JPS6330410A - Antitumor agent - Google Patents

Abstract

PURPOSE:To provide an antitumor agent containing dehydrated schisandrin as an active compound. CONSTITUTION:The objective agent contains the (-)-(7S,R-biar)-7,8- dihydro-1,2,3,10,11,12-hexamethoxy-6,7-dimethyl-dibenzo[a,c]cyclooctene (dehydrated schisandrin) of formula I as an active component. The compound is effective preferably at a dose of 50-100mg daily for adult by oral administration in several divided doses. The compound of formula I can be produced by dehydrating schisandrin of formula II existing in KITA-GOMISHI (dried fruit of Schizandra chinensis of Magnoliaceae family).

Description

[Detailed description of the invention] [Industrial application field] TECHNICAL FIELD The present invention relates to an anti-mass agent.

[Conventional techniques and problems] `` Peptic ulcers have become a major problem as one of the modern diseases associated with the rapid growth of society, but there are various theories regarding its causes: stress theory, gastric juice digestion theory, and nerve abnormality theory. Saki: There are many theories, and research on each is progressing.As research progresses, various drugs are attracting attention as medicines for treating ulcers, and new medicines for treating ulcers are in demand.

Therefore, the present invention provides Stomach+! The purpose of this invention is to provide an anti-ulcer agent that can be used to treat ulcers, duodenal ulcers, etc.

c. Means for Solving the Problems] The present invention and others have conducted tests on various compounds to achieve the above objects, and as a result, they have found that Kita Schisandra
nsis Ba111. Dehydrated Schizandrin, a compound represented by the following formula 0 CH3, is obtained by inducing Schizandrin contained in the dried fruit of ``Dehydrated Schizandrin''.
r(-)-(7S, R-biar), 8-dihydro-1゜2.3,10,11.12-hexamethoxy-
The present invention was completed by discovering that "6,7-dimethyl-dibenzoCa,c]cyclooctene" (hereinafter referred to as the compound of the formula) has a therapeutic effect on ulcers.

The compound of the formula can be obtained, for example, by dehydrating schisandrin represented by the following formula % formula % contained in Kita Schisandra. .

H, Taguchi, 1. Yoshioka and
Il, Kobayashi, 'Chem.

Pharm, Bull, 2 7(6),
1 3 8 3 (1979). That is, Kita Schomiko is petroleum ether, n
- Hot extraction with lower hydrocarbons such as hexane and benzene, the solvent of this extract is removed, the residue is dissolved in water, and the non-essential oil part is subjected to steam distillation to remove the essential oil and subjected to chromatography using silica gel. It can be obtained by developing with n-hexane, benzene, acetone, or a mixed solvent thereof.

A production example of this schisandrin is shown below.

Production example: 1.38 kg of Kita Schisandra is crushed into petroleum ether 3.
Reflux extraction was carried out four times for 8 hours using a sieve, the extracts were combined, and petroleum ether was distilled off under reduced pressure to obtain petroleum ether extract 188
g was obtained. This extract was suspended in 450ml of water and steam distilled for 3 hours to remove the essential oil. After the residue was extracted four times with 200 ml of ether, the ether extracts were combined and the ether was removed to obtain 179 g of a petroleum ether-soluble non-essential oil fraction (referred to as fraction A).

Next, the Northern Schisandra extracted with petroleum ether was extracted with three portions of methanol at the same temperature three times for eight hours each, and the methanol extracts were combined and concentrated to obtain 383 g of methanolic extract. This extract was dissolved in 580 d of water and extracted by shaking three times with 850 ml of ethyl acetate. The ethyl acetate extracts were combined and concentrated under reduced pressure to obtain 78 g of extract. Dissolve this extract in methanol and
Developed in 2 sentences and concentrated the eluate under reduced pressure to give 20.8g.
An extract (referred to as fraction B) was obtained.

Combine A fraction (179 g) and B fraction (20.8 g),
It was subjected to column chromatography using 1200 g of silica gel, and developed first with n-hexane, second with benzene, and third with a mixed solvent of benzene-acetone. Benzene-acetone (7:3) and benzene-acetone (3:2)
The eluted portions were combined and concentrated to give 8.3 g of a residue, which was again subjected to column chromatography using 180 g of silica gel and developed with a mixed solvent of n-hexane and acetone. n-hexane-acetone (22:
The eluted portion of 3) was crystallized with 1-hexane-ether to obtain 3.5 g of schisandrin (yield: 0.25%).

The compound of the formula can be obtained by dehydrating the thus obtained schisandrin with a reagent commonly used for dehydration reactions (phosphorus oxytrichloride, thionyl chloride, paratoluenesulfonic acid, etc.) [Y, 1keya, Il
, Taguchi, 11.5asaki, K, Na
kajimaand 1. Yoshioka, Che
m, Pharm, Bull, 28 (8).

2414 (1980)]. - After the reaction is completed, it can be obtained by a general purification method, such as preparative thin layer chromatography.

Further, recrystallization may be performed using a single solvent or a mixed solvent of more than one selected from rhohexane, ether, methanol, and water.

A specific example of the production of the compound of the formula is as follows.

Specific Examples 4 g of Schisandrin obtained in the production example was dissolved in 20% of anhydrous pyrinone, 4 g of phosphorus oxytrichloride was added, and the mixture was heated at 90° C. for 2 hours. After cooling, the reaction mixture was diluted with ether! The solution was diluted with 50% and added dropwise into cold water.

The residue obtained by removing ether from the ether layer was recrystallized from a mixed solvent of n-hexane and ether to obtain 2.5 g of colorless prism crystals. The science of this crystal.

The scientific properties are based on the literature [Y, 1keya, H, Taguch
i, II; 5asaki.

K, Nakajima and 1. Yoshioka
, Chew, Pharm.

[1u11. , 28(8), 2414 (1980
)] dehydrated sosandrine r(-)-
(7S, rt-biar)-7,8-dihydro-1
,2,3,10,11,12-hexamethoxy-6,7
-Simethylnobenzo[a,c]cyclooctene".

Next, the anti-ulcer effect of the compound of the formula, which is the active ingredient of the anti-ulcer agent of the present invention, will be explained with reference to experimental examples.

Experimental Examples 50 and 100 mg/kg of each of the compounds obtained in the specific examples were orally administered to 10 male Wistar (Qistar) rats, and 10 minutes later they were placed in a University of Tokyo drug-type stress cage and placed in a water tank at 23°C. It was immersed to the level of the xiphoid process and stress was applied. After 7 hours, the animals were removed from the water tank, sacrificed, and their stomachs were removed. A 2% formalin solution was injected into the stomach, and the mice were further immersed in the same solution for 10 minutes for fixation. An incision was made along the greater curvature, and the length (in) of the ulcer that developed in the glandular stomach was measured and determined as the ulcer index. The same values as above were used as control values, except that the compound obtained in the specific example was not administered. As a result, the ulcer index of the control group was 17.9 ± 1.0, while that of the group administered with the compound obtained in the specific example at 50 mg/kg was 14.6 ± 1.2, which was 100 mg/kg. The dose in the treatment group was 10.9±1.3.

From these results, the therapeutic effect of the anti-1 drug of the present invention on ulcers was confirmed.

Next, the compound obtained in the above specific example, which is the active ingredient of the antiulcer agent of the present invention, was orally administered to ddY mice (1
No deaths were observed even when doses up to 2000 mg/kg were administered (10 animals per group).

Furthermore, in consideration of the above experimental results, the appropriate effective dose of the anti-ulcer agent of the present invention is the usual adult daily dose of the compound of the formula: 50 to 100 mg orally divided into several doses. It may be preferable to administer

The compound of the formula, which is the active ingredient of the anti-ulcer agent of the present invention, can be prepared as a solution, powder, granule, or tablet according to a conventional method for manufacturing a formulation using appropriate solvents, excipients, adjuvants, etc. used in formulations. , enteric-coated formulations and capsules can be made.

In the formulation, it can also be combined with medically active ingredients of Ike.

For oral administration, tablets, pills, capsules, powders,
It can be formulated into granules, etc.

Preparations of this type may optionally contain lubricants such as magnesium stearate, sodium lauryl sulfate, talc, etc., dextrin, crystalline cellulose, polyvinylpyrrolidone, gum arabic, corn starch, gelatin, etc. Binder, sodium cellulose gelcholate, potassium cellulose gelcholate, potato starch,
Disintegrants such as carboxymethyl cellulose and fluidity promoters such as light silicic anhydride can be used. In addition, the drug of the present invention can be used in suspensions, emulsions, syrups,
It can also be administered as an elixir, and these various dosage forms may contain flavorings and coloring agents.

Next, the present invention will be explained in more detail with reference to examples, but the present invention is not limited thereto.

Application Example 1 The dehydrated cisandrine obtained in the above specific example 0.
5g was made into a fine powder, mixed with 90.5g of lactose and 9g of magnesium stearate, and this mixture was compressed using a single-shot slug tablet machine to form tablets with a diameter of 20mm and a weight of 2.3g.
A slug tablet was prepared, which was crushed with an oscillator, sized, and sieved to obtain good granules of 20 to 50 mesh particles.

This granule contains 5 dehydrated cisandrin in 1g.
mg, but depending on the symptoms, take 3 to 6 g at a time, three times a day.

Example 2 Dehydrated sysandrine obtained in the above specific example 2.
5g contains 93g of microcrystalline cellulose, 3g of sodium gelcholate and 1.5g of magnesium stearate.
g was added and mixed, and this mixture was compressed using a single-shot tablet machine to produce tablets with a diameter of 9 mm and a weight of 200 mg.

This tablet contains 5 dehydrated cisandrine in each tablet.
mg, but depending on your symptoms, take 3 to 6 tablets at a time, 3 times a day.

Example 3 Dehydrated cisandrin 17 obtained in the above specific example
．． 4g is made into fine powder, which makes 83.5g of lactose.

The mixture was mixed with 0.5 g of light anhydrous silicic acid and 3 g of microcrystalline cellulose, and 100 mg each of the mixture was filled into hard capsules to obtain capsules.

This capsule contains 16.7 mg of dehydrated cisandrine per capsule, and the dosage is 1 to 2 capsules 3 times a day, depending on the symptoms.

Claims (1)

[Claims] The following formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ An anti-ulcer agent containing the compound represented by as an active ingredient.