JP2847695B2 - Hypoglycemic agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a hypoglycemic agent.

[0002]

2. Description of the Related Art In the treatment of diabetes, a diet is essential, but when this alone does not provide sufficient control, insulin or an oral diabetes drug is used as necessary. Conventionally, biguanide compounds and sulfonylurea compounds have been used as diabetes drugs. However, biguanide compounds have the side effect of lactic acidosis, and sulfonylurea compounds have the side effect of severe hypoglycemia, and the development of new therapeutic agents for diabetes that does not have such disadvantages is desired.

[0003] In recent years, glucose toxicity theory 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 increases blood glucose and progresses diabetes [Diabetrolog (Diabetolog).
ia) Volume 28, page 119 (1985), Diabetes Care, No. 1
3, 610 (1990)].

[0004] This theory is verified as follows. That is, it has been confirmed that the condition of diabetic animals is improved and normalized when the blood glucose of diabetic animals is kept normal for a long time without using insulin [Journal of Clinical Investigation (J. Clin. Inve.).
st. 79), 1510 (1987), 80, 1037 (1987), 87, 561 (1991), etc.]. In these verification experiments, phlorizin was used subcutaneously as a reagent for keeping blood glucose normal.

[0005] Phlorizin is a glycoside contained in the bark and root bark of Rosaceae plants such as apples and pears, and has been discovered and studied variously in the last century. Recently, it was found that phlorizin inhibits reabsorption of glucose in the kidney and promotes sugar excretion in this experiment, as it was found to be an inhibitor of the Na ⁺ -glucose cotransporter that is present only in the intestinal and renal chorion. It is interpreted as a correction of hyperglycemia.

However, when phlorizin is administered orally, most of it is hydrolyzed to aglycones, phloretin and glucose, and the rate of absorption as phlorizin is small, and the urinary glucose excretion effect is very weak. In addition, it is known that phloretin, which is an aglycone, strongly inhibits a facilitating diffusion type sugar transporter. For example, it has been reported that intravenous administration of phloretin to rats decreases brain glucose concentration. [Stroke, 1st
4, p. 388 (1983)], and its use over a long period of time may adversely affect various tissues. For that reason, no attempt has been made to use phlorizin as a therapeutic drug for diabetes.

[0007] It is also known that 2 '-(β-D-glucopyranosyloxy) -4,6'-dihydroxydihydrochalcone inhibits the Na ⁺ -glucose cotransporter in the kidney [ For example, Biochimica et Biophysica Acta (Biochim. Biophys. Ac)
ta), Vol. 71, p. 688 (1963)]. However, there is no description that the compound has an urinary glucose increasing effect even when administered orally.

[0008]

DISCLOSURE OF THE INVENTION The present invention relates to a dihydrochalcone derivative which has an excellent urinary glucose increasing action even when administered orally, and whose aglycone has an extremely weak inhibitory action of a facilitating diffusion type sugar transporting carrier. It provides a hypoglycemic agent as a component.

[0009]

According to the present invention, there is provided a compound represented by the general formula [I]:

[0010]

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Wherein Ar represents an aryl group, OZ represents an optionally protected hydroxyl group or a lower alkoxy group;
Is represented by the formula [II]

[0012]

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Or a group represented by the formula [III]

[0014]

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(Where OZ is a hydroxyl group and R is a group represented by the formula [II],
Is a hydroxy-substituted phenyl group, a lower alkoxy-substituted phenyl group or a phenyl group). 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 effect based on the urinary glucose increasing effect. For example, when the active ingredient [I] of the present invention was administered to rats, the amount of glucose excreted in urine in 24 hours was about 6 to 30 times that of the administration of phlorizin. In addition, when the active ingredient of the present invention was orally administered to glucose-loaded diabetic mice, an increase in blood glucose level was significantly suppressed. Therefore, the hypoglycemic agent of the present invention is useful for treating and 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 characteristics not found in conventional hypoglycemic agents.

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

Further, aglycone, which is a hydrolyzate of the active ingredient of the present invention, is different from phloretin in that it has an extremely weak inhibitory effect on sugar incorporation. For example, when human erythrocytes and D- [3- ³ H] glucose were incubated for 1 minute, the radioactivity of the erythrocytes was measured, and the sugar uptake in the erythrocytes was examined. 2 ′, which is the aglycone of the active ingredient of
4,6'-trihydroxydihydrochalcone is 92.2.
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 present invention on the incorporation of sugar into human erythrocytes is significantly smaller than that of phlorizin, which is the aglycone of phlorizin. It is considered that the decrease in the risk is extremely unlikely to occur.

In the dihydrochalcone derivative [I], which is an active ingredient of the present invention, examples of the aryl group include a hydrocarbon aryl group and a heterocyclic aryl group.

Examples of the above-mentioned hydrocarbon aryl group include a phenyl group which may have a substituent and 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 mentioned, and as the heteroaromatic group, a furyl group, And heteroaromatic monocyclic groups such as thienyl and pyridyl.

Further, the above-mentioned phenyl group, naphthyl group,
When the heteroaromatic group has a substituent, the substituent may be a lower alkyl group optionally substituted with a halogen atom or a hydroxyl group; a lower alkoxy group optionally 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 two groups;
Halogen atom; hydroxyl group; carbamoyl group; lower alkylthio group; lower alkylsulfinyl group; lower alkylsulfonyl group; carboxyl group; formyl group;
Di-lower alkylcarbamoyloxy group; phenoxycarbonyloxy group; lower alkylenedioxy group; and benzoyloxy group which may be substituted with lower alkoxy group.

As specific examples of the dihydrochalcone derivative which is an active ingredient of the present invention, in the general formula [I], R is a group represented by the formula [II], and (1) Ar is substituted by a halogen atom or a hydroxyl group. Lower alkyl group optionally substituted: lower alkoxy group substituted by lower alkoxy group:
Lower alkoxycarbonyloxy group optionally substituted by lower alkoxy group: amino group substituted by 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 optionally substituted by one or two 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 phenyl group substituted by a group selected from benzoyloxy group optionally substituted by lower alkoxy group; lower alkyl group, lower alkoxy group and hydroxyl group Choose from A phenyl group substituted by two substituents; a furyl group; a thienyl group; a pyridyl group; or a naphthyl group, wherein OZ is an optionally protected hydroxyl group or lower alkoxy group, or (2) Compounds in which Ar is a lower alkoxy-substituted phenyl group and OZ is a protected hydroxyl group or lower alkoxy group can be given.

In 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 group. A compound wherein OZ is a hydroxyl group or a lower alkoxy group which may be protected.

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

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

In another dihydrochalcone derivative [I] which is preferable from the viewpoint of efficacy, R is a group represented by the formula [III], and Ar is a phenyl group, a lower alkyl-substituted phenyl group, a halogenophenyl group or a lower alkoxy group-substituted group. Compounds that are a phenyl group and a hydroxyl group or a lower alkoxy group in which OZ may be protected.

In the dihydrochalcone derivative [I] exhibiting excellent medicinal effects, R is a group represented by the formula [II], and Ar is a lower alkyl-substituted phenyl group, a lower alkoxycarbonyloxy-substituted phenyl group, or a halogeno group. Compounds that are a phenyl group and a hydroxyl group or a lower alkoxy group in which OZ may be protected.

The active ingredient of the present invention, the dihydrochalcone derivative [I], can be used in the free form or in the form of a pharmaceutically acceptable salt thereof for the purpose of the present invention. Pharmaceutically acceptable salts include inorganic acid salts such as hydrochloride, sulfate and nitrate, and organic acid salts such as acetate and methanesulfonate.

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

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

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

[0032]

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Wherein Ar 'represents an aryl group, OZ' represents a hydroxyl group or a lower alkoxy group which may be protected, and other symbols have the same meanings as described above (provided that OZ '
Is a hydroxyl group and R is a group represented by the formula [II], except that Ar ′ is a lower alkoxy-substituted phenyl group, a hydroxy-substituted phenyl group or a phenyl group). And reducing the chalcone derivative, if necessary, to give a pharmacologically acceptable salt, if desired.

Examples of Ar ′ include the same groups as those described for Ar. Further, when Ar ′ is a phenyl group having a substituent, a naphthyl group having a substituent, or a heteroaromatic group having a substituent, the substituent of each of the above-mentioned groups may be protected. As the protecting group for the substituent of each of the above groups, any group that can be easily removed according to a conventional method such as acid treatment, reduction, or hydrolysis can be used.

When OZ 'is a protected hydroxyl group, the protecting group for the hydroxyl group may be any protecting group for the phenolic hydroxyl group. For example, the same protecting group as the group -OZ may be mentioned. 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 under reduced to heated conditions (particularly at 10 to 30 ° C.) by reduction with a metal hydride, catalytic hydrogen reduction or the like. For example, in the reduction with a metal hydride, in a solvent, a metal hydride [eg, sodium tellurium hydride (Sodium)
(hydrogen telluride), etc.], and the catalytic hydrogen reduction can be carried out by catalytic reduction using a catalyst (eg, palladium-carbon or the like) in a solvent under a normal pressure hydrogen stream.

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

In the starting compound [IV], R represents a compound of the formula [I
The compound represented by the formula (I) is represented by the general formula [Va]

[0039]

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(Provided that OX represents a hydroxyl group which may be protected and other symbols have the same meanings as described above), and an acetophenone derivative represented by the general formula [VI]

[0041]

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

Further, among the starting compounds, the compound represented by the general formula [IV]
Wherein R is a chalcone derivative represented by the formula [III]:
General formula [V-b]

[0044]

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(Wherein the symbols have the same meanings as described above) and an aldehyde compound [VI] are subjected to a condensation reaction, and the protective group is removed if necessary.

When the group -OX of the starting compound [Va] or [Vb] is a protected hydroxyl group, examples of the protecting group include conventional protecting groups such as a lower alkanoyl group. The removal of the protecting group can be performed by a conventional method such as hydrolysis.

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

The starting material compound [Va] of the present invention can be prepared by the method described in Journal of Medicinal and Pharmaceutical Chemistry (J. Med. Pharm.
Chem. ), Vol. 5, p. 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 can be produced by heating and refluxing toluene in the presence of cadmium carbonate. it can.

In the present invention, the lower alkyl group, lower alkoxy group and lower alkylene group include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy,
An ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, a methylene group, an ethylene group, a propylene group and the like having 1 to 6 carbon atoms can be given. Are preferred.

Examples of the lower alkanoyl group include acetyl, propionyl, butyryl, 2-methylpropionyl, valeryl, pivaloyl and the like having 2 to 7 carbon atoms.
And those having 2 to 5 carbon atoms are particularly preferable.

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

[0053]

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Represents the structure represented by

[0055]

[Action]

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

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

The results are as 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 is significantly lower in the sample administration group than in the sample non-administration group.

(Urine glucose increasing action in rats) (Experimental method) Male SD rats (6 weeks old, 3 to 5 per group)
) Was orally administered (dose: 100 mg / kg) twice at 8 hour intervals at a rate of 5 ml / kg. The sample administration solution was prepared by adding Tween 80 (manufactured by Nacalai Tesque, Inc., 0.5% final concentration aqueous solution) to the sample, and suspending it in purified water. On the other hand, 0.5% Twe
Only purified water to which an en80 aqueous solution was added was administered. Twenty-four hours after the first administration, the rats were placed in a metabolic gauge and urine was collected. After measuring the urine volume, remove contaminants by centrifugation, and then use a glucose analyzer (Apec)
The urine sugar concentration was measured with. Urine volume (ml) and urine sugar concentration (mg
/ Dl), the urine sugar (mg) excreted for 24 hours was calculated. In addition, 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 to which the dihydrochalcone derivative [I], which is the active ingredient of the present invention, was administered increased urinary sugar by about 6 to 30 times compared to the group to which phlorizin was administered. 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 a 50% aqueous potassium hydroxide solution is added dropwise, and the mixture is stirred at room temperature overnight. The solvent is distilled off under reduced pressure, water and diethyl ether are added to the residue, and the mixture is stirred, and the aqueous layer is separated. 10% ice-cooled sewage layer
After neutralizing with hydrochloric acid, extract with ethyl acetate. After the obtained organic layer was washed with water and dried, the solvent was distilled off to obtain 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 carried out under normal pressure using 0.5 g of 10% palladium-carbon as a catalyst. After removing the catalyst by filtration, the filtrate 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 = 7.6 Hz), 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.
3 Hz), 7.05 (2H, d, J = 7.8 Hz),
7.14 (2H, d, J = 7.8 Hz), 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, the corresponding
The compounds shown in Tables 1 to 9 are obtained.

[0070]

[Table 4]

[0071]

[Table 5]

[0072]

[Table 6]

[0073]

[Table 7]

[0074]

[Table 8]

[0075]

[Table 9]

Production Example 31 (1) 2 ′-(2,2) was added to 50 ml of dimethylformamide.
4,82 g of 3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) -6′-hydroxyacetophenone and 4.14 g of potassium carbonate 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, and ethyl acetate and water are added to the residue. After stirring, the organic layer is separated. After the obtained organic layer is washed with water and dried, the solvent is distilled off. The residue was purified by silica gel column chromatography, and 3.2 g of 6′-benzyloxy-2 ′-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) acetophenone was obtained. Get.

IR (nujol) cm ^-1 : 1760,1
700,1600 FABMS (m / z): 595 [(M + Na) ⁺ ] (2) 6′-benzyloxy-2 ′-(2,3,4,6
2.9 g of -tetra-O-acetyl-β-D-glucopyranosyloxy) acetophenone and 1.56 g of 4-tetrahydropyranyloxybenzaldehyde were added to 30 ml of ethanol, and 50% aqueous solution of potassium hydroxide 3 was stirred.
Add ml dropwise. Next, the same treatment as in Production Example 1 (1) was performed, and the obtained crude product was dissolved in 50 ml of an acetic acid-water-tetrahydrofuran (2: 1: 2) solution, heated at 50 ° C. for 3 hours, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6′-benzyloxy-2 ′.
1.20 g of-([beta] -D-glucopyranosyloxy) -4-hydroxychalcone are 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 and 0.19 g of triethylamine are dissolved in 30 ml of dimethylacetamide, and 0.20 g of ethyl chlorocarbonate is added dropwise with stirring under 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, and the solvent was distilled off. The residue was purified by silica gel column chromatography to give 6′-benzyloxy-4-ethoxycarbonyloxy-2 ′-(β-D
0.73 g of -glucopyranosyloxy) chalcone are obtained.

FABMS (m / z): 603 [(M + Na) ⁺ ] (4) 0.70 g of 6′-benzyloxy-4-ethoxycarbonyloxy-2 ′-(β-D-glucopyranosyloxy) chalcone Is treated 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. ~ (gradually _{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 = 7.1 Hz), 4.57 (1H, t,
J = 5.7 Hz), 4.91 (1H, d, J = 7.3H)
z), 5.03 (1H, d, J = 5.3 Hz), 5.1
0 (1H, d, J = 4.7 Hz), 5.27 (1H,
d, J = 5.2 Hz), 6.55 (1H, d, J = 8.
2 Hz), 6.68 (1H, d, J = 8.3 Hz),
7.10 (2H, d, J = 8.6 Hz), 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) ⁺ ].

Preparation Examples 32-43 In the same manner as in Preparation Example 31, the compounds shown in Tables 10 to 13 are obtained from the corresponding starting 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 reacted at room temperature for 1 hour. The reaction mixture is poured into ice water, the precipitated insoluble matter is removed by filtration, chloroform is added to the filtrate, and after stirring, the organic layer is separated. The organic layer was dried, concentrated, and the residue was purified by silica gel column chromatography to give 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
With dichloromethane-dimethylformamide (30 ml-
10 ml), and 520 mg of metachloroperbenzoic acid is added to the solution under ice-cooling. After stirring at room temperature for 15 minutes, the mixture is concentrated, and the residue is poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate-tetrahydrofuran. After the organic layer was dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography to give 2 ′-(β-D-glucopyranosyloxy) -6′-hydroxy-4-methylsulfinyldihydrogen. 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. : 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,
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 Examples 1 (1) and (2). Next, the obtained compound was treated with acetic acid-water (2 ml).
-2 ml) at room temperature for 30 minutes.

After diluting with chloroform-methanol (10: 1), the precipitated crystals were recrystallized 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
9 g and 1.56 g of 4-tetrahydropyranyloxybenzaldehyde were added to 30 ml of ethanol.
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 obtain 2′-
(Β-D-glucopyranosyloxy) -6′-benzyloxy-4-tetrahydropyranyloxychalcone
2 g are obtained. The above compound (593 mg) and tetrabutylammonium hydrogen sulfate (136 mg) were subjected to dichloromethane-10%.
An aqueous sodium hydroxide solution (10 ml-5 ml) is added to the biphasic solvent. Then 1.02 g of benzyl chloroformate
And stirred 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 distilled off. The obtained crude product is dissolved in a mixed solution of acetic acid-water-tetrahydrofuran (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 and 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) 816 mg of the above compound, 245 mg of N-benzyloxycarbonylglycine, 266 mg of dicyclohexylcarbodiimide, 1-hydroxy A mixture of 174 mg of benzotriazole hydrate and 10 ml of dimethylformamide is stirred at room temperature for 13 hours. After diluting the reaction solution with ethyl acetate and removing the insoluble matter by filtration, the filtrate is washed with water, dried and the solvent is distilled off. The residue is purified by silica gel column chromatography to give 848 mg of a pale yellow foam.

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

The residue was triturated in diethyl ether, collected by filtration, dried, and 130 mg of 2 ′-(β-D-glucopyranosyloxy) -6′-hydroxy-4-glycyloxydihydrochalcone hydrochloride. 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 = 10.9 Hz), 4.07
(2H, s), 4.69 (1H, bro), 4.91
(1H, d, J = 7.4 Hz), 5.10 (1H, br)
o), 5.19 (1H, bro), 5.29 (1H,
d, J = 4.1 Hz), 6.58 (1H, d, J = 8.
1 Hz), 6.68 (1H, d, J = 8.3 Hz),
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 obtained from the corresponding starting compound.
-([Beta] -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)
oad), 4.91 (1H, d, J = 7.5 Hz),
5.08 (1H, d, J = 4.8 Hz), 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 (1H, 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 In the same manner as in Production Example 48, 2 ′ was obtained from the corresponding starting compound.
-([Beta] -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, 11.4 Hz),
4.51 (1H, dd, J = 5.9, 8.1 Hz),
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,
8.5Hz), 7.24 (1H, t, J = 8.3H)
z), 7.31 (2H, d, J = 8.6 Hz), 7.3
7 (5H, m), 8.88 (3H, broad), 1
0.98 (1H, s) FABMS (m / z): 590 [(M + Na) ⁺ ].

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

After concentrating under reduced pressure, ethyl acetate and water are added to the residue, and after stirring, the organic layer is separated. 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 = 4.9 Hz), 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 to 53 In the same manner as in Production Example 51,
The compounds described in Table 4 are obtained.

[0105]

[Table 14]

Production Example 54 4-methoxy-6'-hydroxy-2 '-(β-D-glucopyranosyloxy) dihydrochalcone (868 mg) was dissolved in dimethylacetamide (10 ml), and triethylamine (212 mg) was added. Ethyl carbonate 2
Add 28 mg. After stirring at the same temperature for 40 minutes, ethyl acetate is added. After stirring, the organic layer is separated, washed with water and 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 = 7.1 Hz), 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 = 7.4 Hz), 5.0
5 (1H, d, J = 5.3 Hz), 5.11 (1H,
d, J = 4.8 Hz), 5.31 (1H, d, J = 5.
5Hz), 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 (1H, 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 compounds shown 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 a 50% aqueous potassium hydroxide solution is added dropwise with stirring. Next, Production Example 1 (1)
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
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)-
[beta] -D-glucopyranosyloxy] -6'-hydroxy-4-methoxydihydrochalcone 931 mg is 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.
4 Hz), 4.97 (1H, d, J = 7.8 Hz),
5.06 (1H, d, J = 3.9 Hz), 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 to 65 In the same manner as in Production Example 61,
The compounds shown in Tables 7 to 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
Of the mixture in a Dean-Stark distillation tube (Dien-S
Reflux while removing the solvent with a mark 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-glucose was removed. 11.42 g of pyranosyl bromide are added and refluxed for 17 hours.
After cooling, the insolubles are filtered off and the filtrate is concentrated. The residue was purified by silica gel column chromatography to give 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)
0.5 Hz), 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
2.5 g of a 50% aqueous solution of potassium hydroxide was added dropwise to a mixture of g and ethanol (25 ml) with stirring, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure.
After adding 0 ml and stirring, the aqueous layer is separated. The aqueous layer is neutralized with 10% hydrochloric acid under ice cooling, and 200 ml of ethyl acetate is added. After stirring, the organic layer is separated, washed with water, dried, and filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in 50 ml of ethanol.
Hydrogen reduction is performed under normal 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 (1 H, d, J = 4.9 H)
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.
3 Hz), 6.81 (2H, d, J = 8.8 Hz),
7.17 (2H, d, J = 8.8 Hz), 7.24 (1
H, t, J = 8.3 Hz), 10.99 (1H, s).

[0121]

The active ingredient of the present invention, dihydrochalcone derivative [I] and a pharmaceutically acceptable salt thereof have a urinary glucose increasing effect which is thought to be due to inhibition of renal glucose reabsorption. Shows an excellent hypoglycemic effect.
Furthermore, the active ingredient [I] of the present invention is unlikely to be hydrolyzed in the intestinal tract unlike the above-mentioned phlorizin, so that both oral and parenteral administration of diabetes (eg, insulin-dependent diabetes (type I diabetes), Dependent diabetes (I
And 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 the feature that the inhibitory action of the facilitated-diffusion-type sugar transporting carrier is extremely weak. high.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Masanori Inamas 3-407-3, Waseda, Misato City, Saitama Prefecture Building No. 407 (72) Inventor Kenji Arakawa 2-38-2, Bessho 2-38-2, Urawa-shi, Saitama 508 (58) Surveyed field (Int.Cl. ⁶ , DB name) A61K 31/70 ADP C07H 15/203 CA (STN) EPAT (QUESTEL) REGISTRY (STN)

Claims (13)

(57) [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 represented by the formula [III]: Wherein OZ is a hydroxyl group and R is a group represented by the formula [II], and Ar is a hydroxy-substituted phenyl group, a lower alkoxy-substituted phenyl group or a phenyl group. except). 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 is 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 optionally substituted with a halogen atom or a hydroxyl group; a lower alkoxy group optionally substituted with a lower alkoxy group; a lower alkoxycarbonyl optionally substituted with a lower alkoxy group An oxy group; an amino group optionally substituted with a lower alkyl group or a lower alkanoyl group; an amino group optionally substituted with one or two groups selected from a lower alkoxy group, a lower alkoxycarbonyl group, an amino group and a 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; Rangeoxy group; or low The hypoglycemic agent according to claim 3, which is a benzoyloxy group optionally substituted with a lower alkoxy group. 5. The hypoglycemic agent according to claim 4, wherein R is a group represented by the formula [II]. (1) Ar is a lower alkyl group optionally substituted by a halogen atom or a hydroxyl group: a lower alkoxy group substituted by a lower alkoxy group: a lower alkoxycarbonyl optionally substituted by a lower alkoxy group Oxy group: Amino group substituted with a group selected from lower alkyl group and lower alkanoyl group: Even when substituted with one or two 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:
A phenoxycarbonyloxy group: a 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, a furyl group, a thienyl group, a pyridyl group, or a naphthyl group, wherein 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 lower alkoxy-substituted phenyl group and OZ is a protected hydroxyl group or 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 by lower alkyl group: lower alkanoyloxy group: halogen atom: lower alkylthio group:
A phenoxycarbonyloxy group: a lower alkylenedioxy group: a phenyl group substituted with a group selected from a benzoyloxy group optionally substituted with a lower alkoxy group; or a naphthyl group, and OZ may be protected. A hydroxyl group or a lower alkoxy group, wherein 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 a hydroxyl group or a lower alkoxy group which may be protected. The hypoglycemic agent according to claim 10. 12. The method according to claim 11, wherein Ar is a 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 an agent for treating or preventing diabetes.