JPH0228596B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel compound (Sangenone C) that has a blood pressure lowering effect and is useful as a pharmaceutical. More specifically, the present invention is based on the following formula It relates to Sunguenon C represented by

Until now, mulberry root bark has been referred to as mulberry white bark in Chinese medicine, and has been included in Chinese medicine preparations as an anti-inflammatory diuretic, laxative, and antitussive expectorant.

In addition, recently, the blood pressure lowering effect of the methanol extract (Proceedings of the 99th Annual Meeting of the Pharmaceutical Society of Japan, p. 162,
29A2-3), hyperglycemic lowering effect of the extract (Japanese Patent Publication No. 53-44530), interferon-inducing effect of the high molecular polysaccharide contained in the extract (Japanese Patent Application Laid-open No. 53-99313), etc. It has been known.

However, regarding the active substance in the blood pressure lowering effect, two types of 8-substituted cyclohexenylflavone derivatives Quanon G and Quanon H [Chemical and Pharmaceutical Bulletin (Chem.
Pharm.Bull.) Volume 28, No. 8, Page 2548 (1980),
HETEROCYCLES Volume 14,
No. 12, p. 1943 (1980)] have not yet been elucidated.

As a result of intensive research, the present inventor extracted a plant of the genus Morus, family Moraceae, with an organic solvent, and discovered that a new compound obtained by isolation from this extracted extract has a blood pressure lowering effect, and has developed the present invention. It was completed and named Sangenon C.

First, a method for producing Sangenone C will be explained.

The mulberry root bark is cut into small pieces, degreased with an organic solvent with relatively low polarity, extracted with lower alcohol, lower fatty acid ester, ether or acetone, and the liquid is dried under reduced pressure to obtain an extracted extract. The extracted extract is subjected to column chromatography according to a conventional method to separate impurities to obtain crude Sangenone C.
Next, this crude product is subjected to preparative thin layer chromatography or high performance liquid chromatography to isolate and purify it to produce Sangenone C.

The mulberry used here is commercially available mulberry bark from China, Morus alba L., Morus alba L.
bombycis Koidz), Morus Lhou
Koidz or Morus multicaulis Perr.), etc. are used, and the root bark thereof is particularly preferred. These should be thoroughly dried into fine powders.

Suitable organic solvents with relatively low polarity for use in the degreasing treatment include n-hexane and benzene.

Lower alcohols for extraction include methanol,
Examples of the lower fatty acid ester include methyl acetate, ethyl acetate, butyl acetate, and the like, and examples of the ether include methyl ether and ethyl ether.

In conventional column chromatography, for example, a column packed with silica gel is used to elute with an acetone-benzene mixture, methanol-benzene mixture, ethyl acetate-benzene mixture, or acetone-n-hexane mixture. Sangenone C can be obtained.

For the subsequent purification operation, for example, by developing and fractionating using silica gel preparative thin layer chromatography using solvents such as hexane, benzene, chloroform, acetone, ethyl acetate, or methanol alone or in combination, Sangenone C can be obtained.

Note that it is also possible to omit the degreasing treatment during the above extraction/separation operation.

The physical and chemical properties of Sangenone C obtained by the above treatment are as follows.

(a) Properties: Pale yellow powder (b) Molecular weight: 708 (field desorption)
(from mass spectrum M ⁺ ) (c) Melting point: 230-240℃ (decomposition) (d) Specific rotation: [α] ¹⁶ _D +304° (C = 0.179, methanol) (e) Infrared absorption spectrum (nujol ) (cm ^-1 ) (1st
(See figure) ν _nax : 3300, 1660 (shoulder), 1645, 1640, 1630,
1600 (shoulder) (f) Ultraviolet absorption spectrum (nm) (see Figure 2) λ ^CH3OH _nax (logε): 220 (4.64), 230 (4.55)
, 283
(4.40), 309 (4.35) λ ^CH3OH+AlCl3 _nax (logε): 225 (4.63), 292 (4
.35),
305 (4.40), 350 (4.01), 420 (3.18) (g) Nuclear magnetic resonance spectrum (CD ₃ COCD ₃ )
(ppm) δ: 1.53, 1.61, 1.88 (3H, s respectively), 2.20~
2.50 (2H, m), 2.50~3.30 (2H, m),
3.80~4.00 (1H, m), 4.00~4.30 (1H,
m), 4.57 (1H, t, J=6Hz), 5.22
(1H, brt, J=7Hz), 5.58 (1H, brs),
5.77 (1H, s), 6.15-6.60 (6H, m),
6.97 (1H, d, J=8Hz), 7.33 (1H,
d, J=8Hz), 8.41(1H, d, J=8
Hz), 12.15 (1H, s), 12.48 (1H, s) (h) Color reaction Ferric chloride reaction Positive (reddish purple) Hydrochloric acid-magnesium reaction Positive (orange) Sodium boron hydroxide reaction Positive (purple) ( i) Molecular formula: C ₄₀ H ₃₆ O ₁₂ (j) Solubility in solvents Poorly soluble: water, hexane, benzene, chloroform, dichloromethane Soluble: ethyl ether, ethyl acetate Easily soluble: methanol, ethanol, dimethylformamide, acetone (k) ) Distinction between acidic, neutral, and basic: Acidic The blood pressure lowering effect of Sangenone C was confirmed by the following animal experiment.

First, the sample was dissolved and prepared in propylene glycol to a concentration of 10 mg/ml, and the sample was injected intravenously into a male rabbit weighing 3.0 kg under anesthesia (pentobarbital 30 mg/Kg, intravenous injection) to measure femoral artery blood pressure. did.

As a result, a dose of 1 mg/Kg transiently caused 15 mm
At a dose of 5 mg/Kg of Hg, a transient drop in blood pressure of 100 mmHg followed by 15 mmHg for over 1 hour was observed.

In addition, the LD ₅₀ for acute toxicity is for mice (5 weeks old,
ddY strain, male) was 132 mg/Kg when administered intraperitoneally.

As mentioned above, Sangenone C having the above-mentioned physical and chemical properties can be produced from mulberry root bark through a relatively simple extraction and purification operation.
In addition, it exhibits an excellent blood pressure lowering effect and has low toxicity, making it suitable as an antihypertensive agent.

The method for producing the Sangenone compound (Sangenone C) of the present invention will be specifically explained below.

Production example: Shredded dried commercially available mulberry bark (produced in Guangdong, China) 8Kg
was degreased twice with n-hexane 40 and then twice with benzene 40 at room temperature for one week, then extracted twice with methanol 40 at room temperature for 3 days each, and the extract was collected and extracted under reduced pressure. After distilling off the solvent, 1 portion of ethyl acetate was added, and the soluble portion was separated.
The solvent was distilled off under reduced pressure from the ethyl acetate soluble portion to obtain 70 g of extracted extract.

36g of this extracted extract was dissolved in the minimum amount of acetone required, adsorbed on 70g of silica gel (Wako Gel C-200, manufactured by Wako Pure Chemical Industries, Ltd.), the solvent was removed by evaporation, and a layer was placed on a column packed with 300g of silica gel. First, elute 10 times using 15% acetone-benzene as a developing solvent, then elute with 20% acetone-benzene.
Elution was performed with 5 portions of benzene, and the eluate was concentrated under reduced pressure to obtain 13.0 g of crude Sangenone C.

This crude Sangenone C was purified by preparative thin layer chromatography [Wako Gel B-5F (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: methanol:chloroform = 1:5] to obtain 3.0 g of Sangenone C. Its physical and chemical properties were as follows.

(a) Properties: Pale yellow powder (b) Molecular weight: 708 (field desorption)
(from mass spectrum M ⁺ ) (c) Melting point: 230-240℃ (decomposition) (d) Specific rotation: [α] ¹⁶ _D +304° (C = 0.179, methanol) (e) Infrared absorption spectrum (nujol ) (cm ^-1 ) ν _nax : 3300, 1660 (shoulder), 1645, 1640, 1630,
1600 (shoulder) (f) Ultraviolet absorption spectrum (nm) λ ^CH3OH _nax (logε): 220 (4.64), 230 (4.55)
, 283
(4.40), 309 (4.35) λ ^CH3OH+AlCl3 _nax (logε): 225 (4.63), 292 (4
.35),
305 (4.40), 350 (4.01), 420 (3.18) (g) Color reaction Ferric chloride reaction Positive (reddish purple) Hydrochloric acid-magnesium reaction Positive (orange) Sodium borohydride reaction Positive (purple) (h) Solubility in solvents Poorly soluble: water, hexane, benzene, chloroform, dichloromethane Soluble: ethyl ether, ethyl acetate Easily soluble: methanol, ethanol, dimethylformamide, acetone (i) Distinction between acidic, neutral, and basic: acidic ( j) Elemental analysis value Experimental value (%); C: 65.61, H: 5.31

[Brief explanation of drawings]

FIG. 1 is a diagram showing the infrared absorption spectrum (nujol) of the sungenone compound of the present invention, and FIG. 2 is a diagram showing the ultraviolet absorption spectrum (in methanol) of the sungenone compound of the present invention.

Claims (1)

[Claims] 1. The following formula Sangenone compound (Sangenone C) represented by: