JPH0827007A - Hypoglycemic agent - Google Patents

Abstract

PURPOSE:To obtain a hypoglycemic agent, capable of manifesting increasing actions on urine sugar and hypoglycemic actions based on inhibition of resorption of glucose in the kidney and useful as a preventing and therapeutic agent for diabetes. CONSTITUTION:This hypoglycemic agent contains a dihydrochalcone derivative of formula I (Ar is an aryl; OZ is OH or a lower alkoxyl which may be protected; R is formula II or III, except that Ar is an OH-substituted phenyl or a lower alkoxy-substituted phenyl or phenyl when R is formula II) or its pharmacologically permissible salt, e.g. 2'-(beta-D-glucopyranosyloxy)-6'-hydroxy-3- methyldihydrochalcone as an active ingredient. The compound of formula I is obtained by reducing a chalcone derivative of formula IV (Ar' is Ar; OZ' is OZ). The compound of formula IV is obtained by condensing an acetophenone derivative of formula V or VI (OX is OH which may be protected) with an aldehyde compound of the Ar'-CHO.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a hypoglycemic agent.

[0002]

2. Description of the Related Art Diet therapy is essential for the treatment of diabetes, but if this alone does not provide sufficient control, insulin or an oral diabetes drug is used as needed. As a diabetes drug, a biguanide compound and a sulfonylurea compound have been conventionally used. However, the biguanide compound has a side effect of lactic acidosis and the sulfonylurea compound has a serious hypoglycemia, and development of a new therapeutic agent for diabetes without such defects is desired.

[0003] In recent years, glucose glucose toxicology (Glucose Toxicity Theo) has been suggested that hyperglycemia itself is involved in the onset and progress of diabetes.
ry) has been proposed. That is, chronic hyperglycemia causes abnormalities in both insulin secretion and insulin action, which further raises blood glucose and progresses diabetes [diabetologia (Diabetolog.
ia) 28, 119 (1985), Diabetes Care, 1st
Volume 3, p. 610 (1990), etc.].

This theory has been verified as follows. That is, it was confirmed that if the blood glucose of a diabetic animal is kept normal for a long time without using insulin, the condition of the diabetic animal is improved and normalized [J. Clin. Inve (J. Clin. Inve
st. ) Volume 79, page 1510 (1987), Volume 80, page 1037 (1987), Volume 87, page 561 (1991), etc.]. In these verification experiments, phlorizin is used subcutaneously as a reagent for keeping blood sugar normal.

Floridin is a glycoside contained in the bark and root bark of plants such as apples and pears, and has been discovered in the last century and variously studied. Recently, it was found to be an inhibitor of the Na ⁺ -glucose cotransporter that exists only in the chorion of the intestine and kidney, and in this experiment, phlorizin inhibits renal glucose reabsorption and promotes glucose excretion. It is interpreted as having corrected the hyperglycemia.

However, when phlorizin is administered orally, most of it is hydrolyzed into aglycone, phloretin and glucose, and the proportion absorbed as phlorizin is small, and the urinary glucose excretion action is very weak. It is known that phloretin, which is an aglycone, strongly inhibits the facilitative diffusion type sugar transporter. For example, it has been reported that intravenous administration of phloretin to rats reduces brain glucose concentration. [Stroke, 1st
4, p. 388 (1983)], it is conceivable that use of this for a long period of time will adversely affect various tissues. Perhaps because of this, no attempts have been made to use phlorizin as a therapeutic drug for diabetes.

It is also known that 2 '-(β-D-glucopyranosyloxy) -4,6'-dihydroxydihydrochalcone inhibits Na ⁺ -glucose cotransporter in the kidney [ For example, Biochim. Biophysica Actor (Biochim. Biophys. Ac
ta), Vol. 71, p. 688 (1963)]. However, nothing is described that the above compound has an action of increasing urinary glucose even after oral administration.

[0008]

DISCLOSURE OF THE INVENTION According to the present invention, a dihydrochalcone derivative having an excellent urinary sugar-increasing effect even when orally administered, and the aglycone having an extremely weak inhibitory effect on a facilitative diffusion-type sugar transport carrier is effective. The present invention provides a hypoglycemic agent as an ingredient.

[0009]

The present invention has the general formula [I]

[0010]

[Chemical 4]

[Wherein Ar represents an aryl group, OZ represents an optionally protected hydroxyl group or a lower alkoxy group, and R represents
Is a formula [II]

[0012]

Embedded image

A group of the formula [III]

[0014]

[Chemical 6]

Represents a group represented by: (provided that OZ is a hydroxyl group and R is a group represented by the formula [II], Ar
Is a hydroxy-substituted phenyl group, a lower alkoxy-substituted phenyl group or a phenyl group). ] The present invention relates to a hypoglycemic agent containing a dihydrochalcone derivative and a pharmacologically acceptable salt thereof as an active ingredient.

The dihydrochalcone derivative [I], which is the active ingredient of the present invention, exhibits an excellent hypoglycemic action based on the action of increasing urinary glucose. For example, when the active ingredient [I] of the present invention was administered to rats, the amount of glucose excreted in the urine in 24 hours was about 6 to 30 times as much as when phlorizin was administered. Moreover, when the active ingredient of the present invention was orally administered to glucose-loaded diabetic mice, the rise in blood glucose level was significantly suppressed. Therefore, the hypoglycemic agent of the present invention is useful for treating / preventing diabetes. Such an action of increasing the urinary glucose of the active ingredient [I] of the present invention is considered to be due to inhibition of glucose reabsorption in the kidney, and has a characteristic that conventional hypoglycemic agents do not have.

The toxicity of the dihydrochalcone derivative [I], which is the active ingredient of the present invention, is low, and for example, 2 '-(β
-D-glucopyranosyloxy) -6'-hydroxy-
3-Methyldihydrochalcone at a rate of 1000 mg / kg was continuously orally administered to rats for 28 days, and no death was observed even when observed.

Furthermore, aglycone, which is a hydrolyzate of the active ingredient of the present invention, is different from phloretin in that it has a remarkably weak inhibitory effect on sugar uptake. For example, human erythrocyte and D- [3- ³ H] glucose for 1 minute, were examined by measuring the radioactivity of erythrocyte uptake sugar in erythrocytes, if the time sample compound not added was 100, the present invention 2 ', which is the aglycone of the active ingredient of
4,6'-trihydroxydihydrochalcone is 92.
7,2 ', 6'-dihydroxy-4-methoxydihydrochalcone is 91.0, while phloretin is 13.
It was 7. Therefore, the inhibitory effect of the aglycone of the active ingredient of the present invention on glucose uptake in human erythrocytes is significantly smaller than that of phloretin, which is an aglycone of phlorizin, and even if the active ingredient of the present invention is partially hydrolyzed, the concentration of sugar in the tissue is low. It is considered that the decrease of the is very unlikely to occur.

In the dihydrochalcone derivative [I], which is an active ingredient of the present invention, the aryl group may be a hydrocarbon aryl group or a heterocyclic aryl group.

Examples of the above-mentioned hydrocarbon-based aryl group include a phenyl group which may have a substituent or a naphthyl group which may have a substituent. A heteroaromatic group containing an oxygen atom, a nitrogen atom or a sulfur atom as an atom (the heteroaromatic group may have a substituent) is exemplified, and the heteroaromatic group is a furyl group, Examples thereof include heteroaromatic monocyclic groups such as thienyl group and pyridyl group.

Further, the above-mentioned phenyl group, naphthyl group,
When the heteroaromatic cyclic group has a substituent, the substituent may be a lower alkyl group which may be substituted with a halogen atom or a hydroxyl group; a lower alkoxy group which may be substituted with a lower alkoxy group; a lower alkoxy group. A lower alkoxycarbonyloxy group optionally substituted with; an amino group optionally substituted with a lower alkyl group or a lower alkanoyl group; 1-2 selected from a lower alkoxy group, a lower alkoxycarbonyl group, an amino group and a phenyl group Lower alkanoyloxy groups optionally substituted with
Halogen atom; Hydroxyl group; Carbamoyl group; Lower alkylthio group; Lower alkylsulfinyl group; Lower alkylsulfonyl group; Carboxyl group; Formyl group; Cyano group;
Examples thereof include a di-lower alkylcarbamoyloxy group; a phenoxycarbonyloxy group; a lower alkylenedioxy group; or a benzoyloxy group which may be substituted with a lower alkoxy group.

Specific examples of the dihydrochalcone derivative which is the active ingredient of the present invention include R in the general formula [I], which is a group represented by the formula [II], and (1) Ar is substituted with a halogen atom or a hydroxyl group. Optionally lower alkyl group: lower alkoxy group substituted with lower alkoxy group:
Lower alkoxycarbonyloxy group optionally substituted with lower alkoxy group: amino group substituted with a group selected from lower alkyl group and lower alkanoyl group: selected from lower alkoxy group, lower alkoxycarbonyl group, amino group and phenyl group Lower alkanoyloxy group which may be substituted with 1 to 2 groups: halogen atom: carbamoyl group: lower alkylthio group: lower alkylsulfinyl group: lower alkylsulfonyl group: carboxyl group: formyl group: cyano group: di-lower Alkylcarbamoyloxy group: phenoxycarbonyloxy group: lower alkylenedioxy group: and a phenyl group substituted with a group selected from a benzoyloxy group which may be substituted with a lower alkoxy group; lower alkyl group, lower alkoxy group and hydroxyl group Choose from A phenyl group substituted with two substituents; a furyl group; a thienyl group; a pyridyl group; or a naphthyl group, and OZ is an optionally protected hydroxyl group or a lower alkoxy group, or (2) A compound in which Ar is a phenyl group substituted with a lower alkoxy group and OZ is a protected hydroxyl group or a lower alkoxy group can be given.

As another specific example, R is a group represented by the formula [III], and Ar is a phenyl group, a lower alkyl group-substituted phenyl group, a halogenophenyl group, a hydroxy group-substituted phenyl group or a lower alkoxy group-substituted phenyl. A compound in which OZ is a hydroxyl group or a lower alkoxy group which may be protected may be mentioned.

When the group represented by OZ is a protected hydroxyl group, the protecting group may be any group which can serve as a protecting group for a phenolic hydroxyl group, such as an acetyl group,
Examples thereof include lower alkanoyl group such as propionyl group and pivaloyl group; lower alkoxycarbonyl group; phenoxycarbonyl group; acyl group such as benzoyl group.

As the dihydrochalcone derivative [I] which is the active ingredient of the present invention which is preferable in terms of medicinal effect, R is represented by the formula [II]
Or a group represented by [III], wherein (1) Ar may be substituted with a halogen atom, lower alkyl group: lower alkoxy group substituted with lower alkoxy group: optionally substituted with lower alkoxy group Lower alkoxycarbonyloxy group: amino group substituted with a lower alkyl group:
Lower alkanoyloxy group: halogen atom: lower alkylthio group: phenoxycarbonyloxy group: lower alkylenedioxy group: and a phenyl group substituted with a group selected from a benzoyloxy group optionally substituted with a lower alkoxy group, or naphthyl Or a compound in which OZ is an optionally protected hydroxyl group or a lower alkoxy group, or (2) Ar is a lower alkoxy group-substituted phenyl group, and OZ is a protected hydroxyl group or a lower alkoxy group. And a compound of the formula [II]
Compounds represented by the group are particularly preferred.

As another dihydrochalcone derivative [I] preferable in view of efficacy, R is a group represented by the formula [III], and Ar is a phenyl group, a lower alkyl group-substituted phenyl group, a halogenophenyl group or a lower alkoxy group-substituted group. Examples thereof include a compound which is a phenyl group and OZ is a hydroxyl group or a lower alkoxy group which may be protected.

As the dihydrochalcone derivative [I] exhibiting excellent drug efficacy, R is a group represented by the formula [II], Ar is a lower alkyl group-substituted phenyl group, a lower alkoxycarbonyloxy group-substituted phenyl group, or halogeno. Examples thereof include a compound which is a phenyl group and OZ is a hydroxyl group or a lower alkoxy group which may be protected.

The dihydrochalcone derivative [I], which is the active ingredient of the present invention, can be used for the purpose of the present invention in the free form or in the form of its pharmaceutically acceptable salt. Examples of the pharmacologically acceptable salt include inorganic acid salts such as hydrochlorides, sulfates and nitrates, and organic acid salts such as acetates and methanesulfonates.

The hypoglycemic agent of the present invention can be administered orally or parenterally, and can be made into a suitable formulation by using a pharmaceutical carrier usually used for oral or parenteral administration. Examples of such pharmaceutical carriers include binders (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose,
Sugar, corn starch, potassium phosphate, sorbit,
Examples thereof include glycine), lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrating agents (potato starch, etc.), wetting agents (sodium lauryl sulfate, etc.) and the like. Further, these pharmaceutical preparations, when administered orally, tablets, capsules,
Solid preparations such as powders and granules may be used, and liquid preparations such as solutions, suspensions and emulsions may be used. On the other hand, in the case of parenteral administration, for example, distilled water for injection, physiological saline, aqueous glucose solution or the like can be used to prepare an injection or drip.

The dose varies depending on the age, body weight, condition of the patient or the degree of disease, but the daily dose is usually 1 to 100 mg / kg, especially 5 to 40 mg / kg in the case of oral administration. In the case of parenteral administration, 0.
1-50 mg / kg, especially 0.5-10 mg / kg
It is preferred that

The dihydrochalcone derivative [I] or a pharmaceutically acceptable salt thereof, which is the active ingredient of the present invention, has the general formula [IV]

[0032]

[Chemical 7]

[Wherein Ar 'represents an aryl group, OZ' represents an optionally protected hydroxyl group or a lower alkoxy group, and other symbols have the same meanings as described above (provided that OZ 'is
Is a hydroxyl group and R is a group represented by the formula [II], except for Ar ′ which is a lower alkoxy group-substituted phenyl group, a hydroxy group-substituted phenyl group or a phenyl group). ] The chalcone derivative represented by the formula [1] is reduced, and if necessary, the protecting group is removed, and a pharmaceutically acceptable salt is produced, if desired.

As Ar ', the same groups as those described for Ar can be mentioned. Further, when Ar ′ is a phenyl group having a substituent, a naphthyl group having a substituent, or a heteroaromatic cyclic group having a substituent, the substituent of each of the above groups may be protected. As the protective group for the substituent of each of the above groups, any group that can be easily removed by a conventional method such as acid treatment, reduction, hydrolysis or the like can be used.

When OZ 'is a protected hydroxyl group, the protecting group for the hydroxyl group may be any group which can serve as a protecting group for the phenolic hydroxyl group, and examples thereof include the same protecting group as the group -OZ. it can. Removal of the protecting group can be carried out by a conventional method.

This reduction reaction can be carried out according to a conventional method by reduction with a metal hydride, catalytic hydrogen reduction or the like under cooling to heating (particularly 10 ° C. to 30 ° C.). For example, for reduction with a metal hydride, a metal hydride [for example, sodium tellurium hydride (Sodium) is used in a solvent.
In addition, the catalytic hydrogen reduction can be carried out by catalytic reduction using a catalyst (for example, palladium-carbon etc.) in a solvent under normal pressure hydrogen flow.

As the solvent, a conventional solvent inert to the reaction (eg, methanol, acetic acid, etc.) can be used.

In the starting compound [IV], R is the formula [I
I] is a group represented by the general formula [Va]

[0039]

Embedded image

(Wherein, OX represents an optionally protected hydroxyl group, and other symbols have the same meanings as described above), and an acetophenone derivative represented by the general formula [VI]

[0041]

[Chemical 9]

(However, the symbols have the same meanings as described above.) The compound can be produced by condensing an aldehyde compound and, if necessary, removing a protecting group.

Among the starting compounds, the compound of the general formula [IV]
In, the chalcone derivative in which R is the formula [III] is
General formula [V-b]

[0044]

[Chemical 10]

(However, the symbols have the same meanings as above.) The acetophenone derivative and the aldehyde compound [VI] are subjected to a condensation reaction and, if necessary, can be produced by removing the protective group.

When the group —OX of the starting compound [Va] or [Vb] is a protected hydroxyl group, the protecting group may be a conventional protecting group such as a lower alkanoyl group. The removal of the protecting group can be carried out by a conventional method such as hydrolysis.

Acetophenone derivative [Va] or [V
The condensation reaction between -b] and the aldehyde compound [VI] can be carried out by a conventional method, for example, in a solvent (organic solvent such as methanol, ethanol or a mixed solvent of these organic solvent and water), a base (water). It can be carried out under cooling to heating (especially 10 ° C to 30 ° C) in the presence of an alkali metal oxide or the like).

The starting material compound [Va] of the present invention was prepared according to the Journal of Medicinal and Pharmaceutical Chemistry (J. Med. Pharm.
Chem. ) It can be manufactured according to the method described in Volume 5, page 1054 (1962).

The starting compound [Vb] is a novel compound, for example, 2 ', 6'-dihydroxyacetophenone and 2,3,6-tri-O-acetyl-4-O-.
(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl) -α-D-glucopyranosyl bromide may be produced by heating and refluxing in toluene in the presence of cadmium carbonate. it can.

In the present invention, examples of the lower alkyl group, lower alkoxy group and lower alkylene group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, methoxy group,
Examples thereof include ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, methylene group, ethylene group, propylene group and the like having 1 to 6 carbon atoms, and particularly 1 to 4 carbon atoms. Those are preferable.

Examples of the lower alkanoyl group include acetyl group, propionyl group, butyryl group, 2-methylpropionyl group, valeryl group, pivaloyl group and the like having 2 to 7 carbon atoms.
The thing of 2 to 5 carbon atoms is especially preferable.

In the present specification, dihydrochalcone is represented by the following formula

[0053]

[Chemical 11]

Represents the structure represented by

[0055]

[Action]

Experimental Example (Hypoglycemic action in mice) (Experimental method) A 6-week-old male ddY mouse (5 mice per group) fasted overnight was orally administered with a sample suspension (dose: 100).
mg / kg) and immediately after that, glucose is subcutaneously administered (1
g / kg / 5 ml physiological saline). The sample suspension was prepared by suspending the sample in a 0.1% NIKKOLHCO-60 (manufactured by Nippon Chemical Co., Ltd.) aqueous solution.

The control group was orally administered with a 0.1% NIKKOL aqueous solution instead of the sample suspension. Immediately before administration and after a certain time after administration, blood samples were collected from the tail blood vessel and the blood glucose level was measured by the glucose oxidase method.

The results are shown in Table 1.

(Sample compound) 2 '-(β-D-glucopyranosyloxy) -6'-hydroxy-3-methyldihydrochalcone

[0059]

[Table 1]

From the above results, it can be seen that the blood glucose level in the sample-administered group is significantly lower than that in the sample-non-administered group.

(Increase in urine sugar in rat) (Experimental method) Male SD rat (6 weeks old, 1 group 3 to 5)
The test compound administration solution was orally administered (dosage: 100 mg / kg) to 8 animals at a rate of 5 ml / kg twice every 8 hours. The sample administration liquid was prepared by adding Tween 80 (manufactured by Nacalai Tesque, Inc., 0.5% final concentration aqueous solution) to the sample and then suspending it in purified water. On the other hand, the control group had 0.5% Twe.
Only purified water containing an en80 aqueous solution was administered. Twenty-four hours after the first administration, the rats were placed in a metabolic gauge and urine was collected. For urine, measure the amount of urine, and then remove the contaminants by centrifugation and then use a glucose analyzer (Apec).
The urine sugar concentration was measured by. Urine volume (ml) and urine sugar concentration (mg
/ Dl), the urinary sugar (mg) excreted in 24 hours was calculated. The urine sugar in the control group during 24 hours was 0-6 mg.

The results are as shown in Tables 2 and 3.

[0063]

[Table 2]

[0064]

[Table 3]

As is clear from the above results, the group administered with the dihydrochalcone derivative [I], which is the active ingredient of the present invention, has an approximately 6 to 30-fold increase in urinary sugar as compared with the group treated with phlorizin. I understand.

Production Example 1 (1) 2 '-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) -6'-hydroxyacetophenone 1000 mg, p-tolualdehyde 3
To a mixture of 73 mg and 10 ml of ethanol, 2 ml of 50% aqueous potassium hydroxide solution is added dropwise, and the mixture is stirred overnight at room temperature. The solvent is distilled off under reduced pressure, water and diethyl ether are added to the residue, the mixture is stirred, and the aqueous layer is separated. 10% ice-cooled sewage layer
After neutralizing with hydrochloric acid, extract with ethyl acetate. The organic layer obtained is washed with water and dried, and then the solvent is distilled off to give a crude 2'-
670 mg of (β-D-glucopyranosyloxy) -6′-hydroxy-4-methylchalcone are obtained.

FABMS (m / z): 417 (MH ⁺ ) (2) The above crude 2 '-(β-D-glucopyranosyloxy) -6'-hydroxy-4-methylchalcone 665.
mg is dissolved in 20 ml of ethanol, and catalytic hydrogen reduction is conducted under atmospheric pressure using 0.5 g of 10% palladium-carbon as a catalyst. After removing the catalyst by filtration, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2 '-(β
-D-glucopyranosyloxy) -6'-hydroxy-
470 mg of 4-methyldihydrochalcone are obtained.

M. p. : 109-111 ° C NMR (DMSO-d ₆ ) δ: 2.25 (3H, s),
2.85 (2H, t, J = 7.6Hz), 3.0-3.
4 (6H, m), 3.45 (1H, m), 3.70 (1
H, dd, J = 5.4, 10.3 Hz), 4.53 (1
H, t, J = 5.6 Hz), 4.91 (1H, d, J =
7.3 Hz), 5.01 (1H, d, J = 4.9H
z), 5.07 (1H, d, J = 4.4 Hz), 5.1
9 (1H, d, J = 4.9 Hz), 6.55 (1H,
d, J = 7.8 Hz), 6.68 (1H, d, J = 8.
3Hz), 7.05 (2H, d, J = 7.8Hz),
7.14 (2H, d, J = 7.8Hz), 7.24 (1
H, t, J = 8.3 Hz), 11.01 (1H, br
s) IR (nujol) cm ⁻¹ : 3440, 3320, 16
20 FABMS (m / z): 441 [(M + Na) ⁺ ].

Production Example 2-30 In the same manner as in Production Example 1, from the corresponding starting material compound to the 4th
To obtain the compounds listed in Table 9.

[0070]

[Table 4]

[0071]

[Table 5]

[0072]

[Table 6]

[0073]

[Table 7]

[0074]

[Table 8]

[0075]

[Table 9]

Production Example 31 (1) 50 ml of dimethylformamide was added with 2 '-(2,-
3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy) -6′-hydroxyacetophenone (4.82 g) and potassium carbonate (4.14 g) were added and the mixture was stirred.
2.56 g of benzyl bromide is added dropwise and stirred at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure, ethyl acetate and water are added to the residue, and after stirring, the organic layer is separated. The obtained organic layer is washed with water and dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography to give 6'-benzyloxy-2 '-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) acetophenone (3.2 g). To get

IR (nujol) cm ^-1 : 1760,1
700,1600 FABMS (m / z): 595 [(M + Na) ⁺ ] (2) 6'-benzyloxy-2 '-(2,3,4,6)
-Tetra-O-acetyl-β-D-glucopyranosyloxy) acetophenone (2.9 g) and 4-tetrahydropyranyloxybenzaldehyde (1.56 g) were added to ethanol (30 ml), and a 50% aqueous potassium hydroxide solution 3 was added with stirring.
Add ml dropwise. Then, the same treatment as in Production Example 1 (1) was performed, and the obtained crude product was dissolved in 50 ml of acetic acid-water-tetrahydrofuran (2: 1: 2) solution, heated at 50 ° C. for 3 hours, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6'-benzyloxy-2 '.
1.20 g of-(β-D-glucopyranosyloxy) -4-hydroxychalcone is obtained.

IR (nujol) cm ^-1 : 3600-3
200, 1660, 1600, 1260 FABMS (m / z): 531 [(M + Na) ⁺ ] (3) 6′-benzyloxy-2 ′-(β-D-glucopyranosyloxy) -4-hydroxychalcone 0 .79
g, 0.19 g of triethylamine are dissolved in 30 ml of dimethylacetamide, and 0.20 g of ethyl chlorocarbonate is added dropwise under stirring with ice cooling. After stirring at room temperature for 1 hour, ethyl acetate and water are added, and after stirring, the organic layer is separated. The obtained organic layer was washed with water and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 6'-benzyloxy-4-ethoxycarbonyloxy-2 '-(β-D.
0.73 g of glucopyranosyloxy) chalcone is obtained.

FABMS (m / z): 603 [(M + Na) ⁺ ] (4) 0.70 g of 6′-benzyloxy-4-ethoxycarbonyloxy-2 ′-(β-D-glucopyranosyloxy) chalcone In the same manner as in Production Example 1 (2),
0.48 g of 4-ethoxycarbonyloxy-2 ′-(β-D-glucopyranosyloxy) -6′-hydroxydihydrochalcone is obtained.

M. p. : 65 ° C- (gradual melting) NMR (DMSO-d ₆ ) δ: 1.28 (3H, t, J
= 7.1 Hz), 2.92 (2H, t, J = 7.1H)
z), 3.1-3.3 (6H, m), 3.4-3.5.
(1H, m), 3.6-3.7 (1H, m), 4.23
(2H, q, J = 7.1Hz), 4.57 (1H, t,
J = 5.7 Hz), 4.91 (1H, d, J = 7.3H)
z), 5.03 (1H, d, J = 5.3Hz), 5.1
0 (1H, d, J = 4.7Hz), 5.27 (1H,
d, J = 5.2 Hz), 6.55 (1H, d, J = 8.
2Hz), 6.68 (1H, d, J = 8.3Hz),
7.10 (2H, d, J = 8.6Hz), 7.24 (1
H, t, J = 8.3 Hz), 7.31 (2H, d, J =
8.6 Hz), 10.94 (1 H, s) IR (nujol) cm ⁻¹ : 3600-3200, 17
60, 1720, 1630, 1600 FABMS (m / z): 515 [(M + Na) ⁺ ].

Production Examples 32-43 In the same manner as in Production Example 31, the compounds shown in Tables 10 to 13 are obtained from the corresponding starting material compounds.

[0082]

[Table 10]

[0083]

[Table 11]

[0084]

[Table 12]

[0085]

[Table 13]

Production Example 44 2 '-(2,3,4,6-tetra-O-acetyl-β-
1.2 g of D-glucopyranosyloxy) -6′-hydroxyacetophenone and 0.57 g of p-methylthiobenzaldehyde were reacted and treated in the same manner as in Production Example 1 (1),
Crude 2 '-(β-D-glucopyranosyloxy)-
1.71 g of 6'-hydroxy-4-methylthiochalcone
Get. This product is added to 20 ml of an ethanol solution of sodium tellurium hydride prepared in advance from 0.3 g of tellurium and 0.23 g of sodium borohydride and allowed to react at room temperature for 1 hour. The reaction mixture is poured into ice water, the precipitated insoluble matter is filtered off, chloroform is added to the filtrate, the mixture is stirred, and the organic layer is separated. The organic layer was dried and then concentrated, and the residue was purified by silica gel column chromatography to obtain 2 '-(β-
D-glucopyranosyloxy) -6'-hydroxy-4
470 mg of methylthiodihydrochalcone are obtained.

M. p. : 135-136 ° C IR (nujol) cm ^-1 : 3600-3200,16
20,1600,1230 FABMS (m / z): 473 [(M + Na) ⁺ ] Production Example 45 2 ′-(β-D-glucopyranosyloxy) -6′-hydroxy-4-methylthiodihydrochalcone 901 mg
Dichloromethane-dimethylformamide (30 ml-
10 ml), and 520 mg of metachloroperbenzoic acid is added to the solution under ice cooling. After stirring for 15 minutes at room temperature, the mixture is concentrated, the residue is poured into saturated aqueous sodium hydrogen carbonate, and the mixture is extracted with ethyl acetate-tetrahydrofuran. After drying the organic layer, the solvent was distilled off, and the residue was purified by silica gel column chromatography to give 2 '-(β-D-glucopyranosyloxy) -6'-hydroxy-4-methylsulfinyldihydro. 507 mg of chalcone and 338 mg of 2 ′-(β-D-glucopyranosyloxy) -6′-hydroxy-4-methylsulfonyldihydrochalcone are obtained.

2 '-(β-D-glucopyranosyloxy) -6'-hydroxy-4-methylsulfinyldihydrochalcone: m.p. p. : 84 ° C .- (gradual melting) IR (nujol) cm ⁻¹ : 3600-3200, 16
30, 1600, 1300, 1230 FABMS (m / z): 489 [(M + Na) ⁺ ]; 2 ′-(β-D-glucopyranosyloxy) -6′-hydroxy-4-methylsulfonyldihydrochalcone: m ． p. : 85 ° C- (gradual melting) IR (nujol) cm ^-1 : 3600-3200,16
30, 1600, 1300, 1230 FABMS (m / z): 505 [(M + Na) ⁺ ].

Production Example 46 In the same manner as in Production Example 44, from the corresponding starting compound,
2 '-(β-D-Glucopyranosyloxy) -6'-hydroxy-3- (2-thienyl) propiophenone is obtained.

M. p. : 62-70 ° C IR (nujol) cm ^-1 : 3600-3000, 16
20,1600,1230 FABMS (m / z): 433 [(M + Na) ⁺ ] Production Example 47 2 ′-(2,3,4,6-tetra-O-acetyl-β-
2 g of D-glucopyranosyloxy) -6′-hydroxyacetophenone and 1.02 g of 4-diethoxymethylbenzaldehyde are reacted in the same manner as in Production Example 1 (1) and (2). Then, the obtained compound was treated with acetic acid-water (2 ml
-2 ml) at room temperature for 30 minutes.

Dilute with chloroform-methanol (10: 1), recrystallize the precipitated crystals from methanol,
531 mg of 2 ′-(β-D-glucopyranosyloxy) -6′-hydroxy-4-formyldihydrochalcone are obtained.

M. p. : 173-174 ° C IR (nujol) cm ^-1 : 3510,3330,16
85,1620,1600 FABMS (m / z): 455 [(M + Na) ⁺ ] Production Example 48 (1) 6′-benzyloxy-2 ′-(2,3,4) obtained in Production Example 31 (1). , 6-Tetra-O-acetyl-
β-D-glucopyranosyloxy) acetophenone 2.
9 g and 1.56 g of 4-tetrahydropyranyloxybenzaldehyde were added to 30 ml of ethanol, and the mixture was stirred under stirring to give 5
3 ml of 0% aqueous potassium hydroxide solution is added dropwise. Then
The same treatment as in Production Example 1 (1) was performed, and the obtained crude product was purified by silica gel column chromatography to give 2′-
(Β-D-glucopyranosyloxy) -6′-benzyloxy-4-tetrahydropyranyloxychalcone 2.
2 g are obtained. 593 mg of the above compound and 136 mg of tetrabutylammonium hydrogensulfate were added to dichloromethane-10%.
Add to the biphasic solvent of aqueous sodium hydroxide (10 ml-5 ml). Then benzyl chloroformate 1.02g
And stir at room temperature for 1 hour. The organic layer is separated, the aqueous layer is extracted with chloroform, the combined organic layers are dried, and the solvent is evaporated. The obtained crude product is dissolved in an acetic acid-water-tetrahydrofuran mixed solution (10 ml-3.5 ml-2 ml), and the mixture is stirred at room temperature for 40 minutes and then at 40 ° C for 30 minutes.
The reaction solution is diluted with ethyl acetate, washed with water, dried and the solvent is distilled off. The residue is purified by silica gel column chromatography to give 847 mg of a yellow foam.

IR (nujol) cm ⁻¹ : 1760, 1750 FABMS (m / z): 1067 [(M + Na) ⁺ ] (2) The above compound 816 mg, N-benzyloxycarbonylglycine 245 mg, dicyclohexylcarbodiimide 266 mg, 1-hydroxy A mixture of 174 mg of benzotriazole hydrate and 10 ml of dimethylformamide is stirred at room temperature for 13 hours. The reaction solution is diluted with ethyl acetate, the insoluble material is filtered off, the filtrate is washed with water, dried and the solvent is distilled off. The residue is purified by silica gel column chromatography to obtain 848 mg of pale yellow foam.

IR (nujol) cm ^-1 : 3400,1
765, 1730, 1650 FABMS (m / z): 1258 [(M + Na) ⁺ ] (3) The compound 811 mg was dissolved in ethanol 10 ml, and 10% palladium-carbon 0.2 g and 19% hydrogen chloride-ethanol 0.2 ml were added. In addition, the resulting mixture is catalytically hydrogenated at room temperature. After completion of the reaction, the catalyst was filtered off,
Concentrate the filtrate.

The residue was pulverized in diethyl ether, collected by filtration and dried, and 2 ′-(β-D-glucopyranosyloxy) -6′-hydroxy-4-glycyloxydihydrochalcone hydrochloride 130 mg To get

M. p. : 72 ° C- (gradual melting) NMR (DMSO-d ₆ ) δ: 2.93 (2H, t, J
= 7.3 Hz), 3.12-3.53 (7H, m),
3.69 (1H, d, J = 10.9Hz), 4.07
(2H, s), 4.69 (1H, bro), 4.91
(1H, d, J = 7.4Hz), 5.10 (1H, br
o), 5.19 (1H, bro), 5.29 (1H,
d, J = 4.1 Hz), 6.58 (1H, d, J = 8.
1Hz), 6.68 (1H, d, J = 8.3Hz),
7.08 (2H, ddd, J = 2.0, 2.6, 8.5
Hz), 7.24 (1H, t, J = 8.3 Hz), 7.
36 (2H, d, J = 8.7 Hz), 8.56 (3H,
bro), 10.99 (1H, s) IR (nujol)
cm ⁻¹ : 3300, 1770, 1630.

Production Example 49 In the same manner as in Production Example 48, 2 ′ was prepared from the corresponding starting material compound.
-(Β-D-Glucopyranosyloxy) -6'-hydroxy-4-L-valyloxydihydrochalcone hydrochloride is obtained.

M. p. : 141 ° C- (gradual decomposition) NMR (DMSO-d ₆ ) δ: 1.08 (3H, d, J
= 7.0 Hz), 1.11 (3H, d, J = 7.0H
z), 2.34 (1H, m), 2.93 (2H, t, J
= 7.3 Hz), 3.12-3.52 (7H, m),
3.70 (1H, d, J = 11.7 Hz), 4.12
(1H, d, J = 4.9 Hz), 4.59 (1H, br
od), 4.91 (1H, d, J = 7.5Hz),
5.08 (1H, d, J = 4.8Hz), 5.17 (1
H, d, J = 2.9 Hz), 5.29 (1H, d, J =
5.1Hz), 6.58 (1H, d, J = 8.4H
z), 6.68 (1H, d, J = 8.3 Hz), 7.0
9 (H, d, J = 8.5 Hz), 7.24 (1 H, t,
J = 8.3 Hz), 7.37 (2H, d, J = 8.5H)
z), 8.74 (3H, broad), 10.99 (1
H, s) FABMS (m / z): 542 [(M + Na) ⁺ ].

Production Example 50 2 ′ was prepared from the corresponding starting material compound in the same manner as in Production Example 48.
-(Β-D-Glucopyranosyloxy) -6'-hydroxy-4-L-phenylalanyloxydihydrochalcone hydrochloride is obtained.

M. p. 182 ° C .- (gradual decomposition) NMR (DMSO-d ₆ ) δ: 2.90 (2H, t, J
= 7.3 Hz), 3.13-3.51 (9H, m),
3.69 (1H, dd, J = 1.2, 11.4Hz),
4.51 (1H, dd, J = 5.9, 8.1Hz),
4.8-5.5 (4H, broad), 4.91 (1
H, d, J = 7.6 Hz), 6.57 (1H, d, J =
8.3 Hz), 6.68 (1H, d, J = 8.3H)
z), 6.86 (2H, ddd, J = 1.9, 2.6,
8.5 Hz), 7.24 (1H, t, J = 8.3H)
z), 7.31 (2H, d, J = 8.6Hz), 7.3
7 (5H, m), 8.88 (3H, broad), 1
0.98 (1H, s) FABMS (m / z): 590 [(M + Na) ⁺ ].

Production Example 51 4-methoxy-6'-hydroxy-2 '-(β-D-glucopyranosyloxy) dihydrochalcone 869 mg,
830 mg of potassium carbonate, 10 m of dimethylformamide
426 mg of methyl iodide are added dropwise to the mixture of 1 and stirred at room temperature overnight.

Concentrate under reduced pressure, add ethyl acetate and water to the residue, stir, and separate the organic layer. After washing with water and drying, the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent: chloroform / methanol),
0.8 g of 4,6′-dimethoxy-2 ′-(β-D-glucopyranosyloxy) dihydrochalcone is obtained.

NMR (DMSO-d ₆ ) δ: 2.80
(2H, t, J = 8.1 Hz), 2.9-3.3 (7
H, m), 3.44 (1H, dd, J = 6.1, 11.
9Hz), 3.71 (6H, s), 4.55 (1H,
t, J = 5.9 Hz), 4.87 (1H, d, J = 7.
7Hz), 5.02 (1H, d, J = 5.3Hz),
5.08 (1H, d, J = 4.9Hz), 5.19 (1
H, d, J = 5.5 Hz), 6.73 (1H, d, J =
8.3 Hz), 6.82 (3H, d, J = 8.7H)
z), 7.15 (2H, d, J = 8.7 Hz), 7.3
0 (1H, t, J = 8.4 Hz) FABMS (m / z): 471 [(M + Na) ⁺ ].

Production Examples 52-53 In the same manner as in Production Example 51, the corresponding starting compounds were converted into the first compound.
The compounds listed in Table 4 are obtained.

[0105]

[Table 14]

Production Example 54 868 mg of 4-methoxy-6′-hydroxy-2 ′-(β-D-glucopyranosyloxy) dihydrochalcone was dissolved in 10 ml of dimethylacetamide, and 212 mg of triethylamine was added, followed by chlorination under ice cooling. Ethyl carbonate 2
Add 28 mg. After stirring at the same temperature for 40 minutes, ethyl acetate is added, and after stirring, the organic layer is separated, washed with water, dried and the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent: chloroform / methanol),
4-methoxy-6'-ethoxycarbonyloxy-2 '
534 mg of-(β-D-glucopyranosyloxy) dihydrochalcone are obtained.

NMR (DMSO-d ₆ ) δ: 1.26
(3H, t, J = 7.1Hz), 2.80 (2H,
m), 3.0-3.5 (7H, m), 3.70 (1H,
m), 3.71 (3H, s), 4.18 (2H, q, J
= 7.1 Hz), 4.57 (1H, t, J = 5.7H
z), 5.02 (1H, d, J = 7.4Hz), 5.0
5 (1H, d, J = 5.3Hz), 5.11 (1H,
d, J = 4.8 Hz), 5.31 (1H, d, J = 5.
5 Hz), 6.82 (2H, ddd, J = 2.1, 3.
0,8.7 Hz), 6.95 (1H, d, J = 8.4H
z), 7.15 (2H, ddd, J = 2.0, 2.9,
8.6 Hz), 7.18 (1H, d, J = 7.9H
z), 7.44 (1 H, t, J = 8.3 Hz) FABMS (m / z): 529 [(M + Na) ⁺ ].

Production Examples 55-60 In the same manner as in Production Example 54, the corresponding starting compounds were converted into the first compound.
The compounds listed in Tables 5 to 16 are obtained.

[0109]

[Table 15]

[0110]

[Table 16]

Production Example 61 (1) 2 '-[2,3,6-tri-O-acetyl-4-
O- (2,3,4,6-tetra-O-acetyl-α-D
-Glucopyranosyl) -β-D-glucopyranosyloxy] -6′-hydroxyacetophenone 4.3 g and p
-1.52 g of anisaldehyde is added to 80 ml of ethanol-methanol (1: 1), and 6 ml of 50% aqueous potassium hydroxide solution is added dropwise with stirring. Then, Production Example 1 (1)
Was treated in the same manner as above, and the resulting crude product was purified by silica gel column chromatography to give 2 '-[4-O- (α-
D-glucopyranosyl) -β-D-glucopyranosyloxy] -6′-hydroxy-4-methoxychalcone 1.
71 g are obtained.

IR (nujol) cm ^-1 : 3600-2
400, 1620 FABMS (m / z): 595 [(M + Na) ⁺ ], 2
71 (2) 2 '-[4-O- (α-D-glucopyranosyl)
1.64 g of -β-D-glucopyranosyloxy] -6'-hydroxy-4-methoxychalcone was dissolved in 30 ml of tetrahydrofuran and treated in the same manner as in Production Example 1 (2) to give 2 '-[4-O. -(Α-D-glucopyranosyl)-
931 mg of β-D-glucopyranosyloxy] -6′-hydroxy-4-methoxydihydrochalcone are obtained.

M. p. : 92 ° C- (gradual decomposition) NMR (DMSO-d ₆ ) δ: 2.83 (2H, t, J
= 7.3 Hz), 3.22 (2H, t, J = 7.3H)
z), 3.0-3.8 (12H, m), 3.71 (3
H, s), 4.55 (2H, m), 4.90 (1H,
d, J = 4.4 Hz), 4.92 (1H, d, J = 5.
4Hz), 4.97 (1H, d, J = 7.8Hz),
5.06 (1H, d, J = 3.9Hz), 5.37 (1
H, d, J = 5.9 Hz), 5.48 (1H, d, J =
5.9 Hz), 5.62 (1H, d, J = 2.9H
z), 6.55 (1H, d, J = 7.8 Hz), 6.6
8 (1H, d, J = 8.3 Hz), 6.82 (2H, d
d, J = 2.9, 8.8 Hz), 7.17 (2H, d
d, J = 2.9, 8.3 Hz), 7.24 (1H, t,
J = 8.3 Hz), 10.95 (1H, brs) IR (nujol) cm ^-1 : 3340,1620 FABMS (m / z): 597 (MH ⁺ ).

Production Examples 62-65 In the same manner as in Production Example 61, the corresponding starting compounds were converted into the first compound.
The compounds listed in Tables 7-18 are obtained.

[0115]

[Table 17]

[0116]

[Table 18]

Reference Example 1 2 ', 6'-dihydroxyacetophenone 1.065
g, cadmium carbonate 4.83 g and toluene 100 ml
The mixture of Dean Stark distillation tube (Dien-S
Reflux while removing the solvent with a tark trap). After removing 30 ml of the solvent, 2,3,6-tri-O-acetyl-4-O- (2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl) -α-D-gluco. Add 11.42 g of pyranosyl bromide and reflux for 17 hours.
After cooling, the insoluble matter is filtered off and the filtrate is concentrated. The residue was purified by silica gel column chromatography and 2'-
[2,3,6-tri-O-acetyl-4-O- (2,
3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl) -β-D-glucopyranosyloxy] -6 ′
4.30 g of hydroxyacetophenone are obtained.

IR (nujol) cm ⁻¹ : 1750, 1630 NMR (CDCl ₃ ) δ: 2.01 (3H, s), 2.
03 (6H, s), 2.04 (3H, s), 2.06
(3H, s), 2.08 (3H, s), 2.10 (3
H, s), 2.59 (3H, s), 3.8-4.35.
(6H, m), 4.46 (1H, dd, J = 2.9, 1
2.2 Hz, 4.87 (1H, dd, J = 4.2, 1)
0.5Hz), 5.06 (1H, t, J = 9.8H
z), 5.21 (1H, d, J = 7.3 Hz), 5.3
2 (1H, d, J = 2.5 Hz), 5.35-5.47
(3H, m), 6.49 (1H, d, J = 8.3H
z), 6.71 (1H, d, J = 8.3 Hz), 7.3
6 (1H, t, J = 8.3 Hz), 12.96 (1H,
s) FABMS (m / z): 793 [(M + Na) ⁺ ].

Reference Example 2 6'-hydroxy-2 '-(2,3,4,6-tetra-
O-acetyl-β-D-glucopyranosyloxy) acetophenone 2.41 g, p-anisaldehyde 1.36
To a mixture of g and 25 ml of ethanol, 2.5 ml of 50% aqueous potassium hydroxide solution was added dropwise with stirring, and the mixture was stirred overnight at room temperature. Concentrate under reduced pressure and add 100 ml of water and 5 ether to the residue.
After adding 0 ml and stirring, the aqueous layer is separated. The ice-cooled lower aqueous layer is neutralized with 10% hydrochloric acid, 200 ml of ethyl acetate is added, and after stirring, the organic layer is separated, washed with water, dried and filtered. The filtrate was concentrated under reduced pressure, the residue was dissolved in 50 ml of ethanol,
Hydrogen reduction is carried out under atmospheric pressure using 10% palladium-carbon as a catalyst. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: chloroform / methanol) to give 4-methoxy-.
1.02 g of 6'-hydroxy-2'-β-D-glucopyranosyloxydihydrochalcone is obtained as a white crystalline powder.

M. p. 127-129 ° C FABMS (m / z): 435 (MH ⁺ ) NMR (d ₆ -DMSO) δ: 2.84 (2H, t, J
= 7.3 Hz), 3.19 to 3.49 (7H, m),
3.7 (1H, m), 3.71 (3H, s), 4.56
(1H, t, J = 5.4 Hz), 4.91 (1H, d,
J = 7.3 Hz), 5.03 (1H, d, J = 4.9H)
z), 5.10 (1H, d, J = 4.4 Hz), 5.2
2 (1H, d, J = 4.9 Hz), 6.55 (1H,
d, J = 8.3 Hz), 6.67 (1H, d, J = 8.
3Hz), 6.81 (2H, d, J = 8.8Hz),
7.17 (2H, d, J = 8.8Hz), 7.24 (1
H, t, J = 8.3 Hz), 10.99 (1H, s).

[0121]

INDUSTRIAL APPLICABILITY The dihydrochalcone derivative [I] and its pharmacologically acceptable salt, which are the active ingredients of the present invention, have an action of increasing urinary glucose which is considered to be based on the inhibition of glucose reabsorption in the kidney. Shows an excellent hypoglycemic effect.
Furthermore, since the active ingredient [I] of the present invention is unlikely to be hydrolyzed in the intestinal tract unlike phlorizin, it can be used for diabetes (eg, insulin-dependent diabetes (type I diabetes), non-insulin) in both oral and parenteral administration. Dependent diabetes (I
It can be effectively used for the prevention and treatment of diabetes mellitus such as type I diabetes). In addition, the active ingredient [I] of the present invention has low toxicity, and its hydrolyzate, aglycone, has a characteristic that the inhibitory action of the facilitated diffusion type sugar transport carrier is extremely weak, and thus it is safe as a medicine. high.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Masanori Inamasu, 3-4, 3-4 Waseda, Misato City, Saitama Prefecture, No. 407 (72) Inventor, Kenji Arakawa 2-38-2, Bessho, Urawa, Saitama 508

Claims (13)

[Claims] 1. A compound of the general formula [I] [Wherein Ar represents an aryl group, OZ represents an optionally protected hydroxyl group or a lower alkoxy group, and R represents a group represented by the formula [I
I] Or a group of the formula [III] (Provided that when OZ is a hydroxyl group and R is a group represented by the formula [II], Ar is a hydroxy group-substituted phenyl group, a lower alkoxy group-substituted phenyl group or a phenyl group. except). ] A hypoglycemic agent containing a dihydrochalcone derivative or a pharmacologically acceptable salt thereof as an active ingredient. 2. The hypoglycemic agent according to claim 1, wherein the aryl group is a hydrocarbon aryl group or a heterocyclic aryl group. 3. The hydrocarbon aryl group is a phenyl group which may have a substituent or a naphthyl group which may have a substituent, and the heterocyclic aryl group has an oxygen atom as a hetero atom, The hypoglycemic agent according to claim 2, which is a heteroaromatic group containing a nitrogen atom or a sulfur atom (the heteroaromatic group may have a substituent). 4. A lower alkyl group which may be substituted with a halogen atom or a hydroxyl group; a lower alkoxy group which may be substituted with a lower alkoxy group; a lower alkoxycarbonyl which may be substituted with a lower alkoxy group. Oxy group; amino group optionally substituted with lower alkyl group or lower alkanoyl group; optionally substituted with 1 to 2 groups selected from lower alkoxy group, lower alkoxycarbonyl group, amino group and phenyl group Lower alkanoyloxy group; halogen atom; hydroxyl group; carbamoyl group; lower alkylthio group; lower alkylsulfinyl group; lower alkylsulfonyl group; carboxyl group; formyl group; cyano group; di (lower alkylcarbamoyloxy group); phenoxycarbonyloxy group; Dioxy group; or low The hypoglycemic agent according to claim 3, which is a benzoyloxy group which may be substituted with a primary alkoxy group. 5. The hypoglycemic agent according to claim 4, wherein R is a group represented by the formula [II]. 6. (1) Ar is a lower alkyl group optionally substituted with a halogen atom or a hydroxyl group: a lower alkoxy group substituted with a lower alkoxy group: a lower alkoxycarbonyl optionally substituted with a lower alkoxy group. Oxy group: Amino group substituted with a group selected from lower alkyl group and lower alkanoyl group: Even if substituted with 1 to 2 groups selected from lower alkoxy group, lower alkoxycarbonyl group, amino group and phenyl group Good lower alkanoyloxy group: halogen atom: carbamoyl group:
Lower alkylthio group: Lower alkylsulfinyl group: Lower alkylsulfonyl group: Carboxyl group: Formyl group: Cyano group: Di-lower alkylcarbamoyloxy group:
Phenoxycarbonyloxy group: lower alkylenedioxy group: and a phenyl group substituted with a group selected from a benzoyloxy group which may be substituted with a lower alkoxy group; two selected from a lower alkyl group, a lower alkoxy group and a hydroxyl group A phenyl group substituted with a substituent of; a furyl group; a thienyl group; a pyridyl group; or a naphthyl group, and OZ is an optionally protected hydroxyl group or a lower alkoxy group, or (2) Ar is The hypoglycemic agent according to claim 5, which is a phenyl group substituted with a lower alkoxy group, and OZ is a protected hydroxyl group or a lower alkoxy group. 7. Ar is a lower alkyl group optionally substituted with a halogen atom: a lower alkoxy group optionally substituted with a lower alkoxy group: a lower alkoxycarbonyloxy group optionally substituted with a lower alkoxy group. : Amino group substituted with lower alkyl group: lower alkanoyloxy group: halogen atom: lower alkylthio group:
Phenoxycarbonyloxy group: lower alkylenedioxy group: and a phenyl group substituted with a group selected from a benzoyloxy group which may be substituted with a lower alkoxy group; or a naphthyl group, and OZ may be protected It is a hydroxyl group or a lower alkoxy group, and R is of the formula [I
The hypoglycemic agent according to claim 6, which is a group represented by I] or [III]. 8. The hypoglycemic agent according to claim 7, wherein R is a group represented by the formula [II]. 9. The hypoglycemic agent according to claim 8, wherein Ar is a lower alkyl group-substituted phenyl group, a lower alkoxycarbonyloxy group-substituted phenyl group, or a halogenophenyl group. 10. The hypoglycemic agent according to claim 4, wherein R is a group represented by the formula [III]. 11. Ar is a phenyl group, a lower alkyl group-substituted phenyl group, a halogenophenyl group, a hydroxy group-substituted phenyl group or a lower alkoxy group-substituted phenyl group, and OZ is an optionally protected hydroxyl group or a lower alkoxy group. The hypoglycemic agent according to claim 10. 12. The phenyl group, a lower alkyl group-substituted phenyl group, a halogenophenyl group or a lower alkoxy group-substituted phenyl group, and OZ is an optionally protected hydroxyl group or a lower alkoxy group. Hypoglycemic agent. 13. The hypoglycemic agent according to claim 1, which is a therapeutic or preventive agent for diabetes.