JPS61197579A - Manufacture of isosilibine-free silibinine and medicine containing same - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application: The present invention relates to a process for the preparation of isosilybin-free silibinin and to pharmaceutical preparations containing this compound.

Prior art: This was known. Munster (R, Munster) is derived from the Frapolidanan produced in the fruit of this fruit.
, Munster's dissertation, Munich 1966]. This compound cutting chemical development is based on Pelter (A, Pe
Tetrahedron Letters (Lter) and Hansel (R, Hansel).
edron Letters), London, Vol. 25, pp. 2911-2916/1968].

It is known that silybin (also formerly called silymarin I) is an effective liver treatment agent (see West German Special Liver Specification No. 1767666). An industrial process for producing silybin (silymarin I) is described, for example, in West German Publication No. 1923082.

In 1974, Wagner (H.), Diesel (P.) and Dinh (M., 5e.
itx)
Vol. 24 (4), pp. 466-471] postulated two tmt isomers related to silybin, namely silybin and insilibin. This refusal was accepted,
Arnune (A, Arnune), Maaraini (L,
Merllni) and Denarotsutei (A, Zana
Rutti) was established experimentally by [Journal op de Chemical Society, Chemical
Communications (J, Chsm, Sac,...
Chem, Cumm, )”.

Volume 16, pages 696-697/1979]. According to this, the known silybin contains two military compounds,
That is, it is composed of compounds of the following structural formulas A and B: From the above structural formulas, it can be recognized that the μ-position 1 of these compounds is an isomer. The compound W of the Seizo-style prisoner was recently recommended by INN (Interna-
tional Nunproprietary Nam
e) General name silibinin (silibln)
in) is given.

This terminology is also used for compounds with structural formulas in this specification.

The two compounds mA and B have hitherto been obtained only by separation using an analytical violet, and no examples are known of the pharmacological actions of the individual isomers.

Means for achieving the invention: The object of the present invention is to obtain a method for producing silibinin that is free of isosilybin.

Therefore, according to the present invention, the lumps of oil and fat present in the fruit of Structural Formula (4) A are liberated by splitting the fruit by high mechanical pressure, and still 5 to 10% of the raft remains. Pressure type with oil-containing lid? The ethyl acetate was evaporated locally, the ethyl acetate was evaporated, and the remaining dry residue, 2 μm of violet in the lower phase consisting of methanol and water, was dissolved in methanol 95'.
A ternary detergent mixture of 5 parts of water and 100 parts of petroleum ether (boiling point 40-6 [1-C)] is used to remove fluffy solid particles. The sharp center portion is concealed until it becomes a straight bend, and the dried residue is uniformly distributed in the bath agent system by doubling in the same flow, thereby keeping the total upper phase/top phase flow ratio equal to 1:1. , and then drained from the upper phase and evaporated to dryness in vacuo.
~80% polyhydroxyphenylchromanone? There is a method for producing silymarin (Silymarin) by isolating it as a brown powder. The resulting suspension was heated with stirring to a temperature of 1°C, at which time about 14~'/S of methanol was removed under reduced pressure, and the concentrate was left at ambient temperature. The resulting precipitated vA was washed 1 to 6 times with cold methanol in a small dish, dried, and heated for 40 to 60 minutes.
One irises of a double violet was dissolved in ethyl chloride, the rge was treated with viscous charcoal under reflux conditions, the activated charcoal was filtered off, and the filtrate was filtered under reduced pressure to form about seven original valleys.゛V□. The concentrate is mixed with about 100 methanol of the concentrate under vigorous stirring and left at ambient temperature for several hours to precipitate and the product is concentrated before being separated by total suction filtration. Stir with a mixer,
The product was filtered with suction, washed with a small amount of ethyl acetate t-1 to 6 times, and dried in vacuo. In addition, silibinin that does not contain insilibin can be obtained by: a) suspending 444-color powdered 1 page weight in 0.7 to 1.5 weight JIt parts of water-condensed ethyl ethyl acetate; After standing for 1 to 2 days, the precipitate was separated by suction filtration, b) The obtained precipitate *1 was washed with city water and 0.07 to 0.15 parts of saturated ethyl acetate, and the precipitate was separated in vacuo. Dry at 60-50″C to form likon*
Add ethyl acetate anhydride 60~503 to the mold part at the temperature of S! Under this me, tst = activated carbon 0.2 to 0.
Treated in quadruple parts for 2 hours, filtered, and vacuumed for 6 hours.
Concentrate into a total valley shape of about 6.1650 stones at 0-50℃, d)
Water-saturated ethyl acetate 0.5-0.8 μm violet was added to the concentrate, 5-10F#f was mixed, and the silybin ta precipitated.
Separate the wax and e) process this silybin with ethyl 0.9~
1. The suspension was predried at 60-50°C in a JIae tank, the pre-dried product was ground, and the suspension was dried in a vacuum at 60-50°C. , m can also be obtained by imitation.

The crude silymarin brown powder used as starting material in step a) is a mixture of silymarin I to ■. By treating the crude silymarin with water-saturated ethyl ethyl esterate, essentially the main portion of silymarin U~■ (silybinin is silymarin L) and the accompanying material in the crude silymarin are removed from 20~60%. Separation takes place with as well as with a part of insilibin.Thus, depending on the purchase of the crude silymarin used in step b), a yield of 80 to 85 h and 60 to 84 h, based on the silibinin content in the crude silymarin, occurs. % crude silibinin is obtained.

As shown in Figure 5, isosilybin and silibinin are crystallized in a ratio of about 1:4 to crude silibinin.

In engineering aC)me), the main part of isosilybin;
Separation of silibinin as well as the remainder of the other said components takes place.

One advantage of this separation method is the use of only one solvent, namely ethyl acetate, which in this case has the specific term M1.

Therefore, anhydrous dispersion of ethyl is used in step C) and water-
The use of saturated ethyl acetate in step d) is royal. According to the method of the present invention, silibinin can be obtained with a yield of 79 to 85% and a concentration of silibinin of 96 to 98% based on the silibinin content in crude silibinin.

According to one preferred implementation of the uninvented process, a) 1 part of the white powder is suspended in water-saturated ethyl 0.9M solution, and the vinegar slurry is Let stand for 48 hours at a time, separate the resulting precipitate by suction filtration, b) This precipitate l! i″4B cold water-cell relative ethyl 0.09m
Wash in vacuum, dry in vacuo at 40°C for 48 hours, and
) The resulting product was poured into a 36-liter bath of anhydrous ethyl acetate at its boiling temperature for 16 minutes, and the bath liquid was refluxed with activated carbon,
Treated for 2 hours in JIL electrical department, filtered, and heated at 50°C in vacuum.
@ Shrinkage to 6.66 circles of violet, d) Water -! 2! Sum σl
: Add 0.6 ethyl arashiobe to Isosuke proboscis at ambient temperature,
The precipitated product was separated by filtration after being left at ambient temperature -C for 12 hours.
．． Suspend in 8 liters of water, filter, and 40″ in JIc air.
Pre-dry for 24 hours at C, grind and further dry at 40-C for 48 #f in a vacuum cleaner.

Insilibin - It is clear that free silibinin is extremely excessive for systematic purposes, but this insilibin-free silibinin is produced by Silysim marianum.
The extract of M. marianum has significant advantages compared to the known preparations. Moreover, it is suitable for a city official whose younger sister has liver cirrhosis and 11 cases of liver disease.

Silibinin, which does not contain insilibin, can be used as a prophylactic, so that the disease will not occur at all.

According to the invention, therefore, medical preparations are also obtained which are enriched with silibinin in a mixture with a solid or cylindrical diluted wound or carrier agent. The preparations are usually used systematically, for example in the form of threads, capsules and liquids together with customary carriers.

The daily weight for an adult human is usually about 50-500 Da, depending on the state of mind and the severity of the medical condition.

Examples: Next, the invention method for producing insilibin-free silibinin - Examples will be described in detail.1. Polyhydroxy-phenylchromanone mixture 500. @(Silymarin 1~■#: Approximately -70%) t meta/- 21cg
(approximately 2.55-e) to a medium Vc suspension and heat this suspension at boiling water for 15 minutes with stirring. At this time, the silibinin from birth can already come out from the bath liquid. Add 0.75 to 1.0 methanol to the dust.
254 (approximately 0.96 to 1.58 p)f:Jc Remove in air, and leave the residue at yam vfA degree for 10 to 28 days.

The precipitated and determined silibinin was filtered off and then washed twice with 50 ml of cold methanol. 40-C,Q(D
After drying, the separated silibinin is preliminarily prepared as follows: Crude silibinin 60&' is bath-dissolved in industrial aF, BAET/l 15-8 while heating, and this bath solution is then dissolved. Mix with 20.9 g of charcoal and stir for a further 2 hours under reflux. Suppose that this bath liquid is made transparent by filtration,
and evaporated to about 250 ml under reduced pressure at 50"C.
Stir for 15 minutes by using a Turrax) dW' and ? Mix with methanol 25- while stirring. Then, leave the mixture at room temperature overnight. 1, before separating the precipitated silybin by suction line passage.
This-a't Ultra Merax (Ultt"a
-Turrax) Stir for 5 minutes on top. next,
Suction filtered precipitate '@2111! l vinegar ethyl 50-
Wash with water and dry overnight at 40°C with a nitrogen dryer. This product was finely ground and pulverized for 48
Dry with rc for a while.

Example 2 The polyhydroxyphenylchromanone mixture IIcg' used as starting stock in Example 1 was added to
ax) Suspend in 1 volume of water-saturated ethyl acetate using a stirrer. Leave to stand for 48 hours at ambient temperature, separate the precipitate by suction filtration, and rinse with cold water.
flc-cleaned at 00t11t and 40-c in vacuo.
Qi fee for 8 hours. In order to obtain silibinin, the rji of 7c silymarin was used.
It is 80 to 85% with respect to the silybinine content of the original silymarin shell, and 80 to 84% in its official content.

Somyo silibinin r ethyl silicate obtained by grinding 40
! Dissolved in the bath at its boiling point, boiled for 2 hours with 660I clear charcoal under reflux, filtered for 1 hour, and then moved in vacuum at 50-G to all four roads of 33301 Rt. do. Water-saturated ethyl acetate (667) was added to this liquid at once, and the image was adjusted while stirring vigorously. After 1-3 hours, crystallization of silibinin begins. After leaving overnight, the precipitated gold was separated by filtration, and suspended twice in 1200 m2 of ethyl acetate for 5 to 10 minutes.
This suspension was again filtered and heated to 40°C in vacuum for 24 hours.
Pre-dry for an hour.

After milling, the product is further dried in vacuo at 40°C for 48 hours. The yield of silibinin to the silibinin charge of crude silibinin is 79 to 85% in a mold of 96 to 98.5 inches of silybinin, depending on the purchase of crude silybinin.

Over the past 10 years, clinical trials with silibinin have seen an increase in the number of people suffering from four-dimensional liver dysfunction. The most common cause of disability is alcohol, which causes problems.

By comparison, we were able to prove the effectiveness of silibinin in comparison with gas meyaku chestnut or other ratios. 66 with alcohol-induced liver damage in two 1st poems.
Human patients were used in a randomized experiment using silibinin (n=31) versus gaseous Wm (n=35).

According to Kasumai, which is statistically used as FF1, it has been found that silibinin is more clearly destroyed than gaseous medicine, and therefore the treatment time is substantially shorter than that of gaseous medicine. ε- is possible.

In a second experiment using 76 patients, 69 of them were given silibinin, and the remaining 67 were given control primordial km and then given silibinin at the same time. , appeared clearly.

In the case of abdominal organ surgery and liver anesthesia using sweetfish, by administering silibinin to the MU, the liver in the dish can be reduced. I was able to prove that 01 was disrespectful. Liver Jw & 1mW, which is caused today by certain hot pot dishes, is also ineffectively blocked by silibinin. This is true even if silibinin is administered at the same time as a treatment for liver disease fermented by G-ephenylhydantoin, which is a drug that inhibits convulsive Qf. L should be standardized in a short period of time.

Furthermore, the positive effect of silibinin was also demonstrated in the case of a patient with liver dysfunction who had schizophrenia and TL disease due to the prescription of chlorzolomasin. Other achievements have been associated with inhibition of the liver-damaging effects of chlorquine and asparaginase, for example. In all cases of liver damage caused by traumatic factors, the increased laboratory findings associated with the lesions in all treated patients are accompanied by a substantial Can make several sounds.

There is ample evidence that silibinin contributes to a substantial number of changes in the length of the liver, even in the case of chronic-prolonged liver stalks. For example, patients suffering from hepatitis were included in two randomized trials in which the effect of silibinin was suppressed in response to gas medication. Judgment for Ichihara's i#f1 song is the survival time. In this case, a clear aging effect of silibinin was shown compared to treatment with gaseous agents.

A comparison of τμ between silibinin, isosilybin, and silybin (silypeen/isosilybin mixture) was carried out by fecal swabbing with a standard form of phalloids and praseosomium intoxication in several mice after intravenous administration.

Silibinin in the form of N-methylglucamine salt, insilibin and silybin for anti-hepatic MAggy gold silibinin at 50 l/g-1 and 100 In9//(y-1
The results were tested by using as a standard a number of mice with phalloids and praseodymium mesophyllum after intravenous administration at zero doses. The trial administration was carried out 1 hour before Phallocun, 1 hour before Noraseozomium Kotoxin, 24 hours later and 48 hours later. In the case of phalloidone, the survival rate is fully determined for 72 hours, and in the case of placenzomium poisoning,
I played a total of 1 song at 72:115 for Kashisa no Chim and Liver Parameter τK4.

In the case of phalloid poisoning, the survival rate of siripinin's pronunciation is 100%, and along with this, if other drugs are used, it is not treated. Wang Zun-$ on the contrasting chest with buds does not exceed 40%.

Inciribin has been proven to be ineffective against Graseodymium Nakafuku, so 100Lht//, <
The dosage form of g-1 had to be divided into two partial doses.

Claims (1)

[Claims] 1. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼
¥Silybum¥¥marianu¥m¥L. ￥￥G
aertn. The oil mass present in the fruit is liberated from the dried fruit of the fruit by dehiscence of the fruit with high, mechanical pressure, and the pressure residue still containing a residual oil content of 5-10% is released. Extract thoroughly with ethyl acetate, evaporate the ethyl acetate, and dissolve the resulting dry residue in an amount of 2% by weight in a lower phase consisting of methanol and water, 95 parts by weight of methanol, 5 parts by weight of water and petroleum ether. 100 parts by weight (boiling point 40-60℃
) in a ternary bath agent mixture, the bath solution is centrifuged until clear for the removal of fluffy solid particles, and the dry residue is homogeneously distributed countercurrently in the solvent system. 70-80% of the polyurethane is removed by application, thereby keeping the total flow ratio of upper phase/lower phase equal to 1:1, and then draining from the lower phase and drying by evaporation in vacuo. In the process of preparing a hydroxyphenylchromanone mixture (silymarin groups I to IV) by isolating it as a brown powder, this brown powder is suspended in 6 to 5 times its weight of methanol; The resulting suspension is heated with stirring until boiling, and then about 1/3 of methanol is added to the suspension.
~2/3 was removed under reduced pressure and the concentrate was allowed to stand at ambient temperature, whereby the precipitated product was washed 1-3 times with the smallest possible amount of cold methanol, dried and heated for 40 min. Dissolve in ~60 times its weight of ethyl acetate, treat this bath with activated carbon under reflux conditions, filter off the activated carbon, and evaporate the filtrate under reduced pressure to about 1/10 of its original volume. , the concentrate is mixed with about 1/10 of the volume of the concentrate with methanol with vigorous stirring, left at ambient temperature for several hours, and stirred in an intensive mixer before separating the precipitated product by suction filtration. A method for producing isosilybin-free silibinin, which is characterized in that the suction-filtered product is washed 1 to 3 times with a small amount of ethyl acetate and dried in vacuo. 2. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Silibinin that does not contain isosilybin is expressed as
￥Silybum￥￥marianum￥￥L. ￥￥G
aertn. The oil lumps present in this fruit are liberated from the dried fruit of the fruit by splitting the fruit with high mechanical power and the pressure residue, which still contains a residual oil content of 5-10%, is extracted with acetic acid. Extract thoroughly with ethyl, evaporate the ethyl acetate, and combine the resulting dry residue with 95 parts by weight of methanol, 5 parts by weight of water and 100 parts by weight of petroleum ether in an amount of 2% by weight in a lower phase consisting of methanol and water. Parts by weight (boiling point 40-6
0 °C), the solution is centrifuged until clear to remove fluffy solid particles, and the dry residue is homogeneously distributed countercurrently in the solvent system. 70-80% of the polyurethane is removed by application, thereby keeping the total flow ratio of upper phase/lower phase equal to 1:1, and then draining from the lower phase and drying by evaporation in vacuo. Hydroxyphenylchromanone mixture (silymarin I ~
Group IV) by isolating the brown powder as a brown powder, comprising: a) suspending 1 part by weight of this brown powder in 0.7 to 1.5 parts by weight of water-saturated ethyl acetate; The suspension was allowed to stand for 1-2 days, and the precipitate was separated by suction filtration; b) The resulting precipitate was washed with cold water - 0.07-0.15 parts by weight of saturated ethyl acetate and in vacuo. 30~
dry at 50°C and c) dissolve the product in anhydrous ethyl acetate 30°C.
~50 parts by weight at its boiling temperature, the bath liquid is treated under reflux with 0.2-0.4 parts by weight of activated carbon for 2 hours, filtered and the filtrate is dissolved in vacuo at 60-50°C for about 3 hours. .Concentrate to a total volume of 330 l and d) water-saturated ethyl acetate 0.5-0.8
parts by weight are added to the concentrate and after 5-10 hours the precipitated silybin is filtered off; e) the silybin is suspended in 0.9-1.5 parts by weight of technical grade ethyl acetate; A process for producing isosilybin-free silibinin, characterized in that the liquid is pre-dried at 30-50°C in vacuo, the pre-dried product is ground and dried again in vacuo at 30-50°C. 6.a) 1 part by weight of brown powder was mixed with 0.0 parts by weight of water-saturated ethyl acetate.
9 parts by weight, this suspension was left at ambient temperature for 48 hours, the resulting precipitate was separated by suction filtration, b
) This precipitate is washed with cold water-0.09 parts by weight of saturated ethyl acetate and dried in vacuo at 40° C. for 48 hours; c) The product obtained is dissolved in 36 parts by weight of anhydrous ethyl acetate at its boiling temperature. Dissolve and treat this bath under reflux with 0.36 parts by weight of activated carbon for 2 hours, filter and add 3.33 l at 50° C. in vacuo.
d) add 0.6 parts by weight of water-saturated ethyl acetate to the concentrate at ambient temperature, stand for 12 hours at ambient temperature and filter off the precipitated product; e) add this product to a total volume of suspended twice in each 1.8 parts by weight of technical grade ethyl acetate,
Process according to claim 2, characterized in that it is filtered, pre-dried in vacuo at 40°C for 24 hours, ground and further dried in vacuo at 40°C for 48 hours. 4. In pharmaceutical preparations for the prevention or treatment of liver cirrhosis and toxic metabolism liver disorders, isosilybin-free silibinin shown by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ is used as a solid or liquid pharmaceutical diluent or A pharmaceutical preparation for the prevention or treatment of liver cirrhosis and toxicant metabolic liver disorders, characterized in that it is contained in a mixture with a carrier.