JPH0733388B2 - New alkaloids - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel alkaloid having a hypotensive effect and useful for treating hypertension and the like.

[Prior art and problems] Powder prevention is Stephani from the family Menispermaceae.
It is a crude drug based on the root of a tetrandra S. MOORE, and as a result of pharmacological studies in China, it has been proved to have analgesic, anti-inflammatory, anti-allergic and antihypertensive effects. It is known that the roots of powdered rice contain about 1.2% of alkaloids such as tetrandrine, funtinorin, menisin, menisidine and cyclanolin, and the present inventors have searched for this alkaloid component, Some new alkaloids (Japanese Patent Application No. 61-4718, Japanese Patent Application No. 61-1362)
No. 60) and a known alkaloid having an angiotensin I converting enzyme inhibitory action (Japanese Patent Application No. 61-48279).

On the other hand, the drugs currently used for the treatment of hypertension have problems such as rapid statement of their effects and short duration of effects, and the development of drugs to improve these problems. Was desired.

[Means for Solving Problems] In order to develop an antihypertensive agent having a sustained antihypertensive effect, the present inventors have focused their attention on the above-mentioned alkaloid, fuantinoline, and have made a chemical modification using this as a raw material. As a result of research, they succeeded in inducing the novel alkaloids of the present invention.

That is, the present invention has the formula (I) It is a novel alkaloid represented by (hereinafter referred to as the compound of the present invention).

To obtain the novel alkaloid of the present invention, for example, the following method can be mentioned.

Powdered powder was extracted with water, alcohols or a mixed solvent of water and alcohols, the residue obtained by removing the solvent from the extract was dissolved in a mixed solvent of water and alcohols, and then n-hexane, petroleum ether, etc. After partitioning with the organic solvent described above to remove the fat-soluble components that migrate to the organic solvent, the mixture is dissolved in ammonia water having a pH of 9 and further extracted with chloroform to obtain an aqueous ammonia extract and a chloroform extract. Then, extract the chloroform extract with Sephadex, such as Sephadex LH 20, and Diaion HP 20, using at least one selected from water, ethanol, chloroform, ether, hexane, benzene, and ethyl acetate as an elution solvent.
Column chromatography using porous polymer such as alumina, silica gel, etc. as a carrier several times, and fractionating while confirming the target component by thin layer chromatography, the following formula (II) To obtain a futaninoline represented by, ethanol, methanol, chloroform, dissolved in a solvent selected from ether, ethylated using an ethylating agent such as diazoethane, phenyltriethylammonium,
After the reaction, the solvent is distilled off, and the compound of the present invention is obtained by subjecting it to column chromatography using alumina or silica gel as a carrier and confirming the target component by thin layer chromatography. Can be done. In some cases, it may be purified by recrystallization using a suitable solvent such as ethanol, water or acetone.

The specific examples of the production of the compound of the present invention are as follows.

Specific Example 7.76 kg of powdered powder was extracted with 30 methanol, and methanol was removed from the extract to obtain 410 g of methanol extract. This methanol extract was mixed with 90% methanol-water mixture 1.5
In water, extracted with n-hexane 1.5 three times to remove fat-soluble components, and then concentrated 90% methanol-water fraction under reduced pressure to a residue obtained by adding 1.5 ammonia water pH 9 to dissolve. Chloroform 1.5 was extracted 5 times, and the aqueous ammonia layer and the chloroform layer were concentrated under reduced pressure to obtain an aqueous ammonia extract and a chloroform extract. Then, the chloroform extract was subjected to alumina (aluminum oxide 90 Merck) column chromatography and eluted with chloroform to obtain Fr-1 (which means a fraction. The same applies hereinafter) and Fr-2, and Fr-2 was obtained. Subjected to silica gel (Kieselgel 60 manufactured by Merck) column chromatography and eluted with chloroform-methanol (20: 1) to obtain Fr2-1, Fr2-2, Fr2-3 and Fr2-4,
By removing the eluting solvent from Fr2-1 and recrystallizing with acetone, an Rf value of 0.34 [thin layer brake: Kieselgel 60
F ₂₅₄ , developing solvent: chloroform-methanol (3: 1),
[Coloring reagent: Dragendorff reagent], colorless needle-like crystals of futaninoline were obtained.

Next, phenyltriethylammonium iodide 150mg
Was dissolved in 10 ml of ethanol, 130 ml of silver oxide was added, and the mixture was stirred overnight and then filtered, and 220 mg of futaninoline was added to the filtrate, and the mixture was refluxed at 120 ° C. for 4 hours, and then the solvent was distilled off under reduced pressure. , Manufactured by Merck)
It was subjected to column chromatography and eluted with chloroform to obtain 225 mg of Rf value 0.37 [thin layer plate: Kieselgel 60F ₂₅₄ , developing solvent: chloroform-methanol (9: 1), color reagent: Dragendorff reagent]. It was This was recrystallized using a mixed solution of ethanol and water to obtain 149 mg of colorless needle crystals having the following physicochemical properties.

Melting point: 109.5 to 111 ° C ▲ [α] ²³ _D ▼: + 276.3 ° (c = 0.68, CHCl ₃ ) EI-Ms m / z (%): 636 (M ⁺ , 65.9), 409 (55.7), 205 (1
00) 2932,2836,2796,1608, 1582,1508,1464,1444, 1416,1354,1268,1230, 1216,1124,838 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 0.80 (3H, t = 7.08), 2.33 (3H, s), 2.59 (3H, s), 3.37 (3H, s), 3.74 (3H, s), 3.93 (3H, s), 5.96 (1H, s), 6.30 (1H, s), 6.32 (1H, dd, J = 8.3,1.95), 6.51 (1H, s), 6.54 (1H, s−1ike), 6.82 (1H, dd, J = 8.3,2.44), 6.85 (1H, dd, J = 8.3) ), 6.90 (1H, d−1ike), 7.15 (1H, dd, J = 8.3,2.44), 7.37 (1H, dd, J = 8.3,1.95) ¹³ C nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 14.8 (Q), 22.3 (t), 24.6 (t), 40.6 (t), 42.0 (t), 42.5 (q), 42.7 (q), 44.4 (t), 45.7 (t), 55.9 (2c, q) , 56.3 (q), 61.6 (d), 64.5 (d), 68.2 (t), 106.0 (d), 111.9 (d), 113.0 (d), 116.3 (d), 120.2 (d), 121.9 (2c, d), 122.9 (d), 123.1 (s), 127.9 (s), 128.2 (2c, s), 130.2 (d), 132.7 (d), 135.0 (s), 135.1 ( ), 136.9 (s), 144.0 (s), 147.2 (s), 148.6 (s), 148.8 (s), 149.5 (s), 151.6 (s), 154.0 (s) The compound of the present invention has a hypotensive action. However, it is useful as a drug as an antihypertensive agent. This will be described with reference to examples.

Experimental example Male stroke-prone spontaneously hypertensive rats (6 per group)
6 days before the start of the experiment, pentobarbital sodium
Anesthesia was performed by intraperitoneal administration at 50 mg / kg, and a cannula filled with 200 U / ml of heparin sodium was inserted from the hip artery into the abdominal aorta. The other end of the cannula equipped with a stopper was subcutaneously fixed to the back of the neck. Rats were bred in a single room cage and fasted the day before the experiment.

On the day of the experiment, replace the arterial cannula with a pressure transducer (CP-
01, Century Technology), blood pressure recorder (PA
-011, Star Medical; Recti-Horiz-8K, San-ei) was used to measure mean blood pressure without anesthesia and without restraint.

The compound of the present invention obtained in the specific example was dissolved in distilled water and orally administered, and blood pressure was measured over time. Only distilled water was orally administered, and the blood pressure measured in the same manner was used as a control group. The results are shown in Table 1.

From the above results, it was confirmed that the compound of the present invention has a long-lasting antihypertensive action.

In addition, the compound of the present invention obtained in a specific example was used in rats (1 group 10
Since no deaths were observed even after oral administration to 1 g / kg), the safety of the compound of the present invention was confirmed.

The compound of the present invention can also be used as a commonly used salt of pharmaceuticals such as hydrochloric acid, sulfuric acid, succinic acid, etc. in order to achieve the effect as a pharmaceutical.

The compound of the present invention can be administered to animals and humans as it is or together with a conventional pharmaceutical carrier. The dosage form is not particularly limited and may be appropriately selected and used as necessary. Oral agents such as tablets, capsules and granules, injections,
Parenteral agents such as suppositories may be mentioned. Oral preparations such as tablets, capsules and granules are manufactured according to a conventional method. Tablets are produced by mixing and shaping the compound of the present invention with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc. It is produced by mixing with an active pharmaceutical filler or diluent and filling it into a hard gelatin capsule, a soft gelatin capsule or the like. Syrups and elixirs are produced by mixing the compound of the present invention with sweeteners such as sucrose, preservatives such as methyl and propylparabens, colorants, seasonings, fragrances, and auxiliary agents.

The parenteral preparation is produced according to a conventional method, and distilled water for injection, physiological saline, dextrose aqueous solution, propylene glycol or the like can be generally used as a diluent. Further, if necessary, a bactericide, a preservative, and a stabilizer may be added.
In addition, from the viewpoint of stability, this parenteral preparation is frozen after filling into a capsule or the like, and water is removed by a normal freeze-drying technique,
A liquid preparation can also be prepared from the lyophilized product immediately before use.

Other parenteral agents include liquid preparations for external use, coating agents such as ointments, suppositories for rectal administration, and the like, and they are manufactured by a conventional method.

Claims (1)

[Claims] 1. A formula (1) A new alkaloid represented by.