RU1838313C - Method of synthesis of spirocompound azolone or its n-oxide derivative or its basic salt with pharmacologically usable cation - Google Patents

Abstract

Usage: as aldose reductase inhibitors to regulate some chronic conditions associated with diabetes. SUMMARY OF THE INVENTION: the product is a spiro compound of azolone of the form N O where X is H, F, Cl, Br; R is H, C1 C4 alkyl, or its N-oxide derivative or its base salt with a pharmacologically applicable cation. Reagent 1: compound f-ly O N O Reagent 2: alkali metal cyanide. Reagent 3: ammonium carbonate. Reaction conditions: in an inert polar organic solvent at 40-90 ° C. 5 zpp-fs, 2 tab. ate with

Description

The invention relates to a method for producing new biologically active compounds, and specifically to a method for producing a spiro compound of an azolone of formula I

Vnh

SC

N about to

where X is H, F, Cl, Br; R is H, C1-C4-alkyl, or its N-oxide derivative or its basic salt with a pharmacologically applicable cation, which has the ability to inhibit aldose reductase, which suggests the possibility of using it in therapy to treat some chronic complications associated with diabetes.

The purpose of the invention is the synthesis of new compounds superior in activity to a structural analogue.

This goal is achieved by a method based on the known reaction 1 for the preparation of a spiro compound of an azolone of formula I or an N-oxide derivative or a basic salt thereof thereof with a pharmacologically applicable cation, in which a suitably substituted carbonyl ring compound of the formula IIO

€ j &

N about

R

s

where X and R have the indicated meanings, are condensed with alkali metal cyanide and ammonium carbonate and the resulting compound of formula I, where X is F, CI or Br, if necessary, is converted by dehalogenation to the compound

formula I, wherein X is H or, if necessary, compounds of formula I are oxidized to produce the corresponding N-oxide derivative and, if desired, the compound of formula I is converted to a basic salt with a pharmacologically applicable cation.

Preferably, the condensation is carried out at least with a small molar excess of both alkali metal cyanide and ammonium carbonate with respect to the compound of formula II.

Preferably, the condensation is carried out in the presence of an inert polar organic solvent at 40-90 ° C. A lower alkanoamide containing 1-4 carbon atoms is used as an inert polar organic solvent.

Preferably, the dehalogenation of the compound of formula I is carried out by hydrogenolysis using a catalytic hydrogenation method. Oxidation of the compound of the formula in its M-oxide derivative is carried out with a 30% aqueous solution of hydrogen peroxide in an acid solvent at 80-90 ° C.

The following examples illustrate the invention.

Synthesis of starting compounds.

PRI me R getting A.

A stirred suspension of 35 g (0.22 mol) of 2-chloronicotinic acid (obtained from Lonza Inc. Fire Laun, NJ) in 400 ml of methanol was treated with 25.4 g (0.47 mol) of sodium methylate, which was added to portion system. Then stirring is continued until a clear solution is formed. Thereafter, the liquid reaction mixture was transferred to a steel autoclave and heated at 125 ° C for about 16 hours (overnight). After completing this step, the resulting reaction mixture was cooled to room temperature (20 ° C), filtered, and the filter cake was washed with methanol. Then, the combined organic filtrate and methanol washings were concentrated in vacuo to give a white solid, which was then dissolved in water. In the resulting aqueous solution, pH 3 was adjusted with 6 N. hydrochloric acid and is immediately filtered to remove (i.e., regenerate) the precipitated solid product, which is then dried in air (to constant weight) for about 16 hours (overnight). Using this method, 21.8 g (64% of pure 2-methoxynicotinic acid, mp 147-149 ° C .; (according to D.E. Kuehl et al., Given in US Pat. No. 3,879,403,

0

5

5

0

0

5 5

0

5

0

so pl. 144-146 ° C). The pure product is further characterized by NMR.

Production Example B.

In a reaction flask equipped with a mechanical stirrer and a refrigerator with dry ice, 25.5 g (0.166 mol) of 2-methoxynicotinic acid (the product from Example A) and 1500 ml of water are placed. Stirring is started and chlorine gas is bubbled through the resulting suspension until saturation with this gas is complete. This step is carried out for 30 minutes. Thereafter, the reaction mixture was stirred at room temperature (20 ° C) for about 16 hours (overnight) and then filtered to remove the crude product. The resulting material was washed with water and dried in air before being transferred to chloroform. Then, the chloroform solution was washed with saturated brine and dried over anhydrous magnesium sulfate. After removing the drying agent by filtration and the solvent by evaporation under reduced pressure, 26.2 g (84%) of pure 5-chloro-2-methoxy-nicotinic acid are obtained as a white solid, mp. 149-151 ° C (in accordance with the data of D.E. Kuehla et al. In US Pat. No. 3,879,403 mp 149-150 ° C). The pure product is further characterized by NMR analysis.

For example, C.

217 g (1.42 mol) of 2-methoxy-nicotinic acid (the product of Example A) are added portionwise to 2.5 L of a well-mixed 5% aqueous solution of sodium hypochlorite (Clorox) at 10 ° C, and sufficient cooling is used. in order to maintain the temperature of the reaction mixture in the addition step below 28 ° C. After completing this step, the resulting mixture was cooled with stirring to room temperature (20 ° C) for about 16 hours (overnight) and then acidified to pH 2.0 with concentrated hydrochloric acid. Then, the precipitated solid product is collected by suction filtration and then treated with two portions of 50 ml hexane and then dried under high vacuum to obtain 201 g (75%) of pure 5-chloro-2-methoxy sinicotinic acid. This product is in all respects identical to the product of Example B, as confirmed by NMR.

Production Example D.

A mixture of 100 g (0.533 mol) of 5-chloro-2-methoxycinnicotinic acid (product of Example C) suspended in 500 ml of methanol containing approximately 3.0 ml of concentrated sulfuric acid was stirred and refluxed for 3 hours in a 1 L round bottom reaction flask. After completing this step, the reaction mixture is cooled to room temperature (20 ° C.) with stirring and then stirred overnight at ambient temperature for about 16 hours. The precipitated crystalline product is isolated from the reaction mixture by suction filtration and thereafter. the collected crystals were washed with fresh methanol to obtain 59.5 g (55%) of pure methyl 5-chloro-2-tags of synicotinate, mp. 86-87 ° C. A second batch containing 18.4 g (17%) of the same pure product was obtained from the mother liquor. The total yield of pure product is 72% of theory. The pure product is further characterized by NMR analysis.

Production Example E.

In a three-necked round-bottom reaction flask equipped with a mechanical stirrer and a nitrogen supply tube, 63.0 g (0.312 mol) of methyl 5-chloro-2-methoxynicotinate (product from Example D) are placed in 300 ml of dry tetrahydrofuran, in a nitrogen atmosphere, after whereupon 27.9 ml (0.373 mol) of acetone and 20.1 g (0.373 mol) of sodium methylate are added to the system with constant stirring, which is carried out during the entire addition step. Then, the resulting reaction mixture was stirred at room temperature (20 ° C) for about 20 hours, after which it was filtered through a glass funnel with a glass filter of 25-50 μm. After washing the filtered product with 100 ml of ethyl acetate and drying in vacuo to a constant weight, 72.65 g (92%) of 3-acetonylcarbonyl-5 chloro-2-methoxypyridine are obtained in the form of the sodium salt, which is a white non-hygroscopic powder, t .pl. 250 ° C.

Production Example F

A solution consisting of 44.5 g (0.177 moles) of the sodium salt of 3-acetonylcarbonyl-5-chloro-2-methoxypyridine (product of Example E) dissolved in 650 ml of glacial acetic acid was placed in a reaction flask and heated to 100 ° C in an oil bath having a temperature of 115 ° C. 65 ml of 48% hydrobromic acid are added to the hot solution, and the temperature of the oil bath is increased from 115 to 130 ° C. Then the reaction mixture is stirred for 15 minutes, the position of the bath is adjusted so that the internal temperature of the reaction mixture to the end

the heating step is 100 ° C. After completion of this step, the reaction mixture is rapidly cooled in an ice bath to 24 ° C, then poured into 2 L of ice water. The resulting aqueous solution was then extracted with three portions of 250 ml of methylene chloride and the combined organic layers were washed successively with two 250 ml portions of water and then with a 2% sodium hydroxide aqueous solution (250 ml each) until the aqueous layers were alkalized. After drying the washed organic layer over anhydrous magnesium sulfate and Filtration to remove the drying agent, the reaction product is isolated from the clear filtrate by concentration in vacuo to give 19.3 g (56%) of pure 8-chloro-2-methyl-4H-pyrano ( 2,) pyridin-4-one. The pure product is characterized by NMR analysis.

Preparative example G.

A stirred mixture of 15.0 g (0.0767 mol) of b-chloro-2-methyl-4H-pyreno (2,) pyridin-4-one (the product from Example F), suspended in 250 ml of tetrahydrofuran, is cooled to -72 ° C in a dry ice bath having a temperature of -78 ° C. To the chilled mass, 3.06 g (0.080 mol) of lithium aluminum hydride was added over a 10 minute period. After completing this step, the resulting mixture was stirred at -78 ° C (bath temperature) for 14 hours. After that, 19.5 ml of glacial acetic acid (4.44 equivalents) dissolved in 25 ml of tetrahydrofuran was added to the stirred the mixture for 15 minutes, during which time the temperature inside the bath is kept below -45 ° С during the entire addition period. Then the reaction mixture is cooled to -70 ° С, then poured into 1 liter of cold water and then extracted with three 300 ml portions mi diethyl ether. After washing the combined organic extracts successively with water (500 ml), 2% sodium hydroxide solution (200 ml) and again with water (2 x 200 ml), the organic solution was dried over anhydrous magnesium sulfate and filtered.

By evaporation of the clear filtrate under reduced pressure, 7.51 g (50%) of pure 6-chloro-2,3-dihydro-2-methyl-4H-pyrano (2,) pyridin-4-one, mp. 84-8b ° C. This pure product is further characterized by mass spectroscopy and NMR.

Preparative Example H

In a dry three-necked round-bottom flask with a capacity of 2 l, equipped with a thermometer,

with a mechanical stirrer and a dropping funnel, 25.13 g (0.128 mol) of 6-chloro-2-methyl-4H-pyrano (2,) -pyridin-4-one (the product from Example F) is placed. Then, a solution containing 615 ml of methylene chloride and 154 ml of tetrahydrofuran is added from a dropping funnel. The resulting solution is stirred and then cooled in a bath of dry ice in acetone, maintaining the internal temperature below -70 ° C. Thereafter, 166 ml of a 1 M solution of diisobutylaluminium hydride (0.166 mol) in toluene was gradually added to the cooled solution from the dropping funnel. This step is carried out for 20 minutes and during this time there is a slight exothermic increase in temperature (about 5 ° C). After stirring for 4 hours in a 78 ° C bath, the reaction was stopped by adding 15.04 g (0.250 mol) of glacial acetic acid dissolved in 15 ml of tetrahydrofuran. After the upper reaction mixture was gradually warmed to room temperature (about 20 ° C), it was poured into 1 liter of water and the resulting aqueous layer was acidified to pH 2.0 by adding dilute hydrochloric acid.

Then, these two layers were separated and the separated aqueous layer was extracted with 500 ml of methylene chloride. Then, the combined organic layers were dried over anhydrous magnesium sulfate and filtered, and the resulting filtrate was evaporated in vacuo to give 23.42 g (93%) of pure 6-chloro-2,3-dihydro-2-methyl-4H-pyra - but (2,) pyridin-4-one in the form of a light brown solid. The product obtained is in all respects identical to the product of Example C, which was further confirmed by NMR data.

Preparative example. To a 1 L round-bottom reaction flask containing a well-stirred suspension of 4.5 g (0.0294 mol) of 2-methoxynicotinic acid (product from Example A) in 500 ml of distilled water, 4.7 g (0, 0294 mol) of bromine in one portion (i.e. immediately) and then the resulting mixture was stirred at room temperature for about 16 hours (overnight). After completing this step, the pale yellow suspension is filtered off and the separated solid product is dried in air on a funnel filter to form 4.64 g of crude material in the form

light yellow solid. Recrystallization of this substance from ethyl acetate gave 3.47 g (51%) of pure 5-bromo-2-methoxynicotinic acid (mp 158-160 ° C) in the form of flocculent white needles. Then the pure product is characterized by NMR data.

Preparative example J.

Into a 50 ml round bottom reaction flask equipped with a stirring core and reflux condenser were added 1.0 g (0.0043 mol) of 5-bromo-2-methoxynicotinic acid (the product of Example I) and 10 ml of methanol, after which was added 50 ml of concentrated sulfuric acid. The resulting reaction mixture was heated under reflux for about 16 hours (overnight). After completion of this step, the mixture was cooled to room temperature (about 20 ° C) and filtered, and the precipitate was dried to constant weight to obtain 695.8 mg (66%) of pure methyl 5-bromo-2-methoxynicotinate (mp. 90-101 ° C) as a flocculent white solid. Further, the pure product is further characterized by NMR data.

Preparative example K.

2.1 g (0.00795 mol) of methyl 5-bromo-2-methoxynotinate (product from Example J) are placed in a 25 ml dry three-necked round-bottom flask equipped with a nitrogen inlet tube, a rubber wall and a glass stopper. , 700 μl (0.00954 mol) of acetone and 15 ml of dry tetrahydrofuran, after which 515.3 mg (0.00954 mol) of dry sodium methylate are added in a portion of a dry nitrogen stream, with a constant throughout the addition stage stirring the system, then the resulting reaction mixture is stirred at room temperature (about 20 ° C) for about 16 hours (overnight), followed by filtration to remove the precipitated product. As a result, after drying under high vacuum, 1.72 g (73.5%) of 2-acetonylcarbonyl-5-bromonicotinate are obtained in the form of a sodium salt in the form of a white solid.

Preparative example L.

1.72 g (0.00585 mol) of sodium salt 2-acetone or carbon-il-5 are placed in a 100 ml three-necked one-reaction flask equipped with a magnetic stirrer, reflux condenser, nitrogen inlet tube, glass stopper and rubber partition. -bromnicotinate (product from freeze K) dissolved in 25 ml of glacial acetic acid (all operations

in a stream of dry nitrogen). Then, the flask with the contents is immersed in an oil bath preheated to 100 ° C.

After 5 minutes, 2.5 ml of 48% hydrobromic acid was added via syringe and the reaction mixture was stirred at 100 ° C for 30 minutes. After completing this step, the mixture is rapidly cooled to room temperature (about 20 ° C) in an ice bath and diluted with 25 ml of water. The resulting aqueous solution was extracted with three portions of 20 ml of chloroform, and the combined organic layers were washed successively with two portions of 10 ml of 0.5 N, an aqueous solution of sodium hydroxide, 10 ml of water and 10 ml of brine. After drying the aqueous organic layer over anhydrous magnesium sulfate and filtering to remove a drying agent, the reaction product is isolated from the clear filtrate by concentration in vacuo to give 880 mg (63%) of pure b-bromo-2-methyl-4H-pyrano ( 2,) pyridin-4-one as a yellow solid. The pure product is characterized by NMR data.

Preparative example M,

In a three-necked round bottom flask equipped with a magnetic stirrer, a nitrogen inlet tube and a glass stopper with a capacity of 35 L, 116.1 mg (0.00305 mol) of lithium aluminum hydride and 3.0 ml of dry tetrahydrofuran were placed under dry nitrogen atmosphere. Then, the resulting suspension was cooled to -78 ° C with stirring, after which 700 mg (0.00291 mol) of 6-bromo-2-methyl-4H-pyrano (2,) pyridin-4-one was carefully added ( the product from Example L) in TO ml of tetrahydrofuran, the addition being carried out by pinning.

After completion of this step, the resulting reaction mixture was stirred at −78 ° C for approximately 16 hours. After this, 721 µl of glacial acetic acid was added to the stirred solution, and the upper mixture was further stirred at −78 ° C for 10 minutes. After adding a 10 ml saturated aqueous solution of sodium potassium tartrate and 10 ml methylene chloride, the cooled mixture was stirred at room temperature (about 20 ° C) for 3 hours and then filtered to remove the yellow solid. The resulting filtrate was stored and the methylene chloride layer was separated from it, followed by washing with water (1 x 10 ml) and brine (1 x 10 ml) and then drying over anhydrous magnesium sulfate. After removal of the drying agent by filtration and the solvent by evaporation under reduced pressure, 467.3 mg of crude product are obtained as a yellow solid. Then carry out additional cleaning method

column chromatography using a column of alumina (20 mm x 175 mm) and a 30% solution of ethyl acetate in hexane as eluent, taking 5 ml samples. The result is 185.8 mg

0 (26%) pure 6-bromo-2,3-dihydro-2-methyl-4-H-pyrano (2,3-b) pyridin-4-one as a pale yellow solid. The pure product is further characterized by NMR data.

5 Preparative example N.

In a three-necked round-bottom reaction flask equipped with a mechanical stirrer and a nitrogen inlet tube, 17.13 g (0.085 mol) of methyl 5-chloro 2-methoxy nicotinate (product of freeze D) and approximately 100 ml of dry tetrahydrofuran in a nitrogen atmosphere were placed, followed by thereto are added 12.5 ml (0.1275 mol) of ethyl acetate (1.5 equivalents) and 6.0 g (0.1105) of sodium metmlat

5 (1.3 equivalents) with constant stirring throughout the entire addition step. The resulting reaction mixture was refluxed for 3 hours, after which 6 ml was added.

0 (0.061 mol) of ethyl acetate and 3.0 g (0.05525 mol) of sodium methylate. After stirring the final reaction mixture at reflux for 6 hours and then cooling to room temperature

5 temperature (about 20 ° C) it is filtered through a funnel with a sintered glass filter with a hole size of 25-50 microns and the separated solid is dissolved in 100 ml of water and acidified to pH 1.0. Water

The 0 layer was extracted with two 50 ml portions of diethyl ether and the combined ether extracts were dried over anhydrous magnesium sulfate and filtered. After removal of the drying agent by filtration and the solvent by evaporation under reduced pressure, 11.73 g (57%) of pure 5-chloro-3-methoxycarbonyl-cetyl-2-methoxypyridine, m.p. 59-61.5 ° C. The pure product is additionally characterized by NMR data.

Preparative Example O. Mixture of 755 g (0.003125 mol) of 5-chloromethoxy-carbonylacetyl-2-methoxypyridine (product of Example N) in 10 ml

5 1 n. an aqueous solution of sodium hydroxide is heated under reflux for 1 hour and then stirred for 16 hours at room temperature. After completion of this step, the stirred reaction mixture is acidified to pH 1.0 s

using 1 n. hydrochloric acid and then extracted with three portions of 15 ml of methylene chloride. The combined organic layers were washed successively with a 2% aqueous bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration and the solvent by evaporation under reduced pressure, 580 mg (71%) of pure 3-acetyl-5-chloro-2-methoxypyridine are obtained as a yellow oil. The pure product is characterized by NMR data.

Preparative example R.

8. A three-necked round-bottom reaction flask equipped with a mechanical stirrer and a nitrogen inlet tube, was charged with 4.60 g (0.0248 mol) of 3-acetyl-5-chloro-2-methoxypyridine (product of Example O) in 50 ml of dry tetrahydrofuran, operation step in a stream of nitrogen followed by the addition of three equivalents (6.0 ml) of ethyl formate and 1.2 equivalents of 50% sodium hydride (1.43 g), the latter substance being added in portions with constant stirring during all stages of addition. The resulting mixture was stirred at room temperature (about 20 ° C.) for about 64 hours, followed by filtration through a funnel filter with a hole size of 25-50 microns. After washing the filtered product with 20 ml of ethyl acetate and vacuum drying to constant weight, 5.37 g (94%) of 3-formylmethylcarbonyl-5-chloro-2-methoxypyridne are obtained in the form of a sodium salt in the form of a light yellow powder, mp . above 250 ° C.

Preparative example Q.

A solution containing 5.37 g (0.233 mol) of the sodium salt of 3-formylmethylcarbonyl-5-chloro-2-methoxypyridine (product from Example P) .. dissolved in 73 ml of glacial acetic acid was stirred at 100 ° C in a reaction flask and then treated with 7.3 ml of 48% hydrobromic acid at the same temperature. The resulting reaction mixture was stirred at 100 ° C. for 15 minutes and cooled to room temperature (approximately 20 ° C.) in an ice bath. After completing this step, the cooled mixture is poured into 100 ml of water and then extracted with three portions of 50 ml of methylene chloride. The organic extracts are then combined and washed successively with 50 ml of a 2% aqueous sodium hydroxide solution and 50 ml of water, followed by drying with anhydrous magnesium sulfate. After removal of the drying agent by filtration and the solvent by evaporation

under reduced pressure, 1.70 g (40%) of pure 6-chloro-4H-pyrano (2,) pyridin-4-one is obtained as the final product. Pure product characterized by data

NMR

Preparative Example R. To a stirred solution of 1.0 g (0.0055 mol) of 6-chloro-4H-pyrano (2,) pyridin-4-one (product about Q) in 18 ml

tetrahydrofuran and 36 ml of toluene at -78 ° C, a 6.0 mm 1 M solution of diisobutylaluminum hydride in toluene was added. The resulting mixture is stirred at −78 ° C. for 2.5 hours. After completion

In this step, the reaction is stopped by adding 0.51 ml of glacial acetic acid dissolved in 3 ml of tetrahydrofuran. After gradually cooling the upper reaction mixture to room temperature

temperature (about 20 ° C) it is poured into 100 ml of water and the resulting aqueous layer is acidified to pH 2.0 by adding dilute hydrochloric acid. Then, these two layers were separated and the separated aqueous layer was extracted twice with 75 ml portions of methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate and filtered, and the resulting filtrate was evaporated in vacuo to give 715 mg (71%) of pure 6-chloro-2,3-dihydro-4H-pyrano (2,) pyridin-4-one in the form of a solid product (mp. 120-123 ° C). The pure product is further characterized by NMR data,

Preparative Example S. The procedure described in Preparative Example D was repeated to prepare methyl l-5-chloro p-2-methoxy nicotine.

with the exception that 2-methoxynicotinic acid (see US Pat. No. 3,879,403 to Kühl et al.) is used as starting material instead of 5 op-2-methoxy nicotinic acid while maintaining molar ratios. In this case, the corresponding end product is 2-methoxy nicotinate (identical to the compound described by Kitagawa et al. In Chem. Pharm. Bull, vol. 26, p. 1403.1978).

Preparative example T.

A stirred solution of 8.6 g (0.050 mol) of methyl 2-methoxy nicotinate (product of example S). dissolved in 25 ml of trifluoroacetic anhydride, treated

6.0 g (0.075 mol) of ammonium nitrate, which is added in portions. After completing this step, the resulting mixture was stirred at room temperature (about 20 ° C) for 2 hours and then poured into 30 ml of a mixture of ice water. The resulting yellow crystals are collected by suction filtration and then dissolved in chloroform. The aqueous layer was separated and the resulting organic solution was dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration and the solvent by evaporation under reduced pressure, 6.5 g (60%) of pure methyl 5-nitro-2-methoxynicotinic acid (mp. 98-99 ° C) are obtained as the remaining material. The pure product is characterized by NMR data.

Preparative example U.

A mixture containing 1.08 g (0.005 mol) of methyl 5-nitro-2-methoxynicotinate (the product of Example T) and 5.64 g (0.0025 mol) of tin chloride dihydrate in 10 ml of ethyl acetate is heated to reflux refrigerator for 20 minutes. After completing this step, the resulting mixture was poured into 50 ml of ice water and treated with sodium bicarbonate to establish a pH of 7.0. Then, the resulting aqueous solution was extracted with three portions of 50 ml of ethyl acetate, and the combined organic extracts were washed with 50 ml of water and then dried. T over anhydrous magnesium sulfate. After removal of the drying agent by filtration and the solvent under reduced pressure, 800 mg (86%) of pure methyl 5-amino-2-methoxynicotinate (mp. 109-110.5 ° C) are obtained as the remaining material. The pure product is characterized by NMR data.

Preparative example V.

A stirred solution containing 1.5 g (0.00806 mol) of methyl 5-amino-2-methoxynicotinate (product from Example U) was dissolved in 25 ml of ethanol and treated with 12 ml of a 23% hydrofluorosilicic acid solution. Then, the resulting reaction mixture was cooled with ice, and the white salt product was collected by suction filtration. The brine is then suspended in 25 ml of glacial acetic acid and the required amount of butyl nitrate is added by pinning so that the salt is completely dissolved. The resulting solution was then diluted with 40 ml of diethyl ether and cooled to 0 ° C. Then, the desired diazonium salt, which is separated as an oil, is collected and suspended in 20 ml of ethanol to form a new harder salt. This solid is collected by suction filtration (under nitrogen), washed with three portions (10 ml) of diethyl ether and dried in deep

vacuum to obtain 550 mg (20%) of 3-carbo-methoxy-2-methoxypyridin-5-diazoniumhydrohexafluorosilicate, so pl. 124-127 ° C (decomposition).

Then, the above diazonium salt (550 mg, 0.0016 mol) is suspended in 10 ml of xylene and heated in an oil bath at 130 ° C, after which the nitrogen transfer is stopped and the reaction mixture becomes oily. Then the temperature of the bath was raised to 140 ° C and heating of the mixture was continued for another 15 minutes. After completion of this step, the reaction mixture is cooled to room temperature (about 20 ° C) and then filtered through a glass wool filter. After concentrating the resulting filtrate almost to dryness under reduced pressure, 293 mg of the desired 5-fluorine compound are obtained. Further purification of the product was carried out by radial chromatography on silica gel using a 15% mixture of ethyl acetate in hexane as the eluent, to give 210 mg (68%) of pure methyl 5-fluoro-2-methoxynicinate. The total yield of pure product based on the starting 5-amino-2-methoxynicotinate was 14% of theory. The pure product is characterized by NMR data.

Preparative Example W.

A stirred solution containing 2.0 g (0.0106 mol) of methyl 5-fluoro-2-methoxynicotinate (product from Example V) dissolved in 20 ml of dry tetrahydrofuran is treated with 0.91 ml of acetone (1, 3 equivalents) and 670 mg of dry sodium methylate (1.3 equivalents), which are added in one portion under dry nitrogen atmosphere. Stirring is then continued at room temperature (about 20 ° C) for about 1 hour, after which the mixture is concentrated under reduced pressure to form a viscous oil. The resulting material was diluted with 20 ml of 1N. hydrochloric acid solution and then the resulting acidified aqueous solution is extracted with three portions (20 ml) of diethyl ether. The ether extracts were combined over anhydrous magnesium sulfate. After removal of the drying agent by filtration and the solvent by evaporation under reduced pressure, 1.94 g (87%) of 3-acetonylcarbonyl-5-fluoro-2-methoxypyridine was obtained as a brown oil. This product is characterized by NMR data.

Preparative example X.

A solution containing 1.94 g (0.00928 mol) of 3-acetonylcarbonyl-5-fluoro 2-methoxypyridine (product from Example W) in 30 ml

glacial acetic acid at 100 ° C is treated with 3.0 ml of 48% hydrobromic acid and stirred for 20 minutes. After completion of this step, the reaction mixture is cooled to room temperature (about 20 ° C) and poured into 100 ml of water. The resulting aqueous solution was further extracted with three portions of 30 ml of methylene chloride and the combined organic layers were washed successively with 50 ml of a 2% sodium hydroxide solution. After drying the organic layer over anhydrous magnesium sulfate and filtering to remove the drying agent, the resulting clear filtrate was concentrated in vacuo to give 645 mg of 6-fluoro-2-methyl-4H-pyrano (2,) pyridin-4-one. As a result of radial chromatography of the obtained material on silica gel using 1% methanol in chloroform as eluite, 440 mg (26%) of pure 6-fluoro-2-methyl-4H-pinone (2,3-5} - are obtained pyridine 4-one. The pure product is characterized by NMR data.

L e rparity and example Y,

To a stirred solution obtained by dissolving 440 mg (0.00246 mol) of 6-fluoro-2-methyl-4-pyran (2,) pyridin-4-one (product from Example X) in 5.0 ml of tetrahydrofuran and 20 ml of toluene at -78 ° C, 3.0 ml of a 1 M solution of diisobutylaluminium hydride in toluene was added. The resulting mixture was then stirred at -78 ° C for 2.5 hours. After completion of this step, the reaction was stopped by adding 0.25 ml of glacial acetic acid. After gradually warming the reaction mixture to room temperature, it is poured into 20 ml of water and the resulting aqueous layer is acidified to pH 3.0 by adding dilute hydrochloric acid. Then, these two layers are separated and the separated aqueous layer is extracted with three 20 ml portions. diethyl ether ether. The combined organic layers were dried over anhydrous magnesium sulfate and filtered, and the resulting filtrate was concentrated in vacuo to give .110 mg (25%) of pure b-fluoro-2,3-dihadro-4H-pyrano (2,) - pyridine 4-one as residual oil, The pure product is further characterized by NMR data.

Synthesis of target compounds.

Example 1. A stirred mixture consisting of 2.3 g (0.0116 mol) of 6-chloro-2,3-dihydro-2-methig.-4H-pyrano (2,3- (5) pyridin-4-one (the product from Example G), 1.5 g (0.232 mol) of potassium cyanide, 6.6 g (0.0696 mol) of ammonium carbonate and 1.2 g (0.116 mol) of sodium bisulfite in 100 ml 50 % aqueous methanol solution is heated in a flask closed with a stopper from the grid at 80-90 ° C for 5 hours for about 16 hours (overnight). After completion of this step, the reaction mixture is poured into a mixture of water with ethyl acetate and acidified 6 N hydrochloric acid After extraction

0 of the resulting aqueous organic solution with ethyl acetate gives several organic extracts which are combined, washed with saturated brine and dried over anhydrous sulfate

5 magnes. After removal of the drying agent by filtration and the solvent by evaporation under reduced pressure, a yellow oil is obtained as the remaining material. By recrystallization of this material from chloroform containing a small amount of methanol, 13 mg of (±) -cis-6-chloro-2, 3-dihydro-2-methyl-spiro-imidazolidin-4,41-4 N-pyrano is obtained (2,) pyridine of -2,5-dione, mp above 250 ° C. Clean

5, the product is additionally characterized by mass spectroscopy and thin-layer chromatography (in addition to elemental analysis).

Calculated,%: C 49.36; H 3.76; N, 15.70.

0 SCNUS GZOZ.

Found,%: C 49.15; H 3.78; N, 15.49. Example 2. A stirred mixture containing 500 mg (0.0025 mol) of 6-chloro-2,3-dihydro-2-methyl-4M-pyrano (2,) pyridin5 4-one (product from example G), 325 mg (0 , 0050 mol) of potassium cyanide, 1.7 g (0.0175 mol) of ammonium carbonate and 2.5 g (0.042 mol) of ammonium carbonate and 2.5 g (0.042 mol) of acetamide, are heated in a flask with a wire stopper

0 at 80 ° C for about 16 hours (i.e., overnight). After completion of this step, the reaction mixture was cooled to room temperature (approximately 20 ° C) to obtain a solid mass, which was partitioned between ethyl acetate and water, followed by acidification with 6 N. hydrochloric acid, the acidified aqueous organic solution is then treated with activated carbon and

0 was filtered, after which the resulting clear aqueous filtrate was extracted with ethyl acetate. The combined organic extracts are then washed with saturated brine and dried over anhydrous

5 magnesium sulfate. After removal of the drying agent by filtration and the solvent by evaporation under reduced pressure, a dark brown oil is obtained as a residual liquid. Recrystallization of this material from a mixture of chloroform / methanol (95: 5, vol.) Yields 20 mg (3%) of pure C +) - cis-6-chloro-2, 3-dihydro-2 - methylspiroimidazolidine-4.4 - 4 N-pyrano (2,) - pyridine -2,5-dione mp. above 250 ° C. This product is in all respects identical to the product of Example 1, which was confirmed by thin layer chromatography. The pure product is characterized by NMR data. . Example 3. A mixture consisting of 5.0 g (0.025 mol) of 6-chloro-2,3-dihydro-2-methyl-4H-pyrano (2,) pyridin-4-one (product from Preparative Example G), 3.25 g (0.050 mol) of potassium cyanide, 16.8 g (0.175 mol) of ammonium carbonate and 2.6 g (0.025 mol) of sodium bisulfite in 50 ml of formamide are placed in a stainless steel autoclave and heated to 40 ° C. within 4 days. After completion of this step, the reaction mixture was cooled to room temperature (about 20 ° C), poured into water and then acidified to pH 3.0 with 6 N. hydrochloric acid. The precipitated product thus obtained was collected by suction filtration and air dried to a constant weight to obtain 3.3 g of crude material. Recrystallization of this material from 125 ml of a mixture of chloroform / methanol (9: 1, vol.) Yields 2.26 g (34%) of pure (±) -cis-6-chloro-2, 3-dihydro-2-methyl-spiro-imidazolidine- 4,4-4 H-pyrano (2,) pyridine -2,5-dione. so pl. above 250 ° C. A second batch of crystals of pure product in an amount of 600 mg (9%) is obtained from the mother liquor. The total yield of pure product was 43% of theory. This product is in all respects identical to the product of Example 1 and is further characterized by NMR data (which are also identical to those for the product of Example 2).

PRI me R 4.

A. A mixture consisting of 39.3 g (0.20 mol) of 6-chloro-2.3-dihydro-2-methyl-4H-pyrano (2,3-5) pyridin-4-one (product of preparative example H) 26 g (0.40 mol) of potassium cyanide, 134.4 g (0.40 mol) of ammonium carbonate and 25 g (0.24 mol) of sodium bisulfite in 400 ml of formamide are placed in a stainless steel autoclave and heated at 50 ° C for three days. After completing this step, the reaction mixture is cooled to room temperature (about 20 ° C), diluted with water (to a volume of 3500 ml) and filtered to remove a small amount of insoluble material. Then, the resulting filtrate was acidified to pH 2.5 with concentrated hydrochloric acid and stirred at room temperature for 30 minutes. Besieged

the product is collected by suction filtration and dried in air to constant weight to obtain 33 g of crude material. Recrystallization of such a substance from 1200

ml of a mixture of chloroform / methanol (9: 1, vol.), which is carried out by reducing the total volume to 600 ml, followed by stirring the resulting solution at room temperature for 16 hours, get 15.4 g (29%) of pure ( +) - cis-6-chloro-2, 3-dihydro-2-methylspiro - imidazolidin-4,41-4 N-pyrano (2,) pyridine -2,5-dione, so pl. 250 ° C, which is in all respects identical to the product of the previous examples, especially with respect to NMR data. The second and third lots of crystals of the same pure product in amounts of 9.1 g (17%) and 2.1 g (4%) are obtained from the mother liquor. Total clean output

the product (2-CH3, 4-MH-cis; 21R, 4 S / 2 S.4 R) is 50% (26.6 g) of theory.

B. The mother liquor also contains a small amount of the trans-isomer, which is isolated by high pressure preparative liquid chromatography (H PIC) using multiple entries into the Zorboy Silica Prep column, 21.2 x 25 cm and alkalization with a 5% solution methanol in chloroform. As a result of the collection

more polar fractions give 40 mg of crude trans isomer. Recrystallization of this substance from ethyl acetate / hexane gave 26.5 mg of pure (+) - trans-6-chloro-2 3-dihydro-2-methyl-spiro-imidazolidin-4, 4 -4 N-pyrano (2,) pi - 2,5-dione retin (mp. 250 ° C). The pure product (2-CH3, 4-MH-trans; 21S, 41S / 2 R, 4 R) is characterized by NMR data.

Example 5. A stirred mixture,

containing 100 mg (0.00037 mol) (+) - cis-6 - chloro-2, 3-dihydro-2-methyl-spiro-imidazolidin-4,4-4-N-pyrano (2,) pyridine} -2, 5-dione (product of Example 4A), 3.0 ml of glacial acetic acid and 1.0 ml of 30% hydrogen peroxide are heated at 85 ° C for about 16 hours (overnight). After completion of this step, the reaction mixture is cooled to room temperature (about 20 ° C), diluted with water and filtered to remove the resulting precipitate. After air drying the recovered product to constant weight, 30 mg (28%) of pure (+) - Cis-6-chloro-21,3-dihydro-2-methyl-spiro-imidazolidin-4, 4- 4 N-pyrano (2 , 3-5} -pyridine -2,5-dione-8-oxide, mp above 250 ° C. In addition to elemental analysis, the pure product is additionally characterized by mass spectroscopy and thin-layer chromatography.

Calculated,%: C 46.58; H 3.55; N, 14.81.

CnHioCINsCM.

Found,%: C 46.42; H 3.56; N, 14.67.

Example b, A mixture consisting of 360.6 mg (0.00149 mol) of b-bromo-2,3-dihydro-2-methyl-4H-pyrano (2,) pyr 1din-4-one (product of the drug Example C), 194.1 mg (0.00298 mol) of potassium cyanide, 1.0 g (0.0105 mol) of ammonium carbonate and 154.8 mg (0.00149 mol) of sodium bisulfite in 10 ml of formamide are placed into a round bottom flask with a 100 ml steel stopper equipped with a magnetic stirrer, and the contents of the flask are heated with stirring at 40-45 ° C for about 16 hours (overnight). After completing this step, the amber-stained solution is cooled to room temperature (about 20 ° C) and then diluted with 10 ml of water (solution pH about 9-10). Then, the pH is adjusted to 2-3 by adding 6N. hydrochloric acid by pinning and the resulting solution was stirred at room temperature for 1.5 hours. The precipitated product thus obtained (as a white solid) was collected by suction filtration and dried in air to constant weight to obtain 178 , 7 mg of crude material, by recrystallization of this substance from. mixtures of isopropyl alcohol - isopropyl ether give 115.5 mg (25.%) of pure (+) - cis-6-bromo-2, 3-dihydro-2-methyl-spir-o-imidazolidin-4,4 4 N-pyrano (2 ,) pyridine-2,5-dione, mp. 250 ° C. The pure product is then characterized by mass spectroscopy and NMR methods in addition to elemental analysis.

Calculated,%: C 42.32; H 3.23; N, 13.45.

CnHioBrNsOs

Found,%; C 41.95; H 3.25; N, 13.18. . Example 7. A mixture consisting of 715 mg (0.00389 mol) of 6-chloro-2,3-dihydro-4H-pyrano (2,) pyridin-4-one (product of preparative example P), 500 mg (0 , 00128 mol) of potassium cyanide, 2.58 g (0.027 mol) of ammonium carbonate and 400 mg (0.00386 mol) of sodium bisulfite in 7.0 ml of formamide, placed in a round bottom flask with a 65 ml wire stopper and loaded with stirring at 52 ° C for 15 hours. After completion of this step, the reaction mixture was cooled to room temperature (20 ° C). No. was diluted with 30 ml of water. The resulting aqueous solution was acidified to pH 3.0 with concentrated hydrochloric acid, and the precipitated product was collected by suction filtration. After washing with water in a funnel with a filter and drying in high vacuum to

constant weight gives 848 mg (84%) of the crude product. Recrystallization of such material from 60 ml of a mixture of chloroform / methanol (9: 1, vol.) Gives 752 mg (52%) of pure

(b-chloro. 3-dihydrospiro imidazolidine -4,4 -4 N-pyrano (2,) pyridine -2,5-dione in the form of a chloroform solvate, mp 265-266 ° С.

Calculated,%: C 35.42; H 2.43; N, 11.26.

SUNEOMZOZ

Found,%: C 36.84; H 2.51; N, 11.55. Example 8. A suspension consisting of 500 μg (0.0018 mol) of (+) - cis-6-chloro-2, 3-dip-1-dro-2-methyl-spiro-imidazolidin-4,4 4 N-pyrano ( 2,) pyridine of -2,5-dione (product from Example 4A) and 50 mg of 10% palladium on carbon as a catalyst in 10 ml of methanol containing 366 mg (0.0036 mol) of triethylzmin (0.5 ml) , pt by mixing the indicated ingredients in a reaction flask under a nitrogen atmosphere. The resulting mixture was then hydrogenated at room temperature at atmospheric pressure for about 16 hours (over

nights). After this, additional hydrogen uptake was not observed. The reaction solution containing the final product is separated from the flask by decantation and filtered through Super-gel (silicon earth) to remove the catalyst, followed by washing the filtered material with a small amount of methanol. The combined filtrate and washings were maintained and concentrated in vacuo to give a white pen. us. Processing this material with chloroform gives a white solid, which is collected by suction filtration and air-dried.

constant weight, the result is. 450 mg (86%) of pure (+) - cis-2, 3-dihydro-2-methylspiroimidazolidin-4,4 -4 N-pyrano (2,) pyridine -2,5-dione, mp . 150 ° C (decomposition). The pure product is additionally characterized by mass spectroscopy, thin layer chromatography and NMR (in addition to elemental analysis).

Calculated,%: C 48.43; H 4.09; N, 14.95. S11NcMzOz-0.4CNaz

Found,%; C 49.01; H 4.12; N, 15.10.

Example 9. A mixture consisting of 110 mg (0.0061 mol) of 6-fluoro-2,3-dihydro-4H-pyrano (2,) pyridin-4-one (product of Preparative Example V), 78 mg (0, 00075 mol)

potassium cyanide, 400 mg (0.00512 mol) of powdered ammonium carbonate and 62 mg (0.0061 mol) of sodium bisulfite and 1.0 ml of formamide are placed in a round bottom flask with a 6 ml mesh stopper and heated to 51 ° with stirring C for 24 hours. After completion of this step, the reaction mixture was cooled to room temperature and stirred for five days before diluting with 10 ml of water. The resulting aqueous solution was then acidified to pH 3.0 with dilute hydrochloric acid and then extracted with three portions of 10 ml of ethyl acetate. The combined organic layers were then dried over anhydrous magnesium sulfate and filtered, and the resulting filtrate was concentrated in vacuo to give a residual oil, which was treated with 3.0 ml of a hot mixture of chloroform / methanol (9: 1, v / v). After cooling to room temperature, 42 mg of a yellow crystalline powder is obtained. Recrystallization of this material from 7.0 ml of a chloroform / methanol mixture (9: 1, vol.) Yields 28 mg (16%) of pure (+) - cis-6-fluoro-2, 3-dihydro-2-methyl-spiro- imidazolidin-4,4-4 H-pyrano (2,) pyridine -2,5-dione in the form of one third of the chloroform solvate in the form of a white powder with so pl. 231-232.5 ° C.

The pure product is further characterized by mass spectroscopy, NMR and IR spectroscopy (in addition to elemental analysis).

Calculated,%: C 46.78; H 3.53: N 14.43.

CiiHioFN303-0.33CHCl3

Found,%: C 46.98: H 3.80: N 14.33.

Example 10

A. cis-Isomer (+) - 6-chloro-2, 3-dihydro-2-methyl-spiro-imidezolidin-4,4-4Н- pyrano (2,) pyridine -2.5-dione, 965 mg, (0, 0036 mol), 1.18 g (0.0036 mol) of cinchonine methahydroxide in 24 ml of water (prepared according to the method of R.T. Maggiore et al. As described in J. Amer. Chem. Soc., T. .63. P. 1368, 1941). The resulting mixture was then evaporated in vacuo, after which the residue was recrystallized from isopropanol-isopropyl ether to give 919 mg of a white solid, which was collected by suction filtration while maintaining the mother liquor. The solid material thus obtained is then recrystallized from isopropanol to give 680 mg (65%) of the enantiomerically pure (4 S) (2 R) salt. Next, a 400 mg sample of such a salt is treated with 17 ml of 1N hydrochloric acid, and the resulting solution is extracted with three portions of 10 ml of ethyl acetate. The ethyl acetate extracts were combined, dried and evaporated to give 172 mg of a white solid, which was then recrystallized from ethyl acetate / hexane to give 129 mg

(70%) pure (4 S) (21, R / -6 -x / iop-2, 3-dihydro-2-methylspiro imidazolidin-4.4 -4 N-pyrano (2,) pyridine -2.5- dione, mp above 250 ° C. But + 235.7 ° (C-1. methanol) Calculated,%: C 49.36; H 3.76: N 15.70.

SpNyuS1№Oz

Found,%: C 49.00; H 3.85; N, 15.34.

B. The original mother liquor obtained above is then concentrated in vacuo to give 990 mg of a white solid. Then 890 mg of this material is treated with 10 ml of 1 N. hydrochloric acid and the resulting solution was extracted with three portions of 15 ml of ethyl acetate.

The ethyl acetate extracts were combined, dried and evaporated to dryness in vacuo to give a residue which, after treatment with an ethyl acetate / hexane mixture, formed a residue of 120 mg of racemic material. By concentration of the mother liquor, followed by recrystallization of the residue from ethyl acetate / hexane, 142.6 mg of pure (2 S) (4H) -6-chloro-2, 3-dihydro-2-methyl-spiro-imidazoline-4,4 -4 are obtained N-pyrano (2,3- (5) pyri-, 5-dione; mp 250 ° С; - 226.3 ° С (С 1, methanol).

Calculated,%: C 49.36; H 3.76; N, 15.70.

SpNyuS1№Oz Found,%: C 49.15; H 3.84; N, 15.37.

Example 11. The cis-Isomer of (+) - 6-chloro-2,3-dihydro-2-methyl-spiro-imidazolidin-4,4 -4 Н-pyrano (2,3- (5) pyridine -2,5- dyne, 2.67 g (0.01 mol), is heated by a condenser in the presence of 15.8 g (0.05 mol) of barium hydroxide octahydrate in 100 ml of water for 4 days. After cooling to room temperature, the aqueous mixture is diluted water and then pinned with a solution of 4.8 g (0.05 mol) of ammonium carbonate.The precipitated solids were then removed by filtration, washed with water and then the resulting filtrate was concentrated in vacuo to give The first batch of 1.4 g (58%) of pure 4-amino-b-chloro-2,3-dihydro-2-methyl-4H-pyridine (2,) pyridin-4 is obtained by recrystallization of this material from methanol. -carboxylic acid, mp 200-203 ° С; mass spectrum, t / e 242.

Calculated,%: C 46.87; H 4.92; N, 10.94,

SyuN1bS1№Oz

Found,%: C 46.89; H 4.62; N, 10.89.

Example 12. A solution of 1.0 g (0.004 mol) of cis-4-amino-b-chloro-2,3-dihydro-2-methyl-4 N-pyrano (2,) pyridine-4-carboxylic acid (product of example 11 ) in 220 ml of water was adjusted to pH 5.0 with 1N. hydrochloric acid and treated in portions with 640 mg (0.008 mol) of calcium cyanate, with the solution being continuously maintained at pH 5.0 for 1 h with 1N. hydrochloric acid. After stirring the resulting mixture overnight (about 16 hours), the pH value, which increased to 8.0, was adjusted to 3.0 by adding 1N. hydrochloric acid. The precipitated solids were collected, washed with water and dried in air to constant weight to give 570 mg (50%) of pure cis-6-chloro-2,3 dihydro-2-methyl-4-ureido-4H-pyrano (2,) pyridine -4-carboxylic acid, mp. 209-210 ° C; mass spectrum, t / e 285.

Calculated,%: C 44.83; H 4.44; N, 14.26.

CiiHi2CIN30 /) 0.5H20

Found,%: C 44.54; H 4.13; N, 14.23.

Example 13, A suspension containing 2.5 g (0.00875 mol) of cis-6-chloro-2,3-dihydro-2-methylureido-4H-pyrano (2,) pyridine-4-carboxylic acid (product of example 12) in 25 ml of methanol, 1.85 g (0.00875 ml) of 3 - (-) - M-benzyl-a-methylbenzylamine are treated and the resulting solution is slowly evaporated at room temperature (about 20 ° C) until crystals form. The crystals were collected by suction filtration and washed with methanol to obtain 2.1 g (97%) of the crude salt (4S / 2R) - hydantainic acid, mp. 168-170 ° C (decomp.). The mother liquor is retained. Recrystallization of solids (mp. 168-170 ° C) from methanol gives 1.0 g (46%) of pure S - (-) - N-benzyl-eg-methylbenzylamine salt (45 / 2P) - as the first batch 6-chloro-2,3-dihydro-2-methyl-4-urea do-4H-pyrano (2,) pyridine-4-carboxylic acid, so pl. 175-177 ° C (decomp.), + 58.7 ° (C 1, methanol).

Calculated,%: C 62.27; H 5.93; N, 11.17.

CnHi2CIN304 0.25H20-Ci5Hi7N

Found,%: C 62.33; H 5.87; N 11.17.

Then, 500 mg (0.01 mol) of the indicated pure salt was dissolved in 5.0 ml of glacial acetic acid at 90 ° C. for 4 hours. After cooling at room temperature (approximately 20 ° C.), the mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate extract was dried and evaporated in vacuo to give 260 mg (97%) of pure (4 S / 2 R) - 6-chloro-2, 3-dihydro-2-methyl-spiro-imide-azolidine-4.4 -41H-pyrano (213-d) pyridine - 2,5-dione, (a) о20о + 205.4 ° (С 1, methanol).

The mother liquor (A) obtained in the first stage is then left to stand at room temperature for three days, after which 87 mg of pure (S) - (-) N-benzyl-a-methylbenzylamine salt (4Н / 25) -6-chloro 2,3-dihydro-2-methyl-4-urea do-4H-pyrano (2,) pyridine-4-carboxylic

acids, mp 164-165 ° C; - 67.6 ° C (C 1, methanol). X-ray diffraction analysis confirms the 4R, 25 configuration of such a compound,

Calculated,%: C 61.30; H, 6.29; N, 10.59.

CllHr2CIN304-Cl5Hl7N-CH30H

Found,%: C 61.04; H 6.24; N, 10.57.

Example 14. A stirred mixture consisting of 100 mg (0.00037 mol) (45) / (2 B) -6-chloro-2, 3-dihydro-2-methyl-spiro-imidazolidine-4.4 -4 N -prano (2,3 (5) pyridine -2,5-dione - (4 S) / (2 R) - product of Example 10A, 3.0 ml of glacial acetic acid and 1.0 ml of 30% hydrogen peroxide , heated at 80-90 ° C for about 16 hours. After completion of the step, the reaction mixture was cooled to room temperature and diluted with water.The precipitated product was isolated by filtration, washed with water and dried in air to constant weight, then dried in vacuum during

nights. Thus, 40 mg (50%) of pure (45) / (2 P) -6-chloro-2, 3-dihydro-2-methyl-spiro-imidazolidine-4.4 -4 N-pyraio (2.3 - (5) pyridine -2,5-dion-8-oxide, mp above 250 ° C. The pure product is additionally characterized by mass spectroscopy and thin-layer chromatography (in addition to elemental analysis).

Calculated,%: C 46.58; H 3.55; N, 14.81. CiiHioC N304

Found,%; C 46.37; H 3.52; N, 14.71.

Example 15. The following spiro-3-heteroazolone compounds of Examples 4A, 4B, 6-9, 10A, 10B and 14 are tested for their ability to lower or inhibit

activity of the aldose reductase enzyme according to the method of S. Hyman et al., described in J. Biol. Chem., Vol. 240, p. 877, 1965, and modified K. Sestange et al. in US patent NJ 3821383. In each case used

the substrate was a partially purified aldose reductase enzyme derived from human placenta. The results obtained for each of the compounds are given below as a percentage of inhibition of enzyme activity relative to the selected concentration level in Table 1.

Example 16. The following spiro-3-heteroazolone compounds of Examples 4A, 4B, 6 and 10A are tested for ability

reduce or inhibit the accumulation of sorbitol in the sciatic nerve and lens of the eyes of streptozotocinated (ie, diabetic) rats according to the method described in detail in US patent No. 3821383. In

In the present study, the amount of accumulated sorbitol in the sciatic nerve and lens of the eye in each of the test animals is measured 27 hours after the induction of diabetes. The compounds of the invention are then administered orally at the doses indicated below, 4.8 and 24 hours after the administration of streptozotocin. The results obtained in this series of experiments are presented in Table 2 as the percentage inhibition from the action of the test compound in comparison with the control experiments without the use of such compounds, control animals had sorbitol content, which usually increased from 50-100 mm / g of tissue to 400 mm / g of tissue when tested for 27 hours.

The closest analogues of the compounds according to the structure and action are compounds of the US patent fsfe 4248882.

From Table 1 it follows that the compounds of formula I are more active than the compounds of the aforementioned US patent.

Thus, the racemic 6-chloro derivative of Example 2 in US Pat. No. 4,248,882 causes 58% inhibition at 10 M, while the corresponding racemic 6-chloro derivative of Example 4A of the present application gives 81% inhibition at M, and the preferred (4 S , 2 P) -enantiomer of the present b-chloro derivative in Example 10A causes 100% inhibition in M.

Similarly, the (45) -enantiomer of the 6-fluorine derivative of Example 4 of US Pat. No. 4,248,882 has only the same activity as the corresponding racemic cis-6-fluorine derivative of the present Example 9 (in both cases 40% inhibition at M), despite the fact that the last compound of the present application was not even subjected to enantiomer separation.

Comparison of the obtained test data also shows similar patterns. For example, you can compare the results obtained for the same two b-chloro derivatives in tests on the sciatic nerve (namely, example 11 of US patent No. 4248882 in comparison with example 16 of this application), according to which the racemic 6-chloro derivative according to U.S. Patent provides a 17% reduction in sciatic sorbitol accumulation compared to the corresponding 34% for the racemic 6-chloro derivative of the present application of Example 4A.

Claims (6)

SUMMARY OF THE INVENTION Htvl N where X is hydrogen, fluorine, chlorine or bromine; R is hydrogen or a C1-C alkyl, or its N-oxide derivative or its basic salt with a pharmacologically applicable cation, characterized in that a suitably substituted carbonyl ring compound of the general formula IIO N O R where X and R have the indicated meanings, they are condensed with an alkali metal cyanide and ammonium carbonate and the resulting compound of formula I, where X is fluoro, chloro or bromo, if necessary, is dehalogenated to a compound of formula I, where X is hydrogen or, if necessary, the compound of formula I is oxidized to obtain the corresponding N-oxide derivative and, if desired, the compound of formula I is converted into a basic salt with a pharmacologically applicable cation. 2. The method according to claim 1, wherein the condensation is carried out at least with a small molar excess of both alkali metal cyanide and ammonium carbonate relative to the compound of formula II, 3. The method according to claim 1, characterized in that the condensation is carried out in the presence of an inert polar organic solvent at a temperature lying in the range of 40-90 ° C. 4. A method according to claim 3, characterized in that lower alkanoamide containing 1-4 carbon atoms is used as an inert polar organic solvent. 5. The method according to claim 1, wherein the dehalogenation of the compound of formula I, where X is fluoro, chloro or bromo, is carried out by hydrogenolysis using the catalytic hydrogenation method to obtain the compound of formula I, where X is hydrogen. 6. The method according to claim 1, characterized in that the oxidation of the compound of formula I to its N-oxide derivative is carried out with a 30% aqueous solution of hydrogen peroxide in an acid solvent at a temperature of 80-90 ° C. 27  1838313 28 table 1 Inhibition of the aldose reductase enzyme by compounds formulas I table 2 Inhibition of sorbitol accumulation by compounds of formula I