JPS5935883B2 - choleretic agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is a choleretic agent containing 4-hydroxybenzyl alcohol as an active ingredient.

4-Hydroxybenzyl alcohol is a compound represented by the following structural formula.

4-Hydroxybenzaldehyde can be produced, for example, by reducing 4-hydroxybenzaldehyde with sodium amalgam under acidic conditions, or by reducing 4-hydroxybenzaldehyde with sodium amalgam in a water-alcohol mixed solvent under dilute sulfuric acid acidity. (Beilstein O
rganischeChemie, Band VI, 8
97 (1923)).

4-Hydroxybenzyl alcohol is also used in plants of the Orchidaceae family, such as Orchis mil 1taris L.
,.

Vanda parishii L.
Gastrodia elata Blume).

For example, by hot extracting the tubers of A. japonica with ether and concentrating the extracted extract, the resulting extract is subjected to chromatography using silica gel and developed with a mixed solvent of benzene and ether, resulting in a yield of about 0.02%. 4-Hydroxybenzyl alcohol is obtained.

A specific example of this manufacturing method is as follows.

1.0 kg of dried crushed Tuber tuber is 31
The ether extracts were combined and concentrated to obtain 4.3 g of extract.

This was subjected to column chromatography using 100 g of silica gel, and developed with a benzene/ether mixed solvent in which the mixing ratio of ether to benzene was gradually increased.
Collect 100ml each and add benzene/ether (9:1~
8:2), which was found to be a single component by thin-layer chromatography, was distilled off, and the residue was recrystallized with a mixed solvent of methanol and water to form colorless frism crystals. 200 μ of 4-hydroxybenzyl alcohol was obtained.

Furthermore, 4-hydroxybenzyl alcohol can be obtained by hydrolyzing 4-β-D-glucopyranosyloxybenzyl alcohol, which is a glucoside of 4-hydroxybenzyl alcohol contained in the tubers of Prunus japonica, using β-glucosidase.

That is, hot-extracting the tubers of P. japonica with methanol,
The extract obtained by concentrating this is dissolved in water, and the aqueous solution is extracted with n-butanol.

The extract obtained by concentrating this n-butanol extract was subjected to column chromatography using activated carbon.
% methanol [mixed solvent of methanol and water (1:1)]
, and methanol, and concentrate the 50% methanol eluate to obtain the crude glycoside.

This crude glycoside portion was subjected to column chromatography using silica gel, developed with a mixed solvent of chloroform/methanol, and the solvent was distilled off from the chloroform/methanol (9:1) eluate. 4-β with a yield of %
-D-glucopyranosyloxybenzyl alcohol is obtained.

The obtained 4-β-D-glucopyranosyloxybenzyl alcohol was added to a 0.1 molar acetate buffer (pH 5,0
) and hydrolyzed with β-glucosidase at 38°C to obtain 4-hydroxybenzyl alcohol.

A specific example of this manufacturing method is as follows.

1.0 kg of dried crushed Tuber tuber is 31
The methanol extracts are combined and concentrated under reduced pressure to obtain 109 g of a dark brown extract.

This extract was dissolved in 11 parts of water and 150 m
Extraction is performed five times with n-butanol from No. 1, and the n-butanol liquids are combined and the n-butanol liquid is concentrated under reduced pressure to obtain about 20 g of extract.

This extract was subjected to graphography on Column Chroma 1 using 150 g of activated carbon, water 61.50% methanol [methanol/water (1:1) mixture "'J51, methanol 10%
1, and the solvent was distilled off from the 50% methanol eluate to obtain 2.8 g of crude glycoside.

This crude glycoside portion was subjected to column chromatography using 50 g of silica gel, developed with a mixed solvent of chloroform and methanol in which the mixing ratio of methanol was increased sequentially to chloroform, and 200 ml portions were collected. (9:1), the solvent was distilled off from the eluate that was found to be a single component by thin layer chromatography.

When the obtained residue is recrystallized with a mixed solvent of methanol and acetic acid ethyl ester, colorless needle crystals of 4-β~D are obtained.
-Glucopyranosyloxybenzyl alcohol 1.46
get g.

Next, this 4-β-D-glucopyranosyloxybenzyl alcohol 500Tn9 was added to 0.1 molar acetate buffer (pH=
5.0) Dissolve in 100ml, add 20m9 of β-glucosidase to this solution, dissolve, and leave at 38°C for 16 hours.

Thereafter, the reaction solution was extracted twice with 20 ml of ethyl acetate in a separating funnel, the ethyl acetate extracts were combined, and the solvent was distilled off to obtain 190 ml of colorless prismatic crystals of 4-hydroxybenzyl alcohol. .

The properties of 4-β-D-glycopyranosyloxybenzyl alcohol and 4-hydroxybenzyl alcohol obtained as above were as follows, and were consistent with literature values (A, Aasen, D.

Behr, and K. Leander, Act.
a Chem.

5cand, Volume B29, Pages 1002-1004
Page (1975): J, Dahmen and K.
.

Leander, Phytochemistry,
15, pp. 1986-1987 (1976)).

4-β-D-glucopyranosyloxybenzyl alcohol Color, properties: Colorless needle crystals Melting point: 150-157°Nuclear magnetic resonance spectrum ('H-NMR) (δin me
thanl -d4) 3.3-3.5 (4H, multiplet, C(2], 31,41,51)-H) 3.6
-4.0 (2H, singlet, C(6/)-H)4
．． 53 (2H, singlet, phCH2-0-
−)゛°″(′1・p゛−jL/゛y“・”−9,5”
-,'14) (AA,BB・,i,.

8. . 0. −□. 7.26 (2H, doublet, J =
9.5 Hz) 4-Hydroxybenzyl alcohol Color, properties: Colorless prism crystal Melting point: 116-117°Next, the fact that 4-hydroxybenzyl alcohol has a choleretic effect will be explained by giving an experimental example.

The rat was subjected to laparotomy under urethane anesthesia (1,57! 7 kg, subcutaneous injection), and a small hole was made in the common bile duct near the small intestine.
Insert the polyethylene cannula from there.

The bile flowing out from this cannula was collected twice for 30 minutes each, and then treated with 4-hydroxybenzyl alcohol.
% polysorbate 80/physiological saline suspension (4-hydroxybenzyl alcohol is dissolved in polysorbate 80 corresponding to 3% of the total solution volume, and then physiological saline is gradually added and mixed) by intravenous administration or intraduodenal administration. After that, bile was collected every 30 minutes, and the amount of bile was measured.

The results are as shown in FIGS. 1 and 2.

That is, FIG. 1 is a diagram showing the development of the choleretic effect of 4-nolambda hydroxybenzyl alcohol upon intravenous administration.
FIG. 2 is a diagram showing the results of the choleretic effect of 4-hydroxybenzyl alcohol when administered into the duodenum.

From the results shown in FIGS. 1 and 2, it is recognized that 4-hydroxybenzyl alcohol clearly has a choleretic effect.

Next, the acute toxicity of 4-hydroxybenzyl alcohol will be explained using experimental examples.

A suspension of 4% gum arabic and physiological saline in 4-hydroxybenzyl alcohol was administered intravenously and orally to mice, and LD5o
(50% lethal dose) was calculated.

Calculations involve up and down
n) method (published by Nanzando in 1969, co-edited by Takagi and Ozawa, p. 204-205) was used.

The results are shown in Table 1. Note 2: The values in parentheses in the table indicate 95% confidence limits. When comparing the LD5o value shown in Table 1 with the amount of choleretic effect, the acute toxicity is weaker than the effective amount of 4-hydroxybenzyl alcohol for choleretic effect. It is recognized that

That is, when 4-hydroxybenzyl alcohol is administered intravenously, the dose is less than one-tenth of the LD5o value (25 to 3
0rnI? /kg), and when administered orally, the LD5o value is 10
The choleretic effect is expressed at a dose less than one-fold (100-120~/ky), and there is a considerable difference between the effective dose of 4-hydroxybenzyl alcohol for the choleretic effect and the LD5o value. It is recognized that

Next, considering the data on choleretic effects, the effective dose of 4-hydroxybenzyl alcohol is 25 to 2801n9 for intravenous injection, and 100 to 99 for oral administration.
00rn9, it is recognized that it is appropriate to take the drug up to three times a day depending on the symptoms.

4-Hydroxybenzyl alcohol is prepared using appropriate solvents, carriers, fillers, adjuvants, etc. used in formulations.
Preparations such as liquids, injections, powders, granules, tablets, and capsules can be prepared according to conventional methods for manufacturing preparations.

Next, the present invention will be explained in more detail by showing actual cases, but the present invention is not limited thereto.

Example 1 50g of 4-hydroxybenzyl alcohol to 150m
1 in polysorbate 80, add sterile physiological saline 4.851 heated to 60°C, and suspend well.
4-Hydroxybenzyl alcohol was aseptically dispensed into vials containing 50 m9 and sealed to produce an injection.

This injection is administered at a dose of 2.528 r per day for adult patients depending on the symptoms.
rLl administered intravenously.

Example 2 20g of 4-hydroxybenzyl alcohol was made into a fine powder, and this was mixed with 89g of lactose and 11g of magnesium stearate.
This mixture is tableted with a single-shot slug tablet machine to make slug tablets with a diameter of 20 mm and a weight of 2.3 g, which is crushed with an oscillator, sized, and sieved to give a A good granule of 50 mesh particles was obtained.

This granule is taken three times a day in doses of 1 to 5 g (equivalent to 180 to 900 g of 4-hydroxybenzyl alcohol) depending on the symptoms.

Example 3 4-Hydroxybenzyl alcohol 10 (1 was made into a fine powder, mixed with 20 g of microcrystalline cellulose and 5 g of magnesium stearate, and this mixture was compressed into tablets with a single-shot tablet machine to form tablets with a diameter of 7 mm and a weight of 125 m9 tablets were produced.

1 tablet of this tablet contains 10% of 4-hydroxybenzyl alcohol.
Contains 0rn9.

Take 1 to 9 tablets at a time, three times a day, depending on your symptoms.

Example 4 4-hydroxybenzyl alcohol 200rITJ?
It was made into a fine powder and filled into gelatin capsules with a thickness of 0.00 mm to obtain capsules.

This capsule formulation takes 1 to 4 capsules at a time, depending on the symptoms.
Take 3 times a day.

[Brief explanation of the drawing]

Figure 1 is a diagram showing the results of the choleretic effect of 4-hydroxybenzyl alcohol upon intravenous administration, and Figure 2 is a diagram showing the results of the choleretic effect of 4-hydroxybenzyl alcohol upon intraduodenal administration. .

Claims (1)

[Claims] A choleretic agent containing 14-hydroxybenzyl alcohol as an active ingredient.