CS221522B2 - Method of making the derivative of the 1,4-dioxanphane - 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

(54) A method for producing a 1,4-dioxanaphthalene derivative

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

X

H where

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

The salt and salt needle are characterized in that the 3,4-dihydroxycinnamic acid aldehyde and the 3,4-dihydroxycinnamic acid alcohol are dimerized by an oxidation addition.

The present invention relates to a process for the preparation of a 1,4-dloxamino-naphthalene derivative of the general formula

° ^C

H where

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

OH

OH and --CH2 OH 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. The novel compound can be obtained by the process of the invention by dimerizing the aldehyde of 3,4-clylidic oleic acid and the alcohol 3,4,4-glycolic acid.

Preferably, it is performed so that an equimolar amount of the aldehyde of 3,4-dihydroxycinnamic acid and 3,4-У alcohol & уУroskoriicové acid are reacted in five times the amount of solvent as' benzene, dioxane, tetrahydrofuran or acetone, with respect to all ^of: the reagent at a temperature 15 to 30 ° C, preferably 23 ° C for 1.5 to 3, preferably 2 hours, under the action of silver oxide in a ratio of 0.5 to 0.6, preferably 0.55 mol per mol All the reagents, the filtered reaction solution were evaporated to dryness and the residue was separated by column chromatography.

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

mp 245-247 ° C decomposed, summary formula:

ΟιβΗιβΟβ, molecular weight:

328, reformer, acetone and formic acid in a 9: 2: 1 ratio by volume, practically insoluble in water, chloroform, benzene and petnol ether, soluble in dimethylsulfoxide, dimethylformamide, tetrahydrofuran, dioxane - and acetone ·, optical rotation [a] _D 17 = + - 23.7, infrared absorption at 3200 cm ^"1 (OH), 1650 cm ^_ i (« ^ -unsaturated C = O), 1610 cm-1 \ / c = ca 1,580, ' - 1510, including 1450 cm ⁴ (aromatic system).

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

The synthetic product obtained here has the same characteristics as the product obtained by isolation from the phytolacca species ...........

The compound obtained can be converted into its physiologically acceptable salts in a conventional manner. Slightly alkaline agents suitable for forming the salts are, for example, alkali metal carbonates and alkali metal hydrogen sulphates 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 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 severity of the case.

Surprisingly, the active substance - americanin and its salts - have been found, in experiments, to have an excellent protective effect on animals against the effects of liver damage. Amerikarnn exerts a particularly potent protective and stabilizing effect on cellular and intracellular biomembranes, especially on liver cells, i.e. a strong protective effect. 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 liver poison Plralloidin (3- mg / kg; i.p.) - and - test animals were additionally treated with Americanan. The americanin was dissolved in diethyl ether and poly (ethylene glycol (1: 1)), administered i.v., at doses of 50 and 100 µg / kg, respectively, one hour prior to infection with Pnalloid. At the same time, a control group that was not treated with Americanin was used.

Result:

Z - mice - poisoned - Phalloidin killed 85%, whereas the number of dead mice could be reduced to 60% / 30% or 30% (observation time:

elementary analysis:

64.98% - C 4.98 -% - H% -28.3 O, R _f value:

0.17, thin layer chromatography using silica gel 60 coated plates (Marek), developed on chlo221522 days; number of 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.

The invention is further illustrated by the following examples.

Example 1

In a 1500 ml flask equipped with a stirrer and a thermometer, 208 g of 3,4-dihydrioxycinnamic acid aldehyde dissolved in 500 ml of benzene are added and a solution of 196 g of alcohol 3,4-dihydroxycinnamic acid in 390 ml of benzene is added dropwise with stirring. . Once the addition of the solution is complete, the reaction mixture is cooled to 23 ° C with continued stirring. At this temperature, 123.9 g of silver oxide are introduced in small portions over 0.5 hours and stirring is continued for a further 1.5 hours. The flask was kept at 23 + 1 ° C during the addition of the silver oxide and during the following interval. The suspension obtained is then filtered and the collected fraction is washed three times with 100 ml of benzene each time. The combined filtrates were evaporated to dryness under reduced pressure at 40 ° C. The residue is dissolved in 250 ml of acetone and filtered again.

After separation of the insoluble material, which was washed three times with 20 ml of acetone each, the acetone solutions were combined and loaded onto a column of hydropropylated three-dimensional cross-linked polysaccharides (Sephadex LH · 20). Elution is carried out with acetone. Fractions containing the active compound were combined and evaporated under reduced pressure at 40 ° C. The residue was recrystallized from methanol.

A product is obtained having the following physical and chemical properties:

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 petroleum ether. '

Melting point:

Mp 246-247 ° C (dec.).

Summary formula:

CsiH16O6.

Molecular mass

328.

Elementary analysis:

Calculated:

65.85 _0/0 c · 4.91% H 29.24% O

Found:

H, 4.98; H, 28.3%.

Thin-layer chrioimatography:

Silica gel finished boards (Merck).

Elution agent:

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

Developing:

ventricular saturation.

Detection:

spraying agent 2,4-dinitrophenylhydrazine, sulfuric acid (10 g of N, N-dinitrophenylhydrazine is suspended in 2 ml of concentrated sulfuric acid and made up to 100 ml with methanol). After spraying, the plate is heated to 120 ° C for 20 minutes. The 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 accompanying 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 it is replaced by benzene with dioxane, tetrahydrofuran or acetone.

Example 3

Galenic examples

Tablet production:

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

10,000 kg of polyvinylpyrrolidone

14.440 kg of microcrystalline cellulose

17.400 gg of amyl sulphate (wheat kkoobu)

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

371,700 kg of lactose DIN 80

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

Production of injectable preparations (ampoules):

For the manufacture of 10,000 ampoules, 1.5945 kg of the methylaminamine compound of the invention are dissolved in 48.6 liters of physiological saline solution to which 4% polyvinylpyrrolidone (mole 221522 spherical weight of 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 of one ampoule is 159.45 mg of the N-methylglucamine salt corresponding to 100 mg of the active ingredient of the invention.

Manufacture of suppositories:

The substances according to the invention are rubbed with 500 g of molten solid fat DAB 7. While stirring, 1181.1 g of molten solid fat are added and the suppositories are poured out of this mass. Each suppository weighing 2.0 g contains 318.9 mg of methylglucamine salt, corresponding to 200 mg of the active ingredient according to the invention.

318.9 g of methylglucamine salt active

Claims (3)

SUBJECT 1. A process for preparing a 1,4-dioxanaphthalene derivative of the general formula II H where R 1 and R 2, which are different from each other, denote groups of the formula INVENTION as. or a salt thereof, characterized in that the aldehyde of 3,4-dihydroxyskofic acid and the 3,4-dihydrioxycinnamic acid alcohol are dimerized by oxidation addition. 2. A method according to claim 1, wherein the equimolar amount of the aldehyde is 3.4% of the acid and the alcohol. The 3,4-dihydric cinnamic acids are reacted in a 5-fold amount of solvent such as benzene, dioxane, tetrahydrofuran or acetone, based on all reactions, at a temperature of 15 to 30 ° C, preferably 23 ° C for 1.5 to 3, preferably 2 hours, filtered with 0.5 to 0.6, preferably 0.55 mol, per mol of total reagents. reaction. the solution was evaporated to dryness and the residue was separated by column chromatography.