JPH06100453A - Blood sugar value elevation-inhibiting agent - Google Patents

Abstract

PURPOSE:To provide a blood glucose value elevation-inhibiting agent containing a monoterpene glucoside as an active ingredient, inhibiting the digestion of saccharides, suppressing the absorption of the saccharides in small intestines, and useful for the prevention of postcibal blood glucose value elevation and for obesity-resistant activity. CONSTITUTION:The agent contains a compound of the formula (R is H, 1-3C alkyl or alkenyl; OR1 is OH, group capable of being easily derived into the OH), e.g. 1-perillyl-beta-D-glycopyranoside as a main ingredient. A conventional recipient, a conventional preparation carrier, other additives, etc., are further added and then prepared into granules, tablets, capsules, etc. The agent is administered at a dose of 0.1-5mg/kg a day for an adult when orally administered. The compound of the formula specifically inhibits sucrase existing in small intestines, and is thereby useful for hyperglycedmia, obesity caused by the hyperglycemia, adiposis, hyperlipemia, diabete, prediabete, etc. The agent is further useful as a healthy food for the prevention of abnormal metabolisms, as an animal feed additive, etc.

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 There are drug therapy and diet therapy for the treatment of diabetes, obesity and hyperlipidemia due to abnormal glucose metabolism. As drug therapy, insulin therapy and hypoglycemic agent are used. I have therapy. Insulin therapy supplements insulin deficiency, which is the cause of impaired glucose metabolism, by external administration, but is expensive and technically problematic because the patient himself injects it, and is effective for non-insulin-dependent diabetes mellitus. There were problems such as not being.

Further, it has been pointed out that the hypoglycemic agents have problems such as side effects and limited usage. The diet is a well-balanced intake of necessary and sufficient nutrition calculated from standard body weight in order to control the blood sugar level, and may be accompanied by limitation of energy intake. Especially when the postprandial high blood glucose level is insufficiently regulated, there is a risk of progression of diabetic complications. Therefore, diet therapy requires devising in cooking, and since it imposes a great mental and physical burden on the patient over a long period of time, satisfactory results are not always obtained.

In order to solve these problems, studies have been conducted to find substances that suppress the digestive absorption of sugars. For example, European Patent Application No. 0474358 discloses that conduritol and its derivatives belonging to cyclohexenetetraol extracted from plants have a blood glucose elevation suppressing effect. Therefore, the inventors have paid attention to the fact that glycosides and pseudo-oligosaccharides widely exist in the plant kingdom, and that monoterpene glycosides derived from Lamiaceae plants inhibit the hydrolysis of disaccharides, and The present invention was completed as a result of finding out that it has an action of suppressing digestive absorption, that is, an action of suppressing blood sugar elevation, and further conducting various studies on various physiological activities of monoterpene glycosides.

[0005]

According to the invention, the formula (I)

[0006]

[Chemical 2] (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 group which can be easily induced to a hydroxyl group.) Provided is a blood glucose elevation inhibitor comprising a monoterpene glycoside as a main component.

In the above formula (I), R has 1 to 3 carbon atoms.
Is 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 introduced into the hydroxyl group in OR ₁ include a hydroxyl-protecting group. As the hydroxyl-protecting group, those commonly used as a hydroxyl-protecting group 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. Examples thereof include ether type protecting groups such as benzyl. The above-mentioned hydroxyl-protecting group is preferably a group which can be easily converted into a hydroxyl group in vivo. The compound (I) of the present invention
In the above, it is not necessary that each OR ₁ is protected by a protecting group so that they are the same, and they may be protected by different protecting groups. It is preferable that all OR _1's 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 (periroside A),
It can be extracted and separated from a Lamiaceae plant by 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 the synthetic method described below. For example, as shown in the following equation,

[0010]

[Chemical 3] (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 group which can be easily induced to a hydroxyl group.) Formula (II) By reacting a compound of formula (III) with an alcohol in the presence of silver carbonate.

This reaction utilizes the Konig-Kunol reaction, and is usually carried out in an organic solvent (eg ethyl ether, dioxane, etc.) at 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 eluent is concentrated, and the concentrate is recrystallized to obtain the desired crystal.

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

The compound (I) of the present invention (particularly a compound in which OR ₁ is a hydroxyl group) specifically inhibits sucrase existing in the small intestine of humans and non-human animals, and therefore has, for example, a blood glucose elevation inhibitory action. The compound is useful for hyperglycemic conditions and various diseases caused by hyperglycemia, such as obesity, hyperlipidemia, hyperlipidemia (arteriosclerosis), diabetes and prediabetes. The compound of the present invention is also suitable for healthy people as a health food for preventing metabolic disorders. Further, it is also useful as a feed additive for livestock for obtaining good-quality edible meat with low fat. That is, the compound of the present invention is useful as a drug, a food additive, a health food, a feed additive for animals, and the like. In addition, for applications other than pharmaceuticals, the above-mentioned extract from blue jelly may be used without being purified.

The compounds of this invention are preferably administered orally. The compounds of the present invention are pharmaceutically acceptable excipients,
Pharmaceutically acceptable carrier for pharmaceuticals, non-toxic carrier or other additives, for example, binder (corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose etc. which have been gelatinized in advance), extender (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.), disintegrant (potato starch, etc.), or wetting agent (sodium lauryl sulfate, etc.) You can In the case of producing these granules, tablets, capsules and the like, after being formulated into granules, tablets, capsules and the like by a known method, as an enteric coating substance, for example,
It is preferable to apply an enteric coating by a known method using benzoin, cellulose derivatives such as cellulose acetate phthalate, phenyl salicylate, methyl methacrylate / methacrylic acid copolymer and the like. 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 may be appropriately adjusted depending on the condition, age and the like.
It is 0.1 to 5 mg / kg / day in an adult, preferably 0.5 to 1.0 mg / kg / day. Further, no acute toxicity or chronic toxicity of the compound of the present invention has been observed.

[0016]

【Example】

1. Extraction and purification of 1-perylyl-β-D-glucopyranoside from blue ginseng To the leaves of blue ginseng (10 kg) was added 100 liters of methanol, and the mixture was extracted at room temperature for 3 days. After filtering, an extract is obtained. After repeating this operation 3 times, at about 60 ℃ or less about 1
The resulting alcohol extract was concentrated under reduced pressure to 1/00, and lipids were removed from the resulting alcohol extract with n-hexane, followed by extraction with chloroform to obtain a chloroform extract. The chloroform extract was subjected to silica gel column chromatography and eluted with a chloroform / methanol mixed solvent.
The component eluted with 30% methanol was concentrated under reduced pressure to obtain a greenish brown oily substance.

This crude target fraction was subjected to Rf0.
After collecting 3-0.4 fractions, they were passed through a reverse phase column (Chemcosolve 5-ODS-H) and eluted with 50% methanol, and the elution part of the target substance was collected and evaporated under reduced pressure. Dry to 1-Perillyl-β-D-glucopyranoside 500.
mg was obtained.

2. Synthesis of 1-ferrandryl-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 at room temperature. 15.0 g of silver carbonate is added with stirring at, and the mixture is stirred at the same temperature for 24 hours. After removing silver carbonate by filtration, the solvent is removed under reduced pressure to obtain a crude reaction oil.

This crude reaction oil was subjected to silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 5).
/ 1), and using the confirmation of the spot (Rf value about 0.3) by thin layer chromatography as an index, the corresponding components were collected and the solvent was distilled off under reduced pressure to obtain a colorless oil. This oily substance was recrystallized from ether-petroleum ether to obtain 5.2 g of 1-ferrandryl-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. The reaction solution was neutralized with glacial acetic acid, methanol was removed under reduced pressure, and the mixture was extracted with chloroform. The chloroform layer was concentrated under reduced pressure to give a colorless oil. This product was recrystallized from chloroform-ether to obtain 1.6 g of white crystalline 1-ferrandryl-β-D-glucopyranoside. 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 = 6.7Hz), 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 = 11.6Hz), 4.21 (1H,
d, J = 11.6 Hz), 4.25 (1H, d, J =
7.9 Hz), 5.73 (1 H, 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 The small intestinal mucosa of normal and streptozotocin diabetic rats
Dahlqvist et al. (Analytical Biochemistry, 7
Vol., P18-25, 1964), sucrose and a sample are added as substrates to the saccharide hydrolase obtained by the method described above, and the glucose produced is subjected to a glucose measurement method (Boehringer Mannheim). (Manufactured by the company). As a result, the 50% activity inhibition rates IC ₅₀ of periloside A and 1-ferrandryl-β-D-glucopyranoside were each about 1 mg / ml.

4. Glucose tolerance test Test animals Wistar rats (4 weeks old) at room temperature 25 ° C and humidity 60
%, Light and darkness 16/8 hours under the conditions of feed (CLEA Japan:
CE-2) and water were given ad libitum and raised for 1 week.
After fasting for 16 hours, it was subjected to a glucose tolerance test.

Test Method 10 mg / kg body weight of periloside A, 1-ferrandryl-β-D-glucopyranoside and the green-brown oily substance which is the blue ginseng extract obtained above (100 mg / g of blue ginseng extract)
Dissolve it in 1 cc of water so that it becomes (kg body weight). Further, sucrose was dissolved so as to have a concentration of 1 g / kg body weight, and the above rat was directly administered to the stomach by a sonde. Also, as a control, 1
Sucrose was dissolved in 1 cc of water to give g / kg of body weight and administered. Then, 5 animals per group were collected for a certain period of time, blood was collected from the tail vein, and the blood glucose level was measured with a sugar measurement kit. The results are shown in Fig. 1.

As is clear from FIG. 1, in the control, the blood glucose level immediately after administration of the sugar water increased, whereas in the control, periloside A, 1-ferrandryl-β-D-glucopyranoside and blue disodium extract were added to the sugar water. It was found that, when administered at the same time, the increase in blood glucose level was suppressed as compared with the control.

5. Formulation Example 10 parts by weight of periloside A, 421.0 parts by weight of lactose and 50 parts by weight of potato starch were mixed well, and this was put in a fluid bed granulator, and the binder hydroxypropyl cellulose
75 parts by weight of 5% aqueous solution was sprayed to obtain granules. Then, disintegrant carboxymethyl cellulose calcium 2
0 parts by weight and 15 parts by weight of lubricant magnesium stearate were added and mixed. The obtained mixture was pressure-molded so that the weight of one tablet was 125 mg to obtain tablets.
An enteric coated tablet was obtained by spraying a coating liquid having the following formulation on the tablet. Cellulose acetate phthalate 5.0 parts by weight 95% ethanol 47.5 parts by weight Acetic acid ethyl ester 47.5 parts by weight

[0026]

INDUSTRIAL APPLICABILITY The compound of the present invention inhibits sugar digestion by inhibiting the digestion of sugar, and is expected to suppress postprandial blood glucose elevation and antiobesity activity.

[Brief description of drawings]

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

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Mitsuru Nakayama 23 Onoshiba-cho, Sakai City Onoshiba Housing 4-105

Claims (1)

[Claims] 1. 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 group which can be easily induced to a hydroxyl group.) A blood glucose elevation inhibitor comprising a monoterpene glycoside as a main component.