JPS607969B2 - choleretic agent - Google Patents

Description

[Detailed description of the invention] The present invention is based on the structural formula It is a choleretic agent containing the compound represented by as an active ingredient.

The compound represented by the above formula (1) is called an adoxoside aglycone.

The above compound adoxoside aglycone is derived from Patriniagi, which is a plant of the Ominae species.
bka saMa phantom m), Okinrei power (Patrini)
atrilobavar. takeuchja skin○hM
) and Adoxam (Adoxam)
11inaL. ) etc.

Adoxoside aglycone can be obtained, for example, from Malva Citrusica by the following method. That is, the roots of the Malva quinella are crushed, extracted with methanol while hot, concentrated, and an aqueous solution obtained by dissolving the extract in water is extracted with n-butanol. The obtained extract was subjected to column chromatography using activated carbon, developed in the order of water and methanol, and methanol was distilled off from the methanol eluate at least once, resulting in a yield of approximately 5.4%. Obtain the crude glycoside part. Furthermore, this crude glycoside part was subjected to column chromatography using silica gel, developed with a mixed solvent of chloroform and methanol in which the mixing ratio of methanol to chloroform was increased sequentially, and the mixture of chloroform and methanol (1
The solvent is removed from the eluate of 00:13) to obtain adoxoside in a yield of about 0.7%. Next, after hydrolyzing this adoxoside with B-glucosidase (dissolved in acetate buffer), the reaction solution is extracted one or more times with ethyl acetate, and the ethyl acetate solutions are combined and concentrated under reduced pressure.
A white solid adoxoside aglycone is obtained with a yield of about 40%. A specific example of the production of adoxoside aglycone by this method is as follows.

10.6k9 of the ground product of the roots of Malvacanus persimmonica is extracted 3 times with 30 methanol at a warm temperature, and the methanol solutions are combined and concentrated under reduced pressure to obtain an extract of 1.72k9.

This extract was dissolved in water for 3 days, this solution was divided into 2 equal parts, each was extracted 3 times with n-butanol during loading, and the n-butanol solutions were combined to distill n-butanol. About 1.24 kg of extract was obtained. This extract was subjected to column chromatography using activated carbon 2k9, developed with 100ml of water to remove sugar, developed with methanol, removed the methanol from the methanol outlet, and dried for 570ml. Obtain the glycoside part. Furthermore, this crude glycoside portion was subjected to column chromatography using silica gel 5K9, developed with a mixed solvent of chloroform and methanol in which the mixing ratio of methanol to chloroform was gradually increased, and fractionated one by one. Chloroform/methanol (
Among the elution parts of 100:13), the solvent was distilled off from the elution part which was found to be a single component by thin layer chromatography to obtain adoxocide 32 as a white solid, and another elution part was obtained. The solvent is removed from the mixture to obtain a viscous liquid containing adoxocide. Add this sticky liquid to silica gel 4k9 again.
The mixture was subjected to column chromatography using a chloroform-methanol mixture and developed in the same manner as above, and the solvent was distilled off from the chloroform-methanol (100:13) eluate to obtain Adoxocide 42 as a white solid. . Next, this adoxoside 42 was dissolved in acetate buffer (pH = 5).
．． 0) Dissolve the solution in 2 minutes, add B-glucosidase to this solution overnight, dissolve, and leave at 370°C for 3 hours.

Thereafter, this reaction solution was extracted twice with ethyl acetate in a separatory funnel, and the ethyl acetate solutions were combined and the solvent was distilled off to obtain 16.5 g of adoxoside aglycon as a white solid. The nuclear magnetic resonance spectrum (6inCDCl3) of this adoxoside aglycone is 3.6
0 (but multiplet, H-10), 3.85 (thin,
Singlet, -COOCH3), 4.88 (IH,
Doublet, J=7 Hertz, H-1), ? ．． 48 (IH
, doublet, J=2 Hz, H-3), and from this it is recognized that the adoxocide aglycon has the structural formula of formula (1). Next, the fact that adoxoside aglycones have a choleretic effect will be explained using experimental examples.

The rat's abdomen is opened under urethane anesthesia (i.5ta'k9, subcutaneous injection), a small hole is made in the common bile duct near the small intestine, and a polyethylene cannula is inserted through the hole. After collecting bile flowing out from this cannula twice for 30 minutes each time,
A physiological saline solution of adoxoside aglycone was administered intravenously and intraduodenally, and bile was collected every three nights thereafter to measure the amount of bile. The results are as shown in the drawing.

That is, Figure 1 is a diagram showing the results of the choleretic effect of adoxoside aglycoso upon intravenous administration, and Figure 2 is a diagram showing the results of the choleretic effect of adoxoside aglycon upon intraduodenal administration. It is. From the results shown in the drawings, it is recognized that adoxoside aglycone clearly has a choleretic effect.

Furthermore, as a result of experiments, it was found that the choleretic effect of this compound when administered orally was almost the same as that when administered intraduodenum. Next, the acute toxicity of adoxoside aglycones will be explained using experimental examples.

A physiological saline solution of adoxoside aglycone was administered to mice intravenously and orally, respectively, and LD5o was calculated by determining whether the mice were alive or dead after 7 hours of incubation.

Calculations involve up and down
n) method [see ``Pharmacological Experiments'', co-edited by Takagi and Ozu, pp. 204 to 205, published by Tanou Nanzando in 196] was used. The results are shown in Table 1. Table 1 LD5 shown in Table 1.

When comparing the amount of the adoxoside aglycone with the choleretic effect, it is found that the acute toxicity is weaker than the effective amount of the adoxoside aglycon. That is, when administered intravenously, adoxoside aglycone is administered at a dose that is less than one-fifth of the LD plaque value (25
female/kg) and LD5 even after oral administration. The choleretic effect is expressed at a dose less than one-fifth of the value (9/k9 of 100), and the effective dose of this compound for the choleretic effect and LD5. The above is confirmed because there is a difference between the two values. Next, considering the data on choleretic effect, the effective dose of adoxoside aglycone is 12.5 to 25 9 for intravenous injection,
For oral administration, the dose is 50 to 100 9, depending on the symptoms.
It is considered appropriate to take the drug up to three times a day.

Adoxoside aglycones can be prepared as liquids, injections, powders, granules, tablets, etc. using the appropriate solvents, carriers, fillers, adjuvants, etc. used in formulations, and according to conventional methods for manufacturing formulations.
Pharmaceutical preparations such as capsules can be made. 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 50 mg of adoxoside aglycon was dissolved in 50 μg of sterile physiological saline filled with 6,000 μl of adoxoside aglycon, and aseptically dispensed into vials to contain 50 mg of adoxoside aglycone, sealed and prepared as an injection. was manufactured.

This injection is administered in an amount of 1.25 to 5 per day depending on the symptoms for adult patients.
Administer intravenously.

Example 2 100 g of adoxoside aglycone was mixed with 99 g of lactose and 1 g of magnesium stearate, and this mixture was compressed into tablets using a single-shot slug tablet machine to form tablets with a diameter of 20 mm and a weight of approx. 2. Slug tablets were prepared for 3 days, crushed with an oscillator, sized, and sectioned to obtain good jaw granules with particles of 20 to 50 mesh.

This chin granule has a dosage of 100 to 200 9 (9) depending on the symptoms.
Adoxoside aglycone (equivalent to 50-100 9) is taken three times a day.

Example 3 Adoxoside aglycone 100 g was mixed with 20 g of microcrystalline cellulose and 5 g of magnesium stearate, and this mixture was compressed using a single-shot tablet machine to form tablets with a diameter of 7 Yanagi, Nine tablets weighing 125 were formulated.

One tablet of this tablet contains 9 out of 100 adoxoside aglycones.

This tablet is to be taken 1 tablet at a time, 3 times a day. Example 4 Adoxoside aglycon 100 9 was finely powdered and No.
．． The gelatin capsules of No. 3 were filled to obtain capsules.

This capsule formulation is taken one capsule at a time, up to three times a day, depending on the symptoms.

[Brief explanation of drawings]

FIG. 1 is a graph showing the choleretic effect of adoxoside aglycone upon intravenous administration, and FIG. 2 is a graph showing the choleretic effect of adoxoside aglycone upon intraduodenal administration. Figure 1 Figure 2

Claims (1)

[Claims] 1 Structural formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ A choleretic agent whose active ingredient is a compound represented by