SU1470194A3 - Method of producing xanthone derivatives - Google Patents

Abstract

NEW MATERIAL:A compound of formula I(X, Y are H, halogen, lower alkyl; Z is H, halogen; A is hydroxymethyl, lower alkoxycarbonyl, carboxyl). EXAMPLE:2,3-Dihydro-11-methyl-5-oxo-5H-furo[3,2-b]xanthene-2-carboxylic acid. USE:Uricosuric, diuretic: it has reduced side-effect on the liver. PREPARATION:For example, a peracid is allowed to act on a compound of formula II (the hydroxyl group and the allyl group are adjacent to each other) such as 2-allyl-3-hydroxy-4-methyl-9-oxo-9H-xanthene to give the compound of formula I where A is hydroxymethyl. The peracid is, e.g., m-chloroperbenzoic acid.

Description

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The invention relates to a method for the production of xanthone membranes that have a diuretic (uricose) action with a low current identity.

The purpose of the invention is to obtain xanthone derivatives possessing valuable biologically active properties.

Example 1. To a mixture of 2-alkyd-3-hydroxy-4-metsh-9-oxo-9H-xanthene (11 g) and chloroform (800 ml) to (5av-9, 9.5 g of meta-chloroperbenzoic caslotte. The resulting the mixture is stirred at room temperature for 5 hours, after which the mixture is allowed to settle overnight. Potassium carbonate (20 g) and water (500 ml) are added to this mixture. The resulting mixture is extracted with chloroform. The chloroform layer is dried, the solvent is distilled off. the distillation product is recrystallized from ethanol.

10 g of 2,3-dihydro-2-hydroxymethyl-11-methyl-5-oxo-5H-furo (3,2-b) xanten are obtained, m.p. 242-243 C.

WITH

four

cm

The target compound has a mass-spectrum including a molecular ion peak at m / e 282.

Example 2, to ice-cooled (1 mixture, 16.1 g of 2,3-dihydro 2-oxymethyl-11-methyl-5-oxo-5H-furo (3,2-b) xan-Uon, prepared according to example 1, and zooo ml acetone is added dropwise with a simultaneous stirring of a mixture of chromium trioxide (57 g), water (280 ml) and concentrated hydrochloric acid (84 g). The resulting mixture is kept overnight and filtered.

Evaporate to dryness under vacuum. After

by adding water, the solid crystals 1 are removed by filtration, washing and drying.

I After recrystallization from a mixture of ijoro solvent of methanol and dichloro-Jethane, 11.1 g of 2,3-dihydro-1-metnp-5-oxr-5H-furo (3,2-b) xanthen-2-carboxylic acid, t pl. : 97-299 C. The target compound has a mass spectrum including a molecular ion peak at m / e - 296.

PRI me R Z. A mixture of 4 allyl-8- (3) tor-3-hydroxy-9-oxo-9H-xanten (1.4 g 1 | 1-chlorophenol-benzoic acid (1.2 g litro form (250 ml) the mixture is stirred at room temperature for ч h and then held for 2 hours after potassium carbonate is added 2 g) and water (50 ml), the mixture is extracted with chloroform, the chloroform layer is dried, the solvent is distilled off. The residue is distilled from ethanol.

1.2 g of 7-fluoro-1, 2-dihyd- () o-2-hydroxymethyl-6-oxo-bN furo (2,3-e) xanten are obtained. m.p. 220-22l c. Target (Compound has a mass spectrum including a molecular peak at W 7 286.

Example4. To the cooled ice fmesi 8.0 g of 7-FTOR-1,2-dihydro-2 0x-methyl-6-o-co-6H-phypo (2,3-c) scan t: ena, prepared according to example 3, and 1000 ml of acetone added And a mixture of chromium trioxide (14 g), water (70 ml) and concentrated sulfuric acid, 24 g) is added dropwise with And-simultaneous stirring. The resulting mixture was incubated overnight and filtered. The filtrate is dry under vacuum. After water is added, the solid crystals are recovered by filtration guthem, p1) is washed with water and dried.

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After recrystallization from N, N-dimethylformamide (DMF), 8.1 g of 7-fluoro-1,2-dihydro-6-oxo-bH-furo (2,3-c) xanthene-2-carboxylic acid are obtained, mp. . 262-265 ° C.

The target compound has a mass spectrum including a molecular ion peak at m / e 300.

PRI me R 5. A mixture of 2-allyl-8-fluoro-3-hydroxy-4-methyl-9-oxo-9H-xantene (9.0 g), meta-chloroperbenzoic acid (8.0 g ) and chloroform (1000 ml) is stirred at room temperature for 5 hours and left overnight. Potassium carbonate (20 g) and water (500 ml) are added to this mixture. The mixture was extracted with chloroform. The chloroform layer is dried, the solvent is distilled off. The residue was dissolved in acetone (1000 ml). A mixture of chromium trioxide (21 g), water (120 ml) and concentrated sulfuric acid (36 g) is added to the stirred solution. The addition is carried out dropwise at room temperature. After overnight, the mixture is filtered, the filtrate is evaporated to dryness in vacuo. After adding water, the resulting solid crystals are removed by filtration, washed with water and dried.

After recrystallization from ethanol, 5.0 g of 6-fluoro-2,3-di-hydro-11-methyl-5-oxo-5H-furo (3,2-b) xanthene-2-carboxylic acid are obtained, m.p. 292-295 ° C.

The target compound has a mass spectrum including an ionic molecular peak at m / e 314.

PRI me R 6. A mixture of 4-allyl-8-chloro-3-hydroxy-9-oxo-9H-xanthene (15 g), metachlorophenol benzoic acid (14 g) and chloroform (1000 ml) is stirred at room temperature in for 5 hours and hold overnight. Potassium carbonate (20 g) and water (500 ml) are added to this mixture. The mixture was extracted with chloroform. The chloroform substrate is dried, the solvent is distilled off. The residue was dissolved in acetone (2000 ml), and a mixture of chromium trioxide (15 g), water (90 ml) and concentrated sulfuric acid (26 g) was added dropwise to the mixture at room temperature. After overnight, the mixture is filtered and the mixture is filtered, the filtrate is evaporated to dryness in vacuo. After the water has been added, the solid crystals are removed by filtration, washed with water and dried.

After recrystallization from ethanol, 0.9 g of 11-chloro-2,3-dihydro-5-oco-5H-phypo (3,2-b) cyantene- is obtained. 2-carboxylic acid, so pl. 290- 2934..

The target compound has a mass spectrum including a molecular ion peak at m / e 316.

PRI me R 9. A mixture of 2-allyl-4-chloro-8-fluoro-3-hydroxy-9-oxo-9H-xantene (2.8 g), meta-chloroperbenzoic acid (4.7 g ) and chloroform (100 ml) is stirred at room temperature for 5 hours and then held overnight. Potassium carbonate (10 g) and water (200 ml) are added to this mixture and the mixture is extracted with chloroform. Chloroform layer

15

20

The filtrate is evaporated to dryness under vacuum. After water is added, the solid crystals are removed by filtration, washed with water and dried. After recrystallization from ethanol, 8.0 g of 7-chloro-1,2-dihydro-6-oxo-bH-furo (2,3-e) xanthene-2-carboxylic acid are obtained, tons. 283-286 c.

The target compound has a mass spectrum including a molecular ion peak at m / e 316.

PRI me R 7. A mixture of 4-ajijraji-3-hydroxy-9-oxo-9H-xanthene (10 g), m-chloroperbenzoic acid (21 g) and chloroform (1000 ml) is transferred at room temperature for 5 h, then hold overnight. Potassium carbonate (40 g) and water (1000 ml) are added to this mixture. The mixture was extracted with chloroform. The chloroform layer is dried and the solvent is distilled off. Residue-GT rLa P. ; "

the thief is added dropwise at room tone (500 ml). To mixed

Ch: -Go p - ™: .i; „Г f - 30 U a;,. 0. O., „.0 .-

Ruut, the filtrate is evaporated Dry in "", ",", all

filtered, the filtrate is evaporated in vacuo to dryness. After water is added, the solid crystals are removed by filtration, washed with water and dried.

After recrystallization from ethanol, 1.0 g of 11-chloro-6-fluoro-2,3-dihydro-5-oxo-5P-furo (3,2-b) xanthene-2-carboxylic acid is obtained, m.p. 300-C.

The target compound has a mass, including an ionic molecular peak at m / e 334.

Example 10. A mixture of 4-allyl-2 - chloro-3-hydroxy-9-oxo-9H-xanten

(2.9 g), m-chloroperbenzoic acid (3.5 g), and chloroform (3000 ml) is stirred at room temperature for 5 hours and then kept at room temperature overnight. Potassium carbonate (10 g) and water are added to this mixture. (200 ml), the mixture was extracted with chloroform. Chloroform layer

The "- -" -, "- was dried, the solvent was distilled off.

a mixed solution of "" avgSS obtained A-chloro-1,2-dihydro-2-okol m at room temperature a mixture of "b-oxo-6H-furr (2,3-c) xanthene chromium trioxide (1.7 d) water (.10 ml; acetone (300 ml). To the stirred solution is added over

vacuum. After water is added, the solid crystals are removed by filtering the radio, washed with water and dried.

After recrystallization from ethanol, 4 g of 1,2-dihydro-6-oxo-6H-phypo (2,3-c) cantan-2-carbox are obtained.

acids, so pl. 283-286 c.

The target compound has a mass spectrum including ionic p-40 ny molecules at m / e 282.

PRI me R 8. A mixture of 2-all-1-4-chloro-3-hydroxy-9-oxo-9H-xanthene (2.0 g), m-chloroperbenzoic acid (3.6 g) and chloroform (100 ml a) stir at room temperature for 5 hours and then incubate overnight. Potassium carbonate is added to this mixture. (8 g) and water (200 ml), the resulting mixture was extracted with chloroform. The chloroform layer is dried, the solvent is distilled off. The residual distillation product is dissolved in acetone (400 ml), K re-JISAWIvriX .ri. . 7 - f g

concentrated sulfuric acid (3 g). After exposure overnight

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the mixture is filtered, the filtrate is evaporated to dryness under vacuum. After the water has been added, the solid crystals are removed by filtration, washed with water and dried.

After recrystallization from ethanol, 0.9 g of 11-chloro-2,3-dihydro-5-oco-5H-phypo (3,2-b) cyantene- is obtained. 2-carboxylic acid, so pl. 290- 2934..

The target compound has a mass spectrum including a molecular ion peak at m / e 316.

PRI me R 9. A mixture of 2-allyl-4-chloro-8-fluoro-3-hydroxy-9-oxo-9H-xantene (2.8 g), meta-chloroperbenzoic acid (4.7 g ) and chloroform (100 ml) is stirred at room temperature for 5 hours and then held overnight. Potassium carbonate (10 g) and water (200 ml) are added to this mixture and the mixture is extracted with chloroform. Chloroform layer

15

20

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drops at room temperature. A mixture of chromium trioxide (3.3 g), water (17 ml) and concentrated sulfuric acid (5 g). After overnight, isopropanol (10 ml) was added to the mixture. The mixture is filtered, the filtrate is evaporated by db dry under vacuum. After the addition, the hard crystals are recovered by filtration, rinsed with water and dried.

After recrystallization from ethanol, 1.7 g are obtained. 4-chloro-1,2-dihyd-: u-6-ohco-6H-phypo (2,3-c) cantan-2-shrboxylic acid, tons. 292-295 СI. The target compound has a mass spectrum, including ionic molecules p- | ny 1tik at m / e 316,

I PRI mme R 11. A mixture of 4-aplil-1-chloro-3-hydroxy-9-oxo-9H xanthene (3.0 g), m-chloroperbenzoic acid (7.2 g) and chloroform (500 ml ) stirred at room temperature for 5 hours and then allowed to stand overnight. Potassium carbrnate was added to this mixture (20 g) and water (400 ml), and the mixture was extracted with chloroform. The chloroform layer is dried, the solvent is distilled | UT. The residue was dissolved in acetone (300 ml), a mixture of chromium trioxide (3.3 g), water (17 ml and concentrated sulfuric acid (5 g)) was added dropwise to the stirred solution at room temperature. After overnight, the mixture is filtered, the filtrate is evaporated to dryness under vacuum.After adding water, the solid crystals are taken out by filtration, washed with water and dried.

After recrystallization from ethanol, 1.6 g of 5-chloro-1,2-dihydro-6-oxo-6H-furo (2,3-c:) xanthene-2-carboxylic acid are obtained, m.p. 255-258 ° C.

The target compound has a mass spectrum including an ionic molecular peak at m / e 316. - Example 12. A mixture of 4-allyl-3-hydroxy-1-metsh-9-oxo-9H-xanthene (3.00 g), meta -chlorobenzoic acid (8 g) and chloroform (500 ml) was stirred at room temperature for 5 hours and then allowed to stand overnight. Potassium carbonate (20 g) and water (400: UL) are added to this mixture, and the mixture is extracted with chloroform. The chloroform layer is dried, the solvent is distilled off. The residue was dissolved in acetone (500 ml). A mixture of chromium trioxide (5.5 g), water (25 ml) and concentrated sulfuric acid (8.5 g) is added dropwise to the stirred solution at room temperature. After overnight, the mixture is filtered and the filtrate is evaporated to dryness in vacuo. After water is added, the solid crystals are removed by filtration, washed with water and dried.

After recrystallization from ethanol, 1.5 g of 1,2-dihydro-5-methyl-6-oxo-6H-furo (2,3-c) xanthene are obtained. 2-carboxylic acid, so pl. 231- 234 ° C.

The target compound has a mass spectrum including an ionic molecular peak at m / e 298.

Example 13. A mixture of 4-allyl-2-chloro-3-hydroxy-1-methyl-9-oxo-9H-xanthene (2.8 g), m-chloroperbenzoic acid (6.4 g) and chloroform (ZOO ml) stirred at room temperature for 5 hours and then incubated overnight. Potassium carbonate (20 g and water (400 ml) is added to this mixture, the mixture is extracted with chloroform. The chloroform layer is dried, the solvent is distilled off. The resulting distillation residue is dissolved in acetone (500 ml) to the stirred solution is added dropwise at , at room temperature, a mixture of chromium trioxide (5 g), water (25 ml) and concentrated sulfuric acid (8 g). After aging overnight, the mixture is filtered, the filtrate is evaporated to dryness in a vacuum. After adding water, the solid crystals are removed by filtration, washed with water and ysushivayut.

After recrystallization from ethanol, 1.6 g of 4-HLOR-1,2-dihydro-5-methyl-6-oco-6H-phypo (2,3-c) xanthene-2-carboxylic acid are obtained, m.p. 284-287 C. The target compound has a mass spectrum, including a 1st molecular ion peak at w / e 330.

EXAMPLE 14 A mixture of 4-allyl-2-bromo-3-hydroxy-9-oxo-9H-xanthene (3.0 m-chloroperbenzoic acid (10 g) and chloroform (250 ml) is stirred at room temperature. for 5 h, then incubated for no9U70194

chi Potassium carbonate (20 g) and water (400 ml) are added to this mixture. The mixture was extracted with chloroform. The chloroform layer is dried, the solvent is distilled off. The residue was dissolved in acetone (300 ml). A mixture of chromium trioxide (5 g), water (25 ml) and concentrated sulfuric acid (8 g) is added dropwise to the stirred solution at room temperature. After standing overnight, the mixture is filtered, the filtrate is evaporated to dryness in vacuo. After adding water, the solid crystals are removed by filtration, washed with water and dried.

Recrystallization from ethanol gives 1.5 g of 4-bromo-1,2-dihydro / rt o -N- rrrrtdTJ JPLP

ten

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can be used to treat edema or hypertension.

Diuretics, previously known, which have the effect of uricosuri, similarly to the proposed compounds, are phenoxyacetic acids, a typical example of which is thienic acid.

Conventional diuretic hypertonic drugs are widely used as essential drugs for treating hypertension, but they can cause hyperuricemia as a side effect. In addition, hypertension is often complicated by hyperuricemia and many cases of hyperuricemia are caused by impaired uric acid secretion.

la get 1.5 g -6P ° "-b / -No. ™" - 6-oxo-6H-furo (2,3-c) xanten-2-car6o-20 f // - ;;, , need for razoO and whether. U and 11 vjjjft v - - -

New acid with melting point 283-286 ° C.

The target compound has a mass spectrum including an ionic p – ny peak molecule at m / e 360.

Example 15. A mixture of 4-allyl-3-hydroxy-2-methyl-9-oxo-9H-xanthene (12 g), m-chloroperbenzoic acid and chloroform (700 ml) is stirred at room temperature for 5 hours, then incubated during the night . 20 g of potassium carbonate and 400 ml of water are added to this mixture. The resulting mixture was extracted with chloroform. The chloroform layer is dried, the solvent is distilled off. The residue was dissolved in acetone (2000 ml). A mixture of chromium trioxide (34 g), water (70 ml) and concentrated sulfuric acid (30 ml) is added dropwise to the stirred solution at room temperature. After standing overnight, the mixture is filtered, the filtrate is evaporated to dryness in

25

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There is a great need for the development of diuretics with urikozuri activity. Thienic acid is a potential diuretic agent with uricosuri activity, but it can cause disorder

the liver. .

As a result of various studies, it was established that xanthone derivatives possess both the action of urikozuri and diuretic action, and at the same time cause minimal side effects.

Pharmacological activity of the proposed compounds.

The diuretic effect of the compounds.

Wistar Imamamshi rats of six weeks of age who are not. food was given for 24 hours, divided into groups of 4 or 5 rats in each, so that the animals of each group produced almost the same amount of urine. After caused by artificial

rut, „,,,,., Urinating in rats injected with vacuum. . After adding ep45 water, the test compounds, code crystals are recovered, J, suspended in physiology, washed with water and dried. solution containing 3%

after and Shfaravyskoy gum. The volume dose of the injected solvent is ethanol and DFT -os., „„

- „l -1 -1 From-gtt-PTT GGTM-L-MR-TTYu j“ |

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8.7 g of 1,2-dihydro-4-methyl-6-OXO-6H-FURO (2,3-c) xanthen-2-car- are obtained. side acid, so pl. 2U / - / UZ ..

The target compound has a mass spectrum including an ion molecular peak at m / e 296., 5

The proposed compounds of the formula may be used as diuretic (or diuretic) agents having the action of uricosuri, and

C L CÜrl-rlV - i -. The -I-1-- dim compound was 25 ml per kg body weight. Suspensions were administered in an amount of 100 mg / kg. Oral physiologic was administered to control rats. salt solution containing 3% gum arabic. Animals were confined in separate metabolic cells. The urine excreted by each animal was collected for 6 hours after administration of the test compounds.

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can be used to treat edema or hypertension.

Diuretics, previously known, which have the effect of uricosuri, similarly to the proposed compounds, are phenoxyacetic acids, a typical example of which is thienic acid.

Conventional diuretic hypertonic drugs are widely used as essential drugs for treating hypertension, but they can cause hyperuricemia as a side effect. In addition, hypertension is often complicated by hyperuricemia and many cases of hyperuricemia are caused by impaired uric acid secretion.

w such circumstances there are 20 f // - ;; ,, the need for such circumstances there is 0 f // - ;; ,, the need for time 5

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35

40

lllJri chsnhggl, V--

There is a great need for the development of diuretics with urikozuri activity. Thienic acid is a potential diuretic agent with uricosuri activity, but it can cause disorder

the liver. .

As a result of various studies, it was established that xanthone derivatives possess both the action of urikozuri and diuretic action, and at the same time cause minimal side effects.

Pharmacological activity of the proposed compounds.

The diuretic effect of the compounds.

Wistar Imamamshi rats of six weeks of age who are not. food was given for 24 hours, divided into groups of 4 or 5 rats in each, so that the animals of each group produced almost the same amount of urine. After caused by artificial

., urination in the organism of rats with intravaginal gum. The volume dose of vvos., „„

C L CÜrl-rlV - i -. The -I-1-- dim compound was 25 ml per kg body weight. Suspensions were administered in an amount of 100 mg / kg. Oral physiological was administered to control rats. salt solution containing 3% gum arabic. Animals were confined in separate metabolic cells. The urine excreted by each animal was collected for 6 hours after administration of the test compounds.

or physiological saline solution after starvation. Urine volume was determined directly using a measuring cylinder after artificial urination into this cylinder. The amount of urine was calculated per 1 kg of animal weight, Using the method of uricase catalase, the amount of urinary acid excreted in the urine was determined. ; The results of biological tests are presented in the table. 1 As can be seen from the table, all compounds exhibit significant diuretic and uricosuric activity. ; In addition, the proposed compounds are low toxic.

: LDjo oral administration dl: mice was mg / kg.

Claims (1)

Invention Formula The method of obtaining xanthone derivatives of general formula ABOUT II .. X where X and Y are independently of each other hydrogen or halogen, or C-C4-alkyl; W is hydrogen or halogen; moreover, W is not hydrogen, when X and Y are each hydrogen, characterized in that the compound of general formula O X , W-E 1 Sn-Sn-SNg is where W, X and Y have the indicated meanings, are reacted with an organic solvent in the medium in an acidic medium, and the resulting compound is formulas 25 CH20N where W, X and Y have the indicated values, by; b (they interact with triok 1470194 lA .. Continuation of the table Note: a: p 0.05; b: p 0.01; c :: p 0.001.