Method of producing derivatives of silibinin

专利摘要:
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.
公开号:SU1436875A3
申请号:SU853985401
申请日:1985-11-21
公开日:1988-11-07
发明作者:Браатц Райнхард；Герлер Клаус；Хальбах Гюнтер；Зойке Хартвиг；Шмидт Карлхайнц
申请人:Др.Мадаус Унд Ко (Фирма)；
IPC主号:

专利说明:


about
This invention relates to a process for the preparation of new silibinin derivatives, which have pharmacological activity and are effective in the treatment of liver cirrhosis and toxic and metabolic liver damage, and also have a pharmacological effect in the treatment of burn wounds and in mushroom poisoning.
The purpose of the invention is to obtain new and out compounds with valuable biological active properties.
Silybin, formerly known as Silymarin 1, which is a valuable medicinal drug for treating liver disease, consists of two isomers: silibinin and isosilybin.
In therapeutic use, Silibin poses difficulties due to the fact that it practically does not dissolve in water, and therefore it is not possible to prepare silybin-containing solutions for injection or preparations for which it is necessary to have a certain solubility in water.
SyLibine derivatives with some solubility in water are described. However, in this case there is a rather complicated mixture of half-esters of succinic acid. This mixture is therefore so complex that silybin has five hydroxyl groups that can esterify. In addition, silybin is a mixture of two-indicated position isomers, and the succinic acid used for the esterification is a dicarboxylic acid, which can form both mono- and diesters. For pharmaceutical; targets produced from a large number of very different unidentified compounds are unsuitable.
This method allows the preparation of suitable water-soluble silibinin derivatives suitable for pharmaceutical purposes, which can be accurately identified as individual chemical compounds. .
Silibinin derivatives of certain alkanoic and alkylene dicanoic acids satisfy this. requirements m
Dr 1. MER 1. Obtaining silibinin, not containing isosilibinin. A suspension of 500 g with a content of silymarin of about 70% with a ratio of isomers of silybin: silydianin: silycristin is 3: 1: 1, and silybin contains about 1/3 of isosilybinin in 2 kg of methanol, which corresponds to 2.53 l, heated with stirring 15 minutes before boiling. After this time a certain amount of silibininao can already precipitate out. After this, distilled off in vacuum 0.75-1.25 kg (0.96-1.58 L) of methanol and the residue is left stand at room temperature for 10-28 days Disposing silibinin fi lters filtered shayut and cold methanol dvalody promshayut portions of 50 ml. After drying at 40 ° C in vacuum, the resulting crude silibinin is further purified as follows.
60 g of crude silibinin is dissolved by heating in 3 liters of technical ethyl acetate, and then the solution is mixed with 20 g of activated carbon and the mixture is boiled with stirring for 2 hours. reflux condenser. It is then filtered until a clear solution is obtained, which is evaporated at 50 ° C under reduced pressure to about 250 ml. The concentrate is stirred for 15 minutes with the aid of an ultra-turrax instrument and 25 ml of methanol is added to it with stirring, after which the mixture is left to stand overnight at room temperature. Before filtering the silibinin precipitate that formed during the precipitate, the mixture is stirred for 5 min again using an ultra-turrax. The precipitate obtained on the suction was washed twice with 50 ml portions of ethyl acetate and dried overnight in a vacuum oven at 40 g. Then, the resulting product was crushed and dried under the indicated conditions for another 48 hours.
PRI mme R 2. Preparation of silybinin-C-2, 3-dihydrosuccinate.
50 g of silibinin is dissolved at 45 ° C in 70 ml of pyridine, 50 g of succinic anhydride is added to the solution, the mixture is stirred for about 8 hours, 30 ml of ethanol is added to it and stirring is continued until a homogeneous mixture is formed. Then, with vigorous stirring, it is added to it to saponify.
314368754
phenyl ethers for about carbonyl functionality for about 30 minutes 60 ml of water. After stirring the pyrone ring group for a period of about an hour, the phenyl esters are quantitatively hydrolyzed. The completeness of the hydrolysis is controlled by high performance liquid chromatography. The hydrolysis is stopped by rapidly adding 1.7 l of ethyl acetate to the mixture.
To separate excess succinic acid and pyridine, the reaction solution was diluted with ethyl acetate and twice shadverted with water in 5 l portions, saturated with ethyl acetate and having a pH of 1.85 (acidification to this pH is carried out using a dilute aqueous solution of hydrochloric acid). acid). Extraction is carried out countercurrently. In this case, a nasch (ennun) acetic acid ester acidified wash water is fed by means of a pump in tsirne wave 1635. The second line has a wavelength of 1730 cm and OVHOCHT- with both ether carbonyl functions.
The H-NMR spectrum confirms that double esterification occurred during the reaction. Thus, the ratio of aromatic protons to protons of methylene of an succinic acid residue (ppm in the region of 5.9-7.1) obtained by integrating is equal to 8: 8. Attitude
15 of these protons of the methylene group
(ppm, 2.6) to the protons of the methyl of the methoxy group (ppm 3.8) is equal to 8: 3, the - in the IMM manner - is consistent with the above value.
20 The chemical shifts found in the C-research process also indicate the esterification of both alcohol OH-groups, since the chemical shifts most strongly change
refers to the carbonyl functional group of the pyrone ring at
not wave 1635. The second line has a wavelength of 1730 cm and OVHOCHT- with both ether carbonyl functions.
The H-NMR spectrum confirms that a double esterification occurred during the reaction. Thus, the ratio of aromatic protons to protons of methylene of an succinic acid residue (ppm in the region of 5.9-7.1) obtained by integrating is equal to 8: 8. Attitude
of these protons of the methylene group
(ppm, 2.6) to the protons of the methyl of the methoxy group (ppm 3.8) is equal to 8: 3, the - in the IMM manner - is consistent with the above value.
The chemical shifts found in the C-research process also indicate the esterification of both alcohol OH-groups, since the chemical shifts most strongly change
a cooling loop oppositely from cVi and neighboring carbon atoms to the diluted reaction solution and maintained by adding diluted hydrochloric acid pH 1.85 to technical pressure until this value remains constant after HNB1M after passing ethyl acetate.
Then, the ethyl acetate phase is extracted twice with 3.4 L portions of 3.4 liters each saturated with ethyl acetate and extracted with countercurrent water to extract the excess hydrochloric acid from it. As soon as the pH of the industrial water becomes greater than 4.5, the organic phase.
quantitatively separated, evaporated at up to P in an amount corresponding to
40-50 ° C under vacuum to 1/12 of the original volume (0.2 L) and diluted in 125 ml of ethanol.
The target compound is obtained by reprecipitation from a mixture of ethanol and in the middle, the precipitating analytical content of the solid substance in this solution is sucked off, the suspension is stirred. for another hour at room temperature and drying at 50 ° C in vacuum for 15 hours.
To obtain a sample for analysis, the target compound was replanted three times from a mixture of ethanol and water and dried at 50 ° C under vacuum for 15 hours.
There is a peak on the FD mass spectrum corresponding to an expected molecular weight of 682.
In the IR spectrum, in the region of the CO-valent frequency, there are two overlapping lines, one of them, as is the case in the case of silibinin
0
five
yes C, -2, (14 as well as at atom C.
Calculated,%: C 58.07; H 4.43; About 37.50.
Cj ,, o.s
Found,%; C 58.05; H 4.57;
About 37.311.
PRI me R 3. Preparation of the disodium salt silibinin-C-2 H-dihydrosuccinate.
To the obtained in accordance with example 2-ethanol solution is added dropwise with stirring and external cooling to 5–9 ° C. 6% ethanol solution is caustic at temperature, the solid content of the solution is sucked off analytically determined, the suspension is mixed. for another hour at room temperature0
a beige dock, suspending it twice (each time for 5 to 10 minutes) using turrax in 150 ml of ethanol and sucking again. To remove residues of ethyl acetate, the product is then suspended for 14 hours at room temperature in 280 ml of ethanol, sucked off again, rinsed with 70 ml of ethanol and dried for 15 hours at 40-45 ° C in a vacuum drying oven. After that, the previously dried product is crushed, sifted to a grain size of less than 0.2 mm and dried for
48 more hours at 40-45 C in vacuum. 52 g of the desired compound are obtained (yield 69%).
The resulting target compound does not have a specific melting point. It begins to bake at a temperature of about 80 s, and at a temperature of about 100 C it melts to form bubbles.
UV spectrum in methanol: d, s, s
288 nm; . e 1.73-10
and
ABOUT
0 CH2-0-CO-CH2-
.
. oi
- - h - Soon
co-night
50 g of ci-shibnnin at 45 ° C are dissolved in 100 ml of pyridine, 150 g of succinic anhydride are added, the mixture is stirred for about 8 hours at 5, 40 ml of ethanol is added and the mixture is stirred until a homogeneous mixture is formed. . Then, with vigorous stirring, 60 ml of water are added over about 30 minutes to saponify the phenyl esters. After about 2 hours of stirring at 30 ° C, the phenyl esters are quantitatively p-dilated. The completeness of the pdrolysis is determined using those high pressures. The hydrolysis is stopped by the rapid addition of 1.7 l of ethyl acetate to the resulting reaction mixture.
Further processing is carried out as described in Example 2.
The physicochemical properties of this compound are u; they are identical to the compounds of Example 2.
The compounds of formula (I), in particular the disodium salt silibinin-C-2, 3-dihydrosuccinate, have a pronounced pharmacological effect in the treatment of burn wounds. In addition, despite the fact that, as a result of the treatment described, these compounds are derived from STB, Iin, they completely retain the pharmacological activity of silibinin, which is a known agent for treating liver diseases. They are especially effective in treating cirrhosis, liver, and toxic and metabolic lesions of the liver.
The molecular weight of the target compound is 726.56. It is a microcrystalline threshold of light beige color with no peculiar smell and a salty taste. It is readily soluble in water and poorly soluble in ethanol and acetone. In diethyl ether and chloroform, it is practically insoluble.
PRI me R 4. Getting silybinnnn-C-2, 3-dihydrosuccinate
five
0
five
0
five
0
five
The compounds of formula (I) have, in addition, an unusually high activity in the treatment of fungal poisoning, especially very dangerous poisoning by the toadstool (Amanita phalloides). They can also successfully treat poisoning with halogenated organic solvents such as carbon tetrachloride, trichlorethylene, chloroform, and the like. In the case of prophylactic use, the compounds of formula (I) prevent the listed diseases.
Drugs containing these compounds are in most cases used systematically, for example, in the form of pills, capsules,
solutions, in composition with OBJECTIVE
carriers and, if desired, with the usual auxiliary additives. The daily dose for an adult is about 50-500 mg, depending on the condition of the patient and the severity of the disease.
Experiments with the disodium salt silibinin-C-2, 3-dihydrosuccinate (silyscane).
The symptoms appearing during burns are caused, in particular, by intoxication of the body with products of thermal tissue necrosis. The fact that autointoxicative processes after severe skin burns are responsible for this has been proven in many ways. Especially convincing are the experiments on cross-transplantation of baked and unbaked
skin healthy animals and, accordingly, animals with burns. It was established that healthy animals with burned skin transplanted to them died, whereas the burned animals did not have healthy skin transplanted to animals with burns.
In the case of skin burns, a variety of different chemical compounds are released in free form or re-formed. Despite their large number, it was possible to establish the structure of some of these compounds.
In particular, it was possible to show that the compounds formed during skin burns are similar to the compounds formed during the over-oxidation of the li-:. pidov. There are also analogues of the toxic effect of these compounds. Particularly striking is the fact of the formation of toxic and saturated properties of unsaturated aldehydes with different chain lengths due to lipid peroxidation and thermal skin lesions. Therefore, it can be assumed that burns cause oxidative damage to cellular structures.
Therefore, autooxidative changes in membrane lipids resulting from autointoxication after severe burns were investigated. In particular, changes in the fatty acid composition of membrane lipids were investigated. In addition, it was determined to what extent the proposed silybin derivatives affect the indicated changes in the composition of fatty acids of membrane lipids.
Fatty acid composition changes of membrane lipids as a result of severe burns.

Male Wistar rats with an average weight of 360 g, divided into three groups, received a sufficient amount of water and dry. Before the experiments, the room temperature was 22 C. After the experiments began, the animals were kept at 30 C.
Skin burns were applied using
l
a copper stamp with a surface of 20 cm at constant pressure and a temperature of 250 s. In order to prevent thermal damage to deeper organs, the skin of animals was pulled on air-cooled spine
ten

| 5 20 25 30
68758
tel. In this way, burn injuries can be very accurately applied, the extraction time from which is strictly constant.
Before starting the experiments, the animals were given anesthesia (50 mg / ke of Nembutal). After applying the burn, 20 ml of Ringer's lactate solution was intraperitoneally administered to prevent shock.
All animals were divided into 5 groups:
a) normal group: animals that have not been burned;
b) control group I: animals that were treated only with silibinin (75.5 mg of siloxane was administered over 6 days);
c) control group .II; allegedly operated animals;
d) animals which were applied 5 0 25 0
five
burns: 25%, 250 C, 20 s, 0.5 at;
e) a group of test animals: animals that were administered intraparenterally with 75.5 mg of sili-sukana for 6 days, starting the day before the burns.
To isolate the microsomes, animals were bled under anesthesia after the end of the experiments. Then they removed the liver, weighed it and immediately immersed in an ice-cooled insulating medium (0.25 mol of sucrose, 1 mmol of EDTA, 10 mmol of Tris HC, pH 7.2). The liver was cut into pieces and homogenized in the medium. By differential centrifugation of a microsome (Q Nuk), the fraction was recruited. Microsomes were again suspended and subjected to centrifugation, after which a suspension was prepared, 1 ml of which corresponded to 1 g of liver tissue. 5 Lipids were determined by the method of J. Folch (a simple method for isolating and purifying the total content of lipids from animal tissues, modified by Bligh and Dyer (Accelerated method of extracting and purifying the total amount of lipids).
Extracted microsomal lipids were bored with caustic soda. Free fatty acids were esterified by adding a mixture of methanol solution BFj to the mixture. After distilling off the methanol and removing the hydrophilic by-products, fatty acid esters are quantitatively determined.
In animals that were not burned, no significant changes in the composition of fatty acids were found. Thus, anesthesia and minor surgery do not lead to a change in micro-MHbiX lipids. Therefore, for further comparison, data on the normal and control groups of animals were combined into one control group.
Comparison of healthy animals and animals, which were burned, with respect to the composition of micro-fatty acids showed a significant shift from unsaturated to hepatic-fatty acids.
When fatty acids are distributed in the microsomal lipids of the liver by the changes caused by thermal injury, it can be seen that the content of palmitic acid (C1 6) increases after the application of burns from 25.1 to 34.4% of the total fatty acids. In the case of stearic acid (C18), its content in animals whose pbw were burned was 46.8% compared to 13.2% in animals from the control group. In the case of oleic acid (C18: 1), a slight decrease was observed. The content of linoleic acid (018: 2) After application: burns decreased to about 1/3 compared with the initial amount, And in the case of arachidonic acid (C20: 4), after applying burns, only 31% of it was found. by the amount of.
The effect of sili-suk on the content of fatty acids in zorovyh animals and alive from which burns were inflicted is shown in the table.
As can be seen in Table 1, treatment with silibinin derivative form (1) in the case of healthy (control) animals: does not lead to significant changes compared with animals not treated with the drug. In the case of animals that have suffered burns, treatment leads to the complete cessation of the reduction of unsaturated fatty acids.
Consequently, burn injuries: lead to a change in the composition of 5kirny acids in microsomal lipids. It can be assumed that this is due to oxidative damage to the membranes.
0
five
0
five
This follows, in particular, from a sharp decrease in the content of unsaturated fatty acids with several double bonds.
The silibinin derivatives of formula (I) used can inhibit the oxidative destruction of cells, and they can thus be successfully used to disrupt the mechanism of o. - sedentary destruction after severe burns.
Autotoxic reactions after severe burns can lead, in particular, to oxidative damage to cells. Therefore, experiments were conducted in which it was studied what effect standardized thermal injuries have on the induced RIA blastogenesis of spleen T-lymphocytes and peripheral blood of rats. The effect that the proposed silibinin derivatives of this type of lymphocyte functional damage after severe burns has also been studied.
The effect of standardized thermal injury on RIA-induced blastogenesis of T-lymphocytes of the spleen and peripheral blood of rats.
Wistar rats were wrinkled onto the skin with a copper stamp and burned as described. As . the control group were animals with imaginary burns, with which the same manipulations were carried out, but without causing burns. After 2,4,7 and 9 days, burned animals and also control animals under ether anesthesia removed the spleen and exsanguinated them.
 Heparinized blood to inject lymphocytes from it was layered on a Ficoll-Hypaque solution (density 5777). Then centrifugation was carried out and the lymphocytes obtained were tested for viability using trypan blue. To isolate the lymphocytes from the spleen, the latter were crushed, rubbed through a sieve, and separated out from the accompanying red blood cells by G-ay using a lysis solution.
After that, in order to reduce the content of single nuclei in the suspension as a result of adhesion on the vessel walls (5%), the cell mixture was incubated for 30 minutes in the vessel; in the presence of 5% inactivated /
five
0
0
five
eleven
thermally serum fetal calf. For cultivation, the cells were placed in flat-bottomed microtiter plates and a 20% shortening of the fetal calf was added to them. Thus, spontaneous blastogenesis was determined by measuring the incorporation of n-thymidine (2 Ci. (Micromole) into DNA cells.
In the course of preliminary experiments, it was found that optimal mitogenic stimulation was observed at a RIA concentration (mitogen-phythemagututinin) of 5 µg / ml. During these experiments to optimize the cell test system, it was also found that the maximum stimulation of DNA re-synthesis occurs after 72 hours. In addition, it was established that the optimal serum concentration of the fetal calf, at which the highest stimulation is observed, is equal to 20%.
Spontaneous blastogenesis was determined by measuring the incorporation of N-thymidine into DNA cells. Cells were selected 18 hours after the addition of H-thymidine, and the zero point for 18 hours coincides with the moment of maximum stimulation.
To determine the effect of the proposed silibinin derivatives, a group of rats were treated with a silibinin derivative. To this end, 75.5 mg of silicone was injected once a day into animals. The treatment continued, starting from the day the burn was applied and to the day the organ was removed (up to a maximum of the ninth day).
To evaluate the results obtained in experiments with control animals, those of them that did not suffer burns, and who underwent treatment with Sil-suk, an index with stimulation was calculated. The e-th numerical value is the quotient of the mean values of stimulated and control samples. From the thus obtained stimulation index for each experimental animal, an average stimulation index was calculated for a group of animals.
The results are expressed through this S1 index.
When studying the effect of the use of force-suk-on on lymphocyte blastogenesis, it can be seen that
burned cells, reduced cell stimulability clearly increased as a result of exposure to silibinin.
Already on the second day, the animals that were injected with Silu-suk-A had a 10-fold increase in the sensitivity of blood lymphocytes relative to RIA. On the fourth day after injury to the treated animals, the stimulation index for blood lymphocytes was 8, while the corresponding value
15 for untreated animals was 1.5.
In the case of spleen cells, all stimulation indices in burned animals and not subjected to treatment are significantly less than 1. Introduction of silibinin to animals leads to a significant improvement on all days, with a maximum observed on the seventh day after application
25 injuries.
Comparative experiments were also carried out, which showed that in healthy animals, seyl-suk-on does not lead to any significant changes in the stimulability of RIA-induced blastogenesis of T-lymphocytes from the spleen and peripheral blood.
Thus, silibinin, used in accordance with the invention, substantially stimulates the blastogenesis of lymphocytes of burned animals.
In addition, it was found that
In animals treated with silibinin derivatives, the overall catabolism was lower, as the animals quickly gained weight again after the thermal injury.
5 Poisoning mushrooms.
Poisonous toadstools poisoning are poisonous medicines known in medicine. Although poisoned by pale
only 10–30% of all mushroom poisonings are poisoning, poisoning by this mushroom due to its danger has long been the cause of the greatest interest of physicians. In early publications
 The death toll from this poisoning is given, which is 30-50%. Thanks to modern intensive medicine, according to Dan
- to statistical research
five
he is about
he
0-SO-A1K-SOOM
where Alk is a carbonyl residue with 14 carbon atoms; M is hydrogen or alkali metal, characterized in that
May 1.4. silibinin formula
Q
- OHS
(Ii)
un-pin
he Oh
dissolve in 1-2 mash. pyridine and subjected to interaction with I- 3 ma.h. dicarboxylic anhydride formula
0 С-А1К-СЮ 0
where Alk is as defined,
40 with stirring at -40-50 ° C, followed by the addition of ethanol to form a homogeneous mixture, to which water is gradually added with vigorous stirring.
45 the esters are hydrolyzed to aromatic OH groups, and after hydrolysis is complete, the reaction mass is diluted with ethyl acetate, washed acidified to
50 PH 1.5-2.5 with water, saturated with ethyl acetate, the resulting ethyl acetate phase is concentrated, treated with ethanol, compounds of formula (I) are isolated, where M is hydrogen, and / or alkali hydroxide (III) the metal is converted to salt. ,
Sn-so-so-lsh-soya
OSSN
(I)
AnimalsC16I CISC18: lC18: 2C20: 4.
Healthy (KOHT-29.8% 37.2% 8.9% 9.6% 16.2%
I group is 6.2 ± 12.3 ± 1.1 ± 3.3 ± 4.9
With 25.4% deposited 37.5% 7.8% 11.4% 18.0%
burns ± 6.0 ± 8.6 ± 1.0 ± 5.3 ± 9.1

权利要求:
Claims (1)
[1]
Claim
A method of obtaining derivatives of silibinin of the general formula (I) where Aik is an alkylene residue with 1-
4 carbon atoms; 40
M is hydrogen or an alkali metal, characterized in that
1 m.ch. silibinin of the formula
OH about dissolved in 1-2 parts by weight pyridine and is subjected to interaction with I3 parts by weight of a dicarboxylic acid anhydride of formula (III) where Aik has the indicated meanings, with stirring at 40-50 C followed by the addition of ethanol to form a homogeneous mixture into which water is gradually added with vigorous stirring, while the esters hydrolyzed to aromatically bound 0H groups, and after hydrolysis is complete, the reaction mass is diluted with ethyl acetate, washed with water saturated with ethyl acetate, acidified to pH 1.5-2.5, the resulting ethyl acetate phase is concentrated, treated with ethanol, the compound is isolated formulas (I), where M is hydrogen, and / or by the action of an alcoholic solution, an alkali metal hydroxide is converted into a salt. ,
fifteen 1436875 16 Animals ] C16 C18 | S18: 1 | S18.-2 C20: 4. Healthy (cont 29.8% 37.2% 8.9% 9.6% 16.2% role group I) 6.2 ± 12.3 ± 1,1 ± 3.3 ± 4.9 With applied 25.4% 37.5% 7.8% 1 1, 4% 18.0% burns ± 6.0 ± 8.6 ± 1.0 ± 5.3 ± 9.1

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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US5262439A|1992-04-30|1993-11-16|The Regents Of The University Of California|Soluble analogs of probucol|

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CN103113359B|2013-02-22|2016-01-06|西安安健药业有限公司|Silybin bis-bias succinate and pharmaceutical salts thereof|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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DE3442639A|DE3442639C2|1984-11-22|1984-11-22|

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