CS221521B2 - Method of making the derivatives 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

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

the compound can be obtained by the method of the invention by treating the finely ground dry fruits of the American make-up (Phytolacca americana L.) with petroleum ether, pre-treating the drug with acetone, purifying the residue of the evaporated product with chloroform and dissolving in n-butanol It is washed with water and evaporated and the residue is dissolved in acetone, the acetone solution is chromatographed on a column of hydropropyloid three-dimensional cross-linked polysaccharide with acetone as the eluent, the pharmacotogically active fractions are combined and evaporated and the residue is recrystallized from methanol.

Preferably, the finely ground, dry fruit of the American make-up (Phytolacca americana L.) is extracted three times with vigorous stirring for 0.5 to 1.5 hours, preferably 1 hour with 2.5 to 4.5 times, preferably 3.5 times by weight of petroleum ether with a boiling range of 60 to 70 ° C, at a temperature of 45 to 55 ° C, preferably 50 ° C, the pretreated drug is extracted three times for 0.5 to 1.5 hours with vigorous stirring , preferably 1 hour with 2.5- to 4.5-fold, preferably 3.5-fold by weight of acetone at a temperature of 45 to 55 ° C, preferably 50 degrees Celsius, the acetone extract is evaporated where R 1 and R 2 are different from each other denotes groups of the formula 'TYf z-NNP' and their salts.

The compound prepared by the process of the invention is known under the trivial name americanine.

The compound has surprisingly favorable antihepatotoxic activity, which is a welcome complement to the spectrum of action of the known liver composition. This new at 35 to 45 ° C, preferably 40 ° C, under vacuum at 0.5 to 5.0, preferably 2.0 kPa, the residue obtained is mixed twice with 1/4 to 1/2 each preferably 1/3 of chloroform based on the weight of the parent drug and filtered, the remaining solid is dissolved in a ratio of 1: 10 to 1:14, preferably 1: 12 in n-butanol, the n-butanol solution is shaken 3X to 5X, with preferably 4X, with 1/3 to 2/3 preferably half the volume of water, the n-butanol phase is evaporated at 35 to 45 ° C, preferably at 40 ° C under vacuum at 0.5 to 5.0, preferably 2.0 kPa, the residue is dissolved in a 0.5 to 15 mole, preferably 0.10 equivalent amount of acetone based on the weight of the parent drug and filtered, the acetone solution is chromatographed on a column of hydropropylated three-dimensional crosslinked polysaccharides using acetone as eluent, the obtained pharmacologically active fractions are combined and evaporated at a temperature of 35 to 45 ° C, preferably 40 ° C under vacuum at 0.5 to 5.0, preferably 2.0 kPa and the residue is recrystallized from methanol.

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

mp 246-247 ° C dec., CieHieOe summary formula, moikull mass 328, elemental analysis 64.98 ° C, 4.98% H, 28.3% O, R _f value 0.17 in thin-layer chromatography Developed with a 9: 2: 1 mixture of chloroform, acetone and formic acid, practically insoluble in water, chloroform, benzene and petroleum ether, soluble in dimethylsulfoxide, dimethylformamide, tetrahydrofuran, dtoxane and acetone, optical rotation. [α] _D ¹⁷ = s + 23.7 °; infrared absorption at 3200 cm ^-1 (—OH), 1650 cm ^-1 (ε-unsaturated, C == 0), 1610 cm ^-1

Z \ a 1580, 1510 as well as 1450 cm ¹ (ariamatic system).

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

The compound obtained can be converted into its physiologically acceptable salts in a conventional manner. Slightly alkaline reagents suitable for. salt formation are, for example, alkali metal carbonates and alkali metal hydrogencarbonates and amines such as triethanolaine, trimethylamine, triethylamine, amino sugars and the like. The product produced by the method of the invention can be used for medical purposes as a liver therapeutic. It can be used in various pharmaceutical forms 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 americanine, the skin and its salts have been found to have an excellent protective effect against liver damaging effects in animal experiments. Amenicanin exerts a particularly potent protective and stabilizing effect on cellular and intracellular biomembranes, in particular liver cells, i.e. a potent 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 the hepatic poison Phalloldin (3 mg / kg; i.p.) and the test animals were additionally treated with americanin. The americanin was dissolved in dimethylsulfoxide and polyethylene glycol (1: 1), administered i.v., at doses of 50 and 100 mg / kg, respectively, one hour prior to the injection of Phalloidin. At the same time, a non-American treated control group was used.

Result:

Of the mice poisoned by Phalloldin, 85% died, while the number of dead mice could be reduced to 60% and 30%, respectively, as a result of treatment with 50 and 100 mg / kg americanin (observation period: 7 days; 20 animals per 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 found.

Further, a method of making the product of the invention is described.

Example

100 kg of finely ground, dried fruits of the American make-up (Phytolacca americana L.) are extracted using an ultra-Turrax apparatus three times each hour with 400 l of petroleum ether (boiling range 60-70 ° C) at 50 ° C. The pretreated drug is subjected to three 1-hour Turrax extraction with 400 L of acetone at 50 ° C. The combined acetone extracts were evaporated in vacuo at 40 ° C. The residue is then stirred twice with 30 l of chloroform. The mixture was filtered and the remaining solid was allowed to dry in 1-butanol; 12. Shake the n-butane solution four times with an amount of water corresponding to half the volume. Then the butanilium phase is evaporated under reduced pressure at 40 ° C and the residue is dissolved in 10 L of acetone. After the insolubles were separated, the solution was chromatographed on a column of hydropropyl three-dimensional cross-linked polysaccharides (Sephadex LH 20) using acetone as eluent. The active ingredient-containing fractions were combined and evaporated at 40 ° C under vacuum. The residue was recrystallized from methanol.

A substance with the following chemical and physical parameters is obtained as the final product:

Appearance:

Light yellow microcrystalline solid

Solubility:

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

Melting point:

246 to 247 [decomposition]

Summary formula:

C18H16O6

Molecular weight:

328

Elementary analysis:

Calculated:

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

Found:

% C, 64.98;% H, 4.98;

Thin layer chromatography:

Silica-Gelloive Finished Plates (Merck)

Elution agent:

chloroform, acetone, formic acid = = 9: 2: 1 (v / v)

Developing:

ventricular saturation

Detection:

2,4-dinophiophenylhydra- spraying agent. zinc and sulfuric acid (1 g of 2,4-dinitrophenylhydrazine is suspended in 2 ml of concentrated sulfuric acid and made up to 100 ml with methanol)

After spraying, the plates were heated to 120 ° C for 20 minutes. The substance looks like an intensely yellow zone on a light yellow background.

Rf value:

0.17

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

Galenic examples

Tablet production:

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

10,000 kg of polyvinylpyrrolldone

14,400 kg microcrystalline cellulose 17,40'0 kg amyluim tritici (wheat starch)

6,500 kg silicic acid s. content

99.8% silica · (aerosHu) 10,000 kg stearic acid 371,700 kg lactose DIN 80

Tablets weighing 0.50 g (70 mg) were then compressed.

Production of injectable preparations:

For the preparation of 10,000 ampoules, 1.5945 kg of the methylglucamine salt of the active compound according to the invention are dissolved in 48.6 liters of physiological sodium salt solution to which 4% of polyvinylpyrrolidone (molecular weight asia 10,000) is added. The pH should not exceed 7.6. The solution is sterile filtered and filled with sterile brown 5. ampoules, so that the content per ampoule is 159.45 mg of the N-methylglucamine salt corresponding to 100 mg of the active ingredient according to the invention.

Manufacture of suppositories:

318.9 g of the methylgamcam axis of the active compound according to the invention are rubbed with 500 g of molten solid fat DAB 7. While stirring, 1181.1 g of molten solid fat (DAB 7) are added and the suppositories are poured out of this mass. Each suppository weighing 2.0 g contains 318.9 milligrams of methyl glucamine salt corresponding to 200 mg of the active ingredient according to the invention.

Claims (2)

THE OBJECT OF THE INVENTION A process for the preparation of 1,4-dloxanaphthalene derivatives of the general formula ox H wherein R 1 and R 8, which are different from each other, denote groups of the formula OH * - CH.OH OH and its 'salts', characterized in that the finely ground 'dry fruits' of the American make-up (Phytolacca americana 'Lj,' is treated with petroleum ether, the pretreated drug is extracted with acetone, the evaporation residue The product is purified by chloroform and dissolved in n-butanol, the n-butanoil solution is washed with water and evaporated and the residue is dissolved in acetone, the acetone solution is chromatographed on a column of hydropropyl three-dimensional crosslinked polysaccharide with acetone as eluent. the residue is recrystallized from methanol. Method according to claim 1, characterized in that the finely ground, dry fruits of the American make-up (Phytolacca americana L.) are extracted three times with vigorous stirring for 0.5 to 1.5 hours, preferably 1 hour with 2. 5- to 4.5-fold, preferably 3.5-fold by weight amount of petroleum ether with a boiling range of 60 to 70 ° C, at a temperature of 45 to 55 ° C, preferably 50 ° C, the pretreated drug is extracted three times with vigorous stirring 0.5 to 1.5 hours, preferably 1 hour with 2.5 to 4.5 times, preferably 3.5 times by weight acetone at a temperature of 45 to 55 ° C, preferably 50 degrees Celsius, the acetone extract is evaporated at a temperature of 35 to 45 ° C, preferably 40 ° C, in an atmosphere of 0.5 to 5.0, preferably 2.0 kPa, the resulting residue is stirred twice with 1/4 to 1/2 each, preferably 1/3 of chloroform based on the weight of the parent drug and filtered, the remaining solids are dissolved in the 1:10 plometer and In 1: 14, preferably 1: 12 in n-butanol, the n-butanol solution is shaken 3X to 5X, preferably 4X, with 1/3 to 2/3, p. preferably with half the volume of water, the n-butanol phase is evaporated at 35 to 45 ° C, preferably at 40 ° C under vacuum at 0.5 to 5.0 kPa, preferably 2.0 kPa, the residue is dissolved in an amount of acetone of 0.05 to 15 times, preferably 0.10 times, based on the weight of the parent drug and filtered, the acetone solution is chromatographed on a column of a hydropropylated three-dimensional cross-linked polysaccharide using acetone as the eluent; it is evaporated at 35 to 45 ° C, preferably 40 ° C under vacuum at 0.5 to 5.0 kPa, preferably 2.0 kPa, and the residue is recrystallized from methanol.