DE3442639A1 - FLAVOLIGNANE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

For obvious spelling mistakes corrected version

NAOHGEREiOHTi

Dr. Madaus & Co.

Ostrnerheimer StraBe 198 W-ίv ^ - << / "->. ^> 'Λ"

5000 Cologne 91 (Merheim) X

Flavol ign.anderivate, process for their preparation and drugs containing these compounds 20

The invention relates to new Πavolignanderivate, Process for their manufacture and pharmaceuticals,

which contain these compounds. IO

The milk thistle -Silybum marianum (L.) Gaertn. (carduus marianus L.) - is a medicinal plant known since ancient times. From the ones in the fruits flavolignans occurring in this plant one component, silybin, isolated by R. Munster, see dissertation R. Munster, Munich, 1966. The chemical structure of this compound was described by A. Pelter and R. Hansel, see Tetrahedron Letters.

London, Volume 25, pp. 2911-2916 (1968). 20th

It is known that silybin, formerly also silymarin I called, is a valuable liver therapeutic, see DE-AS 17 67 666. A technical process for the production of silybin (Silymarin I) is described e.g. in DE-AS 19 23 082.

As early as 1974, H. Wagner, P. Diesel and M. Seitz, Arzneimittelforschung, Volume 24 (4), pages 466-471, in relation to. Silybin suspects two positional isomers, namely silybin and isosilybin. This conjecture was supported by A. Arnone, L. Merlini and A. Zanarotti, Journal Chemical Society Chem. Comm., 1979, volume 16, pages 696/97, specified and confirmed experimentally. Accordingly, the well-known silybin consists of two different compounds, namely the compounds of the following structural formulas A and B:

OB 0

(A) Silibinin

DH O
(B) isosilybine

OCE,

CH ₂ OH

From these structural formulas it can be seen that it is these compounds are positional isomers. The compound of the formula (A) has recently been given the INN name of silibinin. This designation is used from now on in the present application for the compound of formula (A).

The therapeutic use of Sily'bin was difficult because of the fact that Silybin is practically insoluble in water, so that injection solutions or preparations containing silybin where a certain water solubility is required is, were not producible. DE-PS 19 63

Although describes silybin derivatives that have a certain Have water solubility, but it is a very complex mixture of half-esters of succinic acid. This mixture is so complex because there are five esterifiable in silybin Hydroxyl groups are present, and the silybin also has the two positional isomers mentioned above and the succinic acid used for the esterification is a dicarboxylic acid that has both Can form mono- and diesters. For pharmaceutical purposes, a product that consists of a ' There is an unmanageable number of the most varied, unexplained connections, -not usable.

The invention is therefore based on the object of providing water-soluble substances which are suitable for pharmaceutical purposes To provide SiIibininderivate, which as chemical individuals are precisely characterized.

It has now been found that silibinine derivatives of certain alkanoic and alkylenedicarboxylic acids meet these requirements.

The invention therefore relates to silibinin derivatives of the general formula I

OE O

O -COOM,

DCH.

wherein

η ♦ m are each independently O or 1, ■ · "■ · · ■ .- ■.

Alk, and Alk., Each independently denote an alkylene radical having 1-4 carbon atoms or an alkenylene radical having 2-4 carbon atoms and. "

K. and K ₂ each independently of one another mean a hydrogen atom or an alkali metal atom.

Preferred compounds of the formula (I) are compounds in which η and m each independently represent O or 1, Alk. And Alk “each represent an alkylene radical having 2 carbon atoms and M and M each independently represent an alkali metal atom . Preferably η and m, Alk. And AIk ^ and M. and M ₂ each have the same meanings.

SiIibinin-C-2 ', 3-dihydrogen succinate is particularly preferred, Disodium salt.

/ U

The compounds according to the invention are OH groups of the silibinin that are not bound to a benzene nucleus are partially or fully esterified, for example by oxalic acid, malonic acid, succinic acid, Adipic acid, maleic acid, or fumaric acid. Preferably the two are not aromatic bound OH groups of the silibinin by a of the carboxylic acids mentioned are simply esterified.

The inventive method for producing the claimed Si 1ibininderivate is characterized by that about 1 part by weight of silibinin of the formula (A):

OB O

(A) Silibinin

dissolves in 1 to 2 parts by weight of pyridine and with 1 to 3 parts by weight of a dicarboxylic acid anhydride the formula

O = C-Alk -C = O

wherein "Alk" stands for one of the above-defined Al k ^, and AI radicals,
reacts with stirring,

then add ethanol until a homogeneous mixture has formed,

then slowly admixed with water while stirring vigorously, the esters present being the aromatically bound OH groups are hydrolyzed,

as soon as this hydrolysis is complete, dilute with ethyl acetate, saturated with ethyl acetate washes with acidic water, the ethyl acetate phase is concentrated, taken up in ethanol and with an alcoholic Alkali hydroxide solution in the salt of the free, not esterified carboxylic acid residues transferred.

Preferably: the reaction .with the di--. carboxylic acid anhydride at 40 to 50 ° C. ■ The pH of the ethyl acetate saturated is advantageous acidic wash water kept at about 1.5 to 2.4.

These connections, especially the connection SiI ibinin-C-2 ', S-dihydrogen succinate, disodium salt. surprisingly show a pronounced pharmacological Effect in the treatment of burn damage, in addition, despite the described derivatization, they retain full pharmacological Effectiveness of the well-known silybin as a liver therapeutic. They are particularly suitable for the treatment of liver cirrhosis and toxic-metabolic liver damage.

Surprisingly, the compounds according to the invention also proved to be extremely effective in the treatment of fungal poisoning, in particular the very dangerous poisoning by tuber leaf mushrooms (Amanita phalloides). Poisoning by halogenated organic solvents such as carbon tetrachloride, trichlorethylene, chloroform etc: can be treated surprisingly well with it. at

prevent the preventive use of the invention Compounds the damage described above.

The invention therefore also relates to medicaments which contain these compounds. They are mostly used systemically, e.g. in the form of pills, capsules, Solutions, in customary carriers and, if appropriate, together with customary auxiliaries. The daily dose for an adult human is about 50-500 mg depending on the patient's condition and the severity of the Disease symptoms.

Experiments with Si 1ibinin-C-2 ', 3-dihydrogen succinate; Disodium Salζ (Si 1i-suc-na).

The symptoms that occur with burns are particularly caused by intoxication by products of thermal tissue necrosis. The evidence that autointoxicative processes after severe skin burns are responsible for this has been carried out in various ways. Particularly convincing are cross-transplants of burned and unburned skin on healthy or burned recipient animals, whereby sie shows that the unburned recipients of burned skin perish, whereas burned recipients of healthy skin show no damaging effects, see KH Schmidt et al. ', Newer Aspects of Autointoxication after Severe Burns; Burning disease (T. U-Ahnefeld et al., Eds. | _), Springer, Berlin 1982, pages 45-52.

In the case of skin burns, it is released or re-emerged a variety of chemical compounds. Despite their multitude, it was possible to structure some of these Clarify connections.

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It could be shown, among other things, that the skin burns resulting compounds have similarity with those compounds that are involved in lipid peroxidation develop. There are also analogies with regard to the toxic effects of these substances. Particularly The formation of toxic saturated and unsaturated aldehydes of various chain lengths is impressive as a result of lipid peroxidation (Benedetti et al., Identification of 4-hydroxynonenal as a cyt-o toxic product originating from the peroxidation of liver microsomal lipids, Biochim.Biophys.Acta 620, 281-296, Ί980) and der thermal tissue damage (K..B. Schmi_dt et al., Studies on the structure and biological effects of pyrotoxins purified from burned skin, Vorld J. Surg. 3, 361-365, 1979). It is therefore assumed that * burns to oxidative damage to cell structures to lead.

There were therefore auto-oxidative changes in membrane lipids investigated as a result of autointoxication after severe burns. There have been changes in particular in the fatty acid composition of the membrane lipids examined. Furthermore, the extent to which the invention was tested was tested Silibinin derivatives influence changes in the fatty acid composition of the membrane lipids.

Changes in fatty acid composition of membrane lipids after severe burns

Male VJistar rats with an average weight of 360 g were housed in groups of three with free access to water and dry food. Up to the start of the experiment, the room temperature was 22 ^° C. After the start of the experiment, the animals were kept at 30 ° C.

The skin burns were marked with a copper stamp of 20 cm area at constant pressure and a temperature of 250 "C. To avoid thermal damage To exclude deeper organs, the Raut '' pulled over an air-cooled hollow spatula. Hit this one Very precise burn trauma can be set on animal models, which provide constant survival rates.

Before the start of the experiment, the animals were given a Ksrkose 50 mg / kg jVembutal. After the burn, shock prophylaxis was used 20 ml lactated Ringer's solution i.p. injected.

5 test groups were formed:

a) Normal group: completely intact animals

b) Control group I: Only SiIibiniη treatment over

6 days with 75.5 mg Sili-suc-na.

c) Control group II: sham operated animals

d) Group with burned animals: 25 %, 25O ⁰ C,

20 see, 0.5 at

e) Test group: animals given 75.5 mg of Sili-suc-na i.p.

administered over 6 days starting one day prior to the burn

To isolate the microsomes, the animals were taken after the end bled during the test period under anesthesia. The liver was then removed, weighed and immediately placed in ice-cold Isolation medium transferred (0.25 M sucrose, 1 mW EDTA, 10 mmol Tris · HCl, pH 7.2). The liver was cut up and homogenized in the medium. By Differ The microsome fraction was pelleted by centrifugation. The microsomes were resuspended and centrifuged again. A suspension was then made 1 ml of suspension corresponded to 1 g of liver tissue.

The lipids were determined by the method of J. Folch (A simple method for the isolation and purification of total lipids

from animal tissues, J.biol. Chem. 226, 497-508 (1957)), modification by Bligh and Dyer (A rapid method of total lipid extraction and purification, Can. 3. Biochem. Physiol. 37, 911-917 (1959)).

The extracted microsomal lipids were washed with caustic soda saponified. The free fatty acids were esterified by adding BF, methanol. After evaporation of the methanol and Removal of hydrophilic by-products, the fatty acid esters were determined quantitatively.

In the unburned animal groups, no significant change in the fatty acid pattern could be determined. The 'anesthesia' and the minor surgical intervention 'lead / -therefore does not result in a change in microsomal lipids. For this reason we have made further comparisons the normal group and the control group combined to form a control group.

A comparison of the unburned and burned animals with regard to their microsomal fatty acid pattern showed serious shifts - from unsaturated to saturated fatty acids.

FIG. 1 shows the fatty acid distribution in the microsomal Liver lipids and the changes caused by thermal damage to the prey. The proportion of palmitic acid (C16) increases after combustion from 25.1 to 34.4% of the total fatty acids. In the case of stearic acid (C18), the proportion in the burned animals is 46.3%, which is 13.2% higher than that in the control animals The oleic acid (C18: 1) shows a slight, insignificant drop verifiable. The proportion of linoleic acid (C18: 2) decreased to about 1/3 of the initial value after incineration return. For arsidonic acid (C20: 4) after all, only 31% of the initial content was found after incineration.

The following table 1 shows the influence of Sili-suc-na on the fatty acid proportions of the burned and unburned animals.

Table 1

Fettsoureipuster of the microsoaal lipids of rat liver after SiIi-suc-na therapy in burned and unburned animals

C16 ■ C1ß C1ß: 1 C18: 2 C2d: 4

UKBURNED
(ContraΠ group I) 29.8 %
6.2 '37 ·,
Uz. B.
ίι .9 ί
. 1 9.5% '
Ϊ3.3 14th 2 ί "
9 BURNED 25.4 %
ΐ 6.0 .2 Χ "
.3 7th
± 1 .8 %
.D 11.4 %
Ϊ5.3 18th
is. D %
1 37.5 p
ΐ β.6

It turns out that the treatment according to the invention ait a silibinin derivative in the uninhibited control animals no significant changes in comparison to the. untreated animals. Celebrate the burned In animals, the therapy leads to a complete elimination of the loss of unsaturated fatty acids.

In summary, the following can be stated: Burns lead to changes in the fatty acid pattern of microsomalex lipids. It is believed that this is due to attributable to oxidative damage to the membranes is. This is particularly evident in the strong decrease of polyunsaturated fatty acids.

/ f Γ ·

The silibinine derivatives used in accordance with the invention are now able to inhibit oxidative cell damage. They are therefore particularly suitable for oxidative damage mechanisms break through after severe burns.

"As already mentioned, one assumes 2η that autotoxic Reactions after severe burns lead in particular to oxidative cell damage. It was therefore investigated the effect of standardized thermal trauma on ΡΕΑ-induced blastogenesis of T lymphocytes from the "- · HiIi- and 'the peripheral" blood of Rotten - · owns. It was also investigated how the invention usable silibinin derivatives such lymphocyteres Affect malfunctions after severe burns.

"Effect of a standardized thermal trauma on the PHA-induced blastogenesis of T lymphocytes. the spleen and peripheral blood of rats

As previously described, the dorsal skin was made from Vistar rats burned with a copper stamp. As a control group were used sham burned animals to which all operative manipulations were carried out without burns became. Kach 2, 4, 7 and 9 days was the burned ones or the control animals under ether anesthesia blood and MiIZ taken.

Heparinized blood was used to isolate the lymphocytes layered on Ticoll-Hypaque solution (density 1.077). It was then centrifuged and the lymphocytes obtained were tested for vitality with Trypan blue. To isolate the spleen lymphocytes, the organ was comminuted, passed through a sieve and through lysis solution

after Gay freed from the accompanying erytftrocytes.

The cell mixture was then incubated in a vessel in the presence of 5 % heat-inactivated fetal calf serum for 30 minutes in order to reduce the proportion of mononuclear cells in the suspension by adhesion to the vessel wall (5%). For cultivation, the cells were placed in "flat-bottom" microtiter plates. Then 20 X -fötales calf serum was added. In this way, the spontaneous blastogenesis was determined by measuring the incorporation of H-thymidine (2Ci / mM) into the DNA of the cells.

In preliminary tests νβτ. -Cleared.n,. that an · optimal ■ Mitogen stimulation at a PRA concentration (mitogen phythaemagglutinin) of 5ng / ml takes place. With these Experiments to optimize the cellular test system were also found that the maximum stimulation dtr new synthesis of DNA takes place after 72 hours; _ Furthermore it was found "that the optimal concentration fetal calf serum is -20 pounds for the highest stimulation to achieve.

As described above, there was spontaneous blastogenesis. by measuring the incorporation of B-thymidine into DNA of cells determined. The cells were harvested 18 hours after the addition of H-thyrnidine, being the zero point for the 18 hours coincides with the time of maximum stimulation.

To investigate the effect of those which can be used according to the invention SiIibininderivate a group of rats was using treated with a Si 1ibinine derivative. This was 75.5 mg Sili-suc-na injected intraperitoneally once a day. These Therapy was carried out from the day of the burn until the day of organ removal (up to the 9th day at the most).

/ J-

For the evaluation of the control animals and the und ·. burned animals and the animals treated with S-ili-suc-ria The stimulation index was calculated for the results obtained. This numerical value represents the quotient from the Average value of the stimulated gown and the average value of the control sample. The stimulation index thus obtained in each test animal became an average Stimulation index calculated per group of animals. The received Results are expressed by this index Sl.

Figuf'2 shows the influence of the SiI i-suc-na used on the blastogenesis of lymphocytes. Both When the animals were burned, the reduced ability of the cells to be stimulated by silibinin was evident elevated.

As early as day 2, the animals treated with SiIisuc-ria showed an approximately 10 times higher responsiveness of the blood lymphocytes to PHA. On the U. post-traumatic day, the value for the stimulation index in blood lymphocytes for treated animals was 8, while the corresponding value for the untreated animals was 1.5.

The stimulation indices are found in the spleen cells of the burned, untreated animals all well below 1. The administration of Silibinin leads to a significant improvement on all days examined, whereby on 7. Post-traumatic day sets a maximum.

Comparative tests were also carried out, which showed that Sili-suc-na alone in healthy people Animals did not show any significant changes in the Stimulability in PHA-induced blastogenesis of T lymphocytes from the spleen and from the peripheral blood.

The silibinin used according to the invention thus stimulates the blastogenesis of lymphocytes from burned animals in significant "way.

It was also found that those with silibinin derivatives treated animals suffered from general catabolism lesser was there; the animals quickly after the thermal Trauma regained weight.

Mushroom poisoning:

Poisoning by the death cap mushroom is one of the most severe in medicine. Although only 10 to 30 Z of all mushroom poisoning caused by the green death cap mushroom, poisoning with this mushroom is considered Due to their dangerous nature, it has always been of the greatest medical interest.

In older publications the lethality was given as 3 to 50 Z. Thanks to modern intensive care medicine, according to a collective study by FLOERSHEIM et al. at 205 Patients reduced this number to an average of 22.4 Z.

Bas poison of the amanitin, the amanitin, can already at a dose of 7 mg can be fatal to an adult human. This amount of poison is about 50 g of a fresh one Copy included.

After a series of promising animal experiments the active ingredient Sili-suc-na was used in the therapy of tuberous mushroom poisoning included.

There were 28 patients with tubercles 1 poisoning in addition to the usual therapeutic measures additionally treated with Sili-suc-na. Of these 28 patients, only died one who ingested large amounts of the toadstool with suicidal intent would have. This result demonstrates enormous therapeutic progress on ·; this area.

Production of 'isosilybin-free silibinin:

A suspension of 500 g of the product according to. DE-AS 19 23 082 column 8, lines 14-19, with a silymarin content of approx. 70% with an isomer ratio silybin / silidianin / silicristin of ~ 3: 1: 1 -, the silybin containing about 1/3 isosilybin, and
kg · methanol = 2.53 l is heated to boiling for minutes while stirring. After this time, some silibinin can already precipitate from the solution obtained in this way. Then 0.75 to 1.25 kg is pulled in a vacuum

= 0.96-1.58 l of methanol and the residue is left to stand for 28 days at room temperature. The precipitated silibinin is filtered and twice with each
washed ml of cold methanol. After drying

at 4O ⁰ C in vacuum, the isolated Rohsilibinin as will be further purified as follows:

60 g of raw ε i 1 ibinin are in 3 .1 techn. Ethyl acetate dissolved with heating; then mixed with 20 g of activated charcoal and stirred for a further 2 hours under reflux conditions. Thereafter klarfiltriBrt and the solution at 5o C BREAK reduced pressure to approximately 250 ^- tnl concentrated, the concentrate is 15 stirred minute using a Ultra-TurraxgBräts and added under stirring with 25 ϊρΙ Plethahol. The mixture is then left to stand at room temperature overnight. Before sucking off the precipitated silybin, it is stirred again for 5 minutes, also with the help of a tlltra-Turrax device. The suction-filtered precipitate is washed twice with 50 ml of ethyl acetate and dried overnight at 40 ° C. in a vacuum drying tank. The product is then ground and re-dried for 48 hours under the same conditions.

⁴ (33

Example 1

Production of Silibinin-C-2 ', 3-dihydrogen succinate

OCE,

CD - CE ₂ - CE - COOH

50 g of silibinin are dissolved in 70 ml of pyridine at 45 "C. 50 g of succinic anhydride are added, the mixture is stirred for about 8 hours at 45 ° C., 30 ml of ethanol are added and the mixture is stirred until a homogeneous mixture forms. Then you give while stirring vigorously to saponify phenyl esters, add 60 ml of "water" within approx. 30 minutes. The phenyl esters are quantitative for 1 hour of stirring at 30 ° C hydrolyzed. The completeness of the hydrolysis is checked by means of HPLC. The hydrolysis is stopped by 1.7 1 ethyl acetate rapidly to the resultant Reaction mixture there.

For separating excess succinic acid and pyridine the diluted with ethyl acetate is extracted Reaction solution twice with 5 l each of water which is saturated with ethyl acetate and has a pH of 1.85 has (adjusted with dilute aqueous hydrochloric acid), in countercurrent. It is pumped with ethyl acetate saturated, acidified washing water in the circuit against the diluted reaction solution and then stop With the addition of dilute hydrochloric acid, the pH is kept at 1.85 until this pH value has passed through the ethyl acetate remains constant.

The ethyl acetate phase is then extracted to wash out excess hydrochloric acid twice in countercurrent with 3.4 liters of water saturated with ethyl acetate. As soon as the pH of the washing water is greater than 4.5, the organic phase is separated quantitatively and concentrated at -AO - 50'C in vacuo to 1/12 of the initial volume (-0.2 1) and diluted with 12SwI ethanol.

The title compound is obtained by reprecipitation from ethanol / water and drying at 50 ° C. in vacuo for 15 hours.

To prepare an analytical sample, the title compound is precipitated three times from ethanol / water and the like and dried then 15 hours at 50'C in a vacuum.

In the FD spectrum, the molecular peak appears at expected molecular weight of 682.

The IR spectrum shows in the range of the CO valence frequency two overlapping bands, one of which, as is also the case with silibinin, is the carbonyl function of the pyrone ring is to be assigned to the W-elleniange 1635 cm.

- as-

The second band is at 1730 cn "and comes from the both ester carbonyl functions.

The H-NMR spectrum confirms that the esterification is twofold has taken place. The ratio of aromatic protons determined by integration is to methylene protons of the succinic acid residues B: 8 (ppm range 5.9-7.1). The ratio of these methylene protons (ppm 2.6) to the methyl protons of the methoxy group (ppm 3.8) "is 8: 3 and is thus consistent with it.

13 The chemical shifts in the C investigations also show that the esterification has taken place in the two alcoholic OK groups, because the chemical shifts change most strongly with C .. and the adjacent carbon atoms C.- ~ C., as well as with C- - C,

Elemental analysis for Ο ,, Η, -Ο ,, (682,60)

Ber. : Found:

C. 07 E. 43 0 .50 5B, 05 4, 57 37 .31 58 . 4th 37

Example 2

Production of Silibinin-C-2 ' , S-dihydrogen succinate,

Disodium salt

OH 0

- vr-

* ° - ^CD - ^ E ₂ -

OCB

- COHs

2 "" ^CH 2 "~ CONa

To the Ethanpllösung obtained according to Example 1 is added dropwise one with stirring and cooling from the outside at -5 to 9 * C. a "based on a determination-de.s solids content" this solution determined the amount of 6% ethanolic sodium hydroxide solution, If the suspension is stirred for a further hour at room temperature, the beige solid which has precipitated is sucks off, suspended it twice for 5 to 10 minutes each time with the help of a Turrax in 150 ml of ethanol and sucks it off again, lur Removal of the remaining ethyl acetate suspended you then the product 1 * hours at room temperature in 280 ml of ethanol, sucked off again, washed with 70 ml of ethanol and dried for 15 hours at 40-45 ° C. in the vacuum drying cabinet. The pre-dried product is then ground and sieved to a particle size smaller than 2 mm and dries for a further 48 hours at 40-45 ° C. in a vacuum. 52 g of the title compound are obtained in this way (yield 69%).

The title compound does not have a sharp melting point It begins to sinter at approx. 80 * and melts below Bubble formation at approx. 100 ° C.

The UV spectrum in methanol shows: λ _Bax * ^{2B8 nm} »£ -1.73

The molecular weight of the title compound is 726.56. The compound is a light beige, microcrystalline powder

without a specific smell and with a salty taste. It is easily soluble in water, sparingly soluble in ethanol and practically insoluble in acetone, ether and chloroform.

Application example

Production of lyophilisates for i.v. administration

Silibinin-C-2 ', 3-dihydrogen succinate, disodium salt 75.0 mg mannitol 1O ₁ O

for injection ivokes ad 1.5

1.5 »1 Ι» change, in BpieBaapnllen τοπ 5 * 1

tmd. dantoh la known technique freeze-dried. Kit dex finished Lyophilise-t vird rar l & Tbevahrazif in usual Veise Ter »cnlo« »en. . . .

For use, the Lyophllieat is dissolved in 5 »1 sterile, physiologically clear» ■ ■ ■

Claims (9)

Claims 1. Silibinin derivatives of the general formula I. CH ₂ -O-CD- (AIk ₁ ) -COOM ₁ * ■ · ι η ι OCE, OH 0 ,, - COOM, 2 m 2 wherein η + ο independently of one another for 0 or 1 stand,
Alk. And Alk- each independently of one another Alkylene radical. with 1- ^ carbon atoms or an alkenylene radical containing 2-4 carbon atoms mean and K. and K ₂ each independently represent a hydrogen atom or an alkali metal atom. 2. Silibinin derivatives according to claim 1, characterized in that that η and in each independently of one another for 0 or stand, Alk. And Alk_ each have one Alkylene radical .with 2. Mean carbon atoms and M ₁ and M, each independently an alkali metsllaton mean. 3. Silibininäerivate according to claim 1 characterized by that n and m, Alk. and Alk- and M ₁ and M- have the same meanings. 4. Silibinin-C-2 ', JS-dihydrogen succinate, disodium salt the formula: CE " -D-CO- CE" - CE ^ - CODKa CE »~ CE ^ - COOKa 5. Process for the preparation of the silibinine derivatives according to the Claims 1-4, characterized in that 1 part by weight of silibinin of the formula (A): OH (A) Silibinin OCE. Dissolves in 1 - 2 parts by weight of pyridine and with 1-3 parts by weight of a dicarboxylic acid anhydride of the formula: O = C-Alk -C = O wherein "Aik" stands for an AIk ₁ or AIk ₂ remainder according to claim 1, reacted with stirring, then added ethanol until a homogeneous mixture has formed, then slowly mixed with water with vigorous stirring, with existing esters of the aromatically bound OH ^ -Groups are hydrolyzed as soon as this hydrolysis is complete, diluted with ethyl acetate, washed with ethyl acetate-saturated acidic water, the ethyl acetate phase concentrated, taken up with ethanol and converted into the salt of the free carboxylic acid residue with an alcoholic alkali hydroxide solution. 6. The method according to claim 5, characterized in that that the reaction with the dicarboxylic anhydride at c about 40 - 50 C is carried out. 7. The method according to claim 5, characterized in that the ethyl acetate saturated acidic wash water at a pH of about 1.5-2.4 is maintained. 8. Pharmaceutical agents containing at least one Ver. Binding according to any one of claims 1-4, optionally in a pharmaceutical carrier or excipient. 9. Use of the compounds "Hsch claims 1-4 for the treatment of burn damage, liver cirrhosis, toxic-metabolic liver damage and fungal poisoning. 203 / Z,