JP3006513B2 - Pharmaceutical composition - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition.

[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 reduces insulin secretion and reduces insulin sensitivity, which causes a further rise in blood sugar,
It has a vicious cycle of developing diabetes [Diabetologia (No. 28)
Vol. 119, 1985, Diabetes Care, Vol. 13, No. 61
0 (1990)]. Therefore, it is said that by correcting hyperglycemia, the above-described vicious cycle can be broken and diabetes can be prevented or treated.

As one method for correcting hyperglycemia, it is conceivable that excess sugar is directly excreted in urine to normalize blood sugar levels. Phlorizin is a glycoside contained in the bark and root bark of Rosaceae plants such as apples and pears, and inhibits the Na ⁺ -glucose cotransporter present only in the intestinal tract and chorion of the kidney, thereby causing phlorizin in the kidney. Inhibits sugar reabsorption, promotes excretion of sugar, and lowers blood sugar. Based on this action, it has been confirmed that phlorizin is subcutaneously administered daily to diabetic animals to correct hyperglycemia and to maintain blood glucose levels normal for a long period of time, thereby improving the condition of diabetic animals and normalizing them ( Journal of Clinical Investigation (J. Clin. Inves)
t. ) 79, 1510 (1987), 8
0, 1037 (1987), 87, 5
61 (1991)].

However, when phlorizin is administered orally, it is mostly hydrolyzed to the 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.

[0006]

DISCLOSURE OF THE INVENTION The present invention has an excellent urinary glucose increasing effect based on an inhibitory effect of renal glucose reabsorption, thereby exhibiting an excellent hypoglycemic effect, and
The aglycone provides a pharmaceutical composition comprising, as an active ingredient, a propiophenone derivative having an extremely weak inhibitory effect of a facilitated-diffusion-type sugar transport carrier.

[0007]

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

[0008]

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[Where X is an oxygen atom, a sulfur atom or a methylene group, OY is a hydroxyl group which may be protected, Z is a β-D-glucopyranosyl group, 4-O- (α
-D-glucopyranosyl) -β-D-glucopyranosyl group or a group in which one or more hydroxyl groups thereof are acylated, and a dotted line indicates the presence or absence of a double bond. And a pharmacologically acceptable salt thereof as an active ingredient.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In the compound [I] which is an active ingredient of the present invention, when OY is a protected hydroxyl group, the protecting group may be any one which can be a protecting group for a phenolic hydroxyl group. A lower alkoxy lower alkyl group such as a methyl group; an acyl group such as a lower alkanoyl group, a lower alkoxy lower alkanoyl group, a lower alkoxycarbonyl group, a benzoyl group; a benzyl group.

In the compound which is an active ingredient of the present invention, a propiophenone structure and a benzofuran, indene or benzothiophene ring or a ring obtained by dihydrogenating the same (hereinafter referred to as a benzofuran ring etc.) are represented by propiophenone. Position and 5th or 6th position such as benzofuran ring
It is preferably bonded to the 5-position, particularly preferably to the 5-position such as a benzofuran ring.

In the compound [I] which is an active ingredient of the present invention, Z is a β-D-glucopyranosyl group or 4-O-
In the case of a (α-D-glucopyranosyl) -β-D-glucopyranosyl group (one or more hydroxyl groups of these groups are acylated), the acyl group includes a C _2-20 alkanoyl group and a lower alkoxy lower alkanoyl. Group, lower alkoxycarbonyl group, benzoyl group, residue obtained by removing the hydroxyl group of one carboxyl group from an amino acid (the amino group and / or carboxyl group present in the residue may be protected by a conventional protecting group) And the like, as the residue obtained by removing the hydroxyl group of one carboxyl group from an amino acid, for example, glutamic acid, glutamine, serine,
Sarcosine, proline, phenylalanine, leucine,
Examples include natural amino acids such as isoleucine, glycine, tryptophan, cysteine, histidine, tyrosine and valine, and residues obtained by removing the hydroxyl group of one carboxyl group from its enantiomer or racemate.

As a specific example of the propiophenone derivative [I] which is the active ingredient of the present invention, in the general formula [I], Z is a β-D-glucopyranosyl group or 4-O-
(Α-D-glucopyranosyl) -β-D-glucopyranosyl group (these groups are selected from C _2-20 alkanoyl group, lower alkoxy lower alkanoyl group, lower alkoxycarbonyl group and benzoyl group, and one or more hydroxyl groups are Which may be acylated).

As a preferred compound, in formula (I), OY represents a lower alkanoyloxy group or a hydroxyl group, and Z represents a group selected from a C _2-20 alkanoyl group, a lower alkoxy lower alkanoyl group, a lower alkoxycarbonyl group and a benzoyl group. And a β-D-glucopyranosyl group in which the 2- or 3-position hydroxyl group or the 6-position hydroxyl group may be acylated, and a compound in which the dotted line represents the presence of a double bond, wherein X represents an oxygen atom or a sulfur atom, Compounds in which OY is a hydroxyl group are particularly preferred.

As compounds having excellent medicinal effects, X is an oxygen atom or a sulfur atom, OY is a hydroxyl group, and Z is β-D-
Compounds that are a glucopyranosyl group or a 4-O- (α-D-glucopyranosyl) -β-D-glucopyranosyl group are exemplified.

Other compounds having excellent medicinal effects include:
X is an oxygen atom, OY is a lower alkanoyloxy group or a hydroxyl group, Z is 2,3-di-O- (lower alkanoyl)-
β-D-glucopyranosyl group, 2,3-di-O- (lower alkoxy lower alkanoyl) -β-D-glucopyranosyl group, 6-O- (C _2-20 alkanoyl) -β-D-glucopyranosyl group, 6- O- (lower alkoxy lower alkanoyl) -β-D-glucopyranosyl group or 6-O
-Benzoyl-β-D-glucopyranosyl group.

Compounds having superior medicinal effects include:
X is an oxygen atom, OY is a lower alkanoyloxy group or a hydroxyl group, Z is 2,3-di-O- (lower alkanoyl)-
Compounds that are β-D-glucopyranosyl groups can be mentioned, and in particular, 2 ′-[2,3-di-O- (lower alkanoyl) -β-D-glucopyranosyloxy]-
6'-hydroxy-3- (5-benzo [b] furanyl)
Propiophenone or 2 '-[2,3-di-O- (lower alkanoyl) -β-D-glucopyranosyloxy]
Compounds that are -6 '-(lower alkanoyloxy) -3- (5-benzo [b] furanyl) propiophenone are preferred.

Another compound having excellent medicinal properties is 2 '-(β-D-glucopyranosyloxy)-
6'-hydroxy-3- (5-benzo [b] furanyl)
Propiophenone or a pharmaceutically acceptable salt thereof can be mentioned.

The propiophenone derivative [I], which is the active ingredient of the present invention, can be used for the purpose of the present invention either in a free form or in the form of a pharmaceutically acceptable salt thereof. Examples of the pharmaceutically acceptable salt include an alkali metal salt such as a sodium salt.

The compound [I] and the pharmaceutically acceptable salt thereof, which are the active ingredients of the present invention, can be administered orally or parenterally, and the medicaments usually used for oral or parenteral administration An appropriate preparation can be prepared using a carrier. Such pharmaceutical carriers include, for example, binders (syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar,
Corn starch, potassium phosphate, sorbite, 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, powders,
It may be a solid preparation such as a granule, a solution, a suspension,
It may be a liquid preparation such as an emulsion. On the other hand, when administered parenterally, for example, distilled water for injection, physiological saline,
Injectables and infusions can be made using aqueous glucose solutions and the like.

The dose of the propiophenone derivative [I], which is the active ingredient of the present invention, varies depending on the age, weight, condition and degree of disease of the patient. Usually, the daily dose is that of oral administration. Is 0.1 to 100 mg / k
g, especially 1 to 40 mg / kg, in the case of parenteral administration, 0.01 to 50 mg / kg, especially 0.1 to 10 mg / kg.
It is preferably mg / kg.

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

[0023]

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(Wherein, the symbols have the same meanings as described above). The compound can be produced by reducing the acrylophenone derivative represented by the formula (1) and, if desired, converting it into a pharmacologically acceptable salt.

This reduction reaction can be carried out by a conventional method, such as reduction with a metal hydride, catalytic reduction and the like. For example, in the reduction with a metal hydride, a metal hydride [for example, sodium telluride hydride (NaTeH) or the like] is used in a solvent (for example, an organic solvent of methanol or ethanol or a mixed solvent of these organic solvents and water). Sodium tellurium hydride can be prepared according to the method described in Synthesis, page 545 (1978). And in the catalytic reduction, a solvent (eg,
Methanol or ethanol, or a mixed solvent of these organic solvents and water) in a hydrogen atmosphere at normal pressure using a catalyst (eg, palladium-carbon, platinum-carbon, platinum oxide, etc.) under cooling to heating. (Particularly 10 ° C. to 30 ° C.) and can be carried out by catalytic reduction.

In the case where the starting compound [II] is a compound in which the dotted line indicates the presence of a double bond, a compound in which the double bond is also reduced may be produced by the present reduction reaction. The compound obtained in this manner is also included in the compound as the active ingredient of the present invention.

Further, the compound which is the active ingredient of the present invention thus obtained can be mutually converted by the following method.

Among the compounds which are the active ingredients of the present invention, Z
Is a β-D-glucopyranosyl group wherein the hydroxyl group at the 6-position is acylated, that is, a compound of the general formula [I-b]

[0029]

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(Wherein R represents an acyl group, and other symbols have the same meanings as described above). Among the compounds which are the active ingredients of the present invention, Z is a β-D-glucopyranosyl group. A compound represented by the general formula [Ia]

[0031]

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(Wherein, the symbols have the same meanings as described above).

Among the compounds which are the active ingredients of the present invention, Z
Is a β-D-glucopyranosyl group wherein the hydroxyl groups at the 2- and 3-positions are acylated, that is, a compound of the general formula [Ic]

[0034]

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(Wherein the symbols have the same meanings as described above) are represented by the β-D of compound [Ia].
-Protecting the hydroxyl groups at the 4- and 6-positions of the glucopyranosyl group;

[0036]

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(Wherein R'O represents a protected hydroxyl group and the other symbols have the same meanings as described above), and then the compound represented by the formula (2) of the β-D-glucopyranosyl group is obtained.
And acylating the 3-position hydroxyl group and removing the protecting group.

In the compound [III], a conventional protecting group can be used as the protecting group.
Those in which the protecting groups at the 6-position and 6-position hydroxyl groups are bonded to each other to form an alkylidene group such as a benzylidene group or an isopropylidene group can be suitably used.

The acylation of the starting compound [Ia] or [III] is carried out by an organic acid corresponding to a desired acyl group (for example, C _1-19 alkyl carboxylic acid, lower alkoxy lower alkyl carboxylic acid, lower alkoxy carboxylic acid). Benzoic acid, etc.), a salt thereof or a reactive derivative thereof (hereinafter, referred to as an acylating agent) and a starting compound,
Can be implemented.

The reaction between the organic acid corresponding to the acyl group or a salt thereof and the starting compound is carried out in a suitable solvent (eg, dichloromethane) in the presence or absence of a condensing agent (eg, dicyclohexylcarbodiimide). The reaction between the reactive derivative of the organic acid and the starting compound is carried out in a suitable solvent (for example, dichloromethane or the like) or without a solvent in the presence or absence of a deoxidizing agent (for example, an alkali metal hydroxide or the like) under cooling to Under heating (preferably -10C to 100C,
(In particular, 0 ° C. to 50 ° C.).

Examples of the salt of an organic acid include alkali metal salts such as sodium salt, potassium salt and calcium salt, and alkaline earth metal salts. When these organic acid salts are used in the condensation reaction, it is preferable to leave them as free acids during the reaction.

Examples of the reactive derivative include acid halides, acid anhydrides and active esters of the corresponding organic acids.

In the present acylation reaction, when the group OY of the starting compound is a free hydroxyl group, the hydroxyl group may be acylated, and the product obtained in this manner is also an active ingredient of the present invention. Are included in the compounds of

The active ingredient of the present invention is represented by the general formula [Ia]
Is a compound [I] which is an active ingredient of the present invention, wherein Z is a β-D-glucopyranosyl group or a 4-O- (α-D-glucopyranosyl) -β-D-glucopyranosyl group (these are the same). Wherein one or more hydroxyl groups are acylated).

Further, among the compounds which are the active ingredients of the present invention, X is a methylene group and the dotted line indicates the presence of a double bond, that is, a compound of the general formula [Id]

[0046]

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In the indene type compound represented by the formula (wherein the symbols have the same meanings as described above), a leaving group is introduced in advance to a compound in which X is a methylene group and the dotted line indicates the absence of a double bond. Compounds, that is, the general formula [IV]

[0048]

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(Where A represents a leaving group, and other symbols have the same meanings as described above). The compound can also be produced by removing a hydrogen atom and a leaving group A from an indane type compound represented by the following formula: it can.

The elimination reaction is carried out in a suitable solvent (for example, dichloromethane or the like) or without a solvent in the presence or absence of a base (for example, tri-lower alkylamine, pyridine and the like) under cooling to heating ( Preferably, it can be carried out under heating, especially at 100 ° C to 150 ° C).

As the leaving group A, a conventional leaving group, for example, a halogen atom such as a chlorine atom or a bromine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group and the like can be suitably used.

In this elimination reaction, the 5-position bonded to the 3-position of propiophenone and the 5- or 6-position of the indene ring.
The indene-type compound and the 6-indene-type compound may be obtained by mixing, and the mixture obtained in this way is also included in the compound as the active ingredient of the present invention.
Also, if obtained as a mixture, if necessary,
Both compounds can be separated by chromatography or the like.

The starting compound [II] has the general formula [V]

[0054]

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(Provided that Z ′ is a β-D-glucopyranosyl group in which a hydroxyl group may be protected or 4-O- (α-D-glucopyranosyl) in which a hydroxyl group may be protected.
Represents a -β-D-glucopyranosyl group, and other symbols have the same meanings as described above. An acetophenone compound represented by the formula [VI]:

[0056]

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

Z ′ of the starting compound [V] is a hydroxyl-protected β-D-glucopyranosyl group or a hydroxyl-protected 4-O- (α-D-glucopyranosyl) -β-D
In the case of a -glucopyranosyl group, as the protecting group, a conventional protecting group such as a lower alkanoyl group can be used,
The removal of the protecting group can be performed by a conventional method such as hydrolysis.

The condensation reaction between the acetophenone derivative [V] 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). ) And in the presence of a base (such as an alkali metal hydroxide) under cooling to heating (particularly 10 ° C to 30 ° C).

When the acylation of the product is necessary, the acylation can be carried out in the same manner as in the acylation of the compound [Ia] or [III] described above. In addition, the acylation may be performed by differentiating the steric environment of the hydroxyl groups of the raw material compounds and / or by acylating all the hydroxyl groups by adjusting the amount of the acylating agent used, or by selectively converting the hydroxyl groups. It can also be acylated.

Compound [II] obtained by this reaction
May be purified and used for the reaction, but may be used crude for the reduction reaction.

Compound [IV] can be produced, for example, by the method described below.

[0063]

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(Where A 'is a protected hydroxyl group and other symbols have the same meanings as described above). (A) A Grignard reagent is prepared from compound [VII] and magnesium by a conventional method. Then, it is reacted with dimethylformamide or the like in an appropriate solvent (for example, tetrahydrofuran) to obtain a formylated compound [VIII]. As the protecting group for A ′, a conventional protecting group (for example, a tetrahydropyranyl group) that can be easily removed by a conventional method can be used.

(B) Compound [VIII] and Compound [V]
To remove the protecting group, if necessary, and further, if necessary, to obtain the compound [IX]. This reaction can be carried out in the same manner as in the step of producing compound [II].

(C) Compound [IX] is reduced to obtain compound [X]. This reduction reaction can be carried out in the same manner as in the step of producing compound [I].

(D) After removing the protecting group in A ′,
The hydroxyl group is converted to a leaving group A to obtain a compound [IV].
Conversion of a hydroxyl group to a leaving group is carried out by a halogenating agent, methanesulfonyl chloride, p-toluenesulfonyl chloride or the like in a suitable solvent (for example, pyridine) in the presence or absence of a base according to a conventional method. By doing
Can be implemented.

The starting material compound [V] can be obtained from (i) Journal of Medicinal and Pharmaceutical Chemistry (J. Med. Pharm. Chem.), Vol.
According to the method described on page 1054 (1962), for example, 2 ′, 6′-dihydroxyacetophenone and 2,2
Prepared by reacting 3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide in aqueous acetone in the presence of potassium hydroxide and then optionally protecting the phenolic hydroxyl group. Or (ii) for example, 2 ′, 6′-dihydroxyacetophenone and 2,
3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide or 2,3,6-tri-O-acetyl-4-O- (2,3,4,6-tetra-O -Acetyl-α-D-glucopyranosyl) -α-D-glucopyranosyl bromide in toluene in the presence of cadmium carbonate, heating and refluxing, and then, if desired, protecting the phenolic hydroxyl group. it can.

In the present specification, examples of the lower alkoxy group include a methoxy group, an ethoxy group, a propoxy group,
Isopropoxy, butoxy, isobutoxy, te
Examples thereof include a linear or branched alkoxy group having 1 to 6 carbon atoms such as an rt-butoxy group.
Four are preferred.

Examples of the C _2-20 alkanoyl group include acetyl, propionyl, butyryl, 2-methylpropionyl, valeryl, pivaloyl, lauroyl, myristoyl, palmitoyl, stearoyl and the like. 20 linear or branched alkanoyl groups can be mentioned. As a lower alkanoyl group,
Among the above alkanoyl groups, mention may be made of straight-chain or branched alkanoyl groups having 2 to 7 carbon atoms, with those having 2 to 5 carbon atoms being particularly preferred.

In the present specification, β-D-glucopyranosyl is represented by the following formula:

[0072]

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Represents a structure represented by the formula: 4-O- (α-D
-Glucopyranosyl) -β-D-glucopyranosyl is represented by the following formula:

[0074]

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Represents the structure represented by

Experimental Example (Urine sugar increasing effect in rats) (Experimental method) Tween 80 (manufactured by Nacalai Tesque, Inc.) and water were added to a sample (compound described in the following Production Example or phlorizin), and the mixture was added to 5 ml of a 0.5% Tween 80 aqueous solution. A sample administration solution containing 100 mg of the sample was prepared. In the sample administration group, male SD rats (6 weeks old, 3 to 5 rats per group) were orally administered the sample administration solution twice at 8 hour intervals (dose: 10
0 mg / kg / time). On the other hand, 0.5% T
The aqueous solution of ween 80 was administered (dose: 5 ml / kg / time). Twenty-four hours after the first administration, the rats were placed in a metabolic gauge and urine was collected. After measuring the urine volume, the contaminants were removed by centrifugation, and then the urine sugar concentration was measured with a glucose analyzer (Apec). The amount of urinary glucose excreted in 24 hours calculated from the amount of urine (ml) and the concentration of urinary sugar (mg / dl) was calculated as the amount of urinary sugar per 200 g of body weight (mg / 2
4 hr / 200 g body weight). The results are as shown in Table 1.

[0077]

[Table 1]

As is apparent from the above results, the group to which the propiophenone derivative [I], which is the active ingredient of the present invention, was administered increased urinary glucose by about 11 to 100 times compared to the group to which phlorizin was administered. You can see that there is.

[0079]

[Production example]

Production Example 1 2 '-(2,3,4,6-tetra-O-acetyl-β-
To a mixture of 965 mg of D-glucopyranosyloxy) -6'-hydroxyacetophenone, 350 mg of benzo [b] furan-5-carbaldehyde and 10 ml of ethanol, 2 ml of a 50% aqueous potassium hydroxide solution was added dropwise, and the mixture was stirred at room temperature overnight. I do. The solvent is distilled off under reduced pressure, water and diisopropyl ether are added to the residue, and the mixture is stirred, and the aqueous layer is separated.
The aqueous layer under ice cooling is neutralized with 10% hydrochloric acid and extracted with ethyl acetate. After the obtained organic layer was washed with water and dried, the solvent was distilled off to obtain crude 2 ′-(β-D-glucopyranosyloxy).
-6'-Hydroxy-3- (5-benzo [b] furanyl) acrylophenone is obtained. This product was previously prepared from 383 mg of tellurium and 270 mg of sodium borohydride in an ethanol solution of sodium tellurium hydride 15
and react for 2.5 hours at room temperature. The insoluble material is removed by filtration, and water and ethyl acetate are added to the filtrate. After stirring, the organic layer is separated. After the organic layer was washed with water and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography.
480 mg of 2 ′-(β-D-glucopyranosyloxy) -6′-hydroxy-3- (5-benzo [b] furanyl) propiophenone are obtained.

NMR (DMSO-d ₆ ) δ: 3.00
(2H, t, J = 7.5 Hz), 3.1-3.4 (6
H, m), 3.47 (1H, m), 3.71 (1H, d
dd, J = 1.7, 5.1, 11.4 Hz), 4.56
(1H, t, J = 5.7 Hz), 4.93 (1H, d,
J = 7.4 Hz), 5.03 (1H, d, J = 5.2H)
z), 5.10 (1H, d, J = 4.6 Hz), 5.2
5 (1H, d, J = 5.3 Hz), 6.55 (1H,
d, J = 8.2 Hz), 6.68 (1H, d, J = 7.
8 Hz), 6.87 (1H, dd, J = 1.0, 3.2)
Hz), 7.21 (1H, dd, J = 1.8, 8.5H)
z), 7.24 (1H, t, J = 8.3 Hz), 7.4
6 (1H, d, J = 8.5 Hz), 7.53 (1H,
d, J = 1.3 Hz), 7.92 (1H, d, J = 2.
2 Hz), 10.98 (1H, s) FABMS (m / z): 467 [(M + Na) ⁺ ].

Production Example 2 2 '-(2,3,4,6-tetra-O-acetyl-β-
To a mixture of 1500 mg of D-glucopyranosyloxy) -6'-hydroxyacetophenone, 545 mg of benzo [b] furan-5-carbaldehyde and 15 ml of ethanol, 3 ml of a 50% aqueous potassium hydroxide solution was added dropwise, and the mixture was stirred at room temperature overnight. . 10% platinum-carbon 30 was added to the obtained reaction solution.
3 mg is added and catalytic reduction is performed under normal pressure. The catalyst is removed by filtration, the filtrate is concentrated under reduced pressure, toluene and water are added to the residue, and the mixture is stirred, and the aqueous layer is separated. Under ice cooling, the aqueous layer is made acidic with 10% hydrochloric acid and extracted with ethyl acetate. Wash the obtained organic layer with water,
After drying, the solvent was distilled off, the residue was purified by silica gel column chromatography, and 2 ′-(β-D-glucopyranosyloxy) -6′-hydroxy-3- (5-benzo [b] 982 mg of (furanyl) propiophenone are obtained.
Physical properties are as described in Production Example 1.

Production Example 3 2 '-(2,3,4,6-tetra-O-acetyl-β-
1268 mg of D-glucopyranosyloxy) -6′-hydroxyacetophenone and 911 mg of benzo [b] furan-5-carbaldehyde were reacted and treated in the same manner as in Production Example 1 to give crude 2 ′-(β-D-glucose). Pyranosyloxy)
-6'-Hydroxy-3- (5-benzo [b] furanyl) acrylophenone is obtained. Use this product in ethanol 20
The resulting mixture is dissolved in a mixed solvent of 2 ml of acetic acid and 2 ml of acetic acid, and catalytically reduced under normal pressure using 0.5 g of 10% palladium-carbon as a catalyst. The catalyst is removed by filtration, the filtrate is concentrated under reduced pressure, ethyl acetate and water are added to the residue, and the mixture is stirred, and the organic layer is separated. The organic layer is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent is distilled off. The residue was triturated in chloroform-diisopropyl ether, filtered, dried and dried at 2 '-(β-D-
Glucopyranosyloxy) -6'-hydroxy-3-
920 mg of (2,3-dihydro-5-benzo [b] furanyl) propiophenone are obtained.

NMR (DMSO-d ₆ ) δ: 2.81
(2H, t, J = 7.5 Hz), 3.12 (2H, t,
J = 8.6 Hz), 3.15-3.38 (6H, m),
3.46 (1H, m), 3.70 (1H, m), 4.4
6 (2H, t, J = 8.7 Hz), 4.55 (1H,
t, J = 5.7 Hz), 4.91 (1H, d, J = 7.
5Hz), 5.02 (1H, d, J = 5.2Hz),
5.09 (1H, d, J = 4.7 Hz), 5.20 (1
H, d, J = 5.3 Hz), 6.55 (1H, d, J =
8.3 Hz), 6.62 (1H, d, J = 8.1H)
z), 6.67 (1H, d, J = 7.7 Hz), 6.9
5 (1H, dd, J = 1.8, 8.1 Hz), 7.11
(1H, broad-s), 7.24 (1H, t, J =
8.3 Hz), 11.00 (1H, s) FABMS (m / z): 469 [(M + Na) ⁺ ].

Production Example 4 In the same manner as in Production Example 1, 2 ′ was obtained from the corresponding starting compound.
-([Beta] -D-glucopyranosyloxy) -6'-hydroxy-3- (5-benzo [b] thienyl) propiophenone is obtained.

NMR (DMSO-d ₆ ) δ: 3.03
(2H, t, J = 7.3 Hz), 3.1-3.4 (6
H, m), 3.47 (1H, m), 3.71 (1H, d
dd, J = 1.5, 5.1, 11.7 Hz), 4.56
(1H, t, J = 5.7 Hz), 4.93 (1H, d,
J = 7.3 Hz), 5.03 (1H, d, J = 5.1H)
z), 5.10 (1H, d, J = 4.4 Hz), 5.2
6 (1H, d, J = 5.1 Hz), 6.55 (1H,
d, J = 8.1 Hz), 6.69 (1H, d, J = 8.
1Hz), 7.26 (1H, t, J = 8.1Hz),
7.29 (1H, dd, J = 1.5, 8.8 Hz),
7.38 (1H, dd, J = 0.7, 5.5 Hz),
7.70 (1H, d, J = 5.5 Hz), 7.76 (1
H, d, J = 0.7 Hz), 7.87 (1H, d, J =
8.1 Hz), 11.01 (1 H, s) FABMS (m / z): 483 [(M + Na) ⁺ ].

Production Example 5 (1) 3.01 g of 6-bromoindan-1-ol and 1.78 g of dihydropyran were dissolved in 50 ml of dichloromethane, and 178 m of pyridinium p-toluenesulfonate was dissolved.
g and stirred at room temperature for 1.5 hours. The reaction solution is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate) to give 6-bromo-1.
4.10 g of tetrahydropyranyloxyindane are obtained.

MS (m / z): 296, 298 (M ⁺ ) (2) Under an argon atmosphere, a mixture of 228 mg of magnesium and 3 mg of iodine in 3 ml of tetrahydrofuran was heated to 60 ° C. and 6-bromo-1 was stirred. 5 ml of a tetrahydrofuran solution of 2.60 g of tetrahydropyranyloxyindane are added dropwise. After completion of the dropwise addition, the mixture is stirred at 70 ° C. for 1 hour. Next, 2 ml of a tetrahydrofuran solution of 959 mg of dimethylformamide is added dropwise under ice cooling, and the mixture is further stirred for 1 hour under ice cooling. The reaction solution is poured into an ice-acetic acid mixture, extracted with ethyl acetate, washed with water, dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate) to give 1-tetrahydropyranyloxyindane-6-carbaldehyde 1.
081 mg are obtained.

MS (m / z): 246 (M ⁺ ) (3) 2 ′-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) -6′- Hydroxyacetophenone and 1-tetrahydropyranyloxyindan-6-carbaldehyde were treated in the same manner as in Production Example 1 to give 2 ′-(β-D-glucopyranosyloxy) -6 ′.
-Hydroxy-3- (1-tetrahydropyranyloxyindan-6-yl) propiophenone is obtained.

FABMS (m / z): 567 [(M + N
a) ⁺ ] (4) 2 ′-(β-D-glucopyranosyloxy)-
6'-hydroxy-3- (1-tetrahydropyranyloxyindan-6-yl) propiophenone 1160m
g was dissolved in 10 ml of pyridine, 1.63 g of acetic anhydride was added, and the mixture was stirred at room temperature overnight. After the pyridine was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and dried, and the solvent was distilled off to give 2 ′-(2,3,4,6-tetra-O-acetyl-β-D- 1438 mg of glucopyranosyloxy) -6′-acetoxy-3- (1-tetrahydropyranyloxyindan-6-yl) propiophenone are obtained.
This product is dissolved in a mixed solvent of 20 ml of acetic acid, 10 ml of tetrahydrofuran and 5 ml of water, and the mixture is stirred at 45 ° C. for 3 hours.
Then, ethyl acetate and water are added, and the mixture is stirred, and the organic layer is separated. After the organic layer is washed with water and dried, the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent: chloroform: acetone), and 2 ′-(2,3,4,6-
1071 mg of tetra-O-acetyl-β-D-glucopyranosyloxy) -6′-acetoxy-3- (1-hydroxyindan-6-yl) propiophenone are obtained.

FABMS (m / z): 693 [(M + N
a) ⁺ ] (5) 2 ′-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) -6′-acetoxy-3- (1-hydroxyindane-6) -Yl) 1054 mg of propiophenone in 30 ml of pyridine,
329 mg of p-toluenesulfonyl chloride was added, and 7
Stir at 5 ° C. overnight. Further, 150 mg of p-toluenesulfonyl chloride is added, and the mixture is refluxed for 2 days. After the pyridine was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and dried. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (solvent: chloroform: ethyl acetate).
And purified by 2 ′-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) -6′-hydroxy-3- (inden-6-yl) propio 1 of phenone and 2 ′-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) -6′-hydroxy-3- (inden-5-yl) propiophenone : 676 mg of a mixture are obtained.

FABMS (m / z): 633 [(M + N
a) ⁺ ] (6) 2 ′-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) -6′-hydroxy-3- (inden-6-yl) Propiophenone and 2 ′-(2,3,4,6-tetra-O-acetyl-β-
D-glucopyranosyloxy) -6′-hydroxy-3
-Mixture 6 of-(inden-5-yl) propiophenone
Dissolve 60 mg in methanol 20 ml, add potassium carbonate 1 g and water 0.2 ml, and stir at room temperature for 1 hour.
After the reaction solution is neutralized with 10% hydrochloric acid under ice cooling, ethyl acetate is added and stirred, and 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 (solvent; chloroform: methanol), and 2 ′-(β-D-glucopyranosyloxy) -6′-hydroxy-3- (inden-6-yl) was used.
Propiophenone and 2 ′-(β-D-glucopyranosyloxy) -6′-hydroxy-3- (indene-5
Il) 441 mg of a 1: 1 mixture of propiophenone are obtained.

NMR (DMSO-d ₆ ) δ: 2.94
(2H × 2, t, J = 7.5 Hz), 3.1-3.4
(8H × 2, m), 3.46 (1H × 2, m), 3.7
0 (1H × 2, ddd, J = 1.9, 5.3, 11.7)
Hz), 4.55 (1H × 2, t, J = 5.4 Hz),
4.93 (1H × 2, d, J = 7.2 Hz), 5.02
(1H × 2, d, J = 5.2 Hz), 5.09 (1H ×
2, d, J = 4.7 Hz), 5.22 (1H × 2, d,
J = 5.1 Hz), 6.53 (1H, dt, J = 5.
5,2.0 Hz), 6.55 (1H × 2, d, J = 8.
4Hz), 6.58 (1H, dt, J = 5.5, 2.0)
Hz), 6.68 (1H × 2, d, J = 8.1 Hz),
6.88 (1H × 2, m), 7.07 (1H, dd, J
= 1.5, 7.6 Hz), 7.14 (1H, dd, J =
1.5, 7.8 Hz), 7.25 (1H × 2, t, J =
8.3 Hz), 7.29 (1H, d, J = 8.0H)
z), 7.31 (1H, s), 7.36 (1H, d, J
= 7.6 Hz), 7.39 (1H, s), 11.02
(1H × 2, s) FABMS (m / z): 465 [(M + Na) ⁺ ].

Production Example 6 (1) 2 ′-(β-D-glucopyranosyloxy)-
6'-hydroxy-3- (5-benzo [b] furanyl)
4.44 g of propiophenone and 80 ml of dichloromethane
To a mixture of 3.
04 g and 0.19 g of p-toluenesulfonic acid were added,
Stir at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the obtained residue is dissolved in ethyl acetate. The organic layer was washed with water and dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent: chloroform: methanol) to give 2 ′-(4,6-O-benzylidene-β-D-glucopyrrate). Nosyloxy) -6'-hydroxy-3- (5-
5.84 g of benzo [b] furanyl) propiophenone are obtained.

NMR (DMSO-d ₆ ) δ: 3.00
(2H, t, J = 7.6 Hz), 3.2-3.4 (6
H, m), 3.5-3.6 (1H, m), 4.20 (1
H, t, J = 5.1 Hz), 5.17 (1H, d, J =
7.7 Hz), 5.47 (1H, d, J = 5.2H)
z), 5.58 (1H, s), 5.59 (1H, d, J
= 5.8 Hz), 6.57 (1H, d, J = 8.1H)
z), 6.72 (1H, d, J = 8.1 Hz), 6.8
9 (1H, dd, J = 1.0, 2.2 Hz), 7.21
(1H, dd, J = 1.9, 8.5 Hz), 7.25
(1H, t, J = 8.3 Hz), 7.35-7.55
(7H, m), 7.94 (1H, d, J = 2.2H
z), 10.82 (1H, s) FABMS (m / z): 555 [(M + Na) ⁺ ].

(2) 2 ′-(4,6-O-benzylidene-β-D-glucopyranosyloxy) -6′-hydroxy-3- (5-benzo [b] furanyl) propiophenone 78 g is dissolved in 50 ml of pyridine, 6.65 g of acetic anhydride is added, and the mixture is stirred at room temperature for 4 hours. Ethyl acetate is added to the reaction solution, and the mixture is poured into ice-10% hydrochloric acid, stirred, and the organic layer is separated. After the obtained organic layer was washed with water and dried, the solvent was distilled off to obtain crude 2 '-(2,3-di-O-acetyl-
4,6-O-benzylidene-β-D-glucopyranosyloxy) -6′-acetoxy-3- (5-benzo [b]
7.24 g of (furanyl) propiophenone are obtained. This product 5
20 mg is dissolved in 10 ml of acetic acid, and 1.5 ml of water and p
-Add 45 mg of toluenesulfonic acid and stir at 50 ° C for 5 hours. Water and ethyl acetate are added to the reaction solution, and after stirring, the organic layer is separated, washed with water and dried. After distilling off the solvent,
The residue was purified by silica gel column chromatography (solvent; chloroform: methanol) to give 2 ′-(2,3
-Di-O-acetyl-β-D-glucopyranosyloxy) -6′-acetoxy-3- (5-benzo [b] furanyl) propiophenone (360 mg) is obtained.

NMR (DMSO-d ₆ ) δ: 1.88
(3H, s), 2.00 (6H, s), 2.9-3.1
(4H, m), 3.5-3.8 (4H, m), 4.75
(1H, t, J = 5.5 Hz), 4.90 (1H, d
d, J = 8.0, 9.8 Hz), 5.11 (1H, t,
J = 9.2 Hz), 5.50 (1H, d, J = 7.9H)
z), 5.59 (1H, d, J = 5.7 Hz), 6.8
8 (1H, d, J = 7.9 Hz), 6.90 (1H, d, J = 7.9 Hz)
d, J = 2.2 Hz), 7.16 (1H, d, J = 8.
1 Hz), 7.17 (1H, dd, J = 1.7, 8.5)
Hz), 7.44 (1H, t, J = 8.2 Hz), 7.
48 (1H, d, J = 1.8 Hz), 7.49 (1H,
d, J = 8.6 Hz), 7.94 (1H, d, J = 2.
2 Hz) FABMS (m / z): 593 [(M + Na) ⁺ ].

Production Example 7 (1) 2 '-(2,3-di-O-acetyl-4,6-O
-Benzylidene-β-D-glucopyranosyloxy)-
6'-acetoxy-3- (5-benzo [b] furanyl)
7.20 g of propiophenone was dissolved in a mixture of tetrahydrofuran-methanol (40 ml-40 ml), and 4.28 g of sodium hydrogencarbonate and 0.8 ml of water were added.
Stir at 6.5 ° C. for 6.5 hours. The sodium bicarbonate is removed by filtration, the filtrate is concentrated under reduced pressure, and the obtained residue is dissolved in ethyl acetate. After washing with water and drying, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (solvent; chloroform: ethyl acetate) to give 2 ′-(2,3-di-O-acetyl-4,6). -O-benzylidene-β-D-
Glucopyranosyloxy) -6'-hydroxy-3-
(5-benzo [b] furanyl) propiophenone 5.2
0 g are obtained.

NMR (DMSO-d ₆ ) δ: 1.98
(3H, s), 2.01 (3H, s), 2.90-3.
05 (4H, m), 3.70-4.00 (3H, m),
4.25-4.35 (1H, m), 5.05 (1H, d
d, J = 7.9, 9.4 Hz), 5.41 (1H, t,
J = 9.4 Hz), 5.58 (1H, d, J = 7.9H)
z), 5.63 (1H, s), 6.60 (1H, d, J
= 7.7 Hz), 6.68 (1H, d, J = 8.1H)
z), 6.89 (1H, d, J = 2.2 Hz), 7.1
9 (1H, dd, J = 1.8, 8.6 Hz), 7.21
(1H, t, J = 8.3 Hz), 7.38 (5H,
s), 7.45-7.55 (2H, m), 7.94 (1
H, d, J = 2.2 Hz), 10.28 (1H, s) FABMS (m / z): 639 [(M + Na) ⁺ ].

(2) 2 ′-(2,3-di-O-acetyl-4,6-O-benzylidene-β-D-glucopyranosyloxy) -6′-hydroxy-3- (5-benzo [B] Furanyl) propiophenone (1.21 g) was added to acetic acid (1).
Dissolve in 5 ml, add 1.5 ml of water and 43 mg of p-toluenesulfonic acid, and stir at room temperature for 4.5 hours. Water and ethyl acetate are added to the reaction solution, and the mixture is stirred, and the organic layer is separated. After the organic layer is washed with water and dried, the solvent is distilled off. The obtained residue was purified by silica gel column chromatography (solvent; chloroform: methanol) to give 2 ′-(2,3
915 mg of -di-O-acetyl-β-D-glucopyranosyloxy) -6′-hydroxy-3- (5-benzo [b] furanyl) propiophenone are obtained.

M. p. 127-129 ° C NMR (DMSO-d ₆ ) δ: 1.92 (3H, s),
2.00 (3H, s), 2.85-3.05 (4H,
m), 3.45-3.75 (4H, m), 4.75 (1
H, t, J = 5.4 Hz), 4.87 (1H, dd, J)
= 8.0, 9.8 Hz), 5.09 (1H, t, J =
9.7 Hz), 5.36 (1H, d, J = 7.9H)
z), 5.55 (1H, d, J = 5.6 Hz), 6.5
7 (1H, d, J = 7.8 Hz), 6.68 (1H, d, J = 7.8 Hz)
d, J = 8.1 Hz), 6.88 (1H, d, J = 2.
2Hz), 7.17 (1H, d, J = 9.6Hz),
7.19 (1H, t, J = 8.3 Hz), 7.48 (1
H, d, J = 9.3 Hz), 7.49 (1H, d, J =
1.0 Hz), 7.93 (1H, d, J = 2.2H)
z), 10.28 (1H, s) FABMS (m / z): 551 [(M + Na) ⁺ ].

Production Examples 8-10 In the same manner as in Production Example 7, the compounds shown in Table 2 are obtained from the corresponding starting compounds.

[0102]

[Table 2]

[0103]

[Table 3]

Production Example 11 To a 25 ml pyridine solution of 889 mg of 2 '-(β-D-glucopyranosyloxy) -6'-hydroxy-3- (5-benzo [b] furanyl) propiophenone and 250 mg of ethoxyacetic acid. N, N-bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride 152 under ice cooling
Add 7 mg and stir at room temperature for 19 hours. A saturated aqueous sodium hydrogen carbonate solution and chloroform are added to the reaction solution, and the mixture is stirred, and the organic layer is separated. After the organic layer is washed with water and dried, the solvent is distilled off. The residue is dissolved in a methanol-tetrahydrofuran mixture (10 ml-10 ml), triethylamine (202 mg) is added, and the mixture is stirred at 50 ° C. for 40 minutes. After evaporating the solvent under reduced pressure, the obtained residue was dissolved in ethyl acetate,
Wash and dry. The solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; chloroform: methanol) to give 2 ′-(6-O-ethoxyacetyl-
377 mg of β-D-glucopyranosyloxy) -6′-hydroxy-3- (5-benzo [b] furanyl) propiophenone are obtained.

NMR (DMSO-d ₆ ) δ: 1.06
(3H, t, J = 7.0 Hz), 2.99 (2H, t,
J = 7.4 Hz), 3.1-3.3 (5H, m), 3.
41 (2H, q, J = 7.0 Hz), 3.6-3.7
(1H, m), 3.96 (1H, d, J = 16.6H)
z), 4.03 (1H, d, J = 16.6 Hz);
1-4.2 (1H, m), 4.36 (1H, dd, J =
1.8, 11.7 Hz), 4.98 (1H, d, J =
7.3 Hz), 5.22 (1H, d, J = 4.5H)
z), 5.31 (1H, d, J = 5.5 Hz), 5.3
4 (1H, d, J = 5.2 Hz), 6.56 (1H, d, J = 5.2 Hz)
d, J = 8.1 Hz), 6.64 (1H, d, J = 8.
1Hz), 6.87 (1H, dd, J = 1.0, 2.2)
Hz), 7.20 (1H, dd, J = 1.8, 8.1H)
z), 7.23 (1H, t, J = 8.3 Hz), 7.4
6 (1H, d, J = 8.4 Hz), 7.51 (1H,
d, J = 1.4 Hz), 7.93 (1H, d, J = 2.
2 Hz), 10.87 (1H, s) FABMS (m / z): 553 [(M + Na) ⁺ ].

Production Examples 12 to 15 In the same manner as in Production Example 11, the compounds shown in Table 3 are obtained from the corresponding starting compounds.

[0107]

[Table 4]

[0108]

[Table 5]

Production Example 16 2 '-[2,3,6-tri-O-acetyl-4-O-
(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl) -β-D-glucopyranosyloxy]
By treating 1541 mg of -6'-hydroxyacetophenone and 350 mg of benzo [b] furan-5-carbaldehyde in the same manner as in Production Example 1 or 2, 2 '-[4-
415 mg of O- (α-D-glucopyranosyl) -β-D-glucopyranosyloxy] -6′-hydroxy-3- (5-benzo [b] furanyl) propiophenone are obtained.

NMR (DMSO-d ₆ ) δ: 3.00
(2H, t, J = 7.4 Hz), 3.0-3.8 (14
H, m), 4.4-4.6 (2H, broad), 4.
90 (2H, broad), 4.99 (1H, d, J =
7.7 Hz), 5.06 (1H, d, J = 3.7H)
z), 5.38 (1H, d, J = 5.4 Hz), 5.4
7 (1H, broad), 5.60 (1H, broad)
d), 6.56 (1H, dd, J = 0.7, 8.4H
z), 6.69 (1H, d, J = 7.9 Hz), 6.8
8 (1H, dd, J = 1.0, 2.2 Hz), 7.21
(1H, dd, J = 1.8, 8.5 Hz), 7.24
(1H, t, J = 8.3 Hz), 7.46 (1H, d,
J = 8.5 Hz), 7.53 (1H, d, J = 1.2H)
z), 7.92 (1H, d, J = 2.2 Hz), 10.
95 (1H, s) FABMS (m / z): 629 [(M + Na) ⁺ ].

Production Example 17 2 '-[2,3,6-tri-O-acetyl-4-O-
(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl) -β-D-glucopyranosyloxy]
By treating 1541 mg of -6'-hydroxyacetophenone and 389 mg of benzo [b] thiophene-5-carbaldehyde in the same manner as in Production Example 1, 2 '-[4-O
645 mg of-(α-D-glucopyranosyl) -β-D-glucopyranosyloxy] -6′-hydroxy-3- (5-benzo [b] thienyl) propiophenone are obtained.

NMR (DMSO-d ₆ ) δ: 3.03
(2H, t, J = 7.6 Hz), 3.0-3.8 (14
H, m), 4.51 (1H, t, J = 5.5 Hz),
4.57 (1H, t, J = 5.6 Hz), 4.88 (1
H, d, J = 4.9 Hz), 4.91 (1H, d, J =
5.6 Hz), 5.00 (1H, d, J = 7.7H)
z), 5.06 (1H, d, J = 3.8 Hz), 5.4
0 (1H, d, J = 5.7 Hz), 5.47 (1H,
d, J = 6.0 Hz), 5.61 (1H, d, J = 3.
3Hz), 6.56 (1H, d, J = 8.4Hz),
6.69 (1H, d, J = 7.9 Hz), 7.25 (1
H, t, J = 8.3 Hz), 7.29 (1H, dd, J)
= 1.6, 8.7 Hz), 7.39 (1H, d, J =
5.5 Hz), 7.70 (1H, d, J = 5.4H)
z), 7.77 (1H, d, J = 1.6 Hz), 7.8
7 (1H, d, J = 8.2 Hz), 10.97 (1H,
s) FABMS (m / z): 645 [(M + Na) ⁺ ].

Production Example 18 2 '-(2,3,4,6-tetra-O-acetyl-β-
D-glucopyranosyloxy) -6′-hydroxyacetophenone (5 g) and benzo [b] furan-5-carbaldehyde 1.81 g were reacted and treated in the same manner as in (i) Production Example 1 to obtain a crude 2 ′. -(Β-D-glucopyranosyloxy) -6′-hydroxy-3- (5-benzo [b] furanyl) acrylophenone was added to 50 ml of ethanol,
It is dissolved in a mixed solution of 10 ml of 0% potassium hydroxide aqueous solution, and catalytic reduction is performed under normal pressure using 120 mg of platinum oxide as a catalyst. The catalyst is removed by filtration, the filtrate is neutralized with 10% hydrochloric acid under ice cooling, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and after stirring, the organic layer was separated, or (ii) Production Example 1
The crude 2 ′-(β-D
-Glucopyranosyloxy) -6'-hydroxy-3-
(5-Benzo [b] furanyl) acrylophenone was mixed with 50 ml of ethanol and 10 m of 10% aqueous potassium hydroxide solution.
and 2.5 g of 4-N, N-dimethylaminopyridine and 1.1 g of 10% palladium-carbon are added to the solution and subjected to catalytic reduction under normal pressure. The catalyst is removed by filtration, the filtrate is neutralized with 10% hydrochloric acid under ice cooling, and concentrated under reduced pressure. Ethyl acetate is added to the residue, and after stirring, the organic layer is separated. The organic layer is washed with water, dried, and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography to give 2 ′-(β-D-glucopyranosyloxy).
3.4 g of -6'-hydroxy-3- (5-benzo [b] furanyl) propiophenone are obtained. Physical properties are as described in Production Example 1.

Production Example 19 In the same manner as in Production Example 11, the compounds shown in Table 4 are obtained from the corresponding starting compounds.

[0115]

[Table 6]

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) -β-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'-O-
[2,3,6-tri-O-acetyl-4-O- (2,
3.30 g of 3,4,6-tetra-O-acetyl-α-D-glucopyranosyl) -β-D-glucopyranosyl] -6′-hydroxyacetophenone are obtained.

IR (nujol) cm -1: 1750,1
630 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) ⁺ ].

[0118]

The active ingredient of the present invention, the propiophenone derivative [I] and a pharmaceutically acceptable salt thereof, have an excellent urinary glucose increasing action based on an inhibitory action on renal glucose reabsorption, Useful as a hypoglycemic drug. For example, when orally administered to rats, the compound as an active ingredient of the present invention can increase urinary glucose by 11 to 100 times that of phlorizin administration.

The propiophenone derivative [I], which is the active ingredient of the present invention, has low toxicity, for example, 2 ′-(β
-D-glucopyranosyloxy) -6'-hydroxy-
3- (5-benzo [b] furanyl) propiophenone or 2 ′-(2,3-di-O-acetyl-β-D-glucopyranosyloxy) -6′-hydroxy-3- (5-
A single oral administration (3000 mg / kg) of benzo [b] furanyl) propiophenone to mice did not result in death. Further, the compound which is the active ingredient of the present invention includes:
It is also characterized in that the aglycone moiety generated by hydrolysis in the body has a weak inhibitory effect on the facilitated-diffusion type sugar transport carrier.

Therefore, the compound [I], which is an active ingredient of the present invention, can correct hyperglycemia, break the vicious cycle of glucose toxicity, and improve diabetes (eg, insulin-dependent diabetes (type I diabetes), And diabetes mellitus such as non-insulin-dependent diabetes mellitus (type II diabetes)].

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Masanori Iname 3-4-3-407, Waseda, Misato City, Saitama Prefecture (72) Inventor Kenji Arakawa 2-3-2-211, Segasaki, Urawa City, Saitama Prefecture (56) References JP-A-8-27007 (JP, A) JP-A-8-199303 (JP, A) JP-A-6-199886 (JP, A) JP-A-6-298790 (JP, A) (58) Survey Field (Int.Cl. ⁷ , DB name) A61K 31/70 C07H 15/203 CA (STN) REGISTRY (STN)

Claims (11)

(57) [Claims] 1. A compound of the general formula [I] Wherein X is an oxygen atom, a sulfur atom or a methylene group, OY is a hydroxyl group which may be protected, and Z is β
-D-glucopyranosyl group, 4-O- (α-D-glucopyranosyl) -β-D-glucopyranosyl group or a group in which one or more hydroxyl groups thereof are acylated, and the dotted line indicates the presence or absence of a double bond. Represents existence. Or a pharmacologically acceptable salt thereof as an active ingredient. 2. Z is a β-D-glucopyranosyl group or a 4-O- (α-D-glucopyranosyl) -β-D-glucopyranosyl group (these groups are a C _2-20 alkanoyl group, a lower alkoxy lower alkanoyl group, The pharmaceutical composition according to claim 1, wherein one or more hydroxyl groups may be acylated with a group selected from a lower alkoxycarbonyl group and a benzoyl group. 3. OY is a lower alkanoyloxy group or a hydroxyl group; Z is a group selected from a C _2-20 alkanoyl group, a lower alkoxy lower alkanoyl group, a lower alkoxycarbonyl group and a benzoyl group; Is a β-D-glucopyranosyl group which may be acylated, and the dotted line represents the presence of a double bond. 4. X is an oxygen atom or a sulfur atom, OY is a hydroxyl group, Z is a group selected from a C _2-20 alkanoyl group, a lower alkoxy lower alkanoyl group, a lower alkoxycarbonyl group and a benzoyl group; 6
The pharmaceutical composition according to claim 1, wherein the β-D-glucopyranosyl group whose hydroxyl group may be acylated, and the dotted line represents the presence of a double bond. 5. X is an oxygen atom or a sulfur atom, OY is a hydroxyl group, Z is a β-D-glucopyranosyl group or 4-O
The pharmaceutical composition according to claim 1, which is-(α-D-glucopyranosyl) -β-D-glucopyranosyl group. 6. X is an oxygen atom, OY is a lower alkanoyloxy group or a hydroxyl group, Z is 2,3-di-O- (lower alkanoyl) -β-D-glucopyranosyl group, 2,3
-Di-O- (lower alkoxy lower alkanoyl) -β-
D-glucopyranosyl group, 6-O- (C _2-20 alkanoyl) -β-D-glucopyranosyl group, 6-O- (lower alkoxy lower alkanoyl) -β-D-glucopyranosyl group or 6-O-benzoyl-β- The pharmaceutical composition according to claim 3, which is a D-glucopyranosyl group. 7. The pharmaceutical composition according to claim 6, wherein X is an oxygen atom, OY is a lower alkanoyloxy group or a hydroxyl group, and Z is a 2,3-di-O- (lower alkanoyl) -β-D-glucopyranosyl group. . 8. 8 '-[2,3-di-O- (lower alkanoyl) -β-D-glucopyranosyloxy] -6'
-Hydroxy-3- (5-benzo [b] furanyl) propiophenone or 2 '-[2,3-di-O- (lower alkanoyl) -β-D-glucopyranosyloxy]-
A pharmaceutical composition comprising 6 '-(lower alkanoyloxy) -3- (5-benzo [b] furanyl) propiophenone as an active ingredient. 9. Effective use of 2 ′-(β-D-glucopyranosyloxy) -6′-hydroxy-3- (5-benzo [b] furanyl) propiophenone or a pharmaceutically acceptable salt thereof. A pharmaceutical composition as an ingredient. 10. The method according to claim 1, which is a hypoglycemic drug.
The pharmaceutical composition according to 3, 4, 5, 6, 7, 8 or 9. 11. The pharmaceutical composition according to claim 10, which is an agent for preventing or treating diabetes.