JP3253366B2 - Hypoglycemic inhibitor - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a blood glucose elevation inhibitor containing a monoterpene glycoside as a main component.

[0002]

BACKGROUND OF THE INVENTION Treatment of diabetes, obesity, and hyperlipidemia due to abnormal glucose metabolism includes drug therapy and diet therapy. Drug therapy includes insulin therapy and hypoglycemic agents. There is therapy. Insulin therapy supplements insulin deficiency that causes glucose metabolism disorders with external administration, but is expensive, has technical problems due to injection by the patient himself, and is effective for non-insulin-dependent diabetes mellitus There were problems such as no.

[0003] In addition, it has been pointed out that hypoglycemic agents have side effects and their use is restricted. Diet therapy is to balance the necessary and sufficient nutrition calculated from the standard body weight in order to control the blood sugar level, and may be accompanied by limitation of energy intake. In particular, if the postprandial hyperglycemia level is insufficiently regulated, there is a risk of progression of diabetic complications. Therefore, dietary treatment requires a device in cooking and puts a great mental and physical burden on the patient for a long period of time, so that at present, satisfactory results have not always been obtained.

[0004] In order to solve these problems, research has been conducted to find substances that suppress digestion and absorption of carbohydrates. For example, European Patent Application No. 0474358 discloses that conduritol and its derivatives belonging to cyclohexenetetraol extracted from plants have an effect of suppressing an increase in blood glucose. Therefore, the present inventors have noticed that glycosides and pseudo-oligosaccharides are widely present in the plant kingdom, and that monoterpene glycosides derived from Labiatae plants inhibit the hydrolysis of disaccharides, so The present inventors have found that the present invention has an action of suppressing digestion and absorption, that is, an action of suppressing an increase in blood glucose, and further conducted various studies on the physiological activities of a large number of monoterpene glycosides. As a result, the present invention has been completed.

[0005]

According to the present invention, there is provided a compound of formula (I)

[0006]

Embedded image (In the formula, R represents a hydrogen atom or a linear or branched alkyl or alkenyl group having 1 to 3 carbon atoms, and OR ₁ represents a hydroxyl group or a protecting group for a hydroxyl group.) An agent for suppressing an increase in blood glucose comprising a body as a main component is provided.

In the above formula (I), R has 1 to 3 carbon atoms.
A linear or branched alkyl group or alkenyl group, specifically, a methyl group, an ethyl group, an n-propyl group, an isopropyl group or an isopropenyl group, preferably an isopropyl group or an isopropenyl group. is there.

Examples of the group which can be easily derived to a hydroxyl group in OR ₁ include, for example, a protecting group for a hydroxyl group. As the hydroxyl-protecting group, those commonly used as hydroxyl-protecting groups in sugar chemistry, specifically, formyl, acetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, propyl, isopropyl, pivaloyl, benzoyl, p- Acyl-type protecting groups such as nitrobenzoyl, p-phenylbenzoyl, ethoxycarbonyl, isobutyloxycarbonyl, benzyloxycarbonyl, p-nitrophenoxycarbonyl, 3-benzoylpropionyl, benzoylformyl, trimethylsilyl, dimethylethylsilyl, benzyl, p-methoxy And ether-type protecting groups such as benzyl. The hydroxyl-protecting group is preferably a group which can be easily derived into a hydroxyl group in a living body. The compound (I) of the present invention
In the above, each OR ₁ does not necessarily need to be protected with a protecting group so as to be the same, and may be protected with different protecting groups. Preferably, all OR ₁ are hydroxyl groups.

Among the compounds represented by the formula (I), the compound in which R is isopropenyl and OR ₁ is a hydroxyl group is 1-perylyl-β-D-glucopyranoside (peryloside A),
It can be extracted and separated from a Labiatae plant using the method described in JP-A-3-287597. On the other hand, in the formula (I), all compounds in which R is other than isopropenyl are considered to be novel substances, and these can be produced by a synthesis method described later. For example, as shown in the following equation:

[0010]

Embedded image (In the formula, R represents a hydrogen atom or a linear or branched alkyl or alkenyl group having 1 to 3 carbon atoms, and OR ₁ ′ represents a hydroxyl-protecting group.) The alcohol represented by the formula (II) is It is carried out by reacting a compound of the formula (III) in the presence of silver.

This reaction utilizes the Konig Knoll reaction and is usually carried out in an organic solvent (eg, ethyl ether, dioxane, etc.) at a temperature from room temperature to a slightly elevated temperature. After the reaction, the solvent is removed, the residue is subjected to, for example, silica gel column chromatography, the eluate is concentrated, and the concentrate is recrystallized to obtain the desired crystal.

The compound of the formula (I ') can be converted to a compound of the formula (I) wherein all R ₁ are hydrogen atoms (formula (I'')) by subjecting the compound to alkaline hydrolysis. In the above synthesis method, β-D-
When a glucopyranose derivative is used, a β-isomer is obtained, and the corresponding mixture of α-isomer, β-isomer and α-isomer is also included in the compound of the present invention. However, it is preferred that the compounds of the formula (I) according to the invention are β-isomers.

The compound (I) of the present invention (particularly, a compound in which OR ₁ is a hydroxyl group) specifically inhibits sucrose present in the small intestine of humans and non-human animals, and thus has, for example, a blood glucose elevation inhibitory effect. It is a compound useful for hyperglycemic symptoms and various diseases caused by hyperglycemia, for example, obesity, hyperlipidemia, hyperlipidemia (arteriosclerosis), diabetes, prediabetes, and the like. The compounds of the present invention are also suitable for healthy people as health foods for preventing metabolic disorders. Further, it is also useful as a feed additive for livestock to obtain low-fat, high-quality edible meat. That is, the compounds of the present invention are useful as pharmaceuticals, food additives, health foods or animal feed additives. In addition, for uses other than pharmaceuticals, the extract from the above blue sesame may be used without purification.

The compounds of the present invention are preferably administered orally. A compound of the present invention comprises a pharmaceutically acceptable excipient,
Pharmaceutically acceptable carriers for pharmaceutical preparations, non-toxic carriers or other additives, for example, binders (previously gelatinized corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc.), bulking agents (lactose, microcrystalline cellulose, calcium phosphate, etc.) ), Lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.), fillers (lactose, sugars, corn starch,
Formulation into granules, tablets, capsules, etc. by a known method as a composition containing calcium phosphate, sorbitol, glycine, etc.), a disintegrant (potato starch, etc.), or a wetting agent (sodium lauryl sulfate, etc.). Can be. In the case of producing these granules, tablets, capsules, etc., after being formulated into granules, tablets, capsules, etc. by a known method, as an enteric coating substance, for example,
It is preferable to apply an enteric coating by a known method using cellulose derivatives such as benzoin and cellulose acetate phthalate, phenyl salicylate, and methyl methacrylate / methacrylic acid copolymer. Also,
These preparations include, for example, known sweeteners, preservatives, dispersants, coloring agents or flavoring agents, and antioxidants, preservatives,
Alternatively, the components of the thickener may be mixed.

The dose of the compound of the present invention can be appropriately increased or decreased depending on the condition, age, etc.
In adults, the dose is 0.1 to 5 mg / kg / day, preferably 0.5 to 1.0 mg / kg / day. No acute or chronic toxicity of the compound of the present invention has been observed.

[0016]

【Example】

1. Extraction and Purification of 1-Perillyl-β-D-glucopyranoside from Blue Diso 100 l of methanol was added to the leaves (10 kg) of Blue Diso and extracted at room temperature for 3 days. After filtration, an extract is obtained. After repeating this operation three times, at about 60 ° C. or lower, about 1
After concentration under reduced pressure to 1/100 volume, lipids were removed from the obtained alcohol extract with n-hexane, and then extracted with chloroform to obtain a chloroform extract. The chloroform extract was subjected to silica gel column chromatography, and eluted with a mixed solvent of chloroform and methanol.
The component eluted with 30% methanol was concentrated under reduced pressure to obtain a green-brown oily substance.

This crude target fraction was subjected to Rf0.
After collecting the fractions of 3-0.4, the mixture was passed through a column for reversed phase (Chemcosorb 5-ODS-H), eluted with 50% methanol, and the eluted portion of the target substance was collected and evaporated under reduced pressure. Dry to dryness and add 1-perillyl-β-D-glucopyranoside 500
mg was obtained.

Synthesis of 2.1-ferrandolyl-β-D-glucopyranoside 26.7 g of acetobromoglucose (64.9 mmol) and 10.0 g (64.9 mmol) of 1-ferrandrol were dissolved in 140 ml of ether, and the mixture was dissolved at room temperature. While stirring with, 15.0 g of silver carbonate is added, and the mixture is stirred at the same temperature for 24 hours. After filtering off the silver carbonate, the solvent is removed under reduced pressure to give a crude reaction oil.

The crude reaction oil is subjected to silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 5).
/ 1), and using the confirmation of a spot (Rf value about 0.3) by thin layer chromatography as an index, the relevant components were collected and the solvent was distilled off under reduced pressure to obtain a colorless oil. The oil was recrystallized from ether-petroleum ether to give 5.2 g of 1-ferrandolyl-β-D-glucopyranoside tetraacetate as white crystals.

This was dissolved in 50 ml of methanol, and 10%
50 ml of an aqueous potassium hydroxide solution was added, and the mixture was stirred at room temperature for 5 hours. After neutralizing the reaction solution with glacial acetic acid, methanol was removed under reduced pressure and extracted with chloroform. The chloroform layer was concentrated under reduced pressure to obtain a colorless oil. This product was recrystallized from chloroform-ether to obtain 1.6 g of 1-ferrandolyl-β-D-glucopyranoside as white crystals. Melting point 92.0-95.5 ° C IR (KBr): 3400 cm ^-1 , 1075 cm ^-1 , 104
^{0cm -1 1 H-NMR (CD} 3 OD: 270MHz) δ (pp
m): 0.90 (3H, d, J = 6.7 Hz), 0.9
1 (3H, d, J = 6.7 Hz), 1.1-2.2 (8
H), 3.1-3.4 (4H), 3.66 (1H, d
d, J = 5.5 Hz, 11.9 Hz), 3.85 (1
H, dd, J = 2.4 Hz, 11.9 Hz), 4.01
(1H, d, J = 11.6 Hz), 4.21 (1H,
d, J = 11.6 Hz), 4.25 (1H, d, J =
7.9 Hz), 5.73 (1H, brs) ¹³ C-NMR (CD ₃ OD: 67.5 MHz) δ (pp
m): 20.86, 21.12, 28.01, 28.5
1, 30.66, 34.25, 42.27, 63.5
9, 72.49, 75.34, 75.86, 78.6
4, 78.93, 103.72, 127.19, 13
6.42

3. Enzyme inhibition test Intestinal mucosa of normal and streptozotocin-diabetic rats
Dahlqvist et al. (Analytical Biochemistry, 7
Saccharose and a sample as a substrate are added to the saccharide hydrolases prepared by the method of Vol. 18, p. 18-25, 1964), and the resulting glucose is measured by a glucose measurement kit (Boehringer Mannheim) using the glucose oxidase method. (Manufactured by Sharp Corporation). As a result, 50% activity inhibition rate IC ₅₀ of the Periroshido A and 1-Ferrand drill-beta-D-glucopyranoside was about 1mg / ml, respectively.

4. Glucose tolerance test Test animals Wistar rats (4 weeks old) were conditioned at room temperature 25 ° C and humidity 60.
%, Light / dark 16/8 hours, feed (CLEA Japan:
CE-2) and water were given freely and reared for one week.
After being fasted for 16 hours, they were subjected to a glucose tolerance test.

Test method: Perilloside A, 1-ferrandolyl-β-D-glucopyranoside, and a green-brown oily substance obtained as a blue diso extract obtained above at 10 mg / kg body weight (blue diso extract at 100 mg / kg)
dissolve in 1 cc of water to make up Further, sucrose was dissolved to a concentration of 1 g / kg body weight, and administered to the above rats directly to the stomach using a probe. As a control, 1
Sucrose was dissolved in 1 cc of water to give g / kg body weight and administered. After a certain period of time, blood was collected from the tail vein as a group of 5 animals, and the blood glucose level was measured with a glucose measurement kit. The result is shown in FIG.

As is clear from FIG. 1, the blood glucose level of the control was increased immediately after the administration of the sugar water, whereas the periroside A, 1-ferrandolyl-β-D-glucopyranoside and the blue diso extract were treated with the sugar water. Those administered at the same time showed that the increase in blood glucose level was suppressed as compared to the control.

[5] Formulation Example 10 parts by weight of periroside A, 421.0 parts by weight of lactose and 50 parts by weight of potato starch are mixed well, and the mixture is placed in a fluid bed granulator.
75 parts by weight of a 5% aqueous solution was sprayed to obtain granules. Then, disintegrant carboxymethylcellulose calcium 2
0 parts by weight and 15 parts by weight of a lubricant, magnesium stearate, were added and mixed. The resulting mixture was press-molded so that the weight of one tablet became 125 mg, to obtain tablets.
The tablet was sprayed with a coating solution having the following formulation to give an enteric tablet. Cellulose acetate phthalate 5.0 parts by weight 95% ethanol 47.5 parts by weight Ethyl acetate 47.5 parts by weight

[0026]

The compound of the present invention inhibits the absorption of saccharide in the small intestine by inhibiting the digestion of saccharides, and is expected to suppress postprandial rise in blood sugar and anti-obesity activity.

[Brief description of the drawings]

FIG. 1 is a graph showing the results of a glucose tolerance test.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI // C07H 15/18 C07H 15/18 (72) Inventor Mitsuru Nakayama 23 Ono-shiba-cho, Sakai-shi 4-105 (56 References JP-A-3-287597 (JP, A) Am. Chem. Soc. , Vol. 113, No. 21, p. 8166-8167 (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/7028 C07H 15/18 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the formula (I) (In the formula, R represents a hydrogen atom or a linear or branched alkyl or alkenyl group having 1 to 3 carbon atoms, and OR ₁ represents a hydroxyl group or a protecting group for a hydroxyl group.) A blood sugar rise inhibitor comprising a body as a main component.