CS273610B2 - Method of silibinene's new derivatives production - Google Patents

Abstract

Silibinin derivatives of the general formula:- <IMAGE> wherein n and m, independently of one another, stand for 0 or 1, Alk1 and Alk2, independently of one another, are alkylene radicals containing up to 4 carbon atoms or alkenylene radicals containing 2 to 4 carbon atoms and M1 and M2, independently of each other, stand for hydrogen atoms or alkali metal atoms, are used in pharmaceutical compositions for treating burn damage, liver damage or fungal poisoning.

Description

The present invention relates to a process for the production of novel flavolignan derivatives, i. new silibinin derivatives having valuable pharmacological properties and which drugs can be used.

Milk Thistle - Silybum marianum (L.) Gaertn. (Carduus marianus L.) has been a well-known medicinal plant since ancient times. One component, called silybin, was isolated from the flavolignans found in the fruit of this plant (cf. Dissertation R. Munster, Munchen, 1966). The chemical structure of this compound was explained by A. Pelter and R. Hansel, cf. Tetrahedron Letters, London, Vol. 25, pp. 2911-2916 (1968).

It is known that silybin, formerly also referred to as silymarin I, is a valuable liver therapeutic (cf. DE-AS 17 67 666). A technical process for the production of silybin (i.e. silymarin I) is described, for example, in DE-AS 19 23 082.

Already in 1974, H. WAGNER, P. DIESEL and M. SEITZ, Arzneimittelforschung, Vol. 24 (4), pp. 466-471 with respect to silybin, suggested that there are two positional isomers, silybin and isosilybin.

This assumption was refined and experimentally confirmed by A. Arnone, L. Merlini and A. Zanarotti, Journal Chemical Society Chem. Comm., 16, 696-697 (1979). Accordingly, the known silybin consists of two different compounds, i.e. compounds of the following structural formulas A and B:

(A) silibinin

(B) isosilybin

These structural formulas show that these compounds are positional isomers. The compound of formula A is newly referred to as silibinin. This designation is now used in the description of the present invention for a compound of formula A.

The therapeutic use of silybin is hampered by the fact that silybin is practically insoluble in water, so that injectable solutions or formulations containing silybin in which some solubility of the substance in water is required have not been prepared. DE-PS 19 63 318 discloses silybin derivatives having a certain solubility in water, but it is a very complex mixture of semi-esters of succinic acid. This mixture is so complex because five esterifiable hydroxyl groups are present in silybin, silybin also contains both of the above positional isomers and the succinic acid used for esterification is a dicarboxylic acid which can form both monoesters and diesters. However, for pharmaceutical purposes, a product consisting of a confusing number of the most diverse unclear compounds is useless.

It was therefore an object of the present invention to provide water-soluble silibine derivatives which are suitable for pharmaceutical purposes and which can be accurately characterized as chemical individuals.

It has now been found that the silibinin derivatives of certain alkane and alkylenedicarboxylic acids meet these requirements.

Accordingly, it is an object of the present invention to provide novel silibinin derivatives of formula (X)

(I), in which n + m are each independently 0 or 1,

Alk 1 and Alk ₂ are each independently C 1 -C 4 alkylene or C 2 -C 4 alkenylene and and M ₂ are independently hydrogen or alkali metal.

Preferably, the process of the present invention provides compounds of formula I wherein a and m are independently 0 or 1,

Alk 1 and Alk ₂ are each an alkylene radical having 2 carbon atoms and M ₂ is independently an alkali metal atom.

Preference is given to preparing compounds of the formula I in which n, Alk ₁ and Alk ₂ as well as a and a have the same meanings.

Particularly preferably, the disodium salt of silibinin C-2 ', 3-dihydrogensuccinate is prepared according to the process of the invention.

In the compounds of the present invention, hydroxyl groups of silibinin that are not bonded to the benzene nucleus are partially or fully esterified, for example, oxalic acid, malonic acid, succinic acid, adipic acid, maleic acid or fumaric acid. Preferably, the two non-aromatically bonded hydroxyl groups of the silibinin are simply esterified with either of the aforementioned carboxylic acids.

According to the present invention, the novel silibinin derivatives of formula X as defined above are prepared by providing about 1 part by weight of silibinin of formula A

(A), dissolved in 1 to 2 parts by weight. pyridine and this solution is treated with 1 to 3 parts by weight. dicarboxylic acid anhydride of formula

in which

Alk means any of the above-defined Alk ₁ and Alk ₂ residues, with stirring, then ethanol is added until a homogeneous mixture is added, then water is added slowly with vigorous stirring, whereby the aromatic-linked hydroxyl esters present are hydrolyzed once this hydrolysis is complete The reaction mixture is diluted with ethyl acetate, washed with acidic water saturated with ethyl acetate, the ethyl acetate phase is concentrated, taken up with ethanol and converted into a salt of the free carboxylic acid residue by treatment with an alcoholic alkali metal hydroxide solution.

The reaction with the dicarboxylic acid anhydride is preferably carried out at a temperature of 40 to 50 ° C. The pH of the acidic wash water saturated with ethyl acetate is preferably maintained at about 1.5 to 2.4.

The compounds produced by the process according to the invention, in particular the disodium salt of silibinin-C-2 ', 3-dihydrogen succinate, show a surprisingly pronounced pharmacological effect in the treatment of burns. In addition, they retain the full pharmacological activity of the known silybin as a liver therapeutic. These compounds are particularly useful for the treatment of liver cirrhosis and toxic metabolic liver damage.

Surprisingly, the compounds produced by the process of the present invention have also proved to be extremely effective in the treatment of fungal poisoning, in particular the very dangerous poisoning of Amanita phalloides. Surprisingly, the compounds can also be treated with poisoning by halogenated organic solvents such as carbon tetrachloride, trichlorethylene, chloroform, etc. In preventive use, the compounds produced according to the invention prevent the above-mentioned damage.

The present invention therefore also relates to medicaments comprising the compounds produced by the process of the invention. These medicaments are generally used systemically, for example in the form of pills, capsules, solutions, together with the usual carriers and, if appropriate, the usual excipients. The daily dose for adults is about 50-500 mg, depending on the condition of the patient and the severity of the symptoms.

Biological experiments with the disodium salt of silibinin-C-2 ', 3-dihydrogensuccinate (Silicosin) are described in the next section.

Symptoms occurring in burns are mainly caused by intoxication products of thermal tissue necrosis. The evidence that autointoxication processes carry this responsibility after severe skin burns has been performed in various ways. Cross-grafts of burned and non-burned skin to healthy or burned animals (recipient) are particularly convincing, and it has been shown that burned skin is wasted in non-burned recipients, whereas no harmful effects were found in burned healthy skin recipients (cf. KH Schmidt) and others, Neuere Aspekte zur Autointoxikation nach schweren Verbrennungen, Die Verbrennungskrakheit (FW Ahnefeld et al., para. L), Springer, Berlin 1982, pp. 45-52.

A number of chemical compounds are released or re-formed in skin burns. Despite their large number, the structure of some of these compounds has been explained. It has been shown, inter alia, that the compounds produced by skin burns are similar to those produced by lipid peroxidation. There are also analogies to the toxic effects of these substances. Particularly pronounced is the formation of toxic active saturated and unsaturated aldehydes with different chain lengths as a result of lipid peroxidation (Benedetti et al., Identification of 4-hydroxynonenal as and a cytotoxic product derived from the peroxidation of liver microsomal lipids, Biochem. Biophys. Acta 620, 281-). 296, 1980) and thermal tissue damage (KH Schmidt et al., Studies on the Structure and Biological Effects of Pyrotoxins Purified from Burned Skin, World J. Surg. 3, 361-365, 1979). It is therefore believed that burns lead to oxidative damage to the cell structure.

Therefore, autooxidative changes in membrane lipids as a result of autointoxication following severe burns were investigated. In particular, changes in the fatty acid composition of membrane lipids have been investigated. It was further investigated to what extent the silibinin derivatives produced by the process of the invention influence the changes in the fatty acid composition of the membrane lipids.

Changes in membrane lipid fatty acid composition after severe burns:

Male Wistar specimens with an average weight of 360 g are housed in three groups with free access to water and dry food. Until the start of the experiment, the room temperature was 22 c, after the start of the experiment the animals were kept at 30 c. A copper punch of 20 cm ² at constant pressure and at 250 ° C was used to induce skin burns. In order to avoid thermal damage to the underlying organs, the skin is stretched over an air-cooled hollow spatula. In this design of the experiment, very exact burn injuries could be achieved, providing constant survival ratios.

At the start of the experiment, animals were anesthetized with 50 mg / kg nembutal. After burn injury, animals were injected intraperitoneally with 20 ml of Ringer's lactate flow for shock prophylaxis.

5 experimental groups were created:

(a) normal group:

(b) control group I:

(c) control group II completely intact animals animals treated with silibinin only for 6 days using 75.5 mg of silibinin disodium ~ C-2 ', 3-dihydrogensuccinate animals with simulated surgery

(d) group of animals with burns: 25%, 250 c, 20 s, 0.05 MPa

(e) test group:

animals that were i.p. applied 75.5 mg of silicin-C-2 ', 3-dihydrogen succinate disodium salt for 6 days starting the day before the burn.

In order to isolate the microsomes, the animals were bled at the end of the experimental period under anesthesia. The animals were then liver-weighed, weighed and immediately transferred to an ice-cooled isolation medium (0.25 mmol of sucrose, 1 mmol of ethylenediaminetetraacetic acid, 10 mmol of tris buffer, Hel, ph 7.2). The liver is dissected and homogenized in said medium. The microsome fraction is pelleted by differential centrifugation. The microsomes are resuspended and centrifuged again. A suspension is then prepared in which 1 ml of suspension corresponds to 1 g of liver tissue.

Lipids are determined by the method described by J. Folch (A simple method for the isolation and purification of total lipids from animal tissues, J. Biol. Chem. 226, 497-508 (1957), by the modification described by Bligh and Dyer (A). rapid method of total lipid extraction and purification, Can J. Biochem Physiol 37, 911-917 (1959).

The extracted lipids of the microsomes are saponified with sodium hydroxide. The free fatty acids are esterified by the addition of a mixture of boron trifluoride and methanol. After the methanol has been evaporated and the hydrophilic by-products have been removed, the fatty acid esters are quantitatively determined.

No remarkable change in fatty acid samples was found in the groups of non-burned animals. Therefore, narcosis and minor surgical intervention did not lead to a change in microsomal lipids. For this reason, the normal group and the control group were combined into a single control group for further comparison.

Comparison of burn-free animals with burns in terms of their microsomal fatty acid sample indicates shifts in unsaturated fatty acids towards saturated fatty acids.

The distribution of fatty acids in microsomal liver lipids and the changes caused by thermal skin damage is shown in Figure 1.

It can be seen from Figure 1 that the proportion of palmitic acid (C16) increases from 25.1% to 34.4% of the total fatty acid content after the burn. For stearic acid (C18), the proportion in animals with burns is 46.3%, which is 13.2% higher than that obtained in control animals. For oleic acid (C18: 1) there is a slight but not significant decrease. The proportion of linoleic acid (C18: 2) decreased after the burn to about 1/3 of the original value. Finally, arachidonic acid (C20: 4) found that only 31% of its initial value was present after the burn. Columns marked with K express values for control animals, while columns marked with P represent values for burned animals.

TABLE 1

Sample of microsomal lipid fatty acids from rat liver after treatment with silibinin-C-2 ', 3-dihydrogensuccinate (Sili-suc-na) disodium salt in animals with and without burns C16 Cl 8 C18 : 1 C18: 2 C20; animals without burns 29.8% 37.2% 8.9 % 9.6% 16.2% (control group I) + 6.2 + 12.3 + 1,1 + 3.3 + 4.9 animals with burns 25.4% 37.5% 7.8 % 11,4 i 18,0% + 6.0 + 8.6 + 1.0 + 5.3 + 9.1

From the above data, it can be seen that treatment with the silibinin derivative prepared by the process of the invention does not cause any significant changes in control animals without burns as compared to untreated animals. In animals with burns, treatment leads to a complete suppression of the loss of unsaturated fatty acids.

In summary, the following could be ascertained;

Burns lead to changes in the sample of fatty acids of microsomal lipids. This is believed to result in oxidative damage to the membranes. This is particularly evident in the marked decrease in the polyunsaturated fatty acids.

The silibinin derivatives prepared by the process of the present invention are now able to inhibit oxidative cell damage. These compounds are therefore particularly suitable for the disruption of oxidative damage mechanisms after severe burnings ^1.

As already mentioned, it is believed that autotoxic reactions following severe burns lead in particular to oxidative cell damage. Therefore, it was further investigated how standardized thermal injury manifests itself on PHA-induced T-cell blastogenesis from spleen and peripheral blood of rats. It was then investigated how the silibinin derivatives produced according to the present invention affect such lymphocytic functional disorders after severe burns.

Effect of standardized thermal injury on PHA-induced T cell blastogenesis from spleen and peripheral blood of rats.

As previously described, a copper punch is burned to the skin of the backs of rats (Wistar). Simulated burned animals were used as a control group in which all surgeries were performed without burns. After 2, 4, 7 and 9 days, blood and spleen were collected from burned animals or control animals under ether anesthesia.

Heparinized blood was transferred to Ficoll-Hypaque solution (density 1.077) for lymphocyte isolation. The mixture is then centrifuged and the viability of the lymphocytes obtained is determined by trypan blue. To isolate lymphocytes from the spleen, the organ is smeared, passed through a sieve, and freed from the accompanying erythroats (using Lys's Gay solution).

Then the cell mixture is incubated for 30 minutes in the vessel in the presence of 5% heat-inactivated fetal calf serum to reduce the proportion of mononuclear cells in the suspension by adhesion to the vessel wall (5%). For culture, cells are transferred to flat microtiter plates.

20% fetal calf serum is then added. In this way, spontaneous blastogenesis 3 is determined by measuring built-in H-thymidine (2Ci / mmol) in DNA cells.

In preliminary experiments, optimal mitogen stimulation was found to be at a concentration of 5 µg / ml PHA (mitogen-phythaemagglutin). Furthermore, in these experiments to optimize the cellular assay system, it was found that maximum stimulation of new DNA synthesis occurs after 72 hours. Furthermore, it was found that to achieve the highest stimulation, the optimal fetal calf serum concentration was around 20%.

As described above, spontaneous blastogenesis is determined by measuring the built-in ³ H-thy-3 midin into DNA cells. Cells were harvested 18 hours after the addition of H-thymidine, where the zero point for 18 hours coincided with the time of maximal stimulation.

In order to investigate the effect of the silibinin derivatives produced by the process of the invention, a group of rats was treated with a silibinin derivative. To this end, 75.5 mg of silibin-C-2 ', 3-dihydrogensuccinate disodium was injected intraperitoneally once daily.

This therapy was carried out from the day the burn was caused until the day the organ was removed (up to day 9).

A stimulation index was calculated to evaluate the results obtained in control and burn-free animals and animals treated with silibinin-C-23-dihydrogensuccinate disodium. This numerical value represents the quotient of the mean of the stimulated sample and the mean of the control sample. From the stimulation index (SI) thus obtained, the mean stimulation index for the group of animals is calculated for each test animal. The results obtained are expressed by this SI index.

The effect of silibinin-C-2 ', 3-dihydrogensuccinate disodium treatment on lymphocyte blastogenesis is shown in Figure 2. Figure 2a shows the stimulation index of blood lymphocyte blastogenesis, while Figure 2b shows the stimulation index of spleen lymphocyte blastogenesis. Values achieved with silibinin-C-2 ', 3-dihydrogensuccinate disodium salt are indicated by A, while values achieved without this treatment are indicated by B. In both Fig. 2a and Fig. 2b, the index is plotted SI, while the x-axis shows the number of days.

In animals with burns, the reduced cell stimulatability due to silibinin treatment is greatly increased.

Already on the second day, animals treated with silibinin-C-23-dihydrogensuccinate disodium showed approximately ten times higher sensitivity of blood lymphocytes to PHA.

On day 4 after burn injury, the blood lymphocyte stimulation index value for treated animals was 8, while the corresponding value for untreated animals was 1.5.

In spleen isolated cells, the stimulation indices of burned, untreated animals are clearly below 1 in all cases. The application of silibinin leads to a significant improvement on all the days examined, reaching a maximum on day 7 after burn injury.

Furthermore, comparative experiments have been carried out to show that treatment with silibinin-C-2 ', 3-dihydrogensuccinate disodium alone does not lead to any significant changes in the stimulation of spleen and peripheral blood T-cell blastogenesis in healthy animals. induced by PHA.

Therefore, the silibinin produced by the process of the invention stimulates blastogenesis of lymphocytes of animals with burns in a significant manner.

In addition, it was found that animals treated with silibinin derivatives had a general catabolism as the animals started to regain weight rapidly after a thermal injury.

Fungus poisoning:

Poisonous toadstool poisoning is one of the most severe in medicine.

Although only 10 to 30% of fungal poisoning is caused by the fly agaric, the poisoning of this fungus has long been of the highest medical interest because of its danger.

Older publications have reported a mortality rate of 30 to 50%. Thanks to modern intensive medicine, the mortality rate, according to a study conducted by FLOERSHEIM et al., Has been reduced to an average of 22.4% based on 205 patients.

Toadstool poison amanitin can be fatal in adult patients as early as 7 mg. This amount of poison is contained in about 50 g of fresh specimen.

After a number of successful animal experiments, the active substance, i.e., the disodium salt of silibinin-C-2 ', 3-dihydrogensuccinate, was administered in the treatment of poisoning of the fly agaric.

In addition, 28 patients with the toadstool fly agaric poisoning were treated in addition to the usual therapeutic interventions in addition with the disodium salt of silibinin-C-2 ', 3-dihydrogensuccinate. Of these 28 patients, only one died who had consumed a greater amount of poisonous fungus with suicide. This result demonstrates enormous therapeutic advances in this field.

Isosilybin-free silibinin production:

A suspension of 500 g of product, according to DE-AS 19 23 082, column 8, lines 14 to 19, with a silymarin content of about 70% at a silybin: silidianin: silicristin isomer ratio of about 3: 1: 1, silybin containing about 1/3 of isosilybin , and 2 kg of methanol, i.e. about 2.53 liters, are heated to boiling under stirring for 15 minutes. Some silibinin can be precipitated from this solution after this time. Thereafter, 0.75 to 1.25 kg (about 0.96 to 1.58 liters of methanol) are distilled off in vacuo and the residue is left to stand at room temperature for 10 to 28 days. The precipitated silibinin is filtered off and washed twice with 50 ml of cold methanol each time. After drying at 40 ° C under vacuum, the isolated crude silibinin is further purified as follows:

g of crude silibinin was dissolved in 3 liters of technical ethyl acetate with heating. Thereafter, 20 g of activated carbon are added to the obtained solution and the mixture is stirred under reflux for a further 2 hours. The mixture was then filtered to give a clear solution, and the solution was then concentrated under reduced pressure to about 250 ml at 50 ° C. The concentrate was then stirred for 15 minutes using an Ultra-Turrax stirrer and 25 ml of methanol were added with stirring. The mixture is then allowed to stand at room temperature.

Before filtering off the silybin which has precipitated, the mixture is again stirred for 5 minutes using a stirrer of the above type. The precipitate formed is washed twice again with 50 ml of ethyl acetate and dried in a vacuum oven at 40 DEG C. The product is then milled and dried under the same conditions for a further 48 hours.

The following examples illustrate the process according to the invention, but do not limit the scope of the invention in any way.

Example 1

Preparation of silibinin-C-2 ', 3-dihydrogensuccinate

g of silibinin is dissolved at 45 DEG C. in 70 ml of pyridine, 50 g of succinic anhydride are added, the reaction mixture is stirred for about 8 hours at 45 DEG C., 30 ml of ethanol are added and the mixture is stirred until a homogeneous mixture is obtained. 60 ml of water are then added under vigorous stirring to saponify the phenyl esters over about 30 minutes. After about one hour of stirring at 30 ° C, the phenyl esters are quantitatively hydrolyzed. The completeness of the hydrolysis was checked by high performance liquid chromatography. The hydrolysis is stopped when 1.7 liters of ethyl acetate are rapidly added to the reaction mixture thus obtained.

To separate the excess succinic acid and pyridine, the reaction solution diluted with ethyl acetate was extracted twice with 5 liters of water each, saturated with ethyl acetate and having a pH of 1.85 (adjusted with dilute aqueous hydrochloric acid). The extraction is carried out in countercurrent, i.e. the acidified ethyl acetate wash water is pumped upstream of the dilute reaction solution and then the pH is maintained at 1.85 by addition of dilute hydrochloric acid until the pH remains constant.

Then, the ethyl acetate phase is extracted in countercurrent to wash off the excess hydrochloric acid twice with 3.4 liters of water each saturated with ethyl acetate. When the pH of the wash water is greater than 4.5, the organic phase is separated quantitatively, concentrated at 40-50 ° C under vacuum to 1/12 of the initial volume (about 0.2 liters) and diluted with 125 ml of ethanol.

The title compound is obtained by reprecipitation from a mixture of ethanol and water and drying at 50 ° C under vacuum for 15 hours.

To prepare a sample for analysis, the title compound is precipitated three times from ethanol / water and then dried for 15 hours at 50 ° C under vacuum.

For mass spectrometry (field desorption), the molecular peak appears to have an expected molecular weight of 682.

The iC spectrum shows two overlapping bands in the carbonyl group's valence frequency region, one, as in the case of silibinin, which is responsible for the carbonyl function of the pyron ring at 1635 cm R The other band lies at 1730 cm ¹ and derives from both estercarbonyl functions.

The 1 H-NMR spectrum confirms that in this case, the esterification was doubled. This is achieved by integrating the ratio of aromatic protons to methylene protons of the succinic acid residues 8: 8 (ppm range 5.9 to 7.1). The ratio of these methylene protons (ppm 2.6) to the methoxy protons of the methoxy group (ppm 3.8) is 8: 3 and therefore agrees.

Also, chemical shifts in C exploration show that esterification has taken place on both alcoholic hydroxyl groups, since the chemical shifts vary most intensively on the atom and on adjacent carbon atoms to C 1-4 as well as to C 1-4.

Elementary analysis:

for ^C 33 ^H 3q ° x5 (molecular weight 682.60) calculated 58.07% C, 4.43% H, 37.50% O;

Found: C, 58.05; H, 4.57; O, 37.31.

and

Example 2

Silibinin-C-2 ', 3-dihydrogensuccinate disodium salt

A 6% ethanolic sodium hydroxide solution is added dropwise to the ethanol solution obtained according to Example 1 with stirring and cooling from the outside of the reaction vessel at a temperature ranging from -5 to 9 DEG C., in an amount determined by determining the solids content of the solution. the suspension is stirred for an additional hour at room temperature, the precipitated beige solid is filtered off, suspended twice with a Turrax stirrer in 150 ml of ethanol for 5 to 10 minutes and filtered again. The product was then suspended in 280 ml of ethanol for 14 hours at room temperature to remove residual ethyl acetate, filtered again, washed with 70 ml of ethanol and dried in a vacuum oven at 40-45 ° C for 15 hours. The pre-dried product is then ground, sieved to a particle size of less than 0.2 mm and dried for another 48 hours at 40-45 ° C under vacuum. There was thus obtained 52 g of the title compound (yield 69%).

The title compound does not have a sharp melting point. This substance starts to burst at a temperature of about 80 ° C and melts to release bubbles at a temperature of about 100 ° C.

The UV spectrum in methanol shows the following values:

λ _max = 288 mm, £ = 1.73.10 ⁴ ..

The molecular weight of the title compound is 726.56. The compound is a slightly beige microcrystalline powder, with no specific odor and a taste similar to the taste of the salt. It is readily soluble in water, difficult to dissolve in ethanol and practically insoluble in acetone, ether and chloroform.

Example illustrating the application of manufactured compounds:

Production of lyophilisate for i.p. application:

silibinin-C-2 ', 3-dihydrogensuccinate disodium 75.0 mg mannitol 10.0 mg water for injections up to 1.5 ml

1.5 ml of the solution is filled into a 5 ml vial and then freeze-dried in a known manner. The finished lyophilisate vial is sealed in a conventional manner for storage.

In use, the lyophilisate is dissolved in 5 ml of sterile saline to a clear solution.

Claims (6)

A process for the preparation of novel silibinin derivatives of the general formula I (I) in which:. U.S Alk and Alk ^ ^M 1 ^and »2 are each independently 0 or 1, each independently represent an alkylene group having 1 to 4 carbon atoms or alkenylene having 2 to 4 carbon atoms and are independently hydrogen or an alkali characterized in that 1 part by weight of silibinin of formula A (A) is dissolved in 1 to 2 parts by weight of silibinin. pyridine and reacting with 1 to 3 parts by weight of the dicarboxylic acid anhydride of formula II in which: Alk Alk is Alk ₁ or Alk ₂ as defined above, then ethanol is added until a homogeneous mixture is formed, then water is added slowly with vigorous stirring to hydrolyze the aromatic-linked hydroxyl esters present; Once this hydrolysis is complete, the reaction mixture is diluted with ethyl acetate, washed with acidic water saturated with ethyl acetate, the ethyl acetate phases are concentrated, taken up in ethanol and, if necessary, converted into a salt by treatment with an alcoholic alkali metal hydroxide solution. 2. A process according to claim 1, wherein the corresponding compounds of formula (A) and formula (II) are used as starting materials to give compounds of formula (I) wherein n and m are independently 0 or 1, Alk 1 and Alk ₂ are C 2 alkylene and M ₁ is independently an alkali metal atom. 3. The method according to claim 1, characterized in that starting from the corresponding compound of Formula A and Formula II to give compounds of formula I, us, Alk and Alk ^ ,,, i and M ₂ are each the same meanings. 4. A process according to claim 1, wherein the corresponding compounds of formula (A) and formula (II) are used as starting materials to form the disodium salt of silibinin-C-2 ', 3-dihydrogen succinate of the formula. COONa HIM. CO-CH ₂ -CH ₂ -COOH 5. A process according to claim 1 wherein the reaction with the dicarboxylic anhydride is carried out at a temperature of 40-50 ° C. Ř 6. The process of claim 1, wherein the pH of the acidic wash water saturated with ethyl acetate is maintained in the range of 1.5 to 2.4.