JPS6048493B2 - New compound, its production method, and antipyretic agent containing it as an active ingredient - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel compound represented by the structural formula, a method for producing the same, and an antipyretic agent containing this compound as an active ingredient.

The compound represented by the above structural formula is a new compound obtained by the present inventors starting from Kita Schisandra, which is one of the Chinese medicines used in Chinese medicines such as Shoseiryuto and Reikanzenmi Shinkajinto. The present inventors named this compound Gomisin J. In addition, Kita Schizandra belongs to the Schizandra family, Schizandra sinensis.
rachlnebslsBAILL. )] dried fruit. Gomisin J represented by the above structural formula can be obtained by extracting Kita Schisandra with lower hydrocarbons, removing the solvent and volatile components from the extract, and treating the residue with chromatography.

Specific examples of lower hydrocarbons used for extracting Kita Schisandra include petroleum ether, n-hexane, and benzene.

Extraction is carried out by adding and mixing pulverized Kita Schisandra to lower hydrocarbons at a temperature of 30° C. to the boiling point, preferably under reflux.

Extraction is performed several times, the extracts are combined, and lower hydrocarbons are distilled off and concentrated to obtain a workpiece. These engineering scratches are steam distilled to remove volatile components (essential oils, etc.). The residue thus obtained (non-essential oil fraction soluble in lower hydrocarbons) is then subjected to column chromatography using an adsorbent such as silica gel, alumina, florisil, polyamide, celite, etc. N-hexane, benzene, chloroform, acetone, ether, ethyl acetate, ethanol, methanol, etc. “Gomisin J represented by the above structural formula is eluted using an organic solvent or a mixed solvent thereof, and the solvent is removed from the eluate to obtain gomisin J. A suitable example is as follows.The residue obtained by removing lower hydrocarbons and volatile components from the extract as described above is subjected to column chromatography using silica gel, and the following is obtained: First n-hexane, second benzene,
Third, the mixture was developed with a mixed solvent of benzene and acetone, and the portions eluted with benzene and 1 acetone (17:3) were combined and the solvent was removed.

This residue was subjected to column chromatography using silica gel 7 and developed with a benzene-ether mixed solvent.
The benzene-ether (9:1) and benzene-ether (17:3) eluates are combined and the solvent is removed.
This residue was further subjected to column chromatography using silica gel, developed with a mixed solvent of n-hexane-acetone, and eluted with n-hexane-acetone (9:1) and n-hexane-acetone (17:3). Combine the parts and remove the solvent. This residue was subjected to preparative thin layer chromatography using silica gel, developed with a mixed solvent of n-hexane and acetone (7:3), and subjected to RfO. Gomisin J is obtained by extracting the portion showing No. 58 with a chloroform/methanol mixture. By the above-mentioned chromatography, the known substances Gomisin A and Schizandrin can also be separated by selecting a developing solvent.

Note that Gomisin J can also be obtained by extracting Kita Schisandra with lower alcohols such as methanol and ethanol.

In this process, the extract with lower alcohols is concentrated, the resulting scratches are dissolved in water, extracted with ethyl acetate, butanol, ether, benzene, hexane, etc., the extract is concentrated, and the residue is is dissolved in lower alcohols such as methanol and ethanol, and adsorbed on an adsorbent such as celite or cellulose powder, followed by n-hexane, petroleum ether,
Gomisin J can be obtained by eluting with benzene, chloroform, ether, etc., concentrating the eluate, and subjecting the resulting chromatography to the above-mentioned chromatography. The properties of Gomisin J obtained as described above are as follows. Crystal: Colorless needle (shaped) crystal Melting point: 149-150° Molecular formula: C22H28O6 Elemental analysis value: Theoretical value C68. O2H7.27 Experimental value C6
7.7lH7. l5 specific optical rotation: [α] tongue 3Σ0° (C
=0.206, chloroform) Methanol ultraviolet absorption vector λMaxnm (10gε): 214 (4.
70), 248 (4.15), 276 (3.53), Infrared absorption Svector Ni r: ■ 3545, 3450 (0H
), 1610, 1583 (ArOm) cough magnetic resonance spectrum (δInCDCI3): 0.18 (3FI, tablet, J=7 Hz, J7 Hz, 2.4 (2H, multiplet, ), 2.0-2.7 (4H, multiplet, 2x-CH2-), 3.50 (6H, singlet), 3.94 (6FI, singlet) (4x0
CH3), 5.91 (2H, singlet, 0H, D2
0), 6.63 (?, singlet, Ar
Om-H) The present inventors determined the structure of Comisin J from the physical constants of Comisin J and the results of separate research.

That is, when the compound is methylated with diazomethane,
The nuclear magnetic resonance spectrum of this gives dimethyl ether, which has a nuclear magnetic resonance spectrum of deoxyschizandrine (N.K.
Ov, A. KhOrlinandO. S. ChizhO
v, TetrahedrOnreTterS, l96 review 3
pp. 61-363. ) matches. On the other hand, the nuclear Overhauser effect (NOE) of ≦dibenzyl ether obtained by treating the compound with benzyl chloride and potassium carbonate in dimethylformamide was measured, and the CD of the compound (
7) From the measurement results, the structure was determined as described above.
As a result of further research on the biological activity of Gomisin J, the present inventors discovered that Gomisin J has a remarkable antipyretic effect. Based on this, the inventors used Gomisin J represented by the above structural formula as an active ingredient He completed the invention of an antipyretic agent.

Next, the fact that Gomisin J has an antipyretic effect will be explained using experimental examples.

The Ninth Revision Japanese Pharmacopoeia typhoid/paratyphoid fever combination vaccine was given to male mice weighing 22 to 26 years in mice weighing 1k9.
(1.0 mt of vaccine/1 kg of mouse/10 mL of physiological saline)
m1), mice with fever (fever appears approximately 3 hours after vaccine administration) were treated with Gomisin J and Tween 80 (
The mouse was dissolved in Tween 8O) and administered intraperitoneally, and the body temperature of the mouse was compared with that of control mice (vaccine-unadministered mice and vaccine-administered mice), and the body temperature was measured every hour for 4 hours.

The results are as shown in Table 1 and the attached drawings.
Gomisin J has a remarkable transient antipyretic effect, and Gomisin J is recognized to be effective as an antipyretic agent.

Next, acute toxicity by intraperitoneal administration of Gomisin J to mice was not observed even at 750 mg/Kg, and it was determined that no toxicity was observed at the dose.

The effective dose of Gomisin J for humans is 100~
It is permitted to take 150mg three times a day.

Gomisin J is a solvent, carrier, filler, and
Using adjuvants and the like, preparations such as liquids, powders, granules, and tablets can be prepared according to conventional methods for manufacturing preparations. EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 After crushing 1.38 kg of Kita Schisandra, petroleum ether 3
1 and extracted 4 times at 45-50°C for 8 hours.

The extracts were combined and the petroleum ether was distilled off under reduced pressure to obtain 188y. This engineering scratch was suspended in 450 mι of water and steam distilled for 3 hours to remove the essential oil.
After extracting this residue four times with 200 ml of ether,
The ether extracts are combined and the ether is distilled off to obtain 179 da of petroleum ether soluble non-essential oil fraction. This petroleum ether soluble non-essential oil part 179y was converted to 1200y of silica gel.
The mixture was first subjected to column chromatography using n-hexane, secondly benzene, and thirdly developed with a benzene-acetone mixed solvent.

The eluted portions were combined with benzene-acetone (17:3) and the solvent was distilled off under reduced pressure to obtain a residue of 12y. This was subjected to column chromatography using silica gel 240y and developed with a benzene-ether mixed solvent. The eluted portions of benzene-ether (9:1) and benzene-ether (17:3) were combined and the solvent was concentrated under reduced pressure.
Subjected to column chromatography using 0y. By using a mixed solvent of n-hexane-acetone as a developing solvent, Gomisin A, which is a solution of n-hexane-acetone (9:1) and n-hexane-acetone (17:3), is obtained. Also, the first silica gel column chromatography. After combining the eluted parts of benzene-acetone (3:2) with E, the residue obtained by concentration (8.3y) was again subjected to column chromatography using silica gel 180y, and n-hexane-acetone was combined. When applied with a mixed solvent,
Schizandrin, a known substance, is obtained from the n-hexane-acetone (22:3) eluted portion.

Example 2 Comisin J 5y was made into a fine powder, which was mixed with 94 da I of lactose and 1 y of magnesium stearate. 'This mixture was processed into tablets with a diameter of 2077Z771 using a single-shot slug tablet machine.
A slug tablet having a weight of about 2.3 f was prepared, and this was crushed with an oscillator, sized, and sieved to obtain good granules having particles of 20-50 mesh.

This granule is in a single dose of 2y (100mg as Gomisin J).
(equivalent to 1) and is taken 3 times per dose.

Example 3 Gomisin J 15y is made into a fine powder, the fine crystals are combined, the solvent is concentrated under reduced pressure, and the residue is subjected to preparative thin layer chromatography using silica gel.

The plate for thin layer chromatography used here is
Silica gel HF25. (KieselgelHF254
, MerCk) with a size of 20×20C7.
7I) A plate with a thickness of 0.75wL was dried at 110℃ for 1 hour, and compounds were detected using ultraviolet light (25368).
It was done by irradiation. The above plate was coated with n-hexane-acetone mixed solvent (7:3) and RfO. Extract the part showing 58 with a chloroform-methanol mixture to obtain 520
mg of Gomisin J (yield 0.023%) was obtained. Note 1
The silica gel chromatography was continued for the second time using a benzene-acetone mixed solvent, and the eluted portions of benzene-acetone (4:1) and benzene-acetone (3:1) were combined and concentrated, leaving a residue (23. When 5y) was again subjected to column chromatography using silica gel 480 and developed with a benzene-ether mixed solvent, the eluted portion of benzene-ether (4:1) yielded the known compounds cellulose 7.5y) lactose 13y and Mixed with magnesium stearinoate 2y and compressed into tablets with a diameter of 7 using a single-shot tablet machine.
77! 77! , tablets weighing approximately 125 mg were produced.

One tablet contains 50 m9 of Gomisin J.

This tablet is taken 2 tablets at a time, 3 times a day.

[Brief explanation of the drawing]

The figure shows the antipyretic effect of Gomisin J, which is the active ingredient in the present invention, on mice.

Claims (1)

[Claims] 1. A compound represented by the structural formula ▲ Numerical formula, chemical formula, table, etc. ▼. 2 Extract Kita Schisandra with lower hydrocarbons, remove the solvent and volatile components from the extract, and treat the residue with chromatography to obtain a compound represented by the structural formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ A method for producing a compound represented by the above structural formula, characterized in that: 3. An antipyretic agent whose active ingredient is a compound represented by the structural formula ▲Mathematical formula, chemical formula, table, etc.▼.