JPS5855420A - Hypotensor - Google Patents

Abstract

PURPOSE:A hypotensor that contains, as an active ingredient, a specific chromone derivative obtained from a herb medicine, WOLFF, thus showing high safety. CONSTITUTION:The objective hypotensor contains a chromone derivative of the formula (R is H, beta-D-glucopyranosyl) as an active ingredient. The compound of the formula is obtained by extracting WOLFF (dried roots or root stocks of Ledebourilla seseloidae) with a solvent such as petroleum ether, n-hexane or benzene or at first extracting with a lower alconol, then dissolving the extract in water, extracting the solution with the above solvent to obtains the fraction soluble in fat and treating the fraction with chromatography.

Description

[Detailed description of the invention] The present invention relates to antihypertensive agents.

That is, one aspect of the present invention is a hypotensive agent containing as an active ingredient a chromone derivative represented by the general formula (I) [wherein -R represents hydrogen or a β-D-glucopyranosyl group] The expressed compound is obtained from, for example, the Chinese herbal medicine Jumihetokuto and Bofutsu, which is one of the Chinese medicines used in Bofutsu-san. The windbreak is a plant of the Umbelliferae family, Lesobriella cecelloides (Ledebour'j'i).
'la 5eseloides WOLFF) roots and rhizomes are dried.

The compound represented by general formula (I) can be obtained, for example, as follows.

Extract the windbreak with a solvent such as petroleum ether, n-hexane, benzene, or chloroform, or first extract the windbreak with a lower alcohol such as methanol or ethanol, and dissolve the resulting lower alcohol extract in water. A lipophilic fraction was obtained by extracting the ester with ether, n-hexane-benzene, chloroform, etc., and the compound (2
) [compound in which R=H in general formula (I)] is obtained.

Alternatively, the lower alcohol extract obtained by extracting the residue obtained by extracting windbreak with a solvent such as petroleum ether-n-hexane, benzene, or chloroform with a lower alcohol such as methanol or ethanol may be directly chromatographed; - Compound (1) [in general formula (I), R=β-D- glucopyranosyl group] is obtained.

A specific example of the production of the compound represented by the general formula (I) is as follows.

Powdered Windproof/Ky is added and mixed with 3K of n-hexane, and extraction is performed at warm temperature or preferably under reflux. Perform extraction several times, combine the extracts, and distill off one solvent to obtain n-
Obtain hexane extract.

This n-hexane extract was subjected to column chromatography using silica gel as an adsorbent, starting with n-hexane:acetic acid ethyl ester (4:1) (3:1), (2:
1) - Elute sequentially by changing the ratio (1:1).

The solvent was distilled off from the fraction eluted with n-hexane:ethyl acetate (1:1), and the residue was recrystallized from ethanol to give pale yellow needle-like crystals of compound C2)0. lf was obtained. Next, the residue after extraction with n-hexane was mixed with methanol 3!
The mixture is added and mixed and extraction is carried out at warm temperature or preferably under reflux. Extraction is performed several times, the extracts are combined, and the solvent is distilled off to obtain methanol extract 1767. This methanol extract is dissolved in 10ml of distilled water and extracted several times with 10ml of n-butanol. The extracts were combined and the solvent was distilled off to obtain 30 g of n-butanol extract. This n-butanol extract is subjected to column chromatography using silica gel as an adsorbent, and eluted with a mixed solvent of alcohol-chloroform such as methanol-chloroformal or ethanol-chloroform (alcohol content is gradually increased). Elute compound (1) with alcohol-chloroform for 6 to 7 hours. The solvent was distilled off from the fraction containing Compound (1), and the residue was recrystallized from ethanol to obtain Compound (1)/y- in the form of pale yellow needles.

Compound (2) can also be obtained by hydrolyzing compound (1) using a strong acid such as hydrochloric acid or sulfuric acid or a sulfuric acid such as β-glucosidase.

One example is compound (1) 0.4'? was dissolved in a mixed solvent of water and dimethyl sulfoxide (3:1), and ββ-glucosidase Om9 was added to 32C.
So - make a double reaction. The reaction solution was mixed with ethyl acetate 3o
Extract 3 times with mt. Combine the extracts.

Dry using a commonly used desiccant such as Na25O.

After removing the desiccant, the solvent was distilled off and the residue was recrystallized from ethanol to obtain pale yellow needle-like crystals of compound (2) O, UNO. Compound (1) and ( The properties of 2) are shown in Table 1. In Table 1, Glu is β-D
- indicates a glucopyranosyl group.

Table 1 Compound (2) is described in Nitta et al. [Pharmaceutical Journal, No. g].

Volume, 74 pages (1960) - gj volume, - 5 pages (ly6
．． t)), and compound (1) was prepared by Hata et al. [Pharmaceutical Society of Japan No. qg]
Abstracts of the annual meeting, p. 302 (/97g))
A, GRAY).

Next, the fact that the compound represented by the general formula (I) has a blood pressure lowering effect will be explained with reference to experimental examples.

Experimental example Body weight around 300 kg - Blood pressure K O-/00 tn Hi
Six male Hartley guinea pigs were used in each group.

Compounds (1) and (2) were each dissolved in a 4-Tween 80-physiological saline solution and administered intravenously. Blood pressure measurements were recorded on a polygraph via a pressure transducer through a cannula inserted into the carotid artery under bentobarbital anesthesia. The results are shown in Table 2.

The blood pressure lowering effect in Table 2 is based on the amount of decrease from the above blood pressure (
101? ) From the results in Table 2, it is clearly recognized that both compounds (1) and (2) have a blood pressure lowering effect.

Next, a test example will be shown regarding the acute toxicity of the compound represented by the general formula (I).

Acute toxicity test example Compounds (1), b, and (2) were administered to 1 group of IQ male mice of approximately AofDD strain weighing approximately 14 to 8 tweens.
0-Dissolved in physiological saline solution and administered orally or intravenously, LD from the number of deaths 72 hours later. The value was calculated.

The results are shown in Table 3.

Table 3 As is clear from Table 3, the LD5° values of compounds (1) and (2) are - more than 1000 m9/su when administered orally - more than J-00m979 when administered intravenously, indicating pharmacological action. Since the value is large compared to the amount, it is sufficiently safe.0 As is clear from the above-mentioned experimental examples and acute toxicity test examples, the compound represented by m=general formula (I).

They all have a blood pressure lowering effect and are highly safe, and are sufficiently safe at doses that produce a single pharmacological effect. That is, when administered intravenously, a blood pressure lowering effect is expressed at a dose much lower than the LDso value, and the effective amount of the blood pressure lowering effect of these compounds and LD. The above is confirmed as there is a considerable difference between the values.

The effective dose of the compound represented by the general formula (I) is approximately 1 to 2 doses for intravenous injection, and 1 equivalent dose for oral administration.
For QQ~qoom9, it is recognized that it is appropriate to take up to 3 times a day depending on the symptoms. The compound represented by general formula (I) can be formulated using any desired pharmaceutical carrier, solvent, or excipient. It can be prepared into a medical preparation according to conventional manufacturing methods.

Next, examples of the present invention will be shown.

Example 1 10 pieces of compound (1) were finely powdered and lactose g9i!
- and magnesium stearate/l", and compressed the mixed powder into tablets with a diameter of 20 m and a quantity of 2
．． 3i! - After starting out as slug tablets, - crushed with an oscillator, sized and sieved for 14 hours.

Granules of mesh particles were obtained.

Example 2 10 g of compound (2) was made into a fine powder, and this was added to microcrystalline cellulose. and magnesium stearate s! j-
- This mixture was compressed into tablets with a diameter of 7 using a single-shot tablet machine.
Tablets J with fi-weight j2jm9 were obtained.

Claims (1)

[Scope of Claims] A hypotensive agent containing as an active ingredient a chromone derivative represented by the general formula (I) [wherein R represents hydrogen or a β-D-glucopyranosyl group].