SU1591809A3 - Method of producing derivatives of 4-hydroxy-2-substituted chroman-4-acetic acid - Google Patents

Description

MATCEUTICALLY ACCEPTABLE CATION SALTS

(57) The invention relates to heterocyclic compounds, in particular to the preparation of derivatives of 4-hydroxy-2-substituted chroman-4-acetic acid. as a racemic compound or an optically active compound having the absolute stereochemical formula

where K, -C ^ -C ₄ -alkyl or a group (CH ^ Ar, where η = 1 or 2, Ar is phenyl, unsubstituted or substituted by a C1 atom;

K ₂ "L, methyl or ethyl;: K ₃ - H or methyl, provided that if K. ₁ is different from methyl or ethyl, then both K ₂ and

- Η; X is H or the first substituent in the 6-position, such as the G, C1 or Br atom, methyl or nitro group;

X ₃ is H or a first substituent in the 7-position, such as the G or C1 atom, or a second substituent in either the 7-position, such as the G, C1, C ₅ -C ₃ alkyl or C, -Sullkoxy group, or v

5-position, such as a C1 or C, -Cy-alkyl; X 2 - H or a first substituent in the 8-position, such as the C1 atom, or a second substituent in the 8-position, such as the C1 or C ^ C ^ -alkide atom, or their pharmaceutically acceptable cationic salts which have the property . to inhibit the enzyme aldoreductase, and can be used by the property of inhibiting the enzyme aldoreductase, and can be used in the treatment of diabetes. The aim is to identify compounds with high activity without the content of hydantoin Functionality. Preparation is carried out by hydrolysis of the corresponding racemic ester. The target product is isolated as a racemic compound in free or salt form, or it is separated into the corresponding optical isomers and isolated as an optical isomer. 1 tab.

5TS „„ 1591809 AZ

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The invention relates to a method for preparing new compounds - derivative, aqueous 4-hydroxy-2-substituted chroman-4-acetic acid in the form of a racemic compound or an optically active compound, or their pharmaceutically acceptable cationic salts, which have the property of inhibiting the enzyme aldose reductase , and can be used in the treatment of diabetes. ,.

The purpose of the invention is to obtain new derivatives of 2-substituted chroman-4-acetic acid with high de-aldose reductase inhibitory activity without hydantoin functionality.

Example 1. Ethyl 2K, 4K-7-chloro-6-fluoro-4-hydroxy-2-methylchroman-4-20 -acetate.

A solution of 8.7 ml (6.2 mmol) of diisopropylemine in 150 ml of tetrahydrofuran is cooled to 0 ° C and 23.8 ml '(6.2 mmol) of 2.6 M n-butyllithium in hex-25 sane is added, maintaining the temperature below 5 ° C. The reaction mixture is cooled to -78 ° C and 6.0 ml (6.2 mmol) of ethyl acetate are added first, and then pa-. _; target 12.0 g (5.6 mmol) 2Kt7-chloro-6- where -fluoro-2-methylchroman-4-one in 50 ml of tetrahydrofuran, maintaining the temperature of the reaction mixture below 65 ° C. Then the reaction is quenched with 60 mp of water, diluted with 100 ml of diethyl ether and heated to 10 ° C. An additional 60 ml of water is added, and the organic layer is isolated o The aqueous layer is extracted with 150 ml of diethyl ether and the ether LAYERS are combined, WASHED WITH BRINE dd

(150 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give 17.7 g of product as an oil.

-NMR (SOSCC, ppm: 7.10 (l, '45 1H), L = 10); 6.68 (d, 1H, L = 6) *; 4.30 (m, 1H); 4.13 (quo, 2H); 2.73 (s.,

2H); 2.07 (m, 2H); 1.33 (d., ZN),

1.20 (t, ZN).

PRI

To a solution of 0.875 g (15.6 mmol). potassium hydroxide in 43 mp ethanol add 4.3 g (14.2 mmol) of the product obtained / according to example 1. The reaction mixture is stirred at 23 ° C for 4 hours and then concentrated in vacuo. The residue is dissolved in 40 ml

water and washed three times with 40 mp portions of dirtyl ether. The aqueous solution is acidified with 16 ml of 1N hydrochloric acid. hydrochloric acid, and then extracted three times with diethyl ether in portions of 50 ml. The acidic ether extracts are combined, washed with 50 ml of brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give

3.5 g of foam, which is purified chromatographically with flash evaporation, on 200 cm ^{3 of} silica gel using a 1: 1 mixture of diethyl ether: hexane as eluent to obtain 2.7 solid foam, which cures at 42-50 "C and vigorously releases gas at 60-95 ° C; Cd] ^ = 104.9 ° (CH ₃ OH, C = 1, corrected for ether content).

¹ H-NMR (C0Cl ₃ ) ppm: 7.20- (d, 1H); 6.78 (d, 1H); 4.20 (m, 1H);

2.84 (s, 2H); 2.26 (d, 1H); 1.88

(t, 1H); 1.37 (d, 3H). According to

The NMR foam contains about 20 mol% diethyl ether.

Weight for С „Н _п 0 ₄ С1 ^3ί Ρ, w / e: calculated 274.0408; found 274.0378.

Analysis by high performance liquid chromatography gives 1% of the 23-cis-methyl enantiomer.

Example 3. Sodium-2K, 4P-7-. -chloro-6-fluoro-4-hydroxy-2-methylchroman-4-acetate.

The amorphous acid of the preceding example (9.0 g, 32.8 mmol) was dissolved in 65 mp of methylene chloride and covered with 65 ml of distilled water, the pH of the water milking was monitored with a pH meter. To the well-mixed two-layer system, 1 N HCI is added. sodium hydroxide dropwise over a period of 1 hour at 23 ° C, and the pH is kept below 11. The final pH after adding 31 mp 1 n. sodium hydroxide is 7. The layers are separated, the aqueous layer is washed with 50 mp of methylene chloride and then freeze-dried to obtain 9.9 g of an amorphous hygroscopic white powder. After drying at 110 ° C. under vacuum, 9.24 g of an amorphous white solid are obtained. This material is suspended in 100 ml of warm diethyl ether and 50 ml of acetonitrile are added. As a result of heating under reflux in a steam bath, most of the solid product dissolves. After standing for 2 h, add 100 ml of diethyl ether and seed crystals

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thallas of crystalline sodium salt. After stirring for 2 hours, an additional 100 ml of diethyl ether is added and stirring is continued at 23 ° C 'for 20 hours. follow through the microscope as the growth of the crystalline salt begins from the periphery of the amorphous salt lumps. The crystalline salt is isolated by filtration, the solid 15 part is washed with diethyl ether and dried at 110 ° C in a high vacuum to obtain 8.7 g of white crystalline material; ' m.p. 250-253 ° C; 130.5 ° (CH _E OH, C = 1).

¹ H-NMR (ϋΜΟΟ-ό ^ ί, ppm: 8.92 (br s, 1H); 7.24 (d, 1H); 6.75 (d, 1H);

4.21 (m, 1H); 2.27 (m, 2H); 1.99 (d, 1H); 1.62 (t, 1H); 1.26 (d.,

ZN).

Calculated,%: C 48.58; H. 3.74.

S _p n cSgRO ^ a

Found,%: C 48.49; H 3.77.

Example 4. Ethyl 6,7-dichloro-c-4-hydroxy-g-2-methylchroman-4-acetate.

A solution of 0.242 mol of lithium diisopropylamyl obtained at 0 ° C from 93 ml of 2.6 M n-butyllithium in hexane and 0.34 mp (0.242 mol) of diisopropylamine in 825 ml of tetrahydrofuran is cooled to -78 ° C. To this was added 23.7 mp (0.242 mol) of ethyl acetate over 25 minutes, and then 50.9 g (0.220 mol) of 6,7-dichloro-2-methylchroman-4-one, dissolved in 100 ml of tetrahydrofuran, were added dropwise. After the addition is complete, 50 ml of water are added dropwise and the reaction mixture is allowed to slowly warm to 23 ° C. After adding to pe10

twenty

25

thirty

40

the action mixture of 1 l of water, the resulting product is extracted with two portions of diethyl ether, backwashed with 2 x 500 ml of brine and dried over magnesium sulfate. Concentration in vacuo afforded 66.1 g (94%) of the product as a light brown solid. An analytical sample is obtained by thoroughly trituration with hexane to obtain the product,

m.p. 80-84 ° C.

45

50

55

m D.

¹ H-NMR (Me ₂ 5O) L

7.57 (s.,

1H); 6.92 (s', 1H); 4.48 (bs, 1H);

4.24 (m, 1H); 4.24 (q, 2H) ;; 2.80

(s, 2H); 2.21 (m, 1H); 1.94 (m.,

1H); 1.41 (d, 3H); 1.30 (t, ZN).

Calculated,%: C 52.68; H 5.05.

S 74 N / 44

Found,%: C 52.69; H 4.99.

Example 5. 6,7-Dichloro-c-4-hydroxy-r-2-methylchroman-4-acetic acid.

To a solution of 31.3 g (0.475 mol) of KOH in 1.5 ml of absolute ethanol at 23 ° C add $ 151 1 "g (0.473 mol) of the compound obtained in Example 4. The clear solution is stirred at 23 ° C for 4 h. The resulting yellow-brown wet solid is diluted with 600 ml of diethyl ether, and the white potassium salt is collected by filtration, washed well with ether and air-dried to obtain 119 g of salt, mp 247-252 ° С (with decomposition).

117.5 g of salt is added to 1 L of water, stirred with 1 L of diethyl ether at 0 ° C and 30 ml of 12N hydrochloric acid are added. HC1 drop by drop. The ether layer was isolated and the aqueous layer was extracted with 500 ml of ethyl acetate. The combined organic layers were washed with 500 ml rassoda, dried over anhydrous magnesium sulfate and concentrated to an off-white solid ^- product. After thorough trituration with a 1: 1 mixture of methylene chloride: hexane, the title product is obtained as a white powder, 101.1 g (73%), m.p. 164-167 ° C.

'N-NMR (Me ^ 50) <T, ppm: 7.67 (s./

1H); 7.03 (s, 1H); - 5.65 (very br.

with. , 1H); 4.44 (m, 1H); 2.69 (sq.,

2H); 2.56 (m, 1K); 1.75 (t, 1H);

1.34 (d ", 3N).

Example 6. Brucine salt 2E., 4K-6,7-dichloro-4-hydroxy-2-methylchroman-4-acetic acid.

To 2.3 L of acetonitrile add

99.6 g (0.342 mol) of the compound obtained in example 5 and 147.0 g (0.342 mol) of brucine dihydrate. The resulting mixture is brought to a boil under reflux to effect almost complete dissolution of the reagents, and slightly turbid particles of the substance are removed by filtration of the hot solution. The resulting filtrate is left to stand and cool to 23 ° C, and after 20 hours collected by 'filtration'

96.5 g of a white solid ;:

t. pl. 184-187 ° C, [o /] d ⁵ = + 11 ° (CH ₃ 0H,

C = 1). The mother liquor is left for

7

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isolating 25, 45, enantiomer and rademate, and place the entire portion of the white solid in 1.5 megapixels of acetonitrile at reflux until a clear solution is obtained. The volume is reduced to 1.2 l by refluxing with acetonitrile, the solution is allowed to cool to 23 ° C. and after 20 hours the partially purified title product is isolated by filtration, whereby 65 g of white crystals are obtained; m.p. 191-195 ° C; VD- + 30 ° (CH ₃ OH, C = 1) „This last material is dissolved in 1.4 l of acetonitedryl at reflux, the solution is allowed to cool to 23 ° C and after 20 hours it is isolated by filtration, obtaining 52.7 g of the purified target product in the form of white crystals 2θ with so pl. 193-197 ° C; T </ D ιΓ ^{= +} 36 ° (0Η ₃ 0Η,

C-1). The absolute 2K, 4K stereochemistry of the target product was determined by X-ray structural analysis.

Π ρ i me R 7. 2K, 4K, 6,7-Dichloro - ^^ -4-hydroxyu2-methylchroman-4-acetic acid / acid. ·.

The purified product of example 6 (52.0 g) was partitioned between 500 ml of 15.5 N. HC1 and a mixture of 500 ml of diethyl ether and 30 ml of ethyl acetate. The organic layer is washed with 4 x 300 ml of 0.5 N. HC1, and then 300 mp brine, and then dried over magnesium sulfate. After concentration in vacuo, 22.5 g. ·. units of glassy foam still containing solvent; [oO o = + 102 ^b (CH ₃ 0H,

C = 1). This material is treated with 200 ml of a 1: 1 mixture of methylene chloride: hexane at reflux to a peak, and after filtration of the hot solution, about 100 mg of a white gum is recovered. After cooling to 30 ^e * C, more sticky substance is formed and it is removed by filtration 45 (100 mg _; t, size 105 ^e C, mp 157 - 162 ° C). After standing at ²³ C for 20 hours, large crystals formed were collected by filtration to obtain 6.46 g of a solid; unit so pl. 107-111 ° С with gas evolution; '

+ 112.6 ° (CH _E OH, C = 1). The mother liquor is concentrated in vacuo to -> a white solid is obtained,

12.0 g; [οί3ο ⁵ = +121 "(CH ^ CH, C = 1). ₅₅

To this add 50 mp of hexane, the resulting slurry is heated and added -. ether is allowed to dissolve. The solvent is removed when

boiling under reflux until · until the solution becomes slightly cloudy. Upon cooling to 23 ° C, two phases are formed. After 1 hour, crystals begin to grow in both phases. After standing for 20 hours, the crystals formed are removed by filtration from the single phase of the solvent and dried at 23 ° C, resulting in 10.4 h of the target product, so pl. 103-107 ° C

= + 124 ° (CH _E OH, C = 1),

Calculated,%: C 49.50; H 4.15;

C1 24.36. ‘

S _P N _2g 0 4 C1 ₂

> · Found,%: C 48.85; And 4.14;

; C1 .24.15.

Example 8. Ethyl b-nitro-c-4-hydroxy-g-2-methylchroman-4-acetate.

To a solution of 1.0 ml (7.17 mmol) of diisopropyl amine in 10 mP of dry tetrahydrofuran at 0 ° C add 2.66 ml (7.17 mmol) 2 · 7Μ n-butyllithium in hexane. This solution was cooled to -78 C and added ^e 0.7 megapixel ethyl acetate, maintaining the reaction mixture temperature below -65? C. Add a solution of 1.35 g (6.52 mmol) of 6-nitro-2-methylchroman-4-one in 15 ml of tetrahydrofuran while maintaining the temperature below -65 ° C "The reaction is quenched by adding 5 ml of water, heated to 23 ° C. and diluted with 30 ml of water and 30 ml of diethyl ether. The organic layer is isolated, and the aqueous layer is extracted with portions of 30 mp of diethyl ether twice. The combined organic layers were washed with 30 ml brine, dried over magnesium sulfate and concentrated in vacuo to give the product as an oil, 1.57 g (82%).

-NMR (C0Cl ₃ ) “P, ppm: 8.30 (m,>1H); 7.90 (m, 1H); 6.70 (m, 1H); 4.26 (m ,, 1H); 4.13 (q, 2H); 2.80 (s, 2H); 2.47-1.70 (m, 2H); 1.43 (d, 3H); 1.27 (t., ZN).

Example 9. b-Neutro-c-4-hydroxy-g-2-methylchroman-4-acetic acid.

A solution of 1.55 g (5.25 mmol) of example 8 in 5 ml of ethanol is added to a solution of 0.294 g (5.25 mmol) of potassium hydroxide in 10 ml of ethanol and the reaction mixture is stirred at 23 ° C for 4 hours. The reaction mixture is diluted 75 ml of diethyl ether and the crystalline potassium salt of the target product are isolated by filtration and then dissolved in 30 ml of water. Water plant9

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the thief is washed twice with 30 ml portions of diethyl ether, and the aqueous phase is acidified with 5.25 ml of 1N hydrochloric acid. hydrochloric acid, and then extracted with 2 x 30 ml of diethyl ether. The ether is washed with 30 mp brine, dried over magnesium sulfate and concentrated in vacuo to an off-white solid. After thorough trituration with hexane, the desired product is obtained in the form of a solid, 0.92 g (662) t dim. 100-105 ° 0, m.p. 135-138 ° C

gas evolution.

¹ H-NMR (20: 1 I, SPS1 ₃ : ΏΜΟΟ) <D m.d .: 8.40 (m., 1H); 7.90 (m, 1H); 6.73 (m, 1H); 5.93 (bs, 2H); 4.30 (m, 1H); 2.77 (s, 2H); 2.53-1.67 (m, 2H); 1.43 (d., ZN).

An analytical sample is obtained by recrystallization from an ether-hexane mixture.

Calculated, 2: C 53.93; H 4.90;

N 5.24.

C ^ H ^ O, 25

Induced, 2: C 54.00; H 4.94;

N 5.17.

Example 10. Ethyl-7-chloro-6-fluoro · —c — 4 — hydroxy — g — methylchroman — 4 — acetate.

4.07 ml

2.7 M c-butyllithium in hexane. The reaction mixture is cooled to -78 ° C and 1.07 ml (11 mmol) of ethyl acetate ddata are added. A solution of 2.146 g (10 mmol) of 7-chloro-6-fluoro-2-methylchroman-4-one in 10 ml of tetrahydrofuran is added dropwise, maintaining the reaction temperature below -65 ° C. The reaction is quenched by the addition of 10 ml of water and allowed to warm to 23 ° C. Add additional; but 10 ml of water and the organic layer is separated, and the aqueous is washed with 30 ml of diethyl ether. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title product as an oil, 2.5 g (832).

'H-NMR (HPS1 ₃ ) 6 \ ppm: 7.17 (d.,

5 = 10 Hz, 1H); 6.73 (d., L = 6 Hz,

1H); 4.57-3.61 (m, 2 x 1H); 4.17 (kn, 2H); 2.77 (s, 3H); 2.43-1.76 (m, 2H); 1.33 (d, 3H); 1.23 (t.,

ZN).

Example 11 7-Chloro-6-fluoro-c-4-hydroxy-r-2-methylchroman-4-acetic acid.

A solution of 2.5 g (8.26 mmol) of example 10 in 15 ml of ethanol is added to a solution of 0.463 g (8.26 mmol) of potassium hydroxide in 10 ml of ethanol. The reaction mixture was stirred at 23 ° С for ^{1 to} 4 hours. The reaction product was concentrated in vacuo, the residue was taken up in 20 ml of water, and the triads were washed with 20 ml portions of 10 ml of diethyl ether. To the aqueous phase, 9 ml of 1N hydrochloric acid is added. hydrochloric acid, and then extracted. 30 ml of diethyl ether. Wash with brine, dry over magnesium sulfate and con; 5, center in vacuo to give

1.68 g foam. After thorough trituration with hexane and filtration, the desired solid, off-white product, 1.4 g (622) m.p.

20 134-136 ° C.

1 H-NMR (19: 1 SPS1 _e Me ₂ 50) sG. , ppm 7.64 (very wide S., 1H); 7.18 (d., L = 10 Hz, 1H); 6.70 (d., L = 6 1Hz 1H), 4.17 (m., 1H); 2.73 (s., 2H); 2.45 -1.63-1.63 (m, 2H); 1.37 (d., ZN).

Calculated, 2: C 52.47; H 4.40. s, ₂ n, ₂ rsyu ₄

Found 2: C 52.36; H 4.31.

II example R 12. Ethyl 6-chloro-7-fluoro · -c ~ 4-hydroxy-g-2-methylchroman-4-acetate. ·

To a solution of 0.34 ml (2.56 mmol) of diisopropylamine in 8 ml of dry ofuran tetrahydr cooled to 0 ° C, add 0.98 ml (2.56 mmol) of 2.6 M n-butyllithium in hexane, maintaining the reaction temperature below 5 * “p. The resulting solution is cooled to -78 ° C and 0.23 ml (2.56 mmol) of ethyl acetate are added. To the reaction mixture was added a solution of 500 mg (2.33 mmol) of 6-chloro-7-fluoro-2-methylchroman-4-one in 2 ml of tetrahydrofuran at -70 ° C. The reaction is quenched with 5 ml of water, heated to 23 ° C, diluted with 10 ml of water and extracted with 30 ml of diethyl ether. The ether layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford the title product as a yellow oil, 0.611 g (872).

'H-NMR (COC1 _e ) (G, ppm: 7.33 (d.,

1H, l = 8 Hz); 6.34 (d., 1H, L = = 11 Hz); 4.22 (m., 1H); 4.13 (sq., 2H); 2.75 (with., 2H); 2.37-1.57 (m., 2H); 1.37 (d., ZN); 1.25 (t., ZN). NS p and. To ι e p 13. ( > -Chloro-7-fluoro-c-

-4-hydroxy-g-2-methylchroman-4-acetic acid.

eleven

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To a solution of 0.113 g (2.02 mmol) of potassium hydroxide in 6 ml of ethanol was added 0.611 g (2.02 mmol) of the product of example 12. The resulting solution was stirred at 23 ° C for 4 h, then concentrated in vacuo. and the residue is placed in 15 ml of water, washed with 3x15 ml of diethyl ether, acidified

2.5 ml 1 N. hydrochloric acid and extracted with 2x15 ml of diethyl ether. The combined ether extracts are then washed with brine, dried over magnesium sulfate and concentrated in vacuo. After thorough trituration of residue 15 with hexane, the product is obtained as a white solid, 0.336 g (61%), so pl. 133-134 ° C.

'H-NMR (Me ₂ 80) cP, ppm 7.59 (d.,

1H, L = 9 Hz); 6.83 (d., 1H, L = ₂ 0

= 12 Hz); 4.42 (m, 1H); 3.36 (br s .. 1H); 2.70 (q, 2H); 2.54 (m.,

1H); 1.72 (t, 1H); 1.33 (d, 3H).

Calculated. %: C 52.47; H 4.41.

... ^'25

C ₁₂ H ι £ 1ϊΌ 4

Found,%: C 52.85; H 4.51.

Example 14. Ethyl-6-chloro-c-4-hydroxy-g-2-methylchroman-4-acetate.

To a solution of 13.2 ml (94 mmol) of di- 30 isopropylamine in 190 ml of dry tetra + hydrofuran at -20 ° C add 44.8 ml of 94 mmol of 2.4M n-butyllithium in hexane. After stirring for 15 minutes, the reaction mixture is cooled to -78 ° C ββ and 9.17 mp (94 mmol) of ethyl acetate is added dropwise, maintaining the temperature below -70 ° C. After 1.5 h • at -78 ° C, a solution of 2 * 3 g (12 mmol) of 6-chloro-2-methyl-4θ chroman-4-one in 10 ml of tetrahydrofuran is added dropwise, maintaining the temperature below -70 ° C. After 1.5 h at -78 ° C, the reaction is quenched with 10 ml of water and left to warm. . to reach 23 ° С. To the reaction mixture 45 are added 100 ml of water and 100 ml of diethyl ether. The organic layer is separated, and the aqueous layer is extracted with 2x75 ml of diethyl ether. The combined organic layers were washed with brine, βθ dried over magnesium sulfate and concentrated in vacuo to provide 5.7 g of the crude title product. It was flash chromatographed (silica gel, 1: 6 ββ diethyl ether: hexane as eluent) to give the product as a pale yellow oil, 3.5 g.

(100%).

¹ n [-NMR (SOS1 _E ) <G, ppm: 7.35 (m „, 1H); 7.00 (m, 1H); 6.40 (m, 1H); 4.13 (m., 1H); 4.13 (q, 2H); 2.77 (with., 2H); 2.53-1.63 (m, 2H); 1.37 (d., ZN); 1.27 (t., ZN) o NS p and: measures 15.1 3-Chlorine-c-4-guide-

roxy-g-2-methylchroman - 4-acetic acid.

To a solution of 0.672 g (12 mmol) of potassium hydroxide, dissolved in * 20 ml of ethanol, add 3.41 g (12 mmol) of the product of example 14, dissolved in 14 ml of ethanol. After stirring at 23 ° C for 4 hours, the reaction mixture is concentrated in vacuo and the residue is taken up in 40 ml of water. The aqueous phase is washed with 3x10 ml of diethyl ether and then acidified by adding <12 ml of 1N hydrochloric acid. of hydrochloric acid. After extraction with portions of cyethyl ether with brine three times, drying over magnesium sulfate and concentration in vacuo, 2.25 g of a foam are obtained. After thorough trituration with hot hexane and filtration, the product is obtained as a white solid,

1.9 g (61%) ', m.p. 119-121 ° C.

’N [-NMR (С0С1 ₃ ) (P, ppm .: 7, 35 (m 1H); 7.17 (lat. S., 2H); 7.01 (m., 1H); 6.62 (m., 1H); 4.17 (m., 1H); 2.87 (with", ZN); 2.50-1.63 (m., 2H); 1.37 (d., ZN).

Calculated ',%: C 56.15; H 5.11. s _{| 0} n, sy ₂

Found,%: C 56, ^ 25; H 5.07.

Example 16 Ethyl 6-chloro-6-methoxy-c-4-hydroxy-g-2-methylchroman-4-acetate.

To a solution of 4.9 mp (35 mmol) of diisopropylamine in 40 ml of dry tetrahydrofuran cooled to 0 ° C, add 21.8 ml (35 mmol) of 1.6 M n-butyllithium in hexane. The reaction mixture is cooled to -78 ° C and 3.3 ml (35 mmol) of ethyl acetate is added dropwise, keeping the temperature below -70 ° C. 1.0 g [4; 4 mmol) is added to the solution

6-chloro-7-methoxy-2-c-methylchr6man-4-one in 40 ml of tetrahydrofuran. The reaction is quenched by adding 5 ml of water, warmed to 23 ° C and diluted with water. The layers are separated and the aqueous layer is washed with 2x100 ml diethyl ether. The combined organic layers were washed with 100 ml of water and then with brine and dried. over magnesium sulfate and concentrated in vacuo to give 1.4 g of the crude product in the form of an oil. With poi

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flash chromatography on 125 ³ cm silica gel using chloroform as eluent afforded 1.2 g (87%) of product as an oil.

Ή-NMR (С0С1 ₃ ) <Г, ppm ': 7.43 (s.,

1H); 6; 35 (s, 1H); 4.20 (q, 2H);

4.16 (m ", 1H); 3.83 (s, 3H); 2.70

s., 2H); 2.43-1663 (m, 2H); 1.38, θ (d, 3H); 1.27 (t., ZN).

Example 17 6-Chloro-7-methoxy-c-4-hydroxy-r-2-methylchroman-4-acetic acid. ...

To a-solution of 212 mg (3.8 mmol) of potassium hydroxide and 30 ml of ethanol was added 1.2 g (3.8 mmol) of the product of Example 16, and the resulting solution was stirred at 23 ^v for 2 h. The reaction mixture was then poured into 200 ml of ₂₀ water and washed with 2x100 ml of diethyl ether. The aqueous layer is acidified with 6 N. hydrochloric acid, and the aqueous layer was extracted with 2x100 ml of diethyl ether.

These acidic ether washings are combined, washed with brine and concentrated in vacuo to provide the crude title product as a foam.

310 mg (91%).

^F-NMR (FAS-1 ₃₎ Cr, ppm .: 7.32 (s. 30

1H); 7.17 (bs, 1H); 6.27 (s ,, 1H);

4.17 (m, 1H); 3.78 (s, 3H); 2.82 (s, 2H); 2.48-1.60 (m, 2H); 1.38 (d, 3H).

An analytical sample of the dicyclohexylohexylamine salt is prepared by adding two equivalents of dicyclohexylamine to a solution of the free acid diethyl ester. After standing overnight, the formed crystals are collected by filtration and dried to obtain a salt, so pl. 178-180 ° C (with decomposition) <,

Calculated,%: C 63.54; H 8.21;

N 2.96 "45

Οί ^ Η ^^ Ν- H ₂ O

Found,%: C 63.66; H 7.98;

N 2.95.

Example 18. Ethyl 6-fluoro-c-4-hydroxy-g-2-methylchroman-4-acetate 50

To a solution of 24.9 ml (0.178 mol) of diisopropylamine in 350 ml of dry tetrahydrofuran at 0 ° C add 84.8 ml (0.178 mol) of 2.1M n-butyllithium in hexane.

After stirring for 1 hour at 0 ° C, the reaction mixture is cooled to -78 ° C and 17.4 ml (0.178 mol) of ethyl acetate is added dropwise, maintaining

temperature below -70 ° C. After stirring at -78 ° C for 2.5 hours, add 4 g (0.022 mol) of 6-fluoro-2-methylchroman-4-one, dissolved in 25 ml of tetrahydrofuran, keeping the temperature below -70 ° C ". After stirring for 1.5 h at -78 ° C, the reaction is quenched by adding 15 ml of water. The reaction mixture is heated to 23 ° C and diluted with 200 ml of water and 200 '(ml' ether. The aqueous layer is isolated and extracted with 2x150 ml of diethyl ether. The combined organic layers are washed with 150 ml of brine, dried over magnesium sulfate and concentrated in vacuum to give 8.1 g of an orange oil It is purified by flash chromatography on 600 cm3 silica gel using hexane: diethyl ether (6: 1) as eluent to give the product as a yellow oil, 5 g (85 %).

-NMR (SBS1a) Λ ppm: 7.20-6.43 (m, 3H); 4.13 (q, 2H); 4.08 (m, 1H), 2.77 (s, 2H), 2.40-1.58 (m,

2H); 1.33 (to, ZN), 1.25 (t., ZN).

Example 19 b-Fluoro-c-4-hydroxy-g-2-methylchroman-4-acetic acid!

A solution of 4.558 g (17 mmol) of the product of example 18 in 15 ml of dobasl ethanol ^; is added to a solution of 0.952 g (17 mmol) of potassium hydroxide in 30 ml of ethanol. This solution is stirred for 4 hours. at 23 ° C, and then the solvent was removed in vacuo. The residue is taken up in water and washed with 2x100 ml of methylene chloride. The aqueous phase is acidified with 17 ml of 1..N hydrochloric acid and extracted with 2x100 ml of methylene chloride. The acidic methyl enchloride extracts are combined, washed with 100 ml of brine, dried over magnesium sulfate and concentrated in vacuo to give 3.1 g (76%) of the title product as a white solid, m.p. 122-125 ° C.

¹ H-NMR (ϋϋΟίρν, ppm: 8.08 (br s, 2H); 7.17 (m, 1H); 6.73 (m, 2H); 4.20 (m. , 1H); - 2.80 (s, 2H); 2.451.65 (mn, 2H); ί, 38 (d, 3H).

Calculated,%: C 60.00; H 5.45 ,:

^S 11 ^N 13 ^R0 H

Found,%: C 59.76; H 5.37 "

Examples 20-59. Various substituted ethyl-c-4-hydroxy-r-2-substituted chroman-4-acetates.

By the method of examples 1,4,8,10,12,

14,16 and 18 are corresponding substituted

chroman-4-ones are converted into the following

15

1591809

16

substituted ethyl c-4-hydroxy-g-2- (substituted) chroman-4-acetates (the example number, product name, yield (eluent if chromatographic purification on silica gel was carried out) and physical properties are indicated):

20. Ethyl 6-fluoro-4-hydroxy-2,2-dimethylchroman-4-acetate; 96%; white solid; tech Cl 0.4 (1: 1 diethyl ether: hexane) o

21. E.yl 6-fluoro-c-4-hydroxy-g-2-ethylchroman-4-acetate; 77% (1: 6 diethyl ether-hexane); butter; w / e 282 (ΡΌ, 265 (R-OH), 235, 195

p-CH ₂ CO ₂ C ₁ H ₅ -), 177, 139. '

22. Ethyl b-fluoro-c-4-hydroxy-r-2-propylchroman-4-acetate; 38% (1: 6 diethyl ether: hexane); butter; ha / e 296 (P ⁴ ), 235, 209 (P-CH ₂ C00C _g H ^),

191, 139.

ten

twenty

15

23. Ethyl 6-fluoro-c-4-hydroxy-g-2-isopropylchroman-4-acetate; 96%; solid; w / e 296 (Ρ ⁴ ), 235, 209, 191,

139. ‘25

24 o Ethyl 6-fluoro-c-4-hydroxy-r-2- (tert-butyl) chroman-4-acetate; 97%; solid; ha / e 310 (Ρ ⁴ ), 277, 263, 235, 223, 165, 139.

25. Ethyl 6-fluoro-c-4-hydroxy-g-2-30-phenylchroman-4-acetate; 33% (1: 6 diethyl ether: hexane); butter; m / e 330 (P ⁴ ), 312 (P-H ₂ 0), 225, 180, 138.

26. Ethyl 6-fluoro-c-4-hydroxy-r-2, c-3-dimethylchroman-4-acetate; 71% (1: 6 diethyl ether: hexane); ' m.p.

55-58 ° C; ha / e 282 (P +), 249, 195, 177,

139.

27 "Ethyl 6-fluoro-c-4-hydroxy-r-2- (2-phenylethyl) chroman-4-acetate; 71% up to (1: 2 diethyl ether: hexane); butter.

28 “Ethyl-6-fluoro-c-4-hydroxy-r-2- (3,4-dichlorobenzyl) chroman-4-acetate;

95% (toluene); oil, m / e 416, 414, 412 (P ⁺ , 8%), 394 (P-H ₂ O), 325, 307, 325 45 (P * -H ₂ O -CH ₂ C ^ H ₃ SG _g , 100%), 207, 165 (47%), 139, 109.

29. Ethyl 6 ~ fluoro-c-4-hydroxy-r-2-benzylchroman-4-acetate; 81% (toluene); ha / e 344 (P ⁺ , 24%), 257, 235 (.100%), ₅₀ 165, 139, 91. - 'H-NMR (C0C1 ₃ ) A ppm: 1.1 (i.,

ZN); .1.8-2.3 (m ', 2H); 2.7 (τ, 2H);

3.0 (t, 1H); 4.0 (q, 2H); 4.3 (s, 1H); 3.8-4.5 (br m, 1H); 6.6-7.4 "

(m + aryl, s, 8H).

ZOA. Mixtures of 6-fluoro-c-4-hydroxy-g-2-ethyl-methylchroman-4-acetate and 6-fluoro-c-4-hydroxy-2-ethyl-g-2-methyl ~ chroman-4-acetate.

CALL. 35% of a 1: 2 mixture of the more polar and less polar diastereomer and (B) 26% of a 2: 1 mixture of the more polar to less polar diastereoisomer, partial chromatographic separation using 1: 5 diethyl ether: hexane as eluent; both in the form of oil.

31. Ethyl c ^- 4-hydroxy-g-2-methylchroman-4-acetate; 56% (1: 6 diethyl ether: hexane); butter; ha / e 250 (Ρ ^4- ),

233 (P-OI), 163 (P-CH ₂ C0 ₂ C ₂ H ₅ ), 145, 121.

32. Ethyl c-4-hydroxy-g-2,6-dimethylchroman-4-acetate; 77% (1: 6 diethyl ether: hexane); butter; w / e 264 (P ⁴ ), 247 (P-OH), 177 (P-CH ^ C0 ₂ C ₂ H), 159; 135.

33. Ethyl 6-bromo-c-4-hydroxy-g-2-methylchroman-4-acetate; 98% (1: 5 diethyl ether: hexane); butter; t / e -.330 / 328 (ΡΌ, 243/241, 225, 199.

34. Ethyl 6-methanesulfonyl-c-4-hydroxy-g-2-methylchroman-4-acetate; 89%; butter.

35. Ethyl 6-benzoyl-c-4-hydroxy methylchroman-4-acetate; 50% (1: 6 diethyl ether: hexane); butter; ha / e 354 (P ⁺ ), 337 (P-OH), 267, (P-CH ₂ C0 ₂ CH)

105, 77.

IR (CHCl ₃ ) 1720, 1650, 1610 cm '.'

36. Ethyl 6,8-dichloro-c-4-hydroxy-g-2-methylchroman-4-acetate; 79% (1: 6 diethyl ether: hexane); oil; ha / e 320/318 (P *), 301 (P-OH), 285, 271, 231, 213, 189.

Memory. Ethyl 6-chloro-c-4-hydroxy-g-2,8-dimethylchroman-4-acetate; 88%; ha / e 298 (p ⁴ ); 281 (P-OH), 211, 169.

38. Ethyl 6-bromo-8-chloro-c-4-hydroxy-r-2-methylchroman-4-acetate; 91%; butter"

39A. Ethyl 6,7-dichloro-c-4-hydroxy-r-2-methylchroman-4-acetate; - 37%; identical with the product of Example 4 and ethyl 5,6-dichloro-c-4-hydroxy-g-2-methylchroman-4-acetate; 51%; butter.

'H-NMR (0ϋ01 ₃ ) <Γ, ppm: 7.10 (d, 1H); 6.57 (d, 1H); 4.13 (q, 2H);

4.13 (m ", 1H); 3.05 (q, 2H); 2.571.70 (u ", 2H); 1.38 (d, 3H): 1.27 (t, 3H), from about a 1: 16.7 mixture and 5,6-dichloro-2-methylchroman-4-one; this product is separated and purified by chromatography on silica gel using • mixture 1.; 4: 1 diethyl ether: hexane: chloroform as eluent.

17

1591809

eighteen

39B. Ethyl 5,6-dichloro-c-4-hydroxy-r-2-methylchroman-4-acetate; 25X (1:

: 4: 1 diethyl ether: hexane: chloroform); butter; ¹ H-NMR spectrum is identical to that of the product of Example 39A.

40. Ethyl-6-nitro-c-4-hydroxy-g-2,

5-dimethylchroman-4-acetate; ' 31X (2: 1 hexane: diethyl ether as eluent); butter; tekh K. 0.3 (1: 1 divid ethyl ether: hexane)?

41. Ethyl-6-chloro-c-4-hydroxy-g-2,

7-dimethylchroman-4-acetate; 92X; oil, t / e 300/298 (P ⁺ ), 311, 281, 216,

193, no. 69. 15

'H-NMR (SBS1,) /, ppm: 7.37 (s.,

1H); 6.60 (s,? H);: 4.20 (q, 2H);

4.20 (m, 1H); 2.80 (s, 2H); 2.30 (s, 3H); 2.43-1.60 (m, 2H); 1.40 (d, 3H); 1.30 (t, ZN). twenty

42. Ethyl 7-chloro-6-nitro-c-4-hydroxy-g-2-methylchroman-4-acetate; 71X (contaminated with approximately 3XX of the 7-chloro-8-nitro isomer by ¹ H-NMR ;; oil. 25

'H-NMR (SBS1 ₃ ) <G, ppm: 8.17 (s ,,

0.66 N); 7.48 (d, O, ZZN); 6.97 (d, '0.3 3H); 6.90 (s ,, 0.6 6H); 4.20 (q, 2H); 2.60 (s, 0.66 x 2H); 1.45 (d.,

0.66 x ZN); 1.41 (d, 0.33 x 1H); thirty

, 1.27 (t., ZN).

43. Ethyl 6-nitro-c-4-hydroxy-g-2,7-dimethylchroman-4-one; 17X (according to ¹ H-NMR, contaminated with 25X of 5-methyl-6-nitroisomer after chromatography);

2: 1 (hexane: diethyl ether); butter.'

44. Ethyl 7-chloro-c-4-hydroxy-g-2-methylchroman-4-one; 35X (1: 8: 1 diethyl ether, hexane: chloroform). bld

45. Ethyl 6-chloro-c-4-hydroxy-r-2-_ -methyl-3,4-dihydro-2H-benzo (H) chroman-4-acetate; 62X (2: 1 hexane: ethyl acetate); butter.

• 46. Ethyl 5,8-dichloro-c-4-hydroxy-45-g-2-methylchroman-4-acetate; 92X; butter.

47. Ethyl 8-chloro-c-4-hydroxy-g-2-methylchroman-4-acetate; 88X; ha / e 284 / N 286 (P * 3: 1), 267, 251, 237, 221, 197, ₅ θ 179,155, 144.

48. Ethyl 7,8-dichloro-c-4-hydroxy-g-2-methylchroman-4-acetate; 84X; butter .

, 49. Ethyl 6-nitro-7-fluoro-c-hydroxy-r-2-methylchroman -'- 4-acetate 100X.

50. Ethyl 6-nitro-4-hydroxy-.2,2-dimethyl chroman-4-acetate; 100X; butter; t / e 309 (P ⁺ ), 292, 276, 255, 222,

207, 166, 120; those 0.2 (1: 1 diethyl ether,: hexane) o

5 I. Ethyl-6,7-dichloro-4 ~ hydroxy-2

2-dimethylchroman-4-acetate; 56X (4: 1 hexane: diethyl: ether); butter.

52. Ethyl 5,6-dichloro-4-hydroxy-2, 2-dimethylchroman-4-acetate; 100%.

53. Ethyl 7-fluoro-c-4-hydroxy-r-2-methylchroman-4-acetate; 88X.

54. Ethyl 6,7-difluoro-c-4-hydroxy-g-2-methylchroman-4-acetate;: 86X.

55. Ethyl 6-cyano-7-fluoro-c-4-hydroxy-r-2-methylchroman-4-acetate; 100X.

56. Ethyl 6-chloro-7-bromo-c ^ 4-hydroxy ~ ci-r-2-methylchroman ~ 4-acetate; 89X.

57. Ethyl 6-fluoro-7-bromo-c-4-hydroxy-r-2-methylchroman-4-acetate; 51X.

58. Ethyl 5-bromo-6-fluoro-c-4-hydroxy-2-methylchroman-4-acetate; 24X.

59. Ethyl 6-chloro-7-ethyl-c-4-hydroxy-g-2-methylchroman-4-acetate; 92X.

Examples 60-99. Various substituted c-4-hydroxy-r-2-substituted chroman-4-acetic acids.

By the method of examples 2,5,9,11,13,

15 and 19, the esters of the preceding examples are converted to the corresponding substituted c -4-hydroxy-g-2 -s substituted n n: d chroman-4-acetic acids elemental analysis):

60. 6-Fluoro-4-hydroxy-2,2-dnmethylchroman-4-acetic acid; 64X; m.p. 108-111 ° C; m / e 254 (P +), 221, 195, 180.

Calculated X: C 61.41; H 5.95. ^with ί2 Η ι? ΡΟ ₄

Found, X: C 61.33; H 5.67.

61. 6-Fluoro-c-4-hydroxy-r-2-ethylchroman-4-acetic acid; 73X; m.p. "89-9I ^e C; m / e 254 (P ⁺ ), 207, 195, (P-CH ₁ COOH), 139.

Calculated X: C 61.41; H 5.95. s _p n, ₅ P0 ₄

Found, X: C, 61.20; H 5.81.

62. 6-Fluoro-c-4-hydroxy-r-2-propylchroman-4-acetic acid; 70X; m / e 268 (P ⁺ ), 209 (P-CH ₂ C00H), 139.

Calculated, X: C 62.67; H 6.39.

S 74 8 17PO 4

Found, X: C 62.83; H 6.53.

63. 6-Fluoro-c-4-hydroxy-r-2-isopropylchroman-4'-acetic acid; 73X; m.p. 119-122 "C; m / e 26'8 (P ^b ), 209 (P-CH ₂ ), 191, 1.91, 165, 139.

Calculated, X: C 62.67; H 6.39;

7 + P _P GO ₄

19

1591809 20

Found,%: C 62.71; H 6.41.

64. 6-Fluoro-c-4-hydroxy-r-2- (tert. -Butyl) chroman-4-acetic acid;

82%; m.p. 123-125 ° C; ha / e 282 (P ⁺ ), ₅

249, 223 (P-CH ₂ COOH), 207.165, 139.

Calculated,%: C 63.82; H 6.78. s ^ n ₇₉ th ₄

Found,%: C 64.15; H 6.83.

65.6-Fluoro-c-4-hydroxy-r-2-phenyl-? Yu chroman-4-acetic acid; 57%; mp 140-143 ° C; m / e 302 (P +), 284 (P ⁺ H ₂ O), 243, 225 (P-C ^ Well), 180, 138.

Calculated,%: C 67.54; H 5.00.

^S ? 7 ^N 7ί ^Ρθ 4 '15

Found,%: C 67.12; H 4.72.

66. 6-Fluoro-c-4-hydroxy-r-2-c-3-dimethylchroman-4-acetic acid;

67%; m.p. 149-151 ° C; m / e 254 (P +),

221, 195, 180, 139.20

Calculated,%: C 61.41 * ,; H 5.95. s _{/ 3} n _{7 £} to ₄

Found (%): C 61.38; Η 5.95,

67. 6-Fluoro-c-4-hydroxy-r-2- (2-phe | nylethyl) chroman-4-acetic acid, ^ 5 84%; butter; m / e: calculated 330, 1267, found 330, 1245.

68. Dicyclohexylammonium-b7fluoro-c-4-hydroxy-g-2- (3,4-dichlorobenzyl5 chroman-4-acetic acid; 51%; mp 30 168-1 79 ^ C (with decomposition) '; t / e 386,

384 (P +, 42%), 366 (P ⁺ -H _g O), 325

(P ⁴ -CH ₂ COOH), 207 (100%), 181, 165,

159, 138.

Calculated,%: C 63.60; H. 6.76; 35

N 2.47.

C ^ and _T5 () ₄ C1 ₂ F · Ο _ί2 Η _ί3 Ν

Found (%): C63.52, H6.77;

N 2.36.

69. Dicyclohexylammonium-6-fluoro-c-40-4-hydroxy-g-2-benzylchroman-4-acetic acid; 63%; m.p. 166-167 ° C (with decomposition); ha / e 316 (P ⁺ , 4%), 207 (13%), 181 (41%), 152 (13%) 438 (100%),

100, 56,55,44, 45

Calculated,%: C 72.40; H 8.10;

N 2.82.

'Ц Ц | 7 θ 4

Found,%: C 72.49; H 7.98;

N 2.80. 50

70A'1: 2 mixture consisting of

6-fluoro-c-4-hydroxy-g-2-ethyl-2-methylchroman-4-acetic acid and 6-fluoro-c-4-hydroxy-2-ethyl-g-2-methylchroman-4-acetic acid from example mixtures; ZOA; 42%; m.p. 125-128 ° C; _m / e 268 (P *), 235, 221, 209, 199, 180, 139.

Calculated,%: C 62.67; H 6.39.

C _{? +} N _P RO ₄

Found,%: C 62.54,: H 6.25.

70B. 2: 1 mixture consisting of

6-fluoro-c-4-hydroxy-g-2-ethyl-2-methylchroman-4-acetic acid and 6-fluoro-c-4-hydroxy-21 -ethyl-g-2-methylchromo ohma n-4- acetic acid from a mixture of example ZOV; 45%; m.p. 120-122 °; m / e 268 (P ⁺ ), 235, 221, 199, 180, 139.

Calculated,% .: C 62.67; H. 6.39.

С _ί4 Η _ί7 Ρ0 ₄

Found,%: C 62.48; H 6.28.

71. c-4-Hydroxy-g-2-methylchroman-4-acetic acid; 71%; m.p. 99101 ° C (softens at 95 ° C); m / e 222 (P ⁺ ), '163 (P-CH ₂ C00H), 145, 121.

Calculated,%: C 64.85; H 6.35.

^ъ ίΖ m ^ν 4

Found,%: C 64.79; H 6.43.

72. c-4-Hydroxy-g-2,6-dimethylchroman-4-acetic acid; 71%; m / e 236 (P ⁺ ), 177 (P-CH _g COOH>, 159, 135.

Calculated,%: C '66, 08; H 6.83.

^S 1E ^N M ° 4

Found,%: C 66.31; H 6.70.

73. 6-Bromo-c-4-hydroxy-r-2-methylchroman-4-acetic acid; 69%; m.p. £ 135-137; t / e 302/300 (P \ 1: 1), 243 /

// 241, 201/199.,

Calculated,%: C 47.86; H 4.35.

Cy ₂ N ₁₃ VgO ₄

Found,%: C 47.85 (H 4.25.

74. c-Methianesulfonyl-c-4-hydroxy-r-2-methylchroman-4-acetic acid; 43%; m.p. 164-167 ° C.

Calculated,%: C 51.99 ;: H 5.37.

S _1E N

Found,%: C 51.73; H 5.32.

75. 6-Benzoyl-c-4-hydroxy-r-2-methylchroman-4-acetic acid; 49%; m.p. 159-163 ° C; m / e 326 (P ⁺ ), 309 (P-OH), 267 (P-CH _g COOH), 249, 189,

145, 105.77.

Calculated,%: C 69.93; H 5.56.

^S 19 ^N 14 ° 5

Found,%: C 69.99; H 5.73.

76. 6,8-Dichloro-c-4-hydroxy-r-2-methylchroman-4-acetic acid; 68%; mp 143-145 ° C;: ha / e 290/292 (P *), 273 (P-OE), 257, 231 (P-CH ₂ C00H), 213,

189.,

... Calculated,%: C 49.50; n 4.15.

О ЦН ₇₁ С1 ₂ О ₄

Found,%: C 45.50; H 4.13.

77. 6-Chloro-c-4-hydroxy-r-2,8-dimethylchroman-4-acetic acid; 64%; m.p. 118-120 ° C; ha / e 270 (R ^b ), 237,

211 (P-CH ^ COOH) '169.

21

1591809

22

Calculated,%: C 57.61; Η 5.59.

CH 10 ^

Found,%: C 57.67; H 5.47,

78,6-Bromo-8-chloro-c-4-hydroxy-r-2- $ -methylchroman-4-acetic acid; 74%; m.p. 168-171®C (with decomposition).

Calculated,%: C 42.94; H 3.60.

.c η ^ + βγοι

Found,%: C 43.13; H 3.41. _ten

79. 5,6-Dichloro-c-4-hydroxy-r-2-methylchroman-4-acetic acid; 65%; m.p. 144-147 ° C.

Ή-NMR (ΏΜΟΟ) <Γ, (ppm): 7.44 (d.,

1H), -6.83 (d, 1H), 4.41 (m, 1H), 15

3.04 (q, 2H), 2.64 (d, 1H); 1.83 (t, 1H); 1.34 (d, ZN).

Calculated,%: C 49.50; H 4.15.

^C / 2 ^N 1 2 ° 4

Found,%: C 49.24; H 4.251 20

80. 6-Nitro-c-4-hydroxy-g-2,5-dimethylchroman-4-acetic acid; 52%; m.p. 155-158 ° C.

Calculated, D: C 55.51; H 5.38;

N 4.98. 25

s ₇₃ n ₁₅ o ₆ m

Found,%: C 55.87; H 5.25;

N 5.07.

81. 6-Chloro-c-4-hydroxy-r-2,7-di, methylchroman-4-acetic acid; 66%; thirty

'M.p. 134-136 ° C.

Calculated,%: C 57.67; H 5.59. from _{13 to 15 to 4}

Found,%: C 57.95; H 5.64.

1 H-NMR (С0С1 CP, ppm: 7.43 (s., 35 1H); 7.27 (lat. s., 2H); 6.67 (s, 1H); 4.20 (m., 1H); 2.93 (s, 2H); 2.57- ' 1.57 (m., 2H); 2.33 (s., ZN); 1.42 (d., ZN).

82.7-Chloro-6-nitro-c-4-hydroxy-40

-r-2-methylchroman-4-acetic acid (isolated from the 7-chloro-8-nitro isomer by slurrying in ethanol), 34%; m.p. 133-137 ° C.

¹ H-NMR (20: 1 C0C1 ₃ : OMSO) "G, ppm: 45

8.23 (s, 1H); 7.97 (bs, 1H);

6.88 (s, 1H); 4.38 '(m, 1H) ;: 2.78 (s, 2H); 2.57-1.67 (m, 2H).

Calculated,%: C 47.77; H 4.01;

N 4.64. 50

C ₇₂ H, ₂ C1NO ₆

Found,%: C 47.80; H 3.99;

N 4.59.

83. 6-Nitro-c-4-hydroxy ~ r-2,7-dimethylchroman-4-acetic acid; thirty%; 55 m.p. 95-1OO ° C.

Calculated,%: C 55.51; H 5.38;

N 4.98.

s _{| 5} n ₇₅ but ₆

Found,%: C 55.47; Η 5.42;

N 4.82.

84. 7-Chloro-c-4-hydroxy-r-2-methylchroman-4-acetic acid; m.p. 147-150 ° C; 60%.

Calculated,%: C 56.13; H 5.11.

S, ₂ H ₁₃ 0 ₄ C1

Found,%: C 56.15; H 5.17.

85. 6-Chloro-c-4-hydroxy-r-2-methyl-3,4-dihydro-2H-benzo (b) chroman-4-uk acetic acid; 64%; m.p. 143-145 ° C.

Calculated,%: C 62.65; H 4.93.

C, ₂ NzdO ₄ C1

Found,%: C 62.71; H 4.92.

86. 5,8-Dichloro-c-4-hydroxy-r-2-methylchroman-4-acetic acid; 71%; m.p. 104-110 ° C.

Calculated,%: C 49.50; H 4.15;

C ₇₂ O ₊ C1 2

Found,%: C 49.41; H 4.06.

8-7. 8-Chloro-c-4-hydroxy-r-2-methylchroman-4-acetic acid; 58%; m.p. 84-86 ° C.

Calculated,%: C 36.16; H 5.10;

^С 12 ^Н -ge ° 4 ^С1 '*

Found,%: C 56.16; H 5.11.

88. 7,8-Dichloro-c-4-hydroxy-r-2-methylchroman-4-acetic acid; 69%; m.p. 126-131 ° C.

Calculated,%: C 49.50; H 4.15.

C. ι

Found,%: C 49.58; H 4.07.

89. 6-Nitro-7-fluoro-c-4-hydroxy-. -r-2-methylchroman-4-acetic acid; 42%; m.p. 133-137 ° C *

Calculated,%: C 50.53; H 4.24;

N 4.91.

C, _g RKO ₆

Found,%: C 50.23; H 4.30;

N 5.08.

90. 6-Nitro-4-hydroxy-2,2-dimethyl · chroman-4-acetic acid; 64%; go / e 281 (R ⁺ ), 264/248, 222, 207, 266,

120, 83.

Calculated,%: C 55.51; H 5.38;

N 4.88.

Found,%: C 55.48; H 5.27;

N 4.93.

91 6,7-Dichloro-4-hydroxy-2,2-dimegylchroman-4-acetic acid; 76%;

g.pl. 147-149 ° C (with decomposition). Calculated,%: C 51.16; H 4.62.

C 1

Found,%: C 51.47 /: H 4.76.

92. 5,6-Dichloro-4-hydroxy-2,2-dime-gylchroman-4-acetic acid; 22%;

g.pl. 152-155 ° C.

1591809

24

Calculated,%: C 51.46; H 4.62.

S IN _N o ¢ 01 2

Found,%: C 51.09; H 4.57.

... 93.7-Fluoro-c-4 ^ hydroxy-g-2-methyl-5

chroman-4-acetic acid; 53%; m.p. 106- 119 ° C.

Calculated,%: C 60.0; H 5.45;

^C 12 ^H

Found,%: C 59.84} H 5.33,. ten

94. 6,7-Difluoro-c-4-hydroxy-r-2- ", -methylchloroman-4-acetic acid; 62%; m.p. 128-131 ° C.

Calculated,%: C 55.81; H 4.68.

C ^ H ^ P ^ O 15

Found,%: C 55.88; H 4.70.

95 6-Piano-7-fluoro-c-4-hydroxy-g-2- _M methylchroman-4-acetic acid;

54%; m.p. 142-144'S. '

¹ H-NMR. (NMSO) sR, sch „d. : 7.87, (d, ^C 1H, L = 7 Hz); 6.98 d, 1H, L = 12 Hz);

4.52 (m, 1H); 2.68 (d, 2H); 2.50 "

(s, 2H); 1.73 (τ, 1.H); 1.35 (d.,

ZN). 25

96. 6-Chloro-6-bromo-c-4-hydroxy-r-2-methylchroman-4-acetic acid;

67%; m.p. 154-157 * 0.

Calculated,%: C 42.95,: H 3.60. with _ι2 η ₁₂ βγοιο ₄ ЗС

Found,%: C 43.19; H 3.60.

97. 6-Fluoro-7-bromo-c-4-hydroxy-r-2-methylchroman-4-acetic acid;

63%; m.p. 151-154 ° C.

Calculated,%: C 45.16; H 3.79.

C, ₂ N _p VgRO ₊

Found,%: C 45.36; H 3.79.

98 5-Bromo-6-fluoro-c-4-hydroxy-r-2-methylchroman-4-acetic acid;

39%; m.p. 121-124 ⁶ S.

Calculated,%: C 45.16; H 3.7.

C _a H _{? 1} BgP0 ₄

Found,%: C 44.96; H 3.75.

99. 6-Chloro-7-ethyl-c-4-hydroxy-r-2-methylchroman-4-acetic acid; m.p. 99-103 ° C:.

Calculated,%: C 59.05; H 6.02.

C ₁₄ H ₁₇ C10 4

Found,%: C 59.06; H 6.16.

Example 100 2K, 4K-6,7-Dichloro-, -4-hydroxy-2-methyl-4-acetic'acid- ³ .

Under a nitrogen atmosphere a solution of 5.1 ml (3.6 g, 0.036 mol) _{g of} isopropylamine in 22 ml tetrahydrofuran was cooled to '-62'S. While maintaining the temperature from -56 to -60 ° C for 50 min, add 22, £ ml of 1.6 M n-butyllithium in hexane,

"And the resulting mixture is cooled further ___

to -78 ° C. Ethyl acetate (3.5 ml, 0.036 mol) is added dropwise over 80 minutes, maintaining the temperature in the range from -70 to -73 ° C, and the resulting mixture is cooled and stirred at -78 ° C for 30 min. Continuing to maintain the temperature -68 to -74 ^{° C,} for 2 hours, a solution of 7.5 g of 2R-6,7-dihpor-2-metylhroman-4-one (0.032 mol) in Ϊ4 tetragitsrofurana ml and then 5 mp of tetrahydrofuran for wetting. After 4 hours at a temperature of about -70 * 0 over 3 minutes add

1.3 ml of water, and during this time the temperature rises to -61 ° C. The temperature is allowed to rise to 0 ° C in 2 hours, an additional 7.3 mp of water is added and the resulting mixture is warmed to room temperature (26 ° C). It was kept for 3 h, distilled off in vacuo to a volume of 20 ml and diluted with 40 ml of water, extracted with 2x20 mp methylene chloride. The organic layers are combined and backwashed with 20 ml of water. The original aqueous layer and backwash are combined, cooled to 10 ° C, separated by 20 ml of methylene chloride, and then the pH is adjusted from 12.4 to 4.5 with concentrated hydrochloric acid. The organic layer was separated, the aqueous layer was extracted with an additional 20 ml of methylene chloride, which was combined with the first organic layer, backwashed with 40 ml of water and distilled off to obtain an oil (9.9 g).

This oil is placed in 20 yl of isopropyl ether and carefully (foaming) extracted with 30 ml (10 wt.%) Volume of sodium bicarbonate. The carbonate layers are combined, washed with 2x10 ml of isopropyl ether and 3x10 ml of methylene chloride, diluted to 75 ml with water, cooled to 10 ^e C, exfoliate with 75 ml of methylene chloride, and the pH is adjusted to 2.0 with concentrated hydrochloric acid. The aqueous layer is separated and washed with 20 ml of methylene chloride. Both are organized. the layers are combined, dried over magnesium sulfate and distilled off in vacuo to obtain an oil (9.5 g), which crystallizes from 12 ml of stirred methylene chloride by the slow addition of 20 ml of hexane at room temperature, and is isolated by filtration after granulation for 1 h and cooling to 5 ° C 6.0 g of the target product, identical to the product of example 7.

25

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26

Example 101 Ethyl b-fluoro-c-4 -hydroxy-g-2-methylchroman-4-acetate. To a solution of 180.2 mg (1 mmol)

6-fluoro-2-methylchroman-4-one in 0.17 ml of $ (1.5 mmol) ethyl bromoacet.ta in 1 ml of benzene at 23 ° C add 98 mg of metallic zinc (obtained by granulation of zinc). Crystals of iodine are added to initiate the reaction. Careful heating results in unexpected boiling and isothermal reaction. The reaction mass is allowed to cool to 23 ^° C and drunk in 20 ml of 1N hydrochloric acid. hydrochloric acid and 20 ml of diethyl ether. The organic layers are separated, washed sequentially with 10 ml of 1N hydrochloric acid. hydrochloric acid, 10 ml of water and 10 ml of brine, dried over magnesium sulfate and concentrated in vacuo to give the product, 251 mg (95%) as a yellow oil with physical properties identical to those of the product of example 18.

Example 102 Allyl-6,7-dichloro.-c-4-hydroxy-r-2-methylchroman-4-acetate.

To a solution of 2.7 mp (19 mmol) of diisopropylamine in 30 ml of tetrahydrofuran, 7.3 ml (19 mmol) of 30

2.6 M n-butyllithium in hexane, keeping the reaction temperature below 5 ° C. The reaction mass is cooled to -78 ° C and 2.05 ml (19 mmol) of allyl acetate is added, and then 4.0 g (17.3 mmol) ^ 5 .6,7-dichloro-2-methylchroman-4-one in 10 mp of tetrahydrofuran, keeping the temperature below -65 ° C. The reaction mass is quenched with 5 mp of water, diluted with 30 ml of diethyl ether and left to warm to 10 ° C. The layers are separated and the aqueous layer is washed with 20 ml of diethyl ether.

The combined organic layers are washed with 20 ml of brine, dried over 45 magnesium sulfate, and concentrated to. vacuum to obtain 6.1 g of the product in

the form oils • -NMR (SBS1 , ppm: 7.5 0 (p. 1H); 6.85 (with., 1H); 5.43-5.08 (m ,, ZN); 4.62 (m „, 2H); 4.16 (mo, 1H); 2.82 (with., 2H); 2.13 (m, 2H); 1.37 (d., ZN) _o NS ROME e r 103. 6,7-Dichlor -s-4-

-hydroxy-g-2-methylchroman-4-acetic $$ acid.

To a solution of 319 mg (1 mmol) of the product of example 102 in 3 ml of methylene chloride was added 0.7 mp (1.1 mol) of 1.39 M

a solution of sodium-2-ethylhexanate in ethyl acetate, 25 mg of tetranis (triphenylphosphine) palladium in 25 mg of triphenylphosphine.

The reaction mixture is stirred at 23 ° C for 1 hour, then 30 mp of water and 30 ml of diethyl ether are added. The layers are separated, the aqueous layer is washed with 2x20 ml of diethyl ether, acidified with 1 ml of 1N. hydrochloric acid and extracted with 2x20 mp diethyl ether. The latter are combined, sujat over magnesium sulfate and concentrated in vacuo to give 222 mg of a crude solid. Trituration with hexane gave a white solid, 137 mg (47%), collected by filtration, mp 160—

162 ° C.

'H-NMR (OMSO-O <,) <£, ppm: 7.57 (s, 1H); 6.96 (s, 1H); 4.38 (m, 1H);

2.64 (q, 2H); 2.50 (d, 1H); 1.69 (t, 1H); 1.39 (d, 3N), almost identical to the product of example 5.

PRI me R 104. Ethyl-6,7-dichloro-c-4-hydroxy-g-2-trifluoromethyl chroman-4-acetate „

To a solution of 0.11 ml (0.81 mmol) _{g of} diisopropylamine in 4 mp of tetrahydrofuran is added (7.31 ml (0.81 mmol)

2.6 M n-butyllithium in hexane, supported. live reaction temperature is below 5 ^ά 0.. The reaction mixture was cooled to -78 ° C and added 0.08 mL (0.81 mmol) etilch acetate, _with keeping the temperature below -65 ° C. A solution of 0.211 g (0.74 mmol) of 6,7-dichloro-2-trifluorome-. tilchroman-4-she. in 2 ml of tetrahydrofuran, maintaining the temperature below -65 ° C. The reaction is quenched with water, diluted. The mixture is taken up in diethyl ether and heated to -10 ° С. Additional water is added and the layers are separated. The aqueous layer was extracted with 2x25 mp diethyl ether and the combined ether layers were washed with 25 ml brine, dried over magnesium sulfate and concentrated in vacuo to give 251 mg of a solid, which, according to NMR, is an 80:20 mixture of the product to the starting chroman.

¹ H-NMR (SBS1 ppm: 7.50 (s, '1H); 6.97 (s, 1H); 4.50 (m, 1H);

4.20 (q, '2H); 2.76 (s, 211) 2.431.63 (m, 2H); 1.27 (t1, 3N).

Example 105 6,7-Dichloro-c-4-hydroxy-r-2-trifluoromethyl chroman-4-.

-acetic acid.

1591809

28

27

To a solution of 248 mg of the crude product of Example 104 in 3 ml of ethanol was added 41 mg (0.73 mmol) of potassium hydroxide. The reaction mixture was stirred at 23 ° C for 4'h, then concentrated in vacuo at 23 ° C. The residue is partitioned between diethyl ether and water. The aqueous layer was washed with diethyl ether (2x25 mp) and then acidified with 1 ml of 1N HCl. hydrochloric acid and extracted with 2x25 ml of diethyl ether. The ether extracts are then combined, washed with 25 ml of brine, dried over magnesium sulfate and concentrated in vacuo to give 12 mg (5.1%) of the desired product in the form of a gum.

¹ H-NMR (ϋΜ00- _£ ) ί, ppm: 7.65 (s, 1H); 7.21 (s, 1H); 5.15 (m, 1H);

2.85 (m, 1H); 2.70 (q,., 2H); 1.92 20

(t., 1H).

Mass for C ^ HdO ^ C! ³ ^ C1 ^E7 P m / e: calculated 34.5, 9800, found 345,

9840.

PRI me R 106. Allyl-6,7-dichloro-? 5 -c-4-hydroxy-g-2-trifluoromethyl chromai- ¹ -4-acetate. '

To a solution of 0.82 ml (5.85 mmol) of diisopropylamine in 13 mp of tetrahydrofuran, 2.25 ml (15.85 mmol) 30 2.6 M of n-butyllithium in hexane, sup. live temperature below 5 ° C. The reaction mixture is cooled to -78 ° C and 0.63 ml (5.85 mmol) of allyl acetate is added. that, keeping the reaction temperature below 35 ^to -65 C. A solution of 1.516 g (5.32 mol) of 6,7-dichloro-2-triftorme |. Til-chroman-4 in 4 ml of tetrahydrofuran, while maintaining the reaction mixture temperature below -65 ° C. The reaction is quenched to

1.5 ml of water, and then diluted with 15 mp • diethyl ether and heated to 10 ° C .: Add water (15 mp) and diethyl ether (15 ml), isolate the aqueous layer and extract with 15 ml of fresh diethyl ether ... The combined ether solutions were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 1.99 g (97%),

of the title product, as 59 yellow syrup.

... ¹ H-NMR (CCC1 ₃ ) <?,. ppm 7.53 (s.,

1H); 7.00 (s, 1H); 6.12-5.07 (m.,

ZN); 4.63 (d, 2H); 4.33 (m, 1H);

2.83 (s _?, 2H); 2.63-1.92 (m, 2H). ₅₅

Example 107 6,7-Dichloro-c-4-hydroxy-r-2-trifluoromethyl chroman-4-acetic acid.

To a solution of 1.841 g (4.78 mmol) of the product of example 106 in 18 ml of methylene chloride add 4.2 ml (5.26 mmol)

1.25 M sodium 2-ethylhexanate in ethyl acetate, 120 mg (0.0104 mmol) tetranis (triphenylphosphine) palladium and 120 mg (0.0457 mmol) triphenylphosphine. The reaction mixture was stirred at 23 ° С for 1 h, diluted with water, washed with diethyl ether, acidified with 7MP 1N HCl. hydrochloric acid, extracted with diethyl ether. The ethereal extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 741 mg of a colorless oil. When diluted with hexene, crystallization occurs. The target product is isolated in the form of white crystals, mp 130-135 ° C.

Calculated,%: C 41.76; H 2.63. s ₇₂ n ₃ s1. ₂ to _e about ₄

Found,%: C 42.01 ": H 2.63.

Examples 107-1 Y., Various substituted ethyl-4-hydroxy-2-substituted chroman-4-acetate

By the method of examples 1,4,8,10,12 ,. 14, 16 and 18, the corresponding substituted chroman-4-ones are converted to the corresponding substituted ethyl-c-4-hydroxy-g "-2-substituted chroman-4-acetates (indicated as' example number, product name, yield (eluent, if chromatographic purification on silica gel was carried out) and physical properties):

107. Ethyl 6-fluoro-4-hydroxy-2,2-spirocyclopentylchroman-4-acetate; 96%; t / e 308 (P +), 261, 227, 221, 203,

181, 139.

108 o Ethyl 6-fluoro-c-4-hydroxy-r-2- (4-methoxybenzyl) chroman-4-acetate;

'39% (SNC1s). oil: ha / e 374 (P * ^ 3%), 356 (P * -H _g O, 17%), 235 (89%), 165 (49%), Ί39 (22%), 121 (100%) ...

'H-NMR (C1) C1 ₃ ) lH, ppm: 1.2 (t, 3H); 2.2 (d, d, 2H); 3.8 (ς., 3H);

4.1 (q, 2H), 4.3 (s + m, 2H);

6.7-7.3 (m, 7H).

109 o Ethyl 6-fluoro-c-4-hydroxy-r-2- (4-chlorobenzyl) chroman-4-acetate; 95% (toluene); m.p. 116-119 ⁱⁿ C; m / e 380, 387 (P ⁺ , 12%), 291 (Ρί-ΟΗ ^ Ο ^ Η ^, 11%), 273, 235 (100%), 207, 165 (40).

'H-NMR (HPS1 ₅ ) ^>, ppm /. 1.20 (i.e.

ZN); 1.94 (t, 1H); 2, 18 (d, 1H); 2.78 (with., 2H); 2.9 (m. , 1H); 3.06 (m ,, 1H); 4.0-4.4 (m., 38); 4.45 (s., 1H); 6.7-; 7.0 (m, 2H); , 7.1-7.5 (m., 5H).

29 / '

1.591809

thirty

Calculated,%: C 65.00; H 5.52. '.

С _{2 (?} Н _2о О ₄ С1Р «1/4 С ₆ Н ^ СН _e

Found,%: C 64.65; H 5.47,

110 o Ethyl 7-benzyloxy-6 ^- chloro-c-4-hydroxy-g-2-methylchroman-4 ~ acetate; $ .100%; oil (1 H-NMR corresponds to the product).

Numbers 111-114. Various substituted 4-hydroxy-2-substituted chroman-4-acetic acids.

For Examples 2,5,9,11,13,15 and 19, the esters of Examples 20-48 are converted to the following substituted c-4-hydroxy-r-2-substituted chroman-4-acetic acids (example number is indicated, product name, yield and physical _: properties, analysis data):

111 "6 ~ Fluoro-4-hydroxy-2,2-spirocyclopentylchroman-4-acetic acid; ₂₀ 86%; m.p. 110-112 ° C; m / e 280 (I *),

233, 221, 203, 181, 139.

Calculated,%: C 64.27; H 6.11. c ^ n _t7 ro ₄

Found ^%: C 64.22; H 6.02. 25

112, Dicyclohexipammonium-6-fluoro-C-4-HYDROXY-G-2- (4-methoxybenzyl) ι chroman-4-acetate; 46% (salt crystallizes on ether); m.p. 136-139 ° C; m / e 346 (P * -, 2.2%), 328 (P ⁺ -H ₂ O) ₃₀

207 (15%), 181, 165, 139 (100%), 121,

56, 41.

Calculated,%: C 70.56; H 8.02; N2.66.

^S 19 ^N 1E ° 5 ^R ' ^S P ^N 1E ^M 35

Found,%: C 70.93; H 8.06;

(ί 2.47.

113. Dicyclohexylammonium-6-fluoro-c-4-hydroxy-r- (4-chlorobenzyl) chroman-4-acetate; -33% (salt crystallizes from ether); m.p. 171-174 ° C; lp / e 352,

350 (P +, 3.6%), 332 (P ⁺ -H ₂ O), 207 (40%), 18 (13%), 165 (35%), 138 (100%), 56.41.

Calculated,%: C 67.72; H 7.39; ₄ d N 2.63.

С „Н 'С _а Н ₂ ^

Found,%: C 68.03; Ή 7.54;

L 2.48.

114. Dicyclohexylammonium-7-benzyloxy-6-chloro-c-4-hydroxy-r-2-methylchroman-4-acetate; 50% (salt is crystallized from ether); m.p. 192-194 ° C (with decomposition); m / e 362 (Ρ ⁺ ), 303 (p-CH ₂ CO ₂ H), 300, 181.

Calculated,%: C 68.43; H 7.78;

N 2.57.

Found,%: C 68.38; H 7.64;

'N 2.52.

Tests for biological activity.

Compounds of formula (I) were tested ϊη νίΤτο for their ability to restore or inhibit the accumulation of sorbitol in the sciatic nerve, streptozotonized, i.e. diabetic rats according to a known method. The amount of sorbitol accumulated in the sciatic nerve was measured 27 hours later and after the induction of diabetes. Typically, the compounds were administered orally at doses ranging from 2.5 to 100 mg / kg 4.8 and 24 hours after streptozocin administration. The results obtained in this way are presented as the percent inhibition provided by the test compound compared to the case when no compound was administered (i.e., compared to an untreated animal in which the sorbitol level increased from 50 100 to 400 mM / g tissue during the time of the test. ). In this test, values below 20% do not always have experimental and statistical significance.

The compounds of formula (I) can be used for therapeutic use as aldose reductase inhibitors to combat the complications of chronic diabetes in mammals. They are taken, either orally, or pa- *; renterally, or superficially in the form of eye drops in doses ranging from 0.1 to 10 mg / kg of the patient's live weight · ': per day in single or in divided doses. Naturally, in specific cases, according to the doctor's prescription, it is possible to use doses that are not in this range of values.

The compounds of formula (I) can be administered in a wide range of different dosage forms, i. E. they can be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, hard lozenges, powders, sprays, elixirs, syrups, injections or eye drops and the like. Such carriers include solid diluents or fillers, sterile aqueous. media and various non-toxic organic solvents.

For oral administration use

tablets containing such different /

31

32

1591809

excipients such as sodium citrate, calcium carbonate and calcium phosphate, along with various disintegrants such as starch and preferably potato or tapioca, alginic acid and some complex silicates together with binders such as polyvinylpyrrolidone, sucrose, gelatin, and acacia. In the manufacture of tablets, units

very often lubricant additives such as magnesium stearate, sodium lauryl sulfate and talc can be useful. Solid compositions of a similar type are also used as fillers in soft and hard gelatin capsules, preferred materials in this regard are lactose or milk sugar and high molecular weight polyethylene glycols. If aqueous suspensions and / or elixirs are used for oral administration, the main active ingredient can be combined with various sweetening agents: fragrances, coloring agents, emulsifying agents and / or suspending agents, and diluents: water ^ ethanol, propylene glycol, glycerin, and various combinations thereof. ZO

For parenteral administration it is possible. use solutions of hemp or peanut oil, aqueous propylene glycol, and sterile aqueous solutions of the appropriate water-soluble salts of the alkali or alkaline earth metals listed above. Such aqueous solutions should be appropriately buffered if necessary and the liquid diluent dd rendered isotonic at the outset with an appropriate amount of salt or glucose. These special aqueous solutions are especially suitable for intravenous,

35

intramuscular, subcutaneous and intraperitoneal administration. In this regard, all sterile aqueous media used are easy to obtain, using standard methods.

For topical use, dilute, sterile * injection solutions (usually at a concentration of about 0.1 to 5%) otherwise similar to the solutions described — or for parenteral administration — are prepared in containers suitable for drip into the eye.

Known inhibitors of aldozo pe-; ductases, in particular sorbonyl, is50

55

are used to control certain chronic complications arising from diabetes mellitus, containing hzgantoin functionality that is associated with allergic reactions in some patients. The advantages of the compounds of formula (I) are that they retain a high level of aldose reductase inhibitory activity without inhibiting hydantoin functionality.

Moreover, where one agent may be unsuccessful for a given individual, another may be effective, so there is a need for multiple types of drugs for a given medical indication.

Rezudtaty activity, or presented as percent inhibition of aldose reductase at a given concentration, shown as the molarity (M) or as 1S_5- _0. the concentration (as molarity) at which the enzyme is inhibited by 50% is tabulated.

The proposed compounds in the tested doses did not show signs of toxicity and can be classified as low-toxic.

Claims (1)

Claim A method of obtaining derivatives of 4-hydroxy-2-substituted chroman-4-acetic acid in the form of a racemic compound or an optically active compound having the absolute stereochemical formula 'of the general formula 45 where K ₁ - C, -Cf-alkyl or group (CB _d ) _p Ar, where η = 1. or 2, Ar is phenyl, unsubstituted or substituted with chlorine; K ₂ is hydrogen, methyl or ethyl; K is hydrogen or methyl, provided that if K is other than methyl or ethyl, then Ci H ₃ are both hydrogen; X is hydrogen or a first substituent in the 6th position, such as fluorine, chlorine or bromine, methyl or nitro; 33 1591809 34 X is hydrogen or the first substituent in the 7th position, such as fluorine or chlorine, or. the second substituent is either in the 7-position, such as fluoro, chloro, C, -C ₃ -alkyl or C <-C ₃ -alkoxy group, or in the 5-position, such as chloro or C, -C ₃ -alkyl ; X ₂ ~ hydrogen or a first substituent at the 8th position, such as chlorine, or a second substituent at the 8th position, such as chlorine or C ^ -C ^ -alkyl, or their pharmaceutically acceptable cationic salts, characterized in that hydrolysis is carried out the corresponding racemic ester of general formula C00B4 where K /, K. ₂ , K. ₃ , Χ, Χ ,, X ₂ have the indicated values; To ₄ - C ^ Cf-alkyl, allyl or phenyl, and the target product is cured in the form of a racemic compound in free form or c. the form of a salt or separate it into the corresponding optical isomers and isolated as an optical isomer Compound of formula (I) 1C ₅₀ or percent inhibition at a given concentration, M 1 | X / X, / X _g Ζ n n n 1 6-P 0. ... 3.1 x1 (H sn. n n 6-P 0 7.0 x 10 ^'7 ch ₃ ch ₃ n 6-P 0 3.0 * 10 ' ⁶ "(CH ^ a - n 6-r 0 1.0 * 10 s ₂ n / ³ n-s ₃ n ₇ i-s ₃ n ₇ n n n n n n 6-P 6-P 6-P 0 0 0 2.9 * 10 ' ⁷ 6.0 * 10' ⁷ 4.6 * 10 ' ⁷ t ~ S.H □ n n 6-P 0 3.5 * 10- ⁷ f n n 6-P 0 2.0 * 10 "^ CH ₃ CH ₂ CH ₂ F n n cn n 6-P 6-P 0 0 '5.2 * 10' ⁷ 6.9χ10 ' ⁷ (3,4-diC1) CH ₂ F n n 6-P 0 4.6 * 10 ' ^έ ch ₂ f th n 6-P 0 8.3 * 10 ' ⁷ CH ₃ s ₂ N ₅ 7 n 6-P. 0 4.4-6.0 * s ₂ n ₅ CH ₃ ch. ^SN E) n ⁷ n n n n 6-CH, O' 0 1.0 * 10 ' ⁵ 7.6 * 10 ^ sn ' n n. 6-C1 0 8.6 x 10 ^"7 sn, sn. n n 6-Bg 0 ' 1.9 * 10 ^ n n 6-ΝΟί 0 9.0> 10 ' ^£ ch ₃ n n 6-SOF 0 6.3 * 10 ' ⁷ ch ₃ n n 6,8-diC1 0 9.3 * 10 ' ^? CH ₃ n n 6-C1, 0 1.0 * 10 ' ¹ 8-CH CH, n n 6-Bg 0 4.1 x10- ⁶ 8-C1. ^sn z. n n 5-C1, 0 1.0h0 ' ^th 6-C1 -ί ch ₃ n n 5- CH ₃ , 6- ΝΟ ₂ 0 1.0x10 1591809 36 Table continuation Compound of formula (X) | χ / *, / *, I ζ 1C _5a or percent inhibition at a given concentration, M <G h I No. ₃ '' n n 6,7-diC1 0 2.5 * ^{10``7</sup> he <sub>3</sub> ' n. n 6-C1, 0 1,0x10 ' <sup>7</sup> . 7-CH <sub>3</sub> CH n n 6-Ν0 <sub>2</sub> , 0 5.1. * 10 ~ * 7-C1. ... ch <sub>z</sub> ·; ... · n n 6- Ν0 <sub>2</sub> , 7- CH <sub>e</sub> 0 9.5 * 10 "" ch <sub>3</sub> n n 6- C1, 7- 0C1 <sub>3</sub> 0 2.0 * <sup>10``7} CH, n n 6-C'1, 0 5.6 * 10 * " 7-0CH ₃ ch ₃ n n 6-P, 0 5.4 * 10 '" 7-C1 ch ₃ SI n n n n 7-C1 7-C00H 0 0 3.3 * 10 '* 5.6 * 10 "" ch ³ n n 6-C1, 0 5.5 * 10 ' ⁷ 7.8- (CH ₂ ) ₄ ssch n n 5,8-diC1 0 7.5 "1O ~ * ch ₃ n n 8-C1 0 4.7 * 10 '* ch ₃ n n 7,8-diC1 0 9.5 * ^10'7 ch ₃ ch ₃ n n 7-P 0 4.2 * 10 "* n n 6-ΝΟ ₂ , 0 9.2x10 " 7-P ch ₃ n n 6- C1, 7- R 0 4.9 * 10 ' ⁷ CH, n n 6,7-diR 0 6 ,, 3 * 10 “ ch ₃ sn _e n 6-ΝΟ g 0 2.5 * 10 ' ⁷ ch ₃ sn, n 6,7-diC1 0 1.0 * 10 ^ ch ₃ ch ₃ n 5,6-diC1 0 1.0 * 10- ^ ch ₃ ch ₃ n 6-P 0 3.0 * 10- * Note :® is phenyl ί