JPS63179886A - Novel saponin derivative and anti-inflammatory agent containing said derivative as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound expressed by the formula (R represents glucopyranose, glucopyranosylpyranose or glucopyranosylrhamnopyranose). EXAMPLE:3beta,16beta,28-Trihydroxyoleana-9(11),12-diene 3-O-beta-D-glucopyranosyl-(1 4)- alpha-L-rhamnopyranoside. USE:An anti-inflammatory agent. PREPARATION:For example, saikosaponin c is reacted in alcohols such as butanol by an addition of sodium hydroxide or metallic sodium to partially hydrolyze the sugar part. Then an acid such as sulfuric acid, is added and reacted therewith to open the aryl ether ring to afford the derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel saponin derivative that has anti-inflammatory effects and is useful as a pharmaceutical.

[Prior Art and Problems] Saiku is one of the herbal medicines that has been distributed as Japanese and Chinese medicine since ancient times, and various studies have been conducted from the viewpoint of pharmacology. Furthermore, with the development of isolation and purification technology and analytical equipment, the main components of saiko such as saikosaponin a1, saikosaponin d1, saikosaponin e, which are disaccharide glycosides, and saikosaponin C, which is a trisaccharide glycoside, have been improved. Psychosaponins have been isolated, and their pharmacological activities have been investigated. However, it has been reported that saikosaponin C, a trisaccharide glycoside, has no excellent pharmacological activity [Hikoyoshi Oura et al.: Pr.
oc, SymP, WAKAN-Y AKU, 14
.

163 (1981)].

An object of the present invention is to provide saponin derivatives with higher pharmacological activity using saikosaponin C as a starting material.

[Means for Solving the Problems] As a result of intensive studies to find saponin derivatives with higher pharmacological activity and useful as pharmaceuticals, the present inventors found that by partially hydrolyzing the sugar moiety of Saikosaponin C, The present invention was completed based on the discovery that saponin derivatives with higher activity can be obtained.

That is, the present invention provides novel saponin derivatives (hereinafter referred to as compounds of the present invention) represented by the following formula (wherein R represents glucobylanose, glucopyranosylglucopyranose, or glucopyranosyl rhamnopyranose). ) is an anti-inflammatory agent containing the derivative as an active ingredient.

The compound of the present invention can be produced, for example, by reacting Saikosaponin C by adding sodium hydroxide or sodium metal to an alcohol such as butanol, partially hydrolyzing the sugar moiety, and then reacting by adding an acid such as sulfuric acid. , can be derived by opening the aryl ether ring.

First, commercially available Saikosaponin C is reacted in alcohol by adding sodium hydroxide or metallic sodium. Saikosaponin C is a glycoside that has two molecules of glucose and one molecule of rhamnose, and through this reaction, ■ a glycoside from which rhamnose has been eliminated, ■ a glycoside from which one molecule of glucose has been eliminated, ■ rhamnose, glucose A mixture of four compounds, glycoside and aglycon, from which one molecule has been eliminated, is obtained. This mixture is subjected to column chromatography using silica gel and eluted with at least two or more solvents selected from chloroform, methanol, ethanol, acetone, hexane, benzene, ethyl acetate, and water to separate and purify each. .

Next, the ring-opening reaction of the aryl ether ring can be carried out in an acid such as sulfuric acid and an organic solvent such as dioxane at room temperature to 80° C., preferably with stirring. This reaction yields a mixture of a heterodiene having a double bond at the IfS +3 (18) position and a homodiene having double bonds at the 9 (II) and 12 positions. This mixture is subjected to conventional column chromatography using a Rover column or the like to separate and purify the homodiene.

Next, the pharmacological effects of the compounds of the present invention will be explained by giving experimental examples.

Experimental Example: Effect of promoting endogenous corticosterone secretion.
0 and 4 mmol/kg, respectively, in physiological saline.
It was adjusted so that it was and administered intraperitoneally to ddY male mice. Blood was collected by decapitation 60 minutes after administration, and the obtained serum 200
At a time, 2 drops of 0.5N aqueous sodium hydroxide solution and 50 ng of dexamethasone were added as an internal standard. After further extraction with 47 d of methylene chloride, the organic layer was dried under reduced pressure. This was followed by high performance liquid chromatography (HP L) at 50μ.
Methanol for C) was added to dissolve the residue, and 30 sides thereof were subjected to HPLC analysis as a serum sample to measure the amount of endogenous cordicosterone.

In addition, the endogenous corticosterone secretion amount measured in the same manner as in "double" except that the compounds obtained in Examples 1 to 3 described below were not added was used as a control value.

As a result, the control value was 3 rins per 1 ml of serum too, whereas the amount of corticosterone secreted by the compounds obtained in Examples 1.2 and 3 below was 10 ml per 1 ml of serum.
The compound of the present invention was found to have a corticosterone secretion promoting effect.

Furthermore, the compound of the present invention was administered to ddY male mice (group 1).
No deaths were observed when 801,197 kg of the drug was orally administered to O animals), confirming that it is highly safe.

The compounds of the present invention can be administered to animals and humans either neat or with conventional pharmaceutical carriers. The dosage form is not particularly limited and may be selected and used as necessary, including oral preparations such as tablets, capsules, and granules, injection preparations,
Examples include parenteral agents such as halved.

In order to exert the desired effect as an oral agent, although it varies depending on the age, weight, and severity of the disease of the patient, it is usual for adults to administer the compound of the present invention at a dose of 20 to 80 JIll up to three times a day. Oral medication seems appropriate.

In the present invention, oral preparations such as tablets, capsules, and granules are manufactured according to conventional methods. Tablets are made by mixing and shaping the compound of the present invention with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc., and capsules are made by mixing the compound of the present invention with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc. It is prepared by mixing it with an active pharmaceutical filler or diluent and filling it into hard gelatin capsules, soft gelatin capsules, etc. Syrups and elixirs are prepared by mixing the compound of the invention with a sweetening agent such as sucrose, preservatives such as methyl and propylparabens, coloring agents, flavoring agents, flavoring agents, and adjuvants.

In order to exert the desired effect as a parenteral agent, the compound of the present invention should be administered intravenously in an amount of 0.25 to 10 mg per day for adults, although this will vary depending on the age, weight, and severity of the disease of the patient. , subcutaneous injection, and intramuscular injection are considered appropriate.

This parenteral preparation is manufactured according to a conventional method, and distilled water for injection, physiological saline, aqueous dextrose solution, propylene glycol, etc. can generally be used as a diluent. Furthermore, a bactericide, a preservative, and a stabilizer may be added as necessary. In addition, from the viewpoint of stability, this parenteral preparation may be filled into capsules, etc., frozen, water removed by ordinary freeze-drying techniques, and a liquid preparation prepared from the freeze-dried product immediately before use.

Other parenteral preparations include liquid preparations for external use, liniments such as ointments, and halved preparations for intrarectal administration, and are manufactured according to conventional methods.

The compounds of the present invention have not been described in the literature and are therefore novel compounds.

EXAMPLES Next, the present invention will be specifically explained with reference to examples, but the present invention is not limited to the same extent by these examples.

Example 1 Commercially available Zycosaponin C (manufactured by Wako Pure Chemical Industries, Ltd.) 1
g was dissolved in 150° C. of n-butanol, 5 g of sodium hydroxide or metallic sodium was added thereto, and the mixture was stirred at 80° C. for 6 hours. After the reaction is completed, the reaction solution is concentrated and silica gel 20
Using an open column packed with 0 g, separation was carried out in the lower layer of the developing solvent chloroform-methanol-water (60:30:10), and 92.0 μg of the glycoside from which rhamnose was released and one molecule of glucose were released. Glycoside 1.58.9ffg and rhamnose, glycoside 62 with one glucose molecule removed
．． I got 3j19.

Next, glycoside 92 from which rhamnose was removed. OR9 was dissolved in 20-IN sulfuric acid-dioxane (1:1) and reacted at 60°C for 4 hours. After confirming that the raw materials were gone by UV absorption, the reaction was stopped by interrupting the heating, and after being left to cool, the reaction solution was neutralized with a 10% aqueous sodium hydroxide solution.

After extracting the reaction solution with n-butanol, the Rover column RP
-18 (manufactured by Merck & Co., Ltd.) and separated using a developing solvent of methanol and water (3:1). With the above operations, 3β, +
6β,28-)lihydroquine oleana-9(II),1
2-Diene 3-0-β-D-glucopyranosyl-(l
→6)-β-D-glucopyranone 14.0 9 was obtained.

Example 2 Glycoside 15 obtained in Example 1 from which one molecule of glucose was removed
8.9 Shoulder 9 was dissolved in IN sulfuric acid-dioxane (1:1) 20- and reacted at 60°C for 4 hours.

After confirming that the raw material is gone by UV absorption, the reaction is stopped by interrupting the heating, and after being left to cool,
The reaction solution was neutralized with a 10% aqueous sodium hydroxide solution. After extracting the reaction solution with n-butanol, the Roper column RP-
No. 18 was used for separation using a developing solvent of methanol-water (3:1). By the above operations, 3β, +6β, 28-trihydroxyoleaner 9(11), +2-diene 3-
0-β-D-glucopyranosyl-(l→4)-α-L-
Rhamnopyranoside 13.2M9 was obtained.

Example 3 62.3 fflJ of the glycoside from which one molecule of rhamnose and glucose was released in Example 1 was dissolved in 20-IN sulfuric acid-dioxane (1:I) and reacted at 60°C for 4 hours. . After confirming that no raw materials were present by UV absorption, the reaction was stopped by interrupting heating, and after being left to cool, the reaction solution was neutralized with a 10% aqueous sodium hydroxide solution. After extracting the reaction solution with n-butanol, using a Rover column RP-18, the developing solvent methanol-water (3:I) was used.
It was separated at With the above operations, 3β, +6β, 28−
Trihydroxyoleaner 9(11), +2-diene
3-0-β-D-glucopyranoside 6.4~ was obtained.

Example 4 2.5 g of the compound obtained in Example 1 was dissolved in 150-g of polysorbate 80, and this was added with 4.857 g of sterile physiological saline heated to 60'C. of the compound obtained in Example 1 is added to the vial, shaken well, and the compound obtained in Example 1 is 0.5% in 1 vial.
The mixture was aseptically dispensed to contain M9 and sealed to produce an injection.

This injection should be shaken before use, and 0.5 g
~20-Administer intravenously.

Example 5 5 g of the compound obtained in Example 2 is mixed with 10 g of silicic anhydride, 85 g of corn starch is added thereto, and further mixed. To this mixture, 507 d of 10% hydroxypropylcellulose ethanol solution was added, and the mixture was wetted, extruded, dried, and sieved in a conventional manner.
Granules with 0 mesh particles were obtained.

The same amount of this granule is 0.5 to 1.5g depending on the symptoms.
(equivalent to 25-75 mg of the compound obtained in Example 2) three times a day.

Example 6 20 g of the compound obtained in Example 3 was mixed with 20 g of silicic anhydride, 10 g of microcrystalline cellulose, 3.0 g of magnesium stearate, and 65 g of lactose were added and mixed, and this mixture was put into a single-shot tablet machine. Compressed into tablets with a diameter of 7 mm and a weight of 100
Fi! ? tablets were manufactured. .

One tablet of the present invention contains compound 16.931f obtained in Example 3. This tablet is 1 to 4 tablets at a time.
Take 3 times a day.

Example 7 Compound 20~ obtained in Example 1 was added to 20011 g of silicic anhydride.
Add lactose 80jI9 to this and mix, No.
The mixture was filled into gelatin capsules of No. 2 to obtain capsules.

This capsule preparation is taken at a time of 1 to 4 capsules up to 3 times a day, depending on the symptoms.

Claims (2)

[Claims] (1) A novel saponin derivative represented by the following formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents glucopyranose, glucopyranosyl glucopyranose, or glucopyranosyl rhamnopyranose.) (2) A novel saponin derivative represented by the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Anti-inflammatory agent as an active ingredient.