43.1 g (0,252 M) benzyl bromide. This mixture is stirred for 2 h at room temperature, then extracted with ethyl acetate, washed with water and dried over sodium sulfate, and the solvent is evaporated under reduced with davlantes heptane and chloroformate in the ratio of 1:1. Get 35 g of the product in the form of oil.

2.2. [3,3 a,7(R)] -3-Hydroxymethyl-7-[4,4,4-Cryptor-3-benzyloxybenzyl]- and 3,3,4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline-1-it)

Through a solution of 31.5 g (70,4 mm) [3,3 a, (R)]-3-ethynyl-7- [4,4,4-Cryptor-3-benzyloxybenzyl] -3,3 and,4,5-tetrahydro-1H - oxazolo[3,4-a]quinoline-1-she's in 515 ml of dichloromethane and 780 ml of methanol for 3 h, rinsed ozone at a temperature of -30oC. Then, using a stream of nitrogen to remove the used ozone and maintaining the temperature -30oC add to 26.8 g (0,704 M) of sodium borohydride. After 5 min add 21.8 g (0,352 M) dimethyl sulfide and allow this mixture to come to room temperature. Then the resulting mixture is washed with water, an appropriate organic phase is dried over sodium sulfate and concentrating the resulting solution under reduced pressure. The selected product was then purified using chromatography on silicagel column, elution with dichloromethane containing 0-5% methanol. As a result of recrystallization from diethyl ether gain of 26.5 g of the product.

So pl.: 111,6oC.

Example [3,3 a,7(R)] -3-Methoxymethyl-7-[4,4,4-Cryptor-3-benzyloxybenzyl]-3,3 and,4,5 - tetrahydro-1H-oxazolo[3,4-a]quinoline-1-he

To a solution of 7.8 g (17 mm) [3,3 a,7(R)] -3-hydroxymethyl-7-[4,4,4 - romida tetrabutylammonium, and then 6.4 g (51 mm) of dimethyl sulfate. Then for 30 min added dropwise a solution of 2.7 g (67 mm) of sodium hydroxide in 2.7 ml of water. The specified reaction medium is stirred for 30 min, then diluted with ethyl acetate, extracted with an appropriate organic phase is washed with water and dried over sodium sulfate, and the solvent is evaporated under reduced pressure. Using chromatography on silicagel column, elution with a mixture of heptane and ethyl acetate in the ratio of 1:1, allocate 6.2 g of product in the form of oil.

Example 4. [3,3 a,7(R)] -3-Methoxymethyl-7- [4.4.4-Cryptor-3 - hydroxybutane]-3,3 and,4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline-1-he

A solution of 2.8 g (6 mm) [3,3 a,7(R)] 3-methoxymethyl-7-[4,4,4-Cryptor-3-benzyloxybenzyl] -3,3 and,4,5 - tetrahydro-1H-oxazolo[3,4-a]quinoline-1-she is subjected to hydrogenerating for 16 h in 30 ml of ethanol, in the presence of traces of hydrochloric acid and 0.6 g of 10% palladium-carbon catalyst containing 50% water. This mixture is filtered through silica gel and the solvent is evaporated under reduced pressure. The selected product was then purified using chromatography on silicagel column, elution with a mixture of heptane and ethyl acetate 1:1. As a result of recrystallization of diately-3-hydroxymethyl-3,3 and 4,5-tetrahydro-1-H - oxazolo[3,4-a]quinoline-1-he

5.1. TRANS-7-benzyloxy-3-ethynyl-3,3 and 4,5-tetrahydro-1H-oxazolo [3,4-a] quinoline-1-he

To a solution of 10 g (0,043 M) of TRANS-()-3-ethynyl-7-hydroxy - 3,3 and 4,5-tetrahydro-1H-oxazolo[3,4-a] quinoline-1-it (obtained in Stage 2 of Example 1) and 12 g (0,086 M) of potassium carbonate in 250 ml of acetonitrile and 50 ml of dimethylformamide type of 8.9 g (0,052 M) benzyl bromide. This mixture is stirred at a temperature of 80oC for 1 h, and then, as it remains hot, filtered and washed with acetonitrile, and then under reduced pressure evaporated to dryness. The resulting residue is taken in ethyl acetate and washed several times with water, an appropriate organic phase is dried over sodium sulfate and concentrate under reduced pressure. As a result of recrystallization from diisopropyl ether obtain 12.8 g of product.

So pl.: 96oC.

5.2. TRANS-7-benzyloxy-3-hydroxymethyl-3,3 a, 4,5 - tetrahydro-1H-oxazolo[3,4-a]quinoline-1-he

Through a solution of 12.5 g (0,039 M) of TRANS-7-benzyloxy-3-ethynyl-3,3 and 4,5-tetrahydro-1H - oxazolo[3,4-a] quinoline-1-she's in 450 ml of dichloromethane and 350 ml of methanol, cooled to a temperature of -40oC for 3 h 30 min purge the ozone. Then using a stream of nitrogen to remove excess ozone and small pores is ü overnight at room temperature. This mixture is twice extracted with dichloromethane, the corresponding organic phase is washed with water, saturated sodium chloride solution and dried, and the solvent is evaporated under reduced pressure. Post purification using chromatography on silicagel column, elution with a mixture of dichloromethane and methanol in a ratio of 95:5, gain of 10.9 g of the product.

So pl.: 144oC.

5.3. TRANS-7-hydroxy-3-hydroxymethyl-3,3 a, 4,5 - tetrahydro-1H-oxazolo[3,4-a]quinoline-1-he

3.0 g (9.2 mm) of TRANS-7-benzyloxy-3-hydroxymethyl-3,3 and 4,5-tetrahydro-1H-oxazolo [3,4-a] quinoline-1-she dissolved in 20 ml of ethanol and 40 ml of tetrahydrofuran, are hydrogenerating for 1 h in the presence of 1 g of 10% palladium-carbon catalyst containing 50% water. This mixture is filtered through silica gel and the solvent is evaporated under reduced pressure. Obtain 1.1 g of product.

So pl.: 250oC.

5.4. [3,3 a,7(R)] 7-(3-hydroxyethoxy)-3-hydroxymethyl-3,3 and 4,5-tetrahydro-1H - oxazolo[3,4-a]quinoline-1-he

To a solution of 500 mg (2,13 mm) of TRANS-7-hydroxy-3-hydroxymethyl - 3,3 a, 4,5-tetrahydro-1H-oxazolo[3,4-a] quinoline-1-it is in 3 ml of acetonitrile and 2 ml of dimethylformamide added 590 mg (4.26 deaths mm) of potassium carbonate, and then a solution of 623 mg (2,oC for 2 h, then add 20 ml of water and twice extracted with ethyl acetate. Appropriate organic phase is dried over sodium sulfate and concentrate under reduced pressure. The resulting solid is subjected to chromatography on silicagel column, elution with a mixture of ethyl acetate and cyclohexane at a ratio of 1:1, then triturated in diisopropyl ether. Obtain 420 mg of product.

So pl.: 102oC.

Example 6. [3(S), 3A(S), 7(R)1-(+)-3-Methoxymethyl-7-[4,4,4 - Cryptor-3-hydroxybutane]-3,3 and,4,5-tetrahydro-1H-oxazolo[3.4-a]- quinoline-1-he

6.1. 1-Benzoyl-2-cyano-6-methoxy-1,2-dihydroquinoline

A solution of 10 g (63 mm) 6-methoxyquinoline in 80 ml of dichloromethane is mixed with a solution of 12.4 g (188 mm) of potassium cyanide, after which the resulting mixture is added slowly to 14.5 ml (125 mm) benzoyl chloride. This mixture is stirred for 18 h, the organic phase is separated, and the corresponding aqueous phase is extracted with dichloromethane. The resulting organic fraction was washed with aqueous 5% hydrochloric acid, then with water, aqueous sodium hydroxide solution and again with water, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting oil K6-methoxyquinoline

To a solution of 217 g (0,747 M) 1-benzoyl-2-cyano-6-methoxy 1,2-dihydroquinoline in 270 ml of acetic acid are added 270 ml of 48% Hydrobromic acid and maintain the resulting mixture at reflux distilled for 30 minutes Filter this mixture, rinsed her diethyl ether, the resulting solid is suspended in 2 l of water and heated to a temperature of 90oC. Then add aqueous ammonia to pH 8-9 and filter this mixture while it is still hot. At a temperature of 50oC using acetic acid filtrate is acidified to pH 4-5, and then cooled. Filtered crystallized product, rinse it with water, then recrystallized from 250 ml of acetic acid and washed with diethyl ether. Obtain 129 g of the product.

So pl.: 187oC.

6.3. 6-Methoxy-2-methoxycarbonylamino

To a suspension of 129 g (0,635 M) 2-carboxy-6-deoxyinosine in 1200 ml of toluene are added dropwise 230 ml (3,17 M) thionyl chloride and maintain the resulting mixture at elevated temperature for 3 hours and 30 minutes to Concentrate the above solution under reduced pressure and the resulting solid is dissolved in 300 ml of methanol. This mixture is stirred during the in diethyl ether and collected by filtration. The selected solid is taken in ethyl acetate and dilute aqueous ammonia, the appropriate separate the organic phase, process animal charcoal, filtered and concentrated under reduced pressure. Get 90 g of the product.

So pl.: 129oC.

6.4. ()-6-Methoxy-2-methoxycarbonyl-1,2,3,4 - tetrahydroquinolin

To a solution of 50 g (0,23 M) 6-methoxy-2-methoxycarbonylamino in 1000 ml of methanol is added a solution of 6N hydrochloric ethanol to pH 1, and then this mixture is subjected to hydrogenation for 18 h in the presence of 2.6 g of hydrated oxide of platinum. Then use filtering to remove the used catalyst and the solvent is evaporated under reduced pressure. RUB the product in a mixture of diisopropyl ether and petroleum ether, resulting in a gain of 56 g of product in the form of hydrochloride.

So pl.: 129oC.

To obtain pure reason specified product is diluted with aqueous ammonia, extracted with ethyl acetate, dried over sodium sulfate, and the solvent is evaporated under reduced pressure.

So pl.: < 50oC.

6.5. Ethyl ()-6-methoxy-2-methoxycarbonyl-1,2,3,4-tetrahydro-the(0,407 ml) of ethyl chloroformate in 1400 ml of dichloromethane added 85 g (0.63m) of potassium carbonate and maintain the resulting mixture at reflux distilled within 18 PM Filter this mixture corresponding to the filtrate concentrated under reduced pressure and the resulting residue is subjected to chromatography on silicagel column, elution with a mixture of ethyl acetate and cyclohexane in the ratio 3:7. Get 80.4 g of product in the form of oil.

6.6. Ethyl S-(-)-6-methoxy-2-methoxycarbonyl-1,2,3,4 - tetrahydroquinolin-1-carboxylate and

ethyl R-(+)-2-carboxy-6 - methoxy-1,2,3,4-tetrahydroquinolin-1-carboxylate

3G(10.2mm)ethyl()-6-methoxy-2-methoxycarbonyl-1,2,3,4-tetrahydroquinolin-1 - carboxylate are suspended in 80 ml of 0.01 M phosphate buffer (odnozamesheng potassium phosphate + disubstituted potassium phosphate), pH 7. Then the pH of this mixture with aqueous 1 M sodium hydroxide was adjusted to 7.3 and add 7.5 g of acetone powder liver sheep. The resulting mixture is stirred for 14 h at room temperature, maintaining a constant pH with aqueous 1 M sodium hydroxide, then filter this mixture through celite and washed used celite approximately 400 ml of diethyl ether. The corresponding aqueous phase is shaken out three times with 400 ml of diethyl ether, combine the organic fractions dried over magnesium sulfate, filter ronil-1,2,3,4-tetrahydroquinolin-1-carboxylate.

her: 99% by chiral HPLC

[]2D0= -54,7(C = 0,9; dichloromethane).

The corresponding aqueous phase with 10% hydrochloric acid acidified to pH 4.5, then extracted three times with 100 ml of diethyl ether. Combine the obtained ether phase is dried over magnesium sulfate and filtered, after which the solvent is evaporated in vacuum. Obtain 1.04 g of ethyl R-(+)-2 - carboxy-6-methoxy-1,2,3,4-tetrahydroquinolin-1-carboxylate.

her: 88% using chiral HPLC

[]2D0= +66,5(s = 0,99; dichloromethane)

6.7. Ethyl S-(-)-2-formyl-6-methoxy-1,2,3,4-tetrahydroquinolin-1 - carboxylate

To a solution of 34.6 g (amount of 0.118 M) ethyl S-(-)-6-methoxy-2 - methoxycarbonyl-1,2,3,4-tetrahydroquinolin-1-carboxylate in 700 ml of toluene at -70oC added dropwise 235 ml (0,234 M) 1.5 M solution of hydride diisobutylaluminum in toluene. The resulting mixture is stirred for 15 min at -70oC, then while mixing, slowly add 17 ml of methanol, while allowing this mixture to warm to room temperature. Add 1.5 l 1.5 M hydrochloric acid solution, separating the organic phase, and the corresponding aqueous phase is extracted with diethyl EPE the leaders introduce pressure. Get to 23.8 g of the product.

[]2D0= -43,1(c = 1; dichloromethane).

6.8. [3(S),3a(S)] - (+) - [3(R),3A(S)]-3-ethynyl-7-methoxy - 1,2,3,4,-tetrahydro-1H-oxazolo[3,4-a]quinoline-1-he

To a solution of 23.8 g (90 mm) ethyl S-(-)-2-formyl-6-methoxy - 1,2,3,4-tetrahydroquinolin-1-carboxylate in 260 ml of tetrahydrofuran, cooled to a temperature of -40oC in argon atmosphere for 1 h 30 min add 99 ml (99 mm) 1 M bromide vinylmania. The specified reaction medium is stirred for 1 h, then add cold saturated aqueous solution of ammonium chloride. The resulting mixture was twice extracted with diethyl ether, washed with water, dried over sodium sulfate, then the solvent is evaporated under reduced pressure. The resulting oil is again dissolved in 172 ml of toluene and heated with delegacia to remove traces of water. Then at a temperature of 90oC add 0.8 ml of 10% aqueous solution of sodium methoxide in methanol. This mixture is again heated with delegacia, from chasing the formed ethanol, and then allow it to cool to room temperature, and the resulting solution is subjected to chromatography on silicagel column, elution with a mixture of cyclohexane and ethyl acetate in the ratio (C = 1; dichloromethane);

as well as 3 g of the corresponding [3(R),3A(S)]-connection

So pl.: 137-138oC

[]2D0= +41,8(C = 1; dichloromethane).

6.9. [3(S), 3A(S)] -(+)-3-ethynyl-7-hydroxy-3,3 and 4,5 - tetrahydro-1H-oxazolo[3,4-a]quinoline-1-he

To a solution of 5.3 g (22 mm) [3(S),3A(S)]-(+)-3-ethynyl-7-methoxy - -3,3 and,4,5, -tetrahydro-1H-oxazolo[3,4-a] quinoline-1-she's in 13 ml dichloromethane at a temperature of 0oC added dropwise 43 ml (43 mm) 1 M solution tribromide boron in dichloromethane. The resulting mixture is stirred for 30 minutes, then add dilute aqueous ammonia to pH neutral. Then add 5-10 ml of methanol, 2 times concentrated specified reaction medium under reduced pressure and filtered. Resulting precipitate is rinsed with water, then with diethyl ether, and then dried. Allot of 4.7 g of the product.

So pl.: 215oC

[]2D0= +64,8(C = 1; dimethyl sulfoxide).

6.10. [3(S),3A(S),7(R)]-(+)-3-Ethynyl-7-[4,4,4-Cryptor-3 - hydroxybutane]-3,3 and,4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline-1-he

To a solution of 4.7 g (20 mm) [3(S),3A(S)]-(+)-3-ethynyl-7-hydroxy - 3,3 a, 4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline-1-it in 55 ml of acetonitrile added 5.6 g (41 Mut with delegacia for 16 h, then diluted with dichloromethane and washed with water. Further the organic phase is dried over sodium sulfate, and then under reduced pressure, the solvent is evaporated. The selected oil is purified by chromatography on a column of silica gel. After crystallization from diisopropyl ether obtain 6.0 g of product.

So pl. 145-146oC.

[]2D0= +78,4(C = 1; methanol)

6.11. [3(S), 3A(S),7(R)]-(+)-3-Ethynyl-7-[4,4,4-Cryptor-3 - benzyloxybenzyl]-3,3 and,4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline-1-he

To a solution of 6.0 g (17 mm) [3(S),3A(S),7(R)]-(+)-3 - Ethynyl-7-[4,4,4-Cryptor-3-hydroxybutane] -3,3 and,4,5-tetrahydro-1H - oxazolo[3,4-a]quinoline-1-she's in 60 ml of toluene, add a solution of 2.7 g (67 mm) of sodium hydroxide in 2.7 ml of water, of 0.53 g (1.7 mm) of tetrabutylammonium bromide, and then to 6.0 ml (50 mm) benzyl bromide. This mixture was stirred at room temperature for 16 h, then extracted with ethyl acetate, washed with water, dried over sodium sulfate and under reduced pressure, the solvent is evaporated. The selected oil is purified using chromatography on silicagel column, elution with a mixture of cyclohexane and ethyl acetate in the ratio 8:2. Get 7,1 g +111(C = 1; dichloromethane)

6.12. [3(S), 3a(S),7(R)]-(+)-3-Hydroxymethyl-7-[4,4,4-Cryptor - 3-benzyloxybenzyl]-3,3 and,4,5-tetrahydro-1H-oxazolo-[3.4-a]quinoline - 1-he

In a solution of 7.0 g (16 mm) [3(S),3a(S),7(R)]-(+)-3-ethynyl-7-[4,4,4-Cryptor-3-benzyloxybenzyl] - and 3,3,4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline-1-she's in 170 ml of dichloromethane and 240 ml of methanol for 2 h serves ozone at a temperature of -40oC. Then remove the ozone stream of nitrogen, then added 5.9 g (160 mm) of sodium borohydride at the same temperature. After 5 min add 5.7 ml (78 mm) dimethyl sulfide, allow the mixture to warm to room temperature, then washed with water, and the resulting organic phase is dried over sodium sulfate and concentrate under reduced pressure. The isolated product triturated with diethyl ether, and then filtered. Obtain 4.7 g of product.

So pl.: 118oC

[]2D0= +111,1(c = 1; dichloromethane)

6.13. [3(S), 3a(S), 7(R)1-(+)-3-Methoxymethyl-7-[4,4,4-Cryptor - 3-benzyloxybenzyl]-3,3 and,4,5-tetrahydro-1H-oxazolo-[3,4-a] quinoline-1-he

To a solution of 4.6 g (10 mm) [3(S),3A(S),7(R)]-(+)-3 - peroxyketal-7-[4,4,4-Cryptor-3-hydroxybutane]-3,3 and,4,5 - tetrahydro-1H-oxazolo[3,4-a]quinoline-1-she's in 60 ml of toluene added 0.32 g (1 mm) of the bromide tetrabutyl peremeshivayte for 1 h, diluted with ethyl acetate, and then extracted with the organic phase, washed with water, dried over sodium sulfate and under reduced pressure, the solvent is evaporated. Using chromatography on silicagel column, elution with a mixture of cyclohexane and ethyl acetate in the ratio of 7:3, obtain 6.2 g of product in the form of oil.

[]2D0= +115,4(C = 1; dichloromethane)

6.14. [3(S),3a(S),7(R)]-(+)-3-Methoxymethyl-7-[4,4,4-Cryptor - 3-hydroxybutane]-3,3 and,4,5-tetrahydro-1H-oxazolo[3,4-a]- quinoline-1-he

A solution of 4.1 g (8.8 mm) [3(S),3a(S),7(R)]-(+)-3 - methoxymethyl-7-[4,4,4-Cryptor-3-benzyloxybenzyl]-3,3 and,4,5 - tetrahydro-1H-oxazolo[3,4-a]quinoline-1-she's in 80 ml of ethanol are gidrogenizirovanii for 1 h in the presence of 0.8 g of 10% paradiesvogel catalyst containing 50% water and traces of hydrochloric ethanol. This mixture is filtered through silica gel and under reduced pressure, the solvent is evaporated. Named product is crystallized from a mixture of acetone and diisopropyl ether, and then from a mixture of diisopropyl ether and isopropanol in a ratio of 97:3.

Obtain 1.0 g of product.

So PL..: 120,7-120,9oC.

[]2D0= +105,4
7.1. [3(R),3A(S)]-(+)-3-Ethynyl-7-hydroxy-3,3 and 4,5-tetrahydro - 1H-oxazolo[3,4-a]quinoline-1-he

2.0 g (8.0 mm)[3(R),3A(S)]-(+)-3-ethynyl-7-methoxy - 3,3 and 4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline-1-it (obtained in Stage 8 of Example 6) is treated under the conditions described in Stage 9 of Example 6.

Get 1.9 grams of product.

[]2D0= +47,2(C = 1; dimethyl sulfoxide)

7.2. [3(R),3A(S),7(R)]-(+)-3-Ethynyl-7-[4,4,4-Cryptor-3 - hydroxybutane] -3,3 and,4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline-1-he

A solution of 1.9 g (8.0 mm) [3(R),3A(S)]-(+)-3-ethynyl-7-hydroxy - 3,3 and 4,5-tetrahydro-1H-oxazolo[3,4-a] quinoline-1-she's in 26 ml of acetonitrile and 10 ml of dimethylformamide is treated under the conditions described in Stage 10 of Example 6.

Obtain 2.6 g of the product.

So pl.: 143-145oC.

[]2D0= +60,2(C = 1; methanol)

7.3. [3(R), 3a(S), 7(R)]-(+)-3-Ethynyl-7-[4,4,4-Cryptor-3 - benzyloxybenzyl]-3,3 and,4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline - 1-he

2.5 g (7.0 mm) [3(R),3A(S),7(R)]-(+)-3-ethynyl-7-[4,4,4 - Cryptor-3-hydroxybutane] -3,3 and, 4,5-tetrahydro-1H-oxazolo- [3,4-a]quinoline-1-it is treated under the conditions described in Stage 11 of Example 6.

Obtain 3.0 g of product.

So pl.: 73-74oC.

[]2D0= a,4,5-tetrahydro-1H-oxazolo [3,4-a] quinoline-1-he

3.0 g (6.7 mm) [3(R),3A(S),7(R)]-(+)-3-ethynyl-7- [4,4,4-Cryptor-3-benzyloxybenzyl] -3,3 and, 4,5-tetrahydro-1H - oxazolo-[3,4-a]quinoline-1-it is treated under the conditions described in Stage 12 Example 6.

Obtain 2.1 g of product.

So pl. 107oC.

[]2D0= +63,8(C = 1; dichloromethane)

7.5. [3(R), 3a(S), 7(R)] -(+)-3-Methoxymethyl-7-[4,4,4-Cryptor-3 - benzyloxybenzyl]-3,3 and,4,5-tetrahydro-1H-oxazolo[3,4-a]-quinoline-1-he

A solution of 2.1 g (4,7 mm) [3(R), 3A(S), 7(R)] -(+)-3-hydroxymethyl-7- [4,4,4-Cryptor-3-hydroxybutane] -3,3 and, 4,5-tetrahydro-1H-oxazolo [3,4-a] quinoline-1-she's in 30 ml of toluene and 3 ml of dichloromethane is treated under the conditions described in Stage 13 Example 6.

Obtain 1.8 g of product in the form of oil.

[]2D0= +64,8(C = 1; dichloromethane)

7.6. [3(R), 3A(S), 7(R)]-(+)-3-Methoxymethyl-7-[4,4,4 - Cryptor-3-hydroxybutane]-3,3 and,4,5-tetrahydro-1H-oxazolo[3,4 - a]-quinoline-1-he

1.8 g (3.9 mm) [3(R),3A(S),7(R)]-(+)-3 - methoxymethyl-7-[4,4,4-Cryptor-3-benzyloxybenzyl] -3,3 and, 4,5 - tetrahydro-1H-oxazolo[3,4-a]quinoline-1-it is treated under the conditions described in Stage 14 Example 6.

Obtain 0.9 g of product.

So pl.: 165,3-165,5oC.

[]2D0= +16,7C = 1; mean - oxazolo[3.4-a]-quinoline-1-he

8.1. Ethyl R-(+)-6-methoxy-2-methoxycarbonyl-1,2,3,4 - tetrahydroquinolin-1-carboxylate

To 170 ml of methanol are added dropwise to 21.8 ml (302 mm) thionyl chloride at -40oC. After 10 min add to 16.9 g (60,4 mm) ethyl R-(+)-2-carboxy-6-methoxy-1,2,3,4-tetrahydroquinolin-1-carboxylate (obtained in Stage 6 of Example 6), mix this mixture for 3 h, allowing it to heat up to a temperature of 0oC, then pour in a mixture of water and ice, and add ammonia until pH neutral. This mixture is extracted with ethyl acetate, the corresponding organic phase is washed with water, dried over sodium sulfate and the solvent is evaporated. Obtain 18 g of the product in the form of oil.

[]2D0= +52(C = 1; dichloromethane)

8.2. Ethyl R-(+)-2-formyl-6-methoxy-1,2,3,4-tetrahydroquinolin - 1-carboxylate

18 g (0,061 M) ethyl R-(+)-6-methoxy-2-methoxycarbonyl - 1,2,3,4-tetrahydroquinolin-1-carboxylate is treated under the conditions described in Stage 7 of Example 6. Obtain 11.6 g of product.

[]2D0= +67,9(C = 1; dichloromethane)

8.3. [3(R), 3a(R)] - ( - ) - [3(S),3A(R)]-(-)-3-Ethynyl-7-methoxy - 3,3 a, 4,5-tetrahydro-1H-oxazol[3,4-a]quinoline-1-he

11.5g (43,6 mm) ethyl R-(+)-2-fo is P CLASS="ptx2">

Obtain 4.0 g [3(R),3A(R)]-connection

So pl.: 80oC.

[]2D0= -48,8(C = 1; dichloromethane)

and 2.2 g of [3(S),3A(R)]- connection

So pl.: 140oC.

[]2D0= -39(C = 1; dichloromethane)

8.4. [3(R), 3A(R)] -(-)-3-Ethynyl-7-hydroxy-3,3 and 4,5 - tetrahydro-1H-oxazol[3,4-a]quinoline-1-he

4.0 g (16 mm) [3(R),3A(R)]-(-)-3-ethynyl-7-methoxy-3,3 and 4,5 - tetrahydro-1H-oxazol 3,4-a] quinoline-1-it is treated under the conditions described in Stage 9 of Example 6. Obtain 2.5 g of product.

[]2D0= -45,2(C = 1; dimethyl sulfoxide)

8.5. [3(R), 3a(R),7R]-(-)-3-Ethynyl-7-[4,4,4-Cryptor-3 - hydroxybutane] -3,3 and,4,5-tetrahydro-1H-oxazol[3,4-a]quinoline-1-he

A solution of 2.35 g (10 mm) [3(R),3A(R)]-(-)-3-ethynyl - 7-hydroxy-3,3 and 4,5-tetrahydro-1H-oxazol[3,4-a] quinoline-1-it in 25 ml of acetonitrile and 10 ml of dimethylformamide is treated under the conditions described in Stage 10 of Example 6.

Obtain 2.5 g of product.

So PL: 92oC

[]2D0= -31,4(C = 1; dichloromethane)

8.6. [3(R), 3a(R), 7(R)]-(+)-3-Ethynyl-7-[4,4,4-Cryptor-3 - benzyloxybenzyl]-3,3 and,4,5-tetrahydro-1H-oxazol[3,4-a]quinoline - 1-he

1,82 g (5,09 mm) [3(R),3A(R),7(R)]-(-)-3-ethynyl-7-[4,4,4 - Cryptor-3-hydroxybutane] -3,3 a, /P> Obtain 2.1 g of product in the form of oil.

[]2D0= +28,9(C = 1; dichloromethane)

8.7. [3(R), 3a(R), 7(R)]-(+)-3-Hydroxymethyl-7-[4,4,4 - Cryptor-3-benzyloxybenzyl]-3,3 and,4,5-tetrahydro-1H-oxazol [3,4-a]- quinoline-1-he

2.1 g (4,7 mm) [3(R),3A(R),7(R)]-(+)-3-ethynyl-7-[4,4,4 - Cryptor-3-benzyloxybenzyl] -3,3 a, 4,5-tetrahydro-1H-oxazol- [3,4-a]quinoline-1-it is treated under the conditions described in Stage 12 Example 6.

Obtain 1.4 g of product.

[]2D0= +15,5(C =1; dichloromethane)

8.8. [3(R), 3A(R), 7(R)] -(+)-3-Methoxymethyl-7-[4,4,4-Cryptor-3 - benzyloxybenzyl]-3,3 and,4,5-tetrahydro-1H-oxazol[3,4-a]- quinoline-1-he

1.4 g (3.1 mm) [3(R),3A(R),7(R)]-(+)-3-hydroxymethyl-7- [4,4,4-Cryptor-3-benzyloxybenzyl]-3,3 and,4,5-tetrahydro-1H - oxazol[3,4-a]quinoline-1-it is treated under the conditions described in Stage 13 of Example 6. Obtain 1.0 g of the product as oil.

[]2D0= +15,8(c = 1; dichloromethane)

8.9. [3(R),3a(R),7(R)]-(-)-3-Methoxymethyl-7-[4,4,4-Cryptor - 3-hydroxybutane]-3,3 and,4,5-tetrahydro-1H-oxazol[3,4-a]quinoline-1-he

1.0 g (2.2 mm) [3(R),3A(R),7(R)]-(+)-3-methoxymethyl - 7-[4,4,4-Cryptor-3-benzyloxybenzyl] -3,3 and, 4,5-tetrahydro-1H-oxazol [3,4-a] quinoline-1-it is treated under the conditions described in Stage 14 of Example 6. Bicyclohexyl and ethyl acetate in the ratio of 1:1, obtain 0.65 g of product.

So pl.: 90oC.

[]2D0= -35,6(C = 1; methanol)

Example 9.

[3(S), 3A(R), 7(R)] -(+)-3-Methoxymethyl-7-[4,4,4 - Cryptor-3-hydroxybutane]-3,3 and,4,5-tetrahydro-1H-oxazolo [3,4-a]-quinoline-1-he

9.1. [3(S), 3A(R)] -(-)-3-Ethynyl-7-hydroxy-3,3 and 4,5 - tetrahydro-1H-oxazol[3,4-a]quinoline-1-he

2.2 g (9.0 mm) [3(S),3A(R)]-3-ethynyl-7-methoxy-3,3 and 4,5-tetrahydro-1H - oxazolo[3,4-a] quinoline-1-it (obtained in Stage 3 of Example 8) is treated under the conditions described in Stage 9 of Example 6. Obtain 1.8 g of product.

[]2D0= -50,9(c = 1; dimethyl sulfoxide)

9.2. [3(S),3A(R),7(R)]-(-)-3-Ethynyl-7-[4,4,4-Cryptor-3-hydroxyethoxy]- and 3,3,4,5-tetrahydro-1H-oxazol[3,4-a]quinoline-1-he

1.7 g (7.5 mm) [3(S),3A(R)]-(-)-3-ethynyl-7-hydroxy-3,3 and 4,5 - tetrahydro-1H-oxazol[3,4-a] quinoline-1-it is treated under the conditions described in Stage 10 of Example 6. After crystallization from diethyl ether to obtain 1.8 g of product.

So pl.: 145oC.

[]2D0= -16,4(C = 1; methanol)

9.3. [3(S), 3a(R), 7(R)]-(+)-3-Ethynyl-7-[4,4,4-Cryptor-3 - benzyloxybenzyl]-3,3 and,4,5-tetrahydro-1H-oxazol[3,4-a]quinoline-1-he

1.77 g (4,95 mm) [3(R),3A(R),7(R)]-(-)-3-ethynyl-7-[4,4,4 - Cryptor-3-hydroxy is and 6. After purification using chromatography on silicagel column, elution with a mixture of cyclohexane and chloroform in the ratio of 1:9, get 2.0 g of product.

[]2D0= +42,7(C = 1; dichloromethane)

9.4. [3(S), 3a(R), 7(R)]-(+)-3-Hydroxymethyl-7-[4,4,4-Cryptor-3 - benzyloxybenzyl]-3,3 and,4,5-tetrahydro-1H-oxazol[3,4-a]- quinoline-1-he

1.9 grams (4.2 mm) [3(S),3A(R),7(R)]-(+)-3 - ethynyl-7-[4,4,4-Cryptor-3-benzyloxybenzyl] -3,3 and, 4,5 - tetrahydro-1H-oxazol-[3,4-a]quinoline-1-it is treated under the conditions described in Stage 12 of Example 6. Focusing corresponding to the organic phase under reduced pressure to obtain 1.7 g of product.

So pl.: 98oC.

[]2D0= +69,5(C = 1; dichloromethane)

9.5. [3(S), 3a(R), 7(R)] -(+)-3-Methoxymethyl-7-[4,4,4-Cryptor-3 - benzyloxybenzyl]-3,3 and,4,5-tetrahydro-1H-oxazol[3,4-a]-quinoline - 1-he

1.68 g (3,72 mm) [3(S),3A(R),7(R)]-(+)-3-hydroxymethyl-7- [4,4,4-Cryptor-3-benzyloxybenzyl]-3,3 and,4,5-tetrahydro-1H-oxazol [3,4-a]quinoline-1-it is treated under the conditions described in Stage 13 of Example 6. Using chromatography on silicagel column, elution with a mixture of cyclohexane and ethyl acetate in the ratio 6:4, obtain 1.35 g of product in the form of oil.

[]2D0= +61,6 (=what[3,4-a]-quinoline - 1-he

1.29 g (2,77 mm) [3(S),3a(R),7(R)]-(+)-3 - methoxymethyl-7-[4,4,4-Cryptor-3-benzyloxybenzyl]-3,3 and,4,5 - tetrahydro-1H-oxazol[3,4-a]quinoline-1-it is treated under the conditions described in Stage 14 of Example 6. Obtain 0.33 g of the product.

So pl.: 103,6-103,8oC.

[]2D0= +49,1(C = 1; methanol)

Example 10.

7(R)-(4,4,4-Cryptor-3-hydroxyethoxy)-3,3 and, 4,5-tetrahydro-1H - oxazolo[3,4-a]quinoline-1-he

10.1. 7-Methoxy-3,3 and 4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline-1-he

To a solution of 10.9 g (41,4 mm) of ethyl 2-formyl-6-methoxy-1,2,3,4-tetrahydroquinolin-1-carboxylate in 100 ml of methanol, cooled to a temperature of 0oC, the parts add 2.2 g (41,4 mm) of potassium borohydride. The specified medium is stirred for 1 h, and then subjected to hydrolysis, dilute with water and extracted with diethyl ether. Then the corresponding organic phase is washed with water and dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The selected oil again dissolved in 90 ml of toluene, heat the resulting solution to a temperature of reflux distilled to remove traces of water, and add a catalytic amount of 10% sodium methoxide in methanol at a temperature of 90oC. removal of storytell. The obtained residue is taken in ethyl acetate, washed with water, then the corresponding organic phase is dried over sodium sulfate and concentrate under reduced pressure. After chromatography on silicagel column, elution with a mixture of heptane and ethyl acetate in the ratio of 4:1, receive 5.0 g of product.

So pl.: 99oC.

10.2. 7-Hydroxy-3,3 and 4,5-tetrahydro-1H-oxazolo[3,4-a] quinoline-1-he

To a solution of 4.6 g (21 mm) of ethyl 7-methoxy-3,3 and 4,5 - tetrahydro-1H-oxazol[3,4-a] quinoline-1-it in 50 ml of dichloromethane are added dropwise 4 ml (42 mm) tribromide boron at a temperature of 0oC. After 1 h the specified environment is subjected to hydrolysis by adding aqueous ammonia to pH neutral. After that, the precipitate is filtered off and dried in vacuum. Obtain 3.1 g of product.

So pl.: > 260oC.

10.3. 7-(R)-(4,4,4-Cryptor-3-hydroxyethoxy)-3,3 and,4,5 - tetrahydro-1H-oxazolo[3,4-a]quinoline-1-he

To a solution of 2.0 g (9.7 mm) 7-hydroxy-3,3 and 4,5-tetrahydro-1H - oxazolo[3,4-a] quinoline-1-it in 10 ml of acetonitrile and 10 ml of dimethylformamide added 4.3 g (15 mm) 3-(R)-hydroxy-4,4,4 - tripcomputer tosilata and 4.0 g (29 mm) of potassium carbonate. This mixture is stirred for 4 hours at a temperature of 90oC, after which the Oia and evaporated under reduced pressure. The selected oil is purified using chromatography on silicagel column, elution with a mixture of heptane and ethyl acetate in the ratio of 4:1, resulting in a gain of 1.9 g of product.

So pl.: 188oC.

Example 11.

S-(+)-7-(4,4,4-triptoreline)-3,3 and, 4,5-tetrahydro-1H - oxazolo[3,4-a] quinoline-1-he

11.1. S-(+)-7-Methoxy-3,3 a, 4,5-tetrahydro-1H-oxazolo [3,4-a]quinoline-1-he

To a solution of 8.0 g (27 mm) ethyl S-(-)-6-methoxy-2-methoxycarbonyl - 1,2,3,4-tetrahydroquinolin-1-carboxylate (obtained in Stage 6 of Example 6) in 80 ml of diglyme to add parts of 0.90 g (41 mm) of lithium borohydride. The specified medium is stirred for 3 hours at a temperature of 50oC, then poured into water and extracted with ethyl acetate the resulting product. Appropriate organic phase is dried over sodium sulfate and concentrated under reduced pressure, and the selected residue is triturated in petroleum ether containing a small amount of isopropyl alcohol. Obtain 4.4 g of product.

So pl.: 112oC.

[]2D0= +63,7(C = 1; dichloromethane)

In accordance with the specified method, using as the starting material ethyl R-(+)-6-methoxy-2-methoxycarbonyl - 1,2,3,4-Tetra is square: 110oC.

[]2D0= -40,1(C = 1; dichloromethane)

11.2. S-(+)-7-Hydroxy-3,3 a, 4,5-tetrahydro-1H-oxazolo[3,4-a] - quinoline-1-he

To a solution of 4.3 g (20 mm) of ethyl S-(+)-7-methoxy-3,3 and 4,5 - tetrahydro-1H-oxazol[3,4-a] quinoline-1-she's in 40 ml of dichloromethane, cooled to a temperature of 0oC, are added dropwise 39 ml (39 mm) 1M solution tribromide boron in dichloromethane at a temperature of 0oC. the Specified medium is stirred for 1 h while allowing to rise the temperature, then add aqueous ammonia solution until neutral pH, filter the resulting precipitate and dried. Obtain 3.0 g of product.

So pl.: > 250oC.

[]2D0= +51,4(C = 1; dimethyl sulfoxide)

In accordance with the specified method, using as the starting material R-(-)-7-methoxy-3,3 a, 4,5 - tetrahydro-1H-oxazolo[3,4-a]quinoline-1-it, get R-(-)-7 - hydroxy-3,3 and 4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline-1-it.

[]2D0= -46(C = 1; dimethyl sulfoxide)

11.3. S-(+)-7-(4,4,4-Triptoreline)-3,3 and, 4,5-tetrahydro-1H - oxazolo[3,4-a]quinoline-1-he

To a solution of 1.9 g (9.3 mm) 5-(+)-7-hydroxy-3,3 and 4,5-tetrahydro - 1H-oxazolo[3,4-a] quinoline-1-it is in the ATA potassium. This mixture was incubated for 3 h at a temperature of 90oC, then diluted with ethyl acetate and washed with water. Appropriate organic phase is dried over sodium sulfate and concentrated under reduced pressure, and the selected residue is subjected to chromatography on silicagel column, elution with dichloromethane containing 0.5% of methanol. After recrystallization from isopropyl alcohol to obtain 2.1 g of product.

So pl.: 121,3-121,4oC.

[]2D0= +33,8(with = 1: dichloromethane)

Example 12.

CIS-(+)-3-phenyl-7-(4,4,4-triptoreline)-3,3 and, 4,5-tetrahydro-1H - oxazolo[3,4-a]quinoline-1-he

12.1. CIS - and TRANS-()-7-methoxy-3-phenyl-3,3 and 4,5-tetrahydro-1H-oxazolo [3,4-a]quinoline-1-he

Using as starting compounds a solution of ethyl 2-formyl-6-methoxy-1,2,3,4-tetrahydroquinolin-1-carboxylate in methanol, cooled to a temperature of 0oC and bromide vinylmania handle these reagents under conditions similar to those described in Stage 1 of Example 1, to obtain the corresponding CIS-derivative,

so pl.: 99oC; and

TRANS-derived,

so pl.: 126oC.

12.2. CIS-()-7-hydroxy-3-phenyl-3,3 and 4,5-tetrahydro-1H - oxazolo[3,4-a] hinolinol-1-it, which is treated under the conditions described in step 2 of Example 1, receive CIS-()-7-hydroxy-3 - phenyl-3,3 and 4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline-1-it.

So pl.: 242oC.

Using as the starting material TRANS-()-7-methoxy - 3-phenyl-3,3 a, 4,5-tetrahydro-1H-oxazolo[3,4-a] quinoline-1-it, get TRANS-()-7-hydroxy-3-phenyl-3,3 and 4,5-tetrahydro-1H - oxazolo[3,4-a]quinoline-1-it.

So pl.: 216oC.

12.3. CIS-()-3-phenyl-7-(4,4,4-triptoreline)-3,3 and, 4,5 - tetrahydro-1H-oxazolo[3,4-a]quinoline-1-he

To a solution of 0.65 g (2.3 mm) of CIS-()-7-hydroxy-3-phenyl-3,3 and 4,5-tetrahydro-1H - oxazolo[3,4-a] quinoline-1-she's in 15 ml of dimethylformamide added 0.66 g (3.5 mm) 1-bromo-4,4,4-triptorelin and 0.64 g (4.6 mm) of potassium carbonate. This mixture was incubated for 4 h at a temperature of 90oC, then diluted with ethyl acetate and washed with water. Then the corresponding organic phase is dried over sodium sulfate and concentrated under reduced pressure, and the selected residue is subjected to chromatography on silicagel column, elution with cyclohexane containing 20% ethyl acetate. After trituration in diisopropyl ether gain of 0.60 g of the product.

So pl.: 129,5oC.

Example 13.

CIS-(+)-3-methyl-7-(4,4,4-the 1H-oxazolo[3,4-a] quinoline-1-he

Using as starting compounds a solution of ethyl 2-formyl-6-methoxy-1,2,3,4-tetrahydroquinolin-1-carboxylate in diethyl ether, cooled to a temperature of 0oC and bromide Metalmania handle these reagents under conditions similar to those described in Stage 1 of Example 1, to obtain the corresponding CIS-derivative,

so pl.: 138-139oC; and

TRANS-derived,

so pl.: 122-123oC.

13.2. CIS-()-7-hydroxy-3-methyl-3,3 and 4,5-tetrahydro-1H - oxazolo[3,4-a] quinoline-1-he

Using as the starting material CIS-()-7-methoxy-3-methyl-3,3 a, 4,5-tetrahydro-1H-oxazolo [3,4-a] quinoline-1-it, which is treated under the conditions described in step 2 of Example 1, receive CIS-()-7-hydroxy-3 - methyl-3,3 and 4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline-1-it.

So pl.: 258-259oC.

Using as the starting material TRANS-()-7 - methoxy-3-methyl-3,3 a, 4,5-tetrahydro-1H-oxazolo[3,4-a] quinoline-1-it, get TRANS-()-7-hydroxy-3-methyl-3,3 and 4,5 - tetrahydro-1H-oxazolo[3,4-a]quinoline-1-it.

So pl.: 240-241oC.

13.3. CIS-()-3-methyl-7-(4,4,4-triptoreline)-3,3 and, 4,5 - tetrahydro-1H-oxazolo[3,4-a]quinoline-1-he

To a solution 0,70 g( 3.2 mm) of CIS-()-7-hydroxy-3-methyl-3,3 and 4,5-tetrahydro-1H - oxazolo[3,4-a] pinolino mixture is maintained at a temperature of 90oC for 4 h, then diluted with ethyl acetate and washed with water. Then the corresponding organic phase is dried over sodium sulfate and concentrated under reduced pressure, and the selected residue is subjected to chromatography on silicagel column, elution with cyclohexane containing 20% ethyl acetate. After trituration in diisopropyl ether get to 0.80 g of product.

So pl.: 79,1-79,2oC.

Example 14.

[3,3 a,7(R)] 3-Ethyl-7-[4,4,4-trifter-3-hydroxybutane] and 3,3,4,5- -tetrahydro-1H-oxazolo[3,4-a]quinoline-1-he

0,86 g (2.4 mm) [3,3 a,7(R)] 3-ethynyl-7-[4,4,4-Cryptor-3-hydroxybutane] -3,3 and, 4,5-tetrahydro-1H - oxazolo[3,4-a]quinoline-1-it (obtained in Example 1) were hydrogenerating for 3 h in 20 ml of methanol in the presence of 0.2 g of 5% palladium-carbon catalyst containing 50% water. Then this mixture is filtered and concentrated under reduced pressure until dry. The resulting oil purified by chromatography on silicagel column, elution with a mixture of dichloromethane and methanol in a ratio of 95:5, and by crystallization from diisopropyl ether, resulting in a gain of 0.47 g of product.

So pl.: 120-131oC.

Example 15.
15.1. [3(S), 3A(S)]-(+)-7-Benzyloxy-3-ethynyl - 3,3 and 4,5-tetrahydro-1H-oxazol[3,4-a]quinoline-1-he

Using as the starting material [3(S),3a(S)]-(+)- C-ethynyl-7-hydroxy-3,3 a, 4,5-tetrahydro-1H-oxazolo[3,4-a] quinoline-1-he (obtained in Stage 9 Example 6), which is treated under the conditions described in Stage 1 of Example 5, get [3(S),3A(S)]- (+)-7-benzyloxy-C-ethynyl-3,3 and 4,5-tetrahydro-1H-oxazol[3,4-a] quinoline-1-it.

So pl.: 86-90oC.

[]2D0= +71,1(C = 1; dichloromethane).

In accordance with the specified method will have the following connections:

- [3(S), 3A(R)]-(-)-7-Benzyloxy-3-ethynyl-3,3 and 4,5 - tetrahydro-1H-oxazol[3,4-a]quinoline-1-it.

So pl.: 102oC

[]2D0= -45,2.

- [3(R), 3A(S)]-(+)-7-Benzyloxy-3-ethynyl-3,3 and 4,5 - tetrahydro-1H-oxazol[3,4-a]quinoline-1-it.

So pl.: 98oC.

[]2D0= +45,7.

- [3(R),3A(R)]-(-)-7-Benzyloxy-3-ethynyl-3,3 and 4,5-tetrahydro-1H - oxazol[3,4-a]quinoline-1-it.

So pl.: 84oC.

[]2D0= -62,1.

15.2. [3(S),3A(S)]-(+)-7-Benzyloxy-3-hydroxymethyl-3,3 and 4,5 - tetrahydro-1H-oxazol[3,4-a]quinoline-1-he

Using as the starting material Lociniem [3(S),3a(S)]-(+)-7-benzyloxy-3-hydroxymethyl-3,3 and 4,5-tetrahydro-1H - oxazol-[3,4-a]quinoline-1-it.

So pl.: 120-140oC.

[]2D0= +73,8(C = 1; dimethyl sulfoxide).

Using the same method will have the following connections: -

- [3(S), 3A(R)] -(-)-7-Benzyloxy-3-hydroxymethyl-3,3 a, 4,5-tetrahydro - 1H-oxazol[3,4-a]quinoline-1-it is in the form of resin.

[]2D0= -4,2.

- [3(R),3A(S)]-(+)-7-Benzyloxy-3-hydroxymethyl-3,3 and 4,5-tetrahydro-1H- -oxazol[3,4-a]quinoline-1-it.

So pl.: 138-140oC.

[]2D0= +4,8.

- [3(R), 3A(R)]-(-)-7-Benzyloxy-3-hydroxymethyl-3,3 and 4,5 - tetrahydro-1H-oxazol[3,4-a]quinoline-1-it is in the form of resin.

[]2D0= -54,6.

15.3. [3(S), 3A(S)]-(+)-7-Benzyloxy-3-methoxymethyl-and 3,3,4,5 - tetrahydro-1H-oxazolo[3,4-a]quinoline-1-he

To a solution of 1.7 g (0,052 M) [3(S),3A(S)]-(+)-7-benzyloxy-3-hydroxymethyl-3,3 a, 4,5 - tetrahydro-1H-oxazolo[3,4-a]quinoline-1-it in 100 ml of toluene and 100 ml of dichloromethane added 0.17 g (0.005 M) Tetramethylammonium bromide, then 3.0 ml of dimethyl sulfate and finally a solution of 1.7 g (0,041 M) sodium hydroxide dissolved in 1.7 ml of water. This mixture is stirred for 1 h 30 min, then diluted with ethyl acetate. Then separated from the corresponding organic phase is washed with water, you silicagel column, elution with a mixture of cyclohexane and ethyl acetate in the ratio 3:2, receive 1.2 g of product.

So pl.: 118-120oC.

[]2D0= +76,7(C = 1; dichloromethane)

In accordance with the specified method will have the following connections:

- [3(S), 3A(R)] -(-)-7-Benzyloxy-3-methoxymethyl-and 3,3,4,5 - tetrahydro-1H-oxazol[3,4-a]quinoline-1-it.

So pl.: 99oC.

[]2D0= -2,2.

- [3(R), 3A(S)] -(+)-7-Benzyloxy-3-methoxymethyl-and 3,3,4,5 - tetrahydro-1H-oxazol[3,4-a]quinoline-1-it.

So pl.: 96-98oC.

[]2D0= +1,1.

- [3(R), 3A(R)] -(-)-7-Benzyloxy-3-methoxymethyl-and 3,3,4,5 - tetrahydro-1H-oxazol[3,4-a]quinoline-1-it.

So pl.: 122oC.

[]2D0= -74.

15.4. [3(S),3A(S)]-(+)-7-Hydroxy-3-methoxymethyl-and 3,3,4,5 - tetrahydro-1H-oxazolo[3,4-a]quinoline-1-he

A solution of 1.2 g (0,0035 M) [3(S),3A(S)]-(+)-7-benzyloxy-3-methoxymethyl-3,3 a, 4,5 - tetrahydro-1H-oxazolo-[3,4-a] -quinoline-1-it is within 5 h are gidrogenizirovanii in 50 ml of methanol and 40 ml of tetrahydrofuran at an elevated pressure and ambient temperature, in the presence of 0.25 g of 10% palladium-carbon catalyst containing 50% water. Then the product.

So pl.: 172-176oC.

[]2D0= +99(C = 1; dimethyl sulfoxide).

In accordance with the specified method will have the following connections:

- [3(S),3A(R)]-(+)-7-Hydroxy-3-methoxymethyl-and 3,3,4,5 - tetrahydro-1H-oxazol[3,4-a]quinoline-1-it.

So pl.: 170oC.

[]2D0= +11,1.

[3(R), 3a(S)] -(-)-7-Hydroxy-3-methoxymethyl-and 3,3,4,5 - tetrahydro-1H-oxazol[3,4-a]quinoline-1-it.

So pl.: 166oC.

[]2D0= -8,2.

- [3(R),3A(R)]-(-)-7-Hydroxy-3-methoxymethyl-and 3,3,4,5 - tetrahydro-1H-oxazol[3,4-a]quinoline-1-it.

So pl.: 180oC.

[]2D0= -93,3.

15.5. [3(S), 3a(S),7(S)]-(+)-3-methoxymethyl-7-[4,4,4-Cryptor - 3-hydroxybutane]-3,3 and,4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline-1-he

Using as starting substances 0,86 g (3.45 mm) [3(S),3A(S)]-(+)-7-hydroxy-3-methoxymethyl-and 3,3,4,5 - tetrahydro-1H-oxazolo[3,4-a]quinoline-1-she and 1.54 g (5,18 mm) 4,4,4-Cryptor-3(S)-hydroboil p-toluensulfonate handle these reagents under the conditions described in Stage 4 of Example 5, with the receipt of 0.38 g of the product in the form of oil.

[]2D0= +33,2(C = 1; methanol).

Item is authorized in the Table below.

Provided by the present invention compounds have been the target of pharmacological studies have confirmed the ability of these compounds to inhibit the activity of monoamine oxidase a and monoamine oxidase Century

Measurement of the activities of MAO-a and MAO-b were performed in the in vitro system, using the homogenate of rat brain as the source of enzyme (Fowler C. and Strolin-Benedetti M. in J. Neurochem. 40: 1534-1541 (1983)).

The standard test consists in the following: the rat brain homogenized in 20 volumes of 0.1 M phosphate buffer (pH 7,4) and preincubated 100 ml of homogenate (5 mg tissue) at a temperature of 37oC for 20 min in the absence or in the presence of different concentrations of the studied inhibitor. The corresponding reaction of the launch, adding [14C] serotonin ([14C]5HT, the final concentration of 125 μm) for measuring the activity of MAO-a or [14C] phenyl-ethylamine ([14C]PEA, the final concentration of 8 μm) for measuring the activity of MAO-b, in the final volume of 500 ál. After 5 min of incubation in the case of [14C]NT or after 1 min in the case of [14C] PEA indicated the reaction was stopped by adding 200 μl of 4n hydrochloric acid. Then the corresponding radioactive metabolites resulting from oxidative desmineralizacion the light of these metabolites by measuring the radioactivity.

The inhibitory activity shown against MAO-a and MAO-b, represented in the form of inhibition constants KI (MAO-a) and KI (MAO-b).

In the case of compounds provided by the present invention, the value of KI (MAO-A) is in the range from 0.4 to 28 nm, while the value of KI (MAO-b) varies from 0.7 to 1000 nm.

Some compounds provided by the present invention are selective inhibitors of MAO-a, which is possible if the ratio KI(MAO-A) / KI (MAO-b) is in the range from 10 to 1000. Meanwhile, the rest of these compounds are inhibitors of both MAO-a and MAO-b, which occurs when the ratio KI (MAO-A) / KI (MAO-b) in the range from 0.1 to 10.

The ability to inhibit MAO activity was also demonstrated in vivo in the test for enhancing the action of L-5-hydroxytryptophan (L-5HTP) (Jalfre M. , et al., Arch. Int. Pharmacodyn 259: 194-221 (1982)).

The specified test was carried out as follows: the parties rats (10 animals per dose) orally was administered different doses of the investigational product or media, and after 60 min was carried out by intraperitoneal injection of L-5HPT at a dose of 100 mg/kg, which itself does not cause serotoninergicheskie with the do nothing after 30 min after application of L-5HTP. The results obtained for each dose of investigational product, expressed as the percentage of animals, which saw a General convulsions. Then, based on the relationship between effect (percentage characterizing each dose) and the logarithm of the appropriate dose, using the linear regression was determined by the dose at which the total seizures are observed in 50% of animals (ED50) and its 95% confidence interval.

In the case of compounds provided by the present invention, the value of the ED50is in the range from 0.2 to 1.1 mg/kg, which confirms the ability of these compounds to inhibit the activity of MAO in vitro.

In addition, according to the evaluation of their toxicity after in vitro against the hepatocytes of rats and non-human primates single application, provided by the present invention compounds are very well tolerated within the investigated range of doses (up to 100 µm).

The results indicate that provided by the present invention compounds can be used for the production of drugs exhibiting selective inhibitory ability against MAO-a or the inhibitory ability of the military in the treatment of depressive States, panic attacks, phobias, anxiety, migraine, age-related mental disorders, or dementia, as well as in the prevention or treatment of neurodegenerative diseases such as Parkinson's and Alzheimer's disease, and strokes.

Provided by the present invention compounds can be used in combination with the excipients in the form of compositions intended for oral, parenteral or rectal use, for example, in the form of tablets, coated tablets, capsules, solutions, suspensions or suppositories. In the case of oral administration a daily dose of the input of the active ingredient may be varied within the range from 1 to 100 mg/kg as a single dose or multiple doses. When parenteral and rectal use this dose may be in the range from 1 to 100 mg/kg

The applicant provides the following examples of pharmaceutical composition according to p. 12, in which the active substances are used the compounds according to the invention.

Injection

Active substance 5 mg

Glucose is 250 mg

Water for injection - SC. treb. to 5 ml in one ampoule of 5 ml

The active substance and glucose are dissolved in water for injection, p is/BR> Active ingredient 100 mg

Talc - 24 mg

Silica gel per capsule 125 mg 1 mg

Finely ground active ingredient is thoroughly mixed with talc and silica gel and the obtained mixture is filled gelatin capsules.

Tablet

Active substance - 400 mg

Silica gel 10 mg

Stearic acid - 20 mg

Corn starch at one tablet at 475 mg - 45 mg

The active ingredient is thoroughly mixed with other ingredients, the mixture is pressed into tablets of the desired shape and size.

Syrup

The active substance is 5 grams

Methyl ester of 4-hydroxybenzoic acid - 150 mg

Sucrose is 50 mg

Distilled water - SK. treb. to 100 mg per one vial 100 ml

Sucrose is dissolved in water, add the active substance and the methyl ester of 4-hydroxybenzoic acid and the resulting syrup is poured into vials.

1. Derivatives of 3,3 a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline-1-it is responsible of General formula I

< / BR>
in which n is 0 or 1;

R1represents a hydrogen atom or atenilol, methyl, ethyl, phenyl, hydroxymethylene or methoxymethyl group, and

or R2denotes methyl, tchup, and

R4and R5are hydrogen atoms, provided that if R2is stands, R3is not hydrogen, or R2and R4together form a group -(CH2)4-, R3represents a hydroxyl group, and R5denotes a hydrogen atom, or R2and R5together form a group-O-(CH2)3-, and R3and R4are hydrogen atoms; or R2and R5together form a group -(CH2)4-, R3corresponds to the hydroxyl group, and R4represents a hydrogen atom,

in the form of isomers, including in the form of enantiomers and diastereoisomers, as well as mixtures of these various forms, including racemic mixtures.

2. Derived under item 1, characterized in that it is a 3-methoxymethyl-7-(4,4,4-Cryptor-3-hydroxyethoxy)-3,3 a, 4,5-tetrahydro-1H-oxazolo[3,4-a] quinoline-1-he, as well as its enantiomers and diastereoisomers, in pure form or in the form of mixtures.

3. Derived under item 1, characterized in that it is a 3-methoxymethyl-7-(4,4,4-triptoreline)-3,3 a,4,5-tetrahydro-1H-oxazolo[3,4-a] quinoline-1-he, as well as its enantiomers and diastereoisomers, in pure form or is XI)-3,3 a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline-1-it, and its enantiomers in pure form or in the form of mixtures.

5. Derived under item 1, characterized in that it is a 7-(3-hydroxy-4,4,4-triptoreline)-3,3 a, 4,5-tetrahydro-1H-oxazolo[3,4-a] quinoline-1-he, as well as its enantiomers and diastereoisomers, in pure form or in the form of mixtures.

6. Derived under item 1, characterized in that it is a 3-methoxymethyl-7-[2-(1-hydroxycyclopent)ethoxy] -3,3 a, 4,5-tetrahydro-1H-oxazolo[3,4-a] quinoline-1-he, as well as its enantiomers and diastereoisomers, in pure form or in the form of mixtures.

7. The method of obtaining the compounds corresponding to the formula I, characterized in that the compound described by formula II

< / BR>
in which R1represents a hydrogen atom or atenilol, phenyl, hydroxymethylene or methoxymethyl group

is treated with a compound corresponding to the formula III

< / BR>
in which X denotes a halogen atom or a labile group such as mesilate or tailorshop,

obtaining compounds corresponding to the formula I, in which R1corresponds to the above signs, then restore the specified connection, described formula1represents an ethyl group.

8. The method according to p. 7, designed to obtain the enantiomers and diastereoisomers compounds corresponding to the formula I, characterized in that as starting substances are used, the corresponding isomers of the compounds described by formula II.

9. The method according to p. 7, characterized in that the enantiomers and diastereoisomeric compounds corresponding to the formula II, obtained from the enantiomers or diastereomers of the compounds described by formula IV

< / BR>
or V

< / BR>
where R1means atenilol, methyl or phenyl groups, for which carry out the enzymatic hydrolysis of ethyl 2-methoxycarbonyl-6-methoxy-1,2,3,4-tetrahydroquinolin-1-carboxylate, using the extraction of share S(-) enantiomer of ethyl 2-methoxycarbonyl-6-methoxy-1,2,3,4-tetrahydroquinolin-1-carboxylate and R(+) enantiomer of ethyl 2-carboxy-6-methoxy-1,2,3,4-tetrahydroquinolin-1-carboxylate, treated with R(+) enantiomer ethyl 2-carboxy-6-methoxy-1,2,3,4-tetrahydroquinolin-1-carboxylate thionyl chloride and methanol to obtain the corresponding 2-methoxycarbonylamino derived and S(-) and R(+) enantiomers of the specified 2-methoxycarbonylamino derived lead in the interaction or formulas IV, or hydride diisobutylaluminum, resulting in a gain, respectively, of S(-) and R(+) enantiomers of the corresponding 2-fomilenio derived, the enantiomers of 2-formyl derivative process organomagnesium compound described by the formula R1MgX, where R1such as defined above, and X is a halogen atom, and then with sodium methoxide, followed by separation using chromatography, resulting in getting these diastereoisomeric compounds corresponding to the formula V.

10. The method according to p. 8, designed to obtain the enantiomers of ethyl 2-methoxycarbonyl-6-methoxy-1,2,3,4-tetrahydroquinolin-1-carboxylate, wherein the enzymatic hydrolysis is carried out using enzyme extracts, such as esterase pig liver, or acetone powders liver horse, pig, ox, rabbit or sheep.

11. Medicine, exhibiting selective inhibitory activity against MAO-a or inhibitory activity against MAO-a and MAO-b, characterized in that it consists of compounds corresponding to the formula I under item 1.

12. The pharmaceutical composition exhibiting selective inhibitory activity against MAO-a or and the surrounding formula I on p. 1, in combination with any acceptable excipients.

Priority signs

04.09.95 R1is a hydrogen atom, a methyl, ethyl or phenyl group; R2and R3together form a group-O-(CH2)3-, and R3and R4are hydrogen atoms, or R2and R5together form a group -(CH2)4-, R3corresponds to the hydroxyl group, and R4represents a hydrogen atom;

05.09.94 other features in the claims

 

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3 ex

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