JPH0564929B2 - - Google Patents

Description

[Detailed description of the invention] Stephania tetrandra S.MOORE
is a herbal medicine derived from the roots of the Menispermaceae family, and pharmacological research in China has proven that it has analgesic, anti-inflammatory, antiallergic, and antihypertensive effects. It is known that the roots of Koboshu contain about 1.2% of alkaloids such as tetrandrine, phantinoline, menisin, menisidine, and cyclanoline.

Furthermore, various diseases caused by microcirculatory disorders are increasing, and in order to improve microcirculatory disorders, it is important to improve the fluidity of blood itself flowing within blood vessels, that is, to reduce blood viscosity.

The present inventors conducted research on alkaloids that have a blood viscosity-lowering effect among the alkaloid components contained in Kofuji, and found that N,N-dimethyl-phenanthro[3,4-d]-1,3- The present invention was completed by discovering that dioxol-5-ethylamine has a blood viscosity-lowering effect. That is, the present invention is based on the formula A blood viscosity-lowering agent (hereinafter referred to as the drug of the present invention) containing N,N-dimethyl-phenanthro[3,4-d]-1,3-dioxol-5-ethylamine as an active ingredient, represented by It is effective in treating ischemic brain diseases caused by microcirculation disorders.

For example, the following method can be used to obtain N,N-dimethyl-phenanthro[3,4-d]-1,3-dioxole-5-ethylamine, which is the active ingredient of the drug of the present invention.

Extract Powderfish with water, alcohol, or a mixed solvent of water and alcohol, and remove the solvent from the extract and dissolve the residue as it is or, if necessary, in water or a mixed solvent of water and alcohol. ,
After partitioning with an organic solvent such as n-hexane or petroleum ether to remove fat-soluble components that migrate to the organic solvent, add aqueous ammonia to adjust the pH to 9, then extract with chloroform, remove the solvent, and obtain a chloroform extract. obtain. Next, the chloroform extract was subjected to column chromatography using alumina, developed with chloroform as an eluent, and divided into two fractions. The first fraction was concentrated under reduced pressure and recrystallized using methanol to obtain crystals. It can be obtained by removing tetrandrine, the main alkaloid in the powder, and subjecting the crystal mother liquor to column chromatography using methanol (Sephadex LH20).

N,N-dimethyl-phenanthro[3,4-
A specific example of the production of d]-1,3-dioxole-5-ethylamine is as follows.

Specific example: Extract 7.76 kg of Powdered Powder with 30% methanol, remove methanol from the extract, and make methanol extract.
Obtained 410g. Dissolve this methanol extract in 1.5 ml of a 90% methanol-water mixture and add it to n-hexane.
1.5 to remove fat-soluble components, and then concentrate the 90% methanol-water fraction under reduced pressure. To the resulting residue, add 1.5 of ammonia water with a pH of 9 to dissolve it.
Extraction was performed five times with 1.5 liters of chloroform, and the ammonia water layer and chloroform layer were each concentrated under reduced pressure to obtain an ammonia water extract and a chloroform extract. The chloroform extracted extract was then subjected to alumina (aluminum oxide 90 manufactured by Merck) column chromatography, eluted with chloroform and divided into two fractions, the first fraction was concentrated under reduced pressure, and tetrandrine was further extracted using methanol. It crystallized and the crystals were filtered. Next, the crystal mother liquor was subjected to column chromatography (Sephadex LH20) and eluted with methanol.
Rf value 0.38 (thin plate: Kieselgel 60 F ₂₅₄ ,
A colorless oil containing a developing solvent: chloroform-methanol (3:1) and a coloring reagent (Dragendorff's reagent) was obtained. The physical and chemical properties of this substance are described in the literature [ST
Akramov and SYYunusov, Khim.Prir.
Soedin., 4(6) , 390 (1968)] N,N-dimethyl-phenanthro[3,4-d]-1,3-
This was consistent with the physicochemical properties of dioxol-5-ethylamine.

Next, the fact that the compound obtained in the specific example, which is an active ingredient of the drug of the present invention, has a blood viscosity-lowering effect will be explained by giving an experimental example.

Experimental example Blood was collected from the abdominal aorta of male Wistar rats (10-12 weeks old) pre-housed for one week under ether anesthesia, and 40% EDTA/2K was used as an anticoagulant.
(Physiological saline) was added at a rate of 3μ per ml of blood, and centrifugation was performed (3000 rpm, 4°C, 5 min) to separate the supernatant and red blood cell layer. This supernatant was further centrifuged (3000 rpm, 4°C, 15 min), and the resulting supernatant was used as plasma.

The red blood cell layers from several animals were combined, the hematocrit value (hereinafter referred to as HT value) was measured, and the layer was further diluted with plasma to adjust the HT value to 45%, which was then used to measure blood viscosity.

The compound obtained in the specific example was dissolved in 50% ethanol saline to a final concentration of ^4.8
Incubate for minutes. Next, 0.5 ml of the incubated blood was taken out, and the viscosity was measured using a viscosity meter at a shear rate of 7.5 S ^-1 , and the degree of decrease in blood viscosity was calculated from the following formula.

Blood viscosity reduction rate = A - B / A × 100 (%) A: Blood viscosity when the compound obtained in the specific example is not included B: Blood viscosity when the compound obtained in the specific example is added From this, the blood viscosity obtained in the specific example The degree of blood viscosity reduction of the compound was 31.8%, and blood viscosity lowering effect was observed.

Next, an acute toxicity test of the compound obtained in the specific example, which is the active ingredient of the drug of the present invention, was conducted using ddY male mice. There were no examples.

As described above, the compounds obtained in the specific examples have extremely low toxicity and high safety.

In addition, the compounds obtained in the specific examples can also be used as salts commonly used as pharmaceuticals such as hydrochloric acid, sulfuric acid, and succinic acid in order to achieve the desired effects.

Next, the dosage and formulation of the drug of the present invention will be explained.

The compounds obtained in the specific examples can be administered to animals and humans as they are or together with conventional pharmaceutical carriers. The dosage form is not particularly limited and may be selected and used as appropriate, and may include oral preparations such as tablets, capsules, and granules.

In order to achieve the desired effect as an oral agent, it is usually necessary for an adult to administer 120 to 600 mg of the compound obtained in the specific example three times a day, although this will vary depending on the age, weight, and severity of the disease of the patient. It seems appropriate to take it in separate doses.

In the present invention, oral preparations such as tablets, capsules, and granules are manufactured according to conventional methods. Tablets are manufactured by mixing and shaping the compound obtained in the specific example with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc. Capsules are manufactured by mixing the compound obtained in the specific example with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc. It is manufactured by mixing it with an active pharmaceutical filler or diluent and filling it into hard gelatin capsules, soft gelatin capsules, etc. Syrups and elixirs are produced by mixing the compounds obtained in the specific examples with sweeteners such as sucrose, preservatives such as methyl and propylparabens, coloring agents, seasonings, fragrances, and adjuvants.

Next, the present invention will be specifically explained with reference to examples, but the present invention is not limited thereto.

Example 1 Mix 100g of the compound obtained in the specific example with 20g of silicic anhydride, add 75g of corn starch,
Further mixing was performed. To this mixture was added 100 ml of a 10% hydroxypropyl cellulose ethanol solution, and the mixture was stirred in a conventional manner, extruded, dried, and sieved to obtain granules of 20 to 50 mesh particles.

This granule has a dosage of 80 to 400 depending on the symptoms.
mg (40 to 200 mg as the weight of the compound obtained in the specific example)
(equivalent to 3 times a day).

Example 2 Mix 40g of the compound obtained in the specific example with 20g of silicic anhydride, add and mix 10g of microcrystalline cellulose, 0.5g of magnesium stearate, and 49.5g of lactose,
This mixture was compressed using a single-shot tablet machine to produce tablets with a diameter of 7 mm and a weight of 120 mg.

One tablet of the present invention contains 40 mg of the compound of the specific example. This tablet is taken 1 to 5 tablets at a time, three times a day.

Example 3 Mix 40 mg of the compound obtained in the specific example with 100 mg of lactose,
Capsules were obtained by filling No. 0 gelatin capsules.

This capsule preparation is taken 1 to 5 capsules at a time, three times a day, depending on the symptoms.

Claims (1)

[Claims] 1 formula A blood viscosity reducing agent containing N,N-dimethyl-phenanthro[3,4-d]-1,3-dioxol-5-ethylamine as an active ingredient.