JPH01275593A - Novel propanetriol, production thereof and remedy for circulatory disease - Google Patents

Abstract

NEW MATERIAL:1-O-(4-O-alpha-L-Arabinofuranosyl-beta-D-glucopyranosyl)-1,2,-3- propanetriol expressed by the formula. USE:A remedy for circulatory diseases. PREPARATION:A water-soluble organic solvent is added to fractionally precipitate a hot-water extract solution of safflower and the result supernatant is concentrated and redissolved in water. The obtained solution is then injected into a reversed phase liquid chromatographic column to recover only a fraction having the recognized peak at k'=0.5-2.0 when water having weak elution power is passed therethrough as a mobile phase. The above-mentioned fraction is subsequently concentrated and the obtained concentrate is injected into an NH2-I25NI column to recover a safflower extract having the recognized peak at k'=0.5-8 when a 70% acetonitrile solution is passed therethrough in measurement by high-speed liquid chromatography under the following conditions. Column; NH2 4.6phiX250mm, detector: RI or UV (254mm).

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention provides 1-0-(4-0-α-L-arabinofuranosyl-β-D-glucopyranosyl)-1゜2.3-propane The present invention relates to an industrially advantageous production method for extracting triol and a therapeutic agent for cardiovascular diseases containing the compound as an active ingredient.

[Prior Art] Safflower is known to have excellent efficacy as a herbal medicine, and has been used for a long time as a medicine for treating blood circulation disorders, especially as an emmenagogue and a blood thinner. It has been pharmacologically confirmed that hot water, ethanol, or 50% aqueous ethanol extract of safflower has an effect on improving peripheral circulation [Kazuo Nuriuki et al., Kanagawa Dental Science, 18(1).

64 (1983)].

[Problems to be solved by the invention] However, regarding the vasodilatory substance in safflower,
There are no reports at all.

In view of the above circumstances, the present inventors conducted intensive research to isolate a vasodilatory substance in safflower, and found that l-0-(
We succeeded in isolating 4-0-α-L-arabinofuranosyl-β-D-glucopyranosyl-1,2,3-propanetriol and completed the present invention.

[Means for solving the problems] That is, the present invention provides (1) l-0-(4-0-α-L-arabinofuranosyl-β-D-glucopyranosyl)- 1゜2.3-Propanetriol (2) Column: NH24, 6φ x 250mm, eluent niacetonitrile/water = 7/3, detector: R■ or UV
1-0-(
Method for producing 1-0-(4-0-α-L-arabinofuranosyl-β-D-glucopyranosyl)-1,2,3-propanetriol (3) 3. A therapeutic agent for cardiovascular diseases containing syl-β-D-glucopyranosyl)-1,2゜3-propanetriol as an active ingredient.
It consists of an invention.

The configuration of the present invention will be described below.

Compound according to the present invention 1-0- (4-0-α-ri-arabinofuranosyl-β-D-glucopyranosyl) -1,
2,3-propanetriol is a new chemical and metal, and of course its usefulness, mainly its pharmacological action, is unknown. The compound is well soluble in water, aqueous alcohol and aqueous acetone.

Next, compound 1-0- (4-0-α-L-
Arabinofuranosyl-β-D-glucopyranosyl)-1
, 2,3-propanetriol will be described.

By a known method, a water-soluble organic solvent is added to a hot water extract concentrate of safflower, and a supernatant is obtained by fractional precipitation [JP-A-62-875
23]. When the supernatant concentrate was redissolved in water and injected into a column for reversed-phase liquid chromatography, and water, etc. with a weak elution power was passed through as the mobile phase, the main peak appeared at k' = 0.5 to 20. Collect only the amount that is allowed.

Next, the concentrated fraction was injected into a NH2-I25NI-column, and when a 70% acetonitrile solution was passed through it, k'
The main peak seen at =0.5 to 8 was collected and dried under reduced pressure to give 1-0- (4-0-α-L-arabinofuranosyl-β-D-glucopyranosyl)-1°2.3- Propanetriol is obtained. The compound obtained according to this production method is 1-0- (4-0-α-
L-arabinofuranosyl-β-D-glucopyranosyl)
It was identified as -1,2,3-propanetriol.

l-0-(4-0-α-L-arabinofuranosyl-β-
D-glucopyranosyl)-1,2゜3-propanetriol; CH0 Iu472゜molecular weight; mass spectrum = 386 Nuclear magnetic resonance spectrum (solvent: deuterated dimethyl sulfoxide) cr: ppm, 3.32 (L H, multiplet) , 3°34 (IH, multiplet), 3.41 (I
H, triple line), 3.43 (LH, double line), 3.46
~3.52 (7H, multiplet) 3.54 (I H, doublet), 3.64 ~ 3.66 (3H, multiplet) 3.74 (I
H, double line), 3.81 (IH, multiple line) 3°93 (
IH, quartet), 4.16 (IH, doublet), 5.0
1 (IH9 double line).

Stereospecificity of each sugar moiety; ! 3 Coupling constant (C-nuclear magnetic resonance spectrum): 176H
z (arabinose), 160Hz (glucose).

Specific optical rotation (acid decomposition): [α]:= + 52.94
(arabinose), [α];=, + 45.45
(glucose).

Compounds of the present invention 1-0- (4-0-α-ri-arapinofuranosyl-β-D-glucopyranosyl)-1,2,
A vasodilator containing 3-propanetriol as an active ingredient can be used clinically as a drug for treating hypertension, a drug for treating limb circulation failure, and a drug for improving cerebral circulation. The administration method may be oral or parenteral. The dosage varies depending on the patient's age, weight, and severity of the disease, but
Oral administration: 0.5-500mg per dose for adults
In the case of parenteral administration, the appropriate amount is about 0.005 to 25 mg, and it can be used for both prophylactic and therapeutic purposes. Usually, the above effective amount of 1-0- (4-0-α-L
-Arabinofuranosyl-β-D-glucopyranosyl)-
Usually used oral and For parenteral administration, the composition can be formulated into unit dosage forms suitable for parenteral administration, and may optionally contain other agents such as vasodilators.

[Example] Next, the present invention will be explained in more detail by giving examples. The present invention is not limited thereby.

Acute toxicity test ICR female mice (6 weeks old, 5 mice per group) were used. For intraperitoneal administration, the solution was dissolved in physiological saline at a concentration of 2X (wt%) using a 221/2G needle. For oral administration, dissolve the solution in olive oil at 10x (weight 2) using an oral needle, and use the maximum amount technically possible (intraperitoneal administration260ml/kg, oral administration :30ml/kg).

As a result, no deaths, no decrease in body weight, and no notable toxic symptoms were observed during the 7-day observation period, and no other symptoms were observed at the autopsy performed on the 7th day. As is clear from this result, it is possible. usually,
The acute toxicity value (LD5o) of the above effective amount of 1-〇-(4-O-α-L-arabinofuranosyl-β-D-glucopyranosyl)-1,2,3-propanetriol was determined by intraperitoneal administration. 1200mg/kg or more, 3000m for oral administration
g/kg, and was found to have low toxicity.

1”” Gaku 1 eyes 1 sex.

(1) Blood pressure lowering effect Tests were conducted using Japanese native rabbits (male, body weight 2.5-3.5 kg) and SHR rats (male, body weight 350-400 g, systolic blood pressure 180 mmHg or higher).

(i) Test with rabbits Bendoparbital anesthesia (30 mg/kg i, v,)
The rabbit was fixed in a dorsal position, a pressure transducer was connected to a catheter inserted through the common artery, and blood pressure was recorded on a recorder. The test compound was administered intraperitoneally at 100 mg/kg. For comparison, hydralazine hydrochloride was similarly administered at a dose of 1 mg/kg. Systolic blood pressure was measured before administration and 1.5 hours after administration, and the increase and decrease in blood pressure relative to before administration was calculated as a rate of change (%). The results are shown in Table-1.

(ii) Test by SHR A test compound was suspended in 0.5% sodium carboxymethyl cellulose and administered to rats genetically prone to hypertension (SHR) at a dose of 50 mg/kg/day for 3 consecutive days. Blood pressure is measured using R Programmed, manufactured by Nalco, USA.
Electro Spygmomanometer P, E, 30
0. + (Marco Co, Programmed El
electro-3phygmomanollIletter
P, E, 300).

Systolic blood pressure was measured 1.4 and 8 hours after administration, and the rate of change (%) with respect to the same blood pressure before administration was calculated. The results are shown in Table-2.

The test compound numbers are as follows.

1: Control 2: 1-0- (4-0-α-L-arabinofuranosyl-β-D-glucopyranosyl)-1,2,3-propane trio-ru Table 2 – Table 1 and Table – As is clear from 2, 1-〇-(4-
It was found that o-α-L-arabinofuranosyl-β-D-glucopyranosyl-1,2,3-propanetriol has a blood pressure lowering effect.

(2) Aorta, coronary vessels, and cerebral vasodilatory effects (i) Preparation of aorta specimen Urethane-anesthetized rabbit (Japanese native species, male, weight 2.5
~3.5 kg) were sacrificed by exsanguination from the carotid artery, the descending aorta was removed, and a spiral specimen was prepared.

This specimen was suspended in a Magnus tube (10n + L, 37°C) filled with Tyrode's solution with 95% 02 + 5% CO2 aerated using a self-in, and the change in tension caused by the drug was measured via a transducer. (Nihon Kohden Polygraph System).

(ii) Preparation of coronary blood vessel specimen Urethane anesthetized rabbit (Japanese native species, male, weight 2.5
After exsanguination from the carotid artery (~3.5 kg), the hearts were quickly removed and immersed in Tyrode's solution aerated with 95% 02 + 5% CO2. Thereafter, the left coronary artery was removed from the aorta in the same solution, and a spiral specimen with a convergence of about 1 mm and a length of about 10 am was prepared under a stereomicroscope R1. Magnus filled this specimen with Tyrode's solution aerated with 95% 02 + 5% CO2? (10ml, 37
℃), and changes in tension caused by the drug were recorded using a transducer.

(iii) Preparation of cerebral blood vessel specimens This was carried out in accordance with the method described in "Medicinal efficacy screening method for new drug development", Volume 1, Seishi Shoin (1984), supervised by Hikaru Ozawa. i.e. Bendoparbital anesthesia (30
After incising the common artery of an adult dog (1s1 body weight: 15-20 kg) and exsanguinating it to death, the basilar artery was quickly removed under a stereomicroscope.
02 + 5% CO□ in Tyrode's solution.

After removing the attached tissue, convergence I ++1111.
A spiral specimen with a length of approximately 15 mm was prepared.

This specimen was suspended in a Magnus tube (10 ml, 37°C) filled with Tyrode's solution with 95% CO2 and 5% CO2 aerated, and the change in tension caused by the drug was recorded using a transducer.

The aorta, coronary blood vessel, and cerebral blood vessel specimens prepared in (i), (ii), and (iii) above were treated with noradrenaline (2X
After shrinking at 10-8 M), add 0.1 ml of the test substance.
Added into Magnus tube. The degree of action of the test substance was evaluated from the width of contraction or relaxation on the obtained chart, in comparison with the action of noradrenaline, which was used as a control. Evaluation was made on a four-point scale: +++ for marked expansion, ++ for obvious expansion, + for slight expansion, and - for no expansion. The results are shown in Table-3.

Test substance: l-0-(4-0-α-L-arabinofuranosyl-β-D-glucopyranosyl)-1゜2.3-propanetriol As is clear from Table 3, l-0-(4 -0-α-L-
Arabinofuranosyl-β-D-glucopyranosyl)-1
, 2,3-propanetriol was found to have dilating effects on the aorta, coronary vessels, and cerebral blood vessels.

The therapeutic agent for cardiovascular diseases of the present invention is 1-0- (4-0-α-
L-arabinofuranosyl-β-D-glucopyranosyl)
-1,2,3-propanetriol is used alone or as a mixture with pharmaceutically acceptable excipients and other agents.

The above-mentioned additives include lactose, starch, calcium carbonate, magnesium aluminate metasilicate, magnesium aluminum hydroxide, calcium hydrogen phosphate, sucrose, aluminum silicate, microcrystalline cellulose, etc., and carboxymethyl cellulose. Binders such as lace, polyvinylpyrrolidone, gum arabic, gelatin, sodium alginate, lubricants such as talc, calcium stearate, magnesium stearate, humectants such as glycerin, propylene glycol, sorbitol, agar, silicic anhydride, etc. Disintegrants, surfactants, buffers, preservatives, fragrances, dyes, corrigents, etc., and these may be used singly or in combination of two or more. The therapeutic agent for cardiovascular diseases of the present invention can be administered either orally or parenterally. For example, it can be administered orally in the form of tablets, capsules, powders, granules, syrups, etc., enterally in the form of suppositories, and administered as injections.

Further, indications for the therapeutic agent for cardiovascular diseases of the present invention include hypertension, angina pectoris, myocardial infarction, sequelae of cerebral infarction, peripheral circulatory disorders, and the like.

The dosage of the therapeutic agent for cardiovascular diseases of the present invention depends on age, individual differences,
Although it varies depending on the symptoms, etc., in general, when targeting humans, the body weight I kgs per day is 0°5 to 500 when administered orally.
mg, and can be administered once or in divided doses.

Examples of the formulation of the therapeutic agent for cardiovascular diseases of the present invention will be described in more detail below with reference to Examples. Note that the present invention is not limited to this.

■Gogo, Tablet 1-0- (4-0-α-L-arabinofuranosyl-β
Tablets containing 100 mg of -D-glucopyranosyl)-1,2,3-propanetriol and 100 mg of microcrystalline cellulose were prepared in a conventional manner and sugar-coated with syrup gelatin precipitated calcium carbonate.

This tablet is used in a single dose of 1 to 10 tablets.

Next day 5586 Granules 1-0- (4-0-α-L-arabinofuranosyl-β
-D-glucopyranosyl)-1,2,3-propanetriol (20 g), 80 g of lactose, 10 g of water, and 90 g of microcrystalline cellulose were uniformly mixed, crushed, granulated, dried, and sieved to obtain granules. This granule has a single dose of 0.5~
Used in 10g.

LL completed Lf2LL, capsule shoulder l-0-(4-
0-α-L-arabinofuranosyl-β-D-glucopyranosyl)-1,2,3-propanetriol 100mg
, microcrystalline cellulose 1100I1 and lactose 200m
g were mixed uniformly and filled into hard gelatin capsules.

The capsules are used in a single dose of 1 to 10 capsules.

[Effects] According to the above results, the compound according to the present invention 1-0- (
It has been revealed that 4-0-α-L-arabinofuranosyl-β-D-glucopyranosyl)-1,2,3-propanetriol is highly safe and has excellent therapeutic effects on cardiovascular diseases. .

Patent applicant: Shiseido Co., Ltd.

Claims (3)

[Claims] (1) 1-O-(4-O-α-L-arabinofuranosyl-β-D-glucopyranosyl)-1,2,3- shown by the following structural formula ▲ Numerical formula, chemical formula, table, etc. ▼ propanetriol. (2) Column: NH_24.6φ x 250mm, eluent: acetonitrile/water = 7/3, detector: RI or UV
1-O-(4
A method for producing -O-α-L-arabinofuranosyl-β-D-glucopyranosyl)-1,2,3-propanetriol. (3) A therapeutic agent for cardiovascular diseases containing 1-O-(4-O-α-L-arabinofuranosyl-β-D-glucopyranosyl)-1,2,3-propanetriol as an active ingredient.