JP2002255806A - Prophylactic or ameliorating agent for diabetes - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an agent useful for controlling blood sugar value. SOLUTION: This prophylactic or ameliorating agent for diabetes comprises a diacylquinic acid represented by general formula (I), R1 and R2 are each caffeoyl; and formula (II) indicates that the coordination at the 5-position is axial or equatorial] as an active ingredient. Thereby, the agent has inhibitory effects on postprandial hyperglycemia related to crisis or aggravation of diabetes.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound represented by the general formula (I):

Embedded image [Wherein, R ₁ and R ₂ are both caffeine oils;

Embedded image Represents that the coordination of the hydroxyl group at the 5-position is axial or equatorial.] Which is a diacylquinic acid as an active ingredient.

[0002]

2. Description of the Related Art Diabetes is a disease caused by abnormal glucose metabolism. It is said that there are currently 6 million patients in Japan and that there are almost twice as many reserves.

[0003] Diabetes is roughly divided into insulin-dependent (IDDM) and non-insulin-dependent (NIDDM). Insulin-dependent type, β cells of the pancreas are necrotic or stop functioning due to an autoimmune mechanism caused by a virus or the like. As a result, it is a type that cannot synthesize and secrete insulin, accounting for less than 10% of patients. The non-insulin-dependent type is a type in which a genetic predisposition to cause abnormal insulin secretion and insulin action and environmental factors such as obesity, overeating, and lack of exercise due to a change in lifestyle overlap with each other.
More than a percentage is included in this type. Diet therapy and exercise therapy are mainly used for the treatment of mild or moderate patients of this type, and blood glucose levels are stabilized by calorie restriction of diet and promotion of glucose metabolism by exercise.

[0004] However, if the postprandial blood glucose level rises rapidly and its duration (postprandial hyperglycemia) continues for many years, it eventually leads to impaired glucose tolerance, which promotes vascular disorders as the diabetes worsens, and promotes nervous system disorders. Disease, nephropathy, retinopathy, and even myocardial infarction,
There is a risk of developing complications such as stroke. Suppression of postprandial hyperglycemia is said to be effective in preventing the onset and worsening of non-insulin-dependent diabetes mellitus, and α-glucosidase inhibitors such as acarbose and voglibose have recently been used as medicaments. However, even in the case of the α-glucosidase inhibitor, hypoglycemic symptoms are not necessarily expressed in combination with a conventional antidiabetic agent such as a sulfonylurea agent, a sulfonamide agent, a biguanide agent or an insulin sensitizer. Not satisfactory.

[0005] In addition, there is stress as a factor that causes a hyperglycemic state other than diabetes. In today's stressful society, many people, from children to adults, feel stress. In addition, there are not a few people who drink or eat under the stress. It is said that stress excites the sympathetic nerve and promotes the secretion of adrenaline and noradrenaline, thereby increasing the blood sugar level. Therefore, there is a risk of a high blood sugar level if stress is continued in daily life, and if drinking and overeating continue, leading to the onset of complications similar to diabetes, and blood glucose levels due to suppression of postprandial hyperglycemia on a daily basis. You need control.

[0006]

As described above, since abnormal glucose metabolism is associated with many lifestyle-related diseases,
There is a demand for new drugs and foods for the purpose of preventing or exacerbating lifestyle-related diseases.

Until now, the present inventors have reported that the asteraceous plant Yacon [Scientific name Smallanthus so
nchifolia (formerly Polymnia sonchifolia)] reduced the blood sugar level of diabetic patients [Agriculture and Horticulture, Vol. 64, No. 4, 538 (1989)], and examined the effective use of this plant. And, first, the taste is improved by mixing oolong tea leaves, and the combination tea significantly suppresses postprandial hyperglycemia compared to when each is used alone, and reduces neutral fats and cholesterol in the blood. Have been found to have an effect of lowering and further suppressing weight gain [PCT Application Publication WO98 / 08527], and have also been found that mixing mulberry leaves enhances the effect of improving yakon's own abnormal glucose tolerance. [Japanese Patent Application Laid-Open No. 2000-342228] has made a new proposal.

[0008]

In view of the circumstances, the present inventors have conducted repeated research on a substance that suppresses a blood sugar rise contained in the foliage of yacon. As a result, the diacylquinic acid represented by the general formula (I) is The present inventors have found that maltase has an inhibitory activity, in particular, among α-glucosidases, and that it has a significant inhibitory effect on blood glucose increase in a glucose tolerance test, thereby completing the present invention.

The compound which is the active ingredient of the present invention is represented by the above general formula (I). The meanings and examples of the symbols used in this formula are described below.

[0010]

Embedded image Is a symbol indicating the coordination of a hydroxyl group bonded to the carbon at the 5-position of quinic acid, and means that both axial and equatorial coordinations can be taken.

Examples of the diacylquinic acid as the active ingredient of the present invention include the following compounds, but the present invention is not limited to these compounds. In addition, the display in parentheses at the end of the following compound names indicates common names.

3,4-O-dicaffeoyl- (1R, 3R, 4S, 5S)-
1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid [3,4-dicaffeoylquinic acid]

3,4-O-dicaffeoyl- (1α, 3α, 4α, 5
α) -1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid [3,4-dicaffeoyl-epi-quinic acid]

As is clear from the structural formula of the general formula (I), the compound (I) has a stereoisomer or an optical isomer, and any of them can be used as an active ingredient of the present invention.

The compound (I) which is the active ingredient of the present invention comprises
It is a known substance and has been separated and purified by the method described in the following literature. Biosci. Biotech. Biochem. 59 (10), 1887-1890
(1995), Biol. Pharm. Bull. 19 (7), 966-970 (1996), C
hem. Pharm. Bull. 48 (11), 1796-1798 (2000).

As is clear from the above documents, it is known that compound (I) has an immunopotentiating action, an antiallergic action and an antioxidant action. However, these diacylquinic acids have an α-glucosidase inhibitory action and a blood glucose level. There is no document that discloses that the compound has a rise suppressing effect. Further, the compound (I) can be separated and purified from the yakon foliage and coffee beans according to the method described in the above-mentioned literature.

[0017]

EXAMPLES Next, the inhibitory activity of diacylquinic acid on maltase and the effect on blood glucose level will be described using Test Examples 1 and 2 below. Note that these test sample numbers correspond to sample manufacturing example numbers.

In each test, the following samples were used as comparative compounds. Sample A: 4,5-O-dicaffeoyl- (1R, 3R, 4S, 5R) -1,3,4,5
-Tetrahydroxycyclohexane-1-carboxylic acid [4,5
-Dicaffeoylquinic acid] Sample B: 3,5-O-dicaffeoyl- (1R, 3R, 4S, 5R) -1,3,4,5
-Tetrahydroxycyclohexane-1-carboxylic acid [3,5
-Dicaffeoylquinic acid] Sample C: O-4,6-dideoxy-4-[[(1S, 4R, 5S, 6S) -4,5,6-
Trihydroxy-3- (hydroxymethyl) -2-cyclohexen-1-yl] amino] -α-D-glucopyranosyl- (1 → 4) -O-
α-D-glucopyranosyl- (1 → 4) -D-glucopyranose
[Acarbose]

[Test Example 1] Maltase inhibitory activity test The maltase inhibitory activity (IC ₅₀ ) was measured in accordance with the glucose oxidase colorimetric method described in the literature [Analytical Biochemistry 7, 18-25 (1964)]. It is shown in FIG.

[0020]

[Table 1] IC Sample IC ₅₀ (μg / ml) 検 体 Sample 1 25 Sample 2 25 Sample A > 300 Sample B> 300 Sample C 3 ───────────────

From the above results, it was shown that the maltase inhibitory activity of 3,4-diacylquinic acid was particularly strong as compared with the samples A and B having similar structures.

Test Example 2 Glucose Tolerance Test (Oral Administration) Male Wistar rats (7 weeks old, 228.5 ± 2.0 g, 5 rats per group) were fasted for about 17 hours, and then polyethylene glycol (Macrogol 400) 3 A sample (100 mg / kg) dissolved or suspended in distilled water containing 0.1% orally was orally administered using a rat oral probe, and 30 minutes later, a soluble starch dissolved in distilled water was also orally administered. After administration of the soluble starch, blood was collected from the tail vein every 15 minutes up to 120 minutes, plasma was prepared, and the glucose concentration in the plasma was measured using Glucose B-Test Wako (manufactured by Wako Pure Chemical Industries, Ltd.).

The control group was orally administered in the same manner as the above-mentioned test group except that the sample was not contained, and the glucose concentration in plasma showed a peak about 30 minutes after the administration, and then gradually decreased. On the other hand, in the test group, in particular, administration of the diacylquinic acid of the general formula (I) significantly increased the blood glucose level 30 minutes after administration and the AUC value, which is the area under the blood glucose curve 0 to 120 minutes after administration, as shown in Table 2 below. Showed a low value, and the blood glucose elevation inhibitory effect was clearly recognized.

[0024]

[Table 2] 検 体 Sample blood sugar level (mg / dl) AUC (mg / dl ・ min) ─────── ──────────────── Sample 1 163.7 ± 12.1 ** 15,753 ± 1,192 * Sample B 215.6 ± 7.9 19,605 ± 844 Control group 224.7 ± 4.3 20,163 ± 541 ───────有意 Significant difference from control group [*: P <0.01, **: P <0.005]

From the above results, the diacylquinic acid of the general formula (I) has an effect of significantly controlling the blood sugar level, suppressing a rapid increase in blood sugar level such as postprandial hyperglycemia, and stabilizing the blood sugar level. Therefore, the effect of preventing and improving diabetes exacerbation alone or in combination with conventional diabetic drugs is expected.

Further, the drug of the present invention suppresses a rapid rise in blood sugar level due to meals, and is therefore useful for suppressing excessive caloric intake in middle-aged and elderly diabetic reserves, and is expected to have an effect of preventing the onset of diabetes.

When the compound (I) is applied to humans or mammals, it can be administered orally, and the dosage forms include tablets, coated tablets, powders, granules, capsules, microcapsules, syrups and the like. it can. The preparation of these dosage forms may be carried out with pharmaceutically acceptable excipients, binders, lubricants, disintegrants, suspending agents, emulsifiers, preservatives, isotonic agents, stabilizers and dispersants such as lactose , White sugar, starch, dextrin, crystalline cellulose, kaolin, calcium carbonate, talc, magnesium stearate or distilled water.

[0028] When applied to humans, the dosage depends on the condition of the patient,
Depending on the age, body weight, etc., the daily dose for an adult can be administered in a daily dose of 100 to 500 mg in 1 to 4 divided doses.

Next, the present invention will be described in detail with reference to formulation examples and production examples, but the present invention is not limited thereto.

[Formulation Example] [Formulation Example 1] Formulation example (1) of a tablet using diacylquinic acid of Production Example 1)
In 0 tablets) 3,4-dicaffeoylquinic acid 400 mg crystalline cellulose 500 mg partially pregelatinized starch 130 mg lactose 500 mg sucrose fatty acid ester 50 mg hardened oil 20 mg

Formulation Example 2 Formulation example of fine granules using diacylquinic acid of Production Example 1) (in 2 packets) 3,4-dicaffeoylquinic acid 400 mg crystalline cellulose 540 mg lactose 1000 mg sucrose fatty acid ester 60 mg

[Formulation Example 3] Formulation of capsules using diacylquinic acid of Production Example 1) (in 6 capsules) 3,4-dicaffeoylquinic acid 400 mg Calcium hydrogen phosphate anhydrous 170 mg Lactose 600 mg Sucrose fatty acid ester 15 mg 15mg hardened oil

[Production Example] Production Example 1) Separation and purification of 3,4-dicaffeoylquinic acid 2 kg of yacon leaf powder was divided into four parts, and 500 g of each was extracted with boiling water (5 L) for 10 minutes. Each extract was filtered through gauze, and the combined filtrates were concentrated to 1 L under reduced pressure. This was extracted four times with 1 L of water-saturated n-butanol, and the n-butanol phases were combined and concentrated under reduced pressure to obtain 50.3 g of a yellow residue. This was applied to a styrene divinylbenzene-based porous resin column (Diaion HP20, 80φ × 200 mm), first eluted with 7 L of water, and then 9.5 L of 50% methanol [methanol-water (1:
By eluted in 1)], 835 mg of a maltase inhibitory activity fraction was obtained. This fraction was further applied to a modified dextran type gel filtration column (Sephadex LH20, 45φ × 410 mm), and 30%
After elution with methanol [methanol-water (3: 7)], 50%
While fractionating 10 ml each with methanol, 197 mg of a fraction was obtained using maltase inhibitory activity as an index. Next, this fraction was subjected to a hydrophilic vinyl polymer gel filtration column (Toyopearl HW-4).
0), elute with 50% methanol, fractionate 10 mL each, and collect the first inhibitory activity fraction (540 mL eluted after 250 mL elution) using the maltase inhibitory activity as an index. 61 mg of the title compound were obtained as a yellow powder. FAB-MS m / z: 515.1200 [MH] ⁺ NMR (CD ₃ OD) δ: 2.0-2.4 (4H, m), 4.37 (1H, dt, J = 4.0H
z, 9.0Hz), 4.99 (1H, dd, J = 2.5Hz, 7.8Hz), 5.64 (1H, d
d, J = 3.4Hz, 7.5Hz), 6.25 (1H, d, J = 16Hz), 6.28 (1H,
d, J = 16Hz), 6.72 (1H, d, J = 7.8Hz), 6.77 (1H, d, J = 8.
3Hz), 6.86 (1H, dd, J = 1.4Hz, 7.8Hz), 6.92 (1H, dd, J
= 1.6Hz, 7.9Hz), 7.01 (1H, d, J = 1.9Hz), 7.03 (1H, d, J
= 2.0Hz), 7.54 (1H, d, J = 16Hz), 7.57 (1H, d, J = 16Hz)

Production Example 2) Separation and purification of 3,4-dicaffeoyl-epi-quinic acid Extraction and separation from yacon leaf powder in the same manner as in Production Example 1) were carried out using a hydrophilic vinyl polymer gel filtration column. The third maltase inhibitory activity fraction [Preparation Example 1] was eluted with 3,4-dicaffeoylquinic acid and then eluted with 70 mL after eluting another 40 mL of 50% methanol], and the solvent was removed under reduced pressure This gave 5 mg of the title compound as a pale yellow powder. FAB-MS m / z: 515.1217 [MH] ⁺ NMR (CD ₃ OD) δ: 2.0-2.3 (4H, m), 4.18 (1H, q, J = 5.4H
z), 5.14 (1H, dd, J = 2.5Hz, 7.8Hz), 5.62 (1H, t, J = 3.
5Hz), 6.25 (1H, d, J = 16Hz), 6.28 (1H, d, J = 16Hz), 6.
73 (1H, d, J = 7.8Hz), 6.75 (1H, d, J = 8.3Hz), 6.87 (1H,
dd, J = 1.4Hz, 7.8Hz), 6.92 (1H, dd, J = 1.6Hz, 7.9H
z), 7.01 (1H, d, J = 1.9Hz), 7.04 (1H, d, J = 2.0Hz), 7.
50 (1H, d, J = 16Hz), 7.58 (1H, d, J = 16Hz)

[0035]

As described above, according to the present invention, the diacylquinic acid of the general formula (I) contained in Yacon has an inhibitory effect on the carbohydrate-degrading enzyme maltase and is involved in the onset and aggravation of diabetes. It showed an inhibitory effect on postprandial hyperglycemia.

Accordingly, diacylquinic acid of the general formula (I) is a substance useful for controlling blood sugar level,
It can be applied as an improving agent.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 43/00 111 A61P 43/00 111 (72) Inventor Yuji Koide 2-33 Oizumicho, Nerima-ku, Tokyo No. 7 Zenyaku Kogyo Co., Ltd. (72) Inventor Michihiro Taka No. 2-333 Oizumi-cho, Nerima-ku, Tokyo Zenyaku Kogyo Co., Ltd. F-term (reference) 4C206 AA01 AA02 DB20 MA01 MA04 NA14 ZB13 ZC20 ZC35

Claims (3)

[Claims] 1. A compound of the general formula (I) [Wherein, R ₁ and R ₂ are both caffeine oils; Represents that the coordination of the hydroxyl group at the 5-position is axial or equatorial.] A diabetic preventive / ameliorating agent comprising diacylquinic acid as an active ingredient. 2. The drug according to claim 1, wherein the diacylquinic acid is 3,4-dicaffeoylquinic acid. 3. The method according to claim 1, wherein the diacylquinic acid is 3,4-dicaffeoyl-e.
The drug according to claim 1, which is pi-quinic acid.