CS221523B2 - Method of making the derivative of the 1,4-dioxanaphtalene - Google Patents

Abstract

The present invention provides compounds of the formula:- <IMAGE> as well as the salts thereof. The present invention also provides process for the preparation of these compounds and pharmaceutical compositions containing them.

Description

A process for the preparation of a 1,4-dioxanaphthalene derivative of the general formula

where

R 1 and R a, which are different from each other, denote groups of the formula

OH 1-CH.OH

OH

and its salts, characterized in that the aldehyde of 3,4-dihydroxycinnamic acid is oxidatively added by allylpyrocatechin in an organic solvent, the obtained intermediate is acetylated and separated by column chromatography, after which the methyl substituent in the benzodoxane group is oxidized to an alcohol function and the compound obtained is saponified. by weak alkali.

The present invention relates to a process for preparing a 1,4-dtoxanaphthalene derivative of the general formula

O ~ C C H x H where ·

R 1 and R 2, which are different from each other, denote groups of the formula

A _CW-F OW and salts thereof. The compound prepared by the process of the invention is known under the trivial name americanine.

The compound has surprisingly favorable antihepatotoxic efficacy, which is a welcome complement to the spectrum of action of the known liver agent. The novel compound can be obtained by the process of the invention by oxidatively adding allylpyrocatechin in an organic solvent to the aldehyde of 3,4-dihydroxycinnamic acid in an organic solvent, the intermediate obtained is acetylated and separated by column chromatography, then the methyl substituents in the benzodioxane group are oxidized to alcohol functions and The obtained compound is saponified by the action of a &quot; weak ¹ &quot; alkali.

Preferably, an equimolar amount of 3,4-dihydroxycinnamic acid aldehyde and allylpyrocatechin is reacted in a 5-fold amount of solvent such as benzene dioxane, tetrahydrofuran or acetone, based on all reagents, at a temperature of 15 ° C. to 30 ° C, preferably 23 ° C, for 1.5 to 3, preferably 2 hours, under treatment. silver oxide in a ratio of 0.5 to 0.6, preferably 0.55 mol per mole of total reagents, the product obtained is subjected to acetylation and then isolated by column chromatography and then the methyl substituent on the benzodioxane group is oxidized to an alcohol function.

The product thus obtained is a pale yellow crystalline substance having the following properties:

melting point:

246 to 247 ° C decomposition, summary formula:

CisHwOe.

Molecular weight:

328, elemental analysis:

% C, 64.98;% H, 4.98;% O, 28.3;

0.17 in thin-layer chromatography using finished plates coated with silica gel 60 (Merck), · Developed in a 9: 2: 1 by volume mixture of chloroform, acetone and formic acid, practically insoluble in water, chloroform, benzene and petroleum ether, soluble in dimethylsulfoxide, dimethylformamide, tetrahydrofuran, dioxane and acetone, optical rotation [a] D ¹⁷ = + + + 23.7, infrared absorption at 3200 CMI (-OH), 1650 ^{cm _} i ( «^ -unsaturated C = O) , 1610 cm -1

·. ·. C = C:

.................. OF ·: \\ .·. - ^; and 1580, -1510, as well as 1450 cm -1 (aromatic system).

The infrared and mass spectra of the product are shown in Figures 1 and 2.

The product obtained by the process of the invention has the same characteristics as the product obtained by isolation from the phytolacca species.

To illustrate the above, the reaction scheme of the process according to the invention is as follows:

II o = c no

3,4-dihydroxycinnamic acid aldehyde

0.55 mol / mol Ag 2 O / 23 ° C 2h.

--------------->

in benzene traces of methanol oxidation

----->

allylpyriocatechin

The compound obtained can be converted by conventional means. in its physiologically acceptable salts. Weak alkaline agents suitable for salt formation are, for example, alkali metal carbonates and alkali metal bicarbonates and amines such as ^; triethanolamine, trimethylamine, triethylamine, amino sugars and the like.

The product produced by the method of the invention may be used for medical purposes as a liver therapeutic. It can be used in various pharmaceutical forms, such as tablets, capsules, granules, dragees, suppositories or as a liquid preparation orally, anally or parenterally. The human dose is about 200 to 450 mg per day, depending on the difficulty of the case.

Surprisingly, the active substance americanin and its salts have been found to have an excellent protective effect against liver-damaging effects in animal experiments. Americanin exerts a particularly potent protective and stabilizing effect on cellular and intracellular biomembranes, especially liver cells, i.e. a strong protective effect on the liver and can therefore be used in the treatment of liver diseases.

To demonstrate the anti-hepatotoxic efficacy of the product of the invention, female mice were injured with hepatic poison Phaloidin (3 mg / kg; i.p.) and the test animals were additionally treated with Americanan.

Amerinine was dissolved in dimethylsulfoxide and polyethylene glycol (1: 1), administered i.v., at doses of 50 or 100 mg / kg, one hour prior to Phalloidin injection, and a control group not treated with amerinine was used.

Result:

Of the Phalloidin-poisoned mice, American% died, while the number of dead mice could be reduced as a result of treatment with 50 or 100 mg / kg of American and 60% or · 30% (observation period: 7 days; 20 animals in each group).

The toxicity (i.v.) of the novel compound of the invention was tested in male and female mice, respectively. 820 mg / kg (in male mice) and 800 mg / kg (in female mice) were observed.

The invention. They illustrate in more detail, but do not limit the examples below.

He did

To a 1500 ml flask equipped with a stirrer and a thermometer was added 208 g of 3,4-dihydrinnamic acid aldehyde dissolved in 500 ml of benzene and a solution of 150 g of allylpyrocatechin dissolved in 390 ml of benzene was added dropwise over 1 hour. Once the addition of the solution is complete, the reaction mixture is allowed to cool to 23 ° C with continued stirring. At this temperature, 124 g of silver oxide are introduced in small portions over a half hour and stirring is continued for 1.5 hours. The temperature is maintained at 23 ° C. Then the suspension obtained is filtered and the filter cake is washed three times with 100 ml of benzene each. The combined filtrates were evaporated to dryness under reduced pressure. pressure at 40 ° C. The residue is dissolved in 250 ml of acetone and filtered again, and the insoluble material is washed three times with 20 ml of acetone each, and the acetone solutions are combined and applied to a column of hydropropyl three-dimensional cross-linked polysaccharide (Sephadex LH 20). Elution is carried out with acetone. The active ingredient-containing fractions were combined. . and evaporated under reduced pressure at 40 ° C. The residue is dissolved in methanol and 100 g of acetyl chloride are added to the solution. The solution was allowed to stand for one hour and then evaporated under reduced pressure ^1. The acetylated derivative is obtained by column chromatography similarly. as above. The product is added to 150 ml of an aqueous methanol solution and 120 g of sodium carbonate are gradually introduced under stirring. After the oxidation is complete, the insoluble matter is filtered off and the filtrate is evaporated under reduced pressure at a temperature not exceeding 40 ° C.

The product has the following physical and chemical properties:

Appearance:

Light yellow micro-crystalline solid.

Solubility:

Soluble in dimethylsulfoxide, dimethylformamide, tetrahydrofuran, dioxane, and acetone, slightly soluble in methanol, ethanol and butanol, practically insoluble in water, chloroform, benzene and petroleum ether.

Melting point:

Mp 246-247 ° C (dec.).

Summary formulas:

C18H16O6.

Molecular mass

328.

Elementary analysis:

Calculated:

% C, 65.85;% H, 4.91;% O, 29.24;

Found:

64.98 O / ₀ C, 4.98 ·% H, 28.3 ·% · O.

Thin-layer chromatography: Silica gel finished plates. (Gauges).

Elution agent:

Chloroform, acetone, formic acid = 9: 2: 1 (volume ^1).

Developing:

ventricular saturation.

Detection:

the spraying agent 2,4-dltrophenylhydrazine and sulfuric acid (1 g · 2,4-dltrophenylhydrazine · are suspended in 2 ml of concentrated sulfuric acid and make up to 1 ml with methanol). After spraying, the plates are heated to 120 ° C for 20 minutes. Substance · looks like an intensely yellow zone on a light yellow background.

R _f value:

0.17

The infrared and mass spectra are apparent from the attached Figures 1 and 2.

Example 2

The same results as in Example 1 are obtained when the procedure described in Example 1 is followed except that in the first production phase benzene is replaced by dioxane, tetrahydrofuran or acetone.

Example 3

Tablet production:

kg of active compound according to the invention is mixed with the following excipients:

10,000 kg of polytrinylpyrrolidone

14.400 kg of microcrystalline cellulose

17.400 kg amylum tritici (wheat starch)

6,500 kg of silicic acid containing 99,8% silica, which form amorphous spherical particles (aerosil) 10,000 kg of stearic acid

371,700 kg of lactose DIN 80

Tablets weighing 0.50 g (70 mg of active ingredient) are then compressed.

Production of injectable preparations (ampoules):

For the production of 10,000 ampoules, 1.5945 kg of the methylglucamine salt of the active compound of the invention are dissolved in 48.6 liters of physiological saline solution to which 4% polyvinylpyrrolidone (molecular weight about 10,000) is added. The pH should not exceed 7.6. The solution is sterile filtered and filled into sterile brown 5 ml ampoules so that the content for one ampoule is 159.45 m 2 g of salt. N-methylglucamine corresponding to 100. mg of active ingredient according to the invention.

Manufacture of suppositories:

318.9 g of the methyl-fluoroglucamide active compound according to the invention are shaken with 500 g of molten solid fat (DAB 7). While stirring, add 1181.1 g of molten solid fat (DAB) and pour the suppositories out of this mass. Each suppository weighing 2.0 g contains 318.9 milligrams of methylglucamine salt, which corresponds to 200 mg of the active ingredient according to the invention.

Claims (3)

OBJECT OF THE INVENTION 1. A process for producing 'a 1,4-diOxanaftalenu of formula - C ^c H X ’H where R 1 and R 2, which are different from each other, denote groups of the formula yy = [IIa] -hydroxy-cinnamic acid oxidatively adds allylpyroacetate in an organic solvent, the obtained intermediate. The methyl sulfide in the benzodioxane group is oxidized to an alcoholic function and the resulting compound is saponified by the action of a weak alkali. 2. The method of method 1, characterized in that an equimolar amount of aldehyde is used 3,4-dihydroxyskoronic acid and allylpyrocatechin are reacted in a 5-fold amount of solvent, such as benzene, dioxane, tetrahydrofuran or acetone, based on all reagents, at a temperature of 15 to 30 ° C, preferably 23 ° C, for 1.5 to 3 , preferably 2 hours, under the action of 0.5 to 0.6, preferably 0.55 moles per mole of silver oxide, of all reagents, the product obtained is subjected to acetylation and then isolated by column chromatography and then the methyl substituent on benzodioxane oxidation to alcohol function.