JPH07149630A - Vasodilator - Google Patents

Abstract

PURPOSE:To obtain a vasodilator, having excellent vasodilator actions and slight side effects and useful for diseases caused by hypertension such as cerebral apoplexy or cerebral hemorrhage. CONSTITUTION:This vasodilator contains a compound, expressed by the formula and isolated from a galenical Sargentodoxae Caulis [a dried stem of Sargentodoxa cuneata (Oliv.) Rehd. et Wils.] as an active ingredient. The compound is obtained by extracting the Sargentodoxae Caulis with water, methanol, ethanol, acetone, ethyl acetate, methyl ethyl ketone or a mixed solvent thereof, suspending the resultant extract solution in water, carrying out the partitioning extraction using a low polar solvent, removing low polar impurities, performing the partitioning extraction of the residual water-soluble part with ethyl acetate, butanol or methyl ethyl ketone, providing an extract solution, treating the prepared extract solution by the column chromatography, separating and collecting an eluate and recrystallizing or powdering the resultant fraction.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention provides a vasodilator with few side effects and high safety.

[0002]

2. Description of the Related Art In recent years, with the aging of society, diseases caused by hypertension such as stroke and cerebral hemorrhage are always the top causes of death, and the development of excellent vasodilators Still required.

[0003]

[Means for Solving the Problems] As a result of intensive studies to solve the above problems, the present inventors have found that the herbal medicines conventionally used for acute and chronic cecalitis, numbness and pain due to rheumatism, bruising and the like. It was found that a certain compound obtained from Taito-to has a hypotensive effect, and based on this, the present invention was completed.

It has been known that the large blood wilt has an antibacterial action, but it is not yet known that it has a vasodilatory action, and it is represented by the formula I which is one of the components of the large blood widow. It was first revealed by the present inventors that the compound to be described has a vasodilatory action.

That is, the present invention provides the following formula I It is a vasodilator having a compound represented by as an active ingredient.

Hereinafter, the compound represented by the formula I will be referred to as the compound of the formula.

The compounds of formula have excellent vasodilatory action,
Since it has few side effects, it is useful for diseases caused by hypertension such as stroke and cerebral hemorrhage as described above.

The compound of the formula can be obtained, for example, as follows.

Large blood widow (Sargentodoxa cu
neata (Oliv.) Rehd. et Wil
s. Dried stem) of water, methanol, ethanol, acetone, ethyl acetate, methyl ethyl ketone, or a mixed solvent of more than one, is heated to a temperature below the boiling point of the solvent used from 0 ° C. Alternatively, the extract is obtained by leaching from 0 ° C at room temperature.

This extract was suspended in water, distributed and extracted using a low-polarity solvent such as benzene, chloroform, ether, hexane, cyclohexane, etc., and the remaining water-soluble portion from which low-polarity impurities had been removed was converted to acetic acid. Partition extraction is performed using a single solvent or a mixed solvent thereof selected from ethyl, butanol, and methyl ethyl ketone to obtain an extract.

The extract obtained here is directly or dried and subjected to column chromatography using a carrier such as silica gel, ODS-silica gel, porous polymer gel, Sephadex, etc., and the eluate is fractionated to obtain a fraction. .

At this time, water, methanol,
Ethanol, acetone, ethyl acetate, tetrahydrofuran (hereinafter abbreviated as THF), acetonitrile, benzene,
A single solvent or a mixed solvent of ether, chloroform, petroleum ether, hexane, cyclohexane and the like can be used.

The fraction thus obtained is treated with water or methanol, ethanol, acetone, ethyl acetate, T
The compound of the formula can be obtained by recrystallization or powdering with a mixed solvent of HF, acetonitrile, benzene, ether, chloroform, petroleum ether, hexane and the like alone or in combination.

Next, specific examples of the production of the compound of the formula will be described.

SPECIFIC EXAMPLE 1 Sargentodoxa cuneata
(Oliv.) Rehd. et Wils. Dried stem) of 9.4 kg with water-ethanol (1: 1) 50 l
The room temperature cold immersion extraction was performed 3 times. The obtained extracts were combined and the solvent was distilled off under reduced pressure to obtain 1.29 kg of a dried extract.

This extract was suspended in 10 liters of water and mixed with hexane 1
Partition extraction was performed 3 times each with 0 l and 20 l of chloroform. The remaining aqueous layer was partitioned and extracted with 10 l of butanol three times to obtain a butanol extract. The solvent of butanol extract was distilled off under reduced pressure to obtain 432.1 g of dried extract.

The dried extract was diluted with 3 l of water and subjected to a column chromatography on a porous polymer gel (Diaion HP-20, 5 l, manufactured by Mitsubishi Kasei Co.) to obtain 40 l of water.
Elution was performed successively with 40 liters of water-methanol (1: 1) and 50 liters of methanol.

The solvent in the eluate of water-methanol (1: 1) was distilled off under reduced pressure to obtain 184.5 g of dried extract. This extract was applied to silica gel (Kieselgel 60, 70).
-230 mesh, manufactured by Merck & Co., Inc.) subjected to column chromatography (12 mφ x 70 cm), and chloroform-
The ratio of methanol was gradually increased with methanol, and the content ratio of methanol was developed at (5% to 50%).

Chloroform-methanol (75:25)
To (70:30) mixed solvent ratio was applied to MCI gel CHP20P (500 ml, Mitsubishi Kasei Co.) column chromatography, and the fraction eluted with water-methanol (75:25) was fractionated liquid chromatography. Graphography (YMC, R-354, ODS, 5c
mφ × 50 cm, manufactured by Yamamura Chemical Co., Ltd., and separated and purified with a mixed solvent of water-acetonitrile-methanol (12: 2: 1) to obtain 900 mg of the compound of the formula I.

The physicochemical properties of the compound of formula I are as shown below, and these data are shown in the literature [J. C. S. P
erkin I, 1217 (1982)], and it was confirmed to be procyanidin B-2.

High resolution first atom bombardment mass spectrometry (HR-FAB-MS): C ₃₀ H ₂₇ O ₁₂ [M + H] ⁺ Theoretical value: 597.1503 Actual value: 597.1501 Infrared absorption spectrum (IR, ν max cm ^-1 , K
Br): 3340, 1610, 1518, 1448, 8
24 UV absorption spectrum [λ max nm (log
ε), MeOH]: 231 (4.52), 281 (3.
92) Proton nuclear magnetic resonance spectrum (δ ppm in a
cetone-d ₆ + D ₂ O): 2.77 (1H, br
d, J = 14 Hz), 2.92 (1H, brd, J = 1)
4Hz), 3.98 (1H, s), 4.69 (1H, b)
rs), 5.00 (1H, brs), 5.11 (1H,
brs), 6.03-6.06 (2H, br), 6.7.
0-7.21 (7H, m) ¹³ C-nuclear magnetic resonance spectrum (δ ppm in ac
_{etone-d 6 + D 2 O} ): 29.0 (t), 36.7
(D), 66.1 (d), 72.7 (d), 76.6
(D), 79.1 (d), 95.7 (d), 96.2
(D), 96.9 (d), 100.4 (s), 101.
4 (s), 107.0 (s), 115.0 (d), 11
5.3 (d), 115.7 (d), 115.8 (d),
119.1 (d), 119.2 (d), 131.6
(S), 132.1 (s), 144.8 (s), 14
5.0 (s x 2), 145.2 (s), 153.9
(S), 155.5 (s), 157.3 (s), 15
5.7 (s), 157.8 (s x 2)

Next, the usefulness of the compound of the formula as a vasodilator will be described with reference to experimental examples.

Experimental Example 1 (relaxing action on contraction of potassium chloride) [Test solution] The compound of the formula (procyani) obtained in the specific example
din B-2) 50% dimethyl sulfoxide (DM
The SO) solution was diluted to obtain a test solution. [Animal] Japanese CLEA SD male rat Body weight: 290-350 g [Experimental conditions] Nutrient solution: Krebs-Henserite buffer solution (Krebs-)
Henseleit buffer) Temperature: 37 ° C ± 0.5 ° C Specimen: Thoracic aortic ring specimen Resting tension: 1-1.5 g Measured isometrically by the Magnus method. 60-90 samples
After allowing to stand for a minute and stabilizing, the reaction was confirmed by adding 30 mM potassium chloride (KCl), and then the experiment was started.

Contraction was induced by the addition of 30 mM KCl, and the effect of the drug thereafter was examined. At the end of the reaction, 1
× 10 ^-4 M of papaverine was added, and this value was set as 100% relaxation to calculate the effect of the compound of the formula.

The results are as shown in Table 1.

Table 1 30 mM KCl

Experimental Example 2 (relaxing action on norepinephrine contraction) [Test solution] The compound of the formula (procyani) obtained in the specific example
din B-2) 50% dimethyl sulfoxide (DM
The SO) solution was diluted to obtain a test solution. [Animal] Japanese CLEA SD male rat Body weight: 290-350 g [Experimental conditions] Nutrient solution: Krebs-Henserite buffer solution (Krebs-)
Henseleit buffer) Temperature: 37 ° C ± 0.5 ° C Specimen: Thoracic aortic ring specimen Resting tension: 1-1.5 g Measured isometrically by the Magnus method. 60-90 samples
After allowing to stand for a minute and stabilizing, the reaction was confirmed by adding 30 mM potassium chloride (KCl), and then the experiment was started.

Contraction was induced by addition of 1 × 10 ^-7 M norepinephrine, and the effect of the drug thereafter was examined. At the end of the reaction, 1 × 10 ^-4 papaverine was added and this value was taken as 100% relaxation to calculate the effect of the compound of formula.

The results are as shown in Table 2.

Table 2 10 ^-7 M norepinephrine

Further, in the acute toxicity test using male mice of the ddY strain, the compound of the formula did not show any toxicity even after the oral administration of 1 g / kg, and no toxicity was observed.

Therefore, the compound of the formula has a vasodilatory action and is considered to be useful as a vasodilator because of its high safety.

Next, the dose and formulation of the compound of formula will be explained.

The compounds of formula can be administered to animals and humans either neat or together with conventional pharmaceutical carriers. The dosage form is not particularly limited and may be appropriately selected and used as needed, and examples thereof include oral preparations such as tablets, capsules, granules, fine granules and powders, parenteral preparations such as injections and suppositories. To be

In order to exert the intended effect as an oral preparation, it varies depending on the age, body weight and degree of disease of the patient, but usually 10 mg to 5 g as the weight of the compound of the formula is used in adults.
It seems appropriate to take it several times a day.

Oral preparations include, for example, starch, lactose, sucrose,
Mannitol, carboxymethyl cellulose, corn starch, inorganic salts and the like are used in a conventional manner.

In this type of preparation, a binder, a disintegrating agent, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a flavoring agent, etc. may be appropriately used in addition to the above-mentioned excipients. You can
Specific examples of each are as follows.

[Binder] Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch,
Methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose.

[Surfactant] sodium lauryl sulfate,
Soy lecithin, sucrose fatty acid ester, polysorbate 80.

[Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

[Fluidity promoter] Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The compounds of the formula can also be administered as suspensions, emulsions, syrups and elixirs, and these various dosage forms may contain flavoring agents and coloring agents. .

In order to exert a desired effect as a parenteral agent, it depends on the age, weight and degree of disease of the patient.
1 mg to 10 m daily as a compound of formula weight in an adult
Intravenous injection up to g, intravenous drip injection, subcutaneous injection, and intramuscular injection seem appropriate.

This parenteral preparation is manufactured by a conventional method, and is generally used as a diluent in distilled water for injection, physiological saline, glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol. Etc. can be used. Further, if necessary, a bactericide, a preservative, and a stabilizer may be added. Further, from the viewpoint of stability, this parenteral preparation may be filled in a vial or the like, frozen, and then water may be removed by an ordinary freeze-drying technique, and a liquid preparation may be re-prepared from the freeze-dried product immediately before use. Further, an isotonicity agent, a stabilizer, a preservative, a soothing agent and the like may be added as needed.

Other parenteral agents include external preparations, coating agents such as ointments, and suppositories for rectal administration.
It is manufactured according to a conventional method.

Next, the formulation examples of the present invention will be described. [Formulation Example 1] Corn starch 44 g Crystalline cellulose 40 g Carboxymethyl cellulose calcium 5 g Light anhydrous silicic acid 0.5 g Magnesium stearate 0.5 g Compound of the formula obtained in specific examples 10 g Total 100 g According to the above formulation, Then, compression molding was performed using a tableting machine to obtain 200 mg tablets. This tablet contains 20 mg of the compound of the formula obtained in the specific example, and 3 to 10 tablets for adults are to be taken in divided doses.

[Formulation Example 2] Crystalline cellulose 84.5 g Magnesium stearate 0.5 g Carboxymethyl cellulose calcium 5 g Compound of formula obtained in specific example 10 g Total 100 g According to the above-mentioned prescription, a part of and was uniformly mixed. After compression molding, the mixture was crushed, and the remaining amount of the mixture was added and mixed, and the mixture was compression molded with a tableting machine to obtain 200 mg tablets. This tablet contains 20 mg of the compound of the formula obtained in the specific example, and 3 to 10 tablets for adults are to be taken in divided doses.

[Formulation Example 3] Crystalline cellulose 79.5 g 10% Hydroxypropyl cellulose ethanol solution 50 g Carboxymethyl cellulose calcium 5 g Magnesium stearate 0.5 g Compound of the formula obtained in a specific example 10 g Total 145 g According to the above formulation, and Are evenly mixed, kneaded by a conventional method, granulated by an extrusion granulator, dried and crushed, and are mixed, and compression-molded by a tableting machine to give 200 mg tablets. Obtained. This tablet contains 20 mg of the compound of the formula obtained in the specific example, and 3 to 10 tablets for adults are to be taken in divided doses.

[Formulation Example 4] Corn starch 84 g Magnesium stearate 0.5 g Carboxymethyl cellulose calcium 5 g Light anhydrous silicic acid 0.5 g Compound of the formula obtained in the specific example 10 g Total 100 g According to the above formulation, After compression molding with a compression molding machine, it was crushed with a crusher and sieved to obtain granules. 1 g of this granule contains 100 mg of the compound of the formula obtained in the specific example, and an adult daily dose of 0.6-2
Take g in several divided doses.

[Formulation Example 5] Crystalline cellulose 86.5 g 10% Hydroxypropyl cellulose ethanol solution 35 g Compound of the formula obtained in the specific example 10 g Total 131.5 g According to the above formulation, the . After granulating with an extrusion granulator, it was dried and sieved to obtain granules. 1 g of this granule contains 100 mg of the compound of the formula obtained in the specific example, and an adult daily dose of 0.6
Take ~ 2g in divided doses.

[Formulation Example 6] Cornstarch 89.5 g Light anhydrous silicic acid 0.5 g Compound of formula obtained in specific example 10 g Total 100 g
Was filled in a No. 2 capsule. One capsule of this capsule contains 20 mg of the compound of the formula obtained in the specific example, and 3 to 10 capsules for an adult are to be taken in several divided doses.

[Formulation Example 7] Distilled water for injection 89.5 g Soybean oil 5 g Soybean phospholipid 2.5 g Glycerin 2 g Compound of the formula obtained in the specific example 1 g Total amount 100 g Dissolved in and according to the above formulation. The solution of (ii) was added and emulsified to obtain an injection.

Claims (1)

[Claims] 1. A vasodilator containing a compound represented by the following formula I as an active ingredient.