JP2000080041A - Medicine composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine composition comprising a specific propiophenone derivative as an active ingredient, having excellent urine sugar increasing action based on glucose resorption inhibition in the kidney, showing excellent blood sugar lowering action, forming its aglycon showing extremely weak inhibitory action on a sugar transporting carrier of facilitated diffusion type. SOLUTION: This medicine composition contains a propiophenone derivative of the formula [OH is a (protected) OH; Y is a lower alkyl; Z is a (protected) β-D-glucopyranosyl]propiophenone, preferably 3-(5-benzo[b]furanyl)-2'-(β-D- gluconopyranosyloxy)-6'-hydroxy-4'-methylpropiophenone or its pharmacologically acceptable salt (e.g. sodium salt, etc.), as an active ingredient. The compound of the formula can be made into a preparation by using a medicine carrier (e.g. binder, excipient, etc.). Preferably the daily dose of the compound of the formula is 0.5-15 mg/kg in the case of oral administration and 0.05-3 mg/kg in the case of parenteral administration.

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 cut off to prevent and treat diabetes.

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 Na + -glucose cotransporters that are present only in the intestinal tract and chorion of the kidney. Inhibits sugar reabsorption, promotes excretion of sugar, and lowers blood sugar. Based on this effect, it has been confirmed that daily administration of phlorizine to diabetic animals subcutaneously daily to correct hyperglycemia and maintain normal blood sugar levels for a long period of time, thereby improving and normalizing the condition of hyperglycemic animals. [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. Therefore, no attempt has been made so far 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 inhibition of renal glucose absorption, thereby exhibiting an excellent hypoglycemic effect, and its aglycone is extremely weak. An object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, a 4'-lower alkylpropiophenone derivative exhibiting an inhibitory effect of a facilitated diffusion type sugar transport carrier.

[0007]

The present invention provides a compound represented by the general formula (I):

[0008]

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(In the formula, OX represents an optionally protected hydroxyl group, Y represents a lower alkyl group, and Z represents a β-D-glucopyranosyl group in which one or more hydroxyl groups may be protected.) The present invention relates to a pharmaceutical composition comprising a propiophenone derivative or a pharmaceutically 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 OX is a protected hydroxyl group, any protective group may be used as long as it can be a protective group for a phenolic hydroxyl group. Specifically, lower alkoxy lower alkyl groups such as methoxymethyl group, allyl group, lower alkanoyl group, lower alkoxy lower alkanoyl group, lower alkoxycarbonyl group, lower alkoxy lower alkoxycarbonyl group, arylcarbonyl group (for example, benzoyl group) and the like Acyl groups such as a lower alkanoyl group, a lower alkoxy lower alkanoyl group, a lower alkoxycarbonyl group, and a lower alkoxy lower alkoxycarbonyl group are preferred, and a lower alkanoyl group and a lower alkoxycarbonyl group are particularly preferred.

In the compound (I) which is an active ingredient of the present invention, when Z is a β-D-glucopyranosyl group in which one or more hydroxyl groups are protected, the protecting group may be acid treatment, hydrolysis, A conventional hydroxyl-protecting group which can be easily removed by a conventional method such as reduction or the like can be used. As a β-D-glucopyranosyl group in which one or more hydroxyl groups are protected by such a group,
(1) β- having one or more hydroxyl groups acylated
D-glucopyranosyl group, (2) β-D in which two hydroxyl groups together with a protecting group form 1-lower alkoxy lower alkylidenedioxy group, benzylidenedioxy group, phosphinicodioxy group, carbonyldioxy group and the like. −
A glucopyranosyl group, or (3) one or two hydroxyl groups are acylated, and two hydroxyl groups together with their protecting groups are 1-lower alkoxy lower alkylidenedioxy group, benzylidenedioxy group, phosphinicodioxy group And a β-D-glucopyranosyl group forming a carbonyldioxy group. However, the hydroxyl-protecting group of the β-D-glucopyranosyl group is not limited to these, and may be any as long as it has a function of deprotecting and giving a hydroxyl group after administration to a living body. Any substance having a function of facilitating absorption or administration into a living body, or a function of increasing fat-solubility or water-solubility can be more preferably used.

When the hydroxyl group of the β-D-glucopyranosyl group is acylated, the acyl group may be a lower alkanoyl group, a lower alkoxy lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkoxy lower alkoxycarbonyl group, an arylcarbonyl group (for example, Benzoyl group) and the like can be suitably used. As the acyl group, a residue obtained by removing a hydroxyl group of one carboxyl group from an amino acid (an amino group, a carboxyl group and / or a hydroxyl group present in the residue may be protected) may be used. Examples of the residue obtained by removing a hydroxyl group of one carboxyl group from an amino acid include, for example, aspartic acid, glutamic acid, glutamine, serine, sarcosine, proline, phenylalanine, leucine, isoleucine, glycine, tryptophan, cysteine, histidine, tyrosine, and valine. And the residue obtained by removing the hydroxyl group of one carboxyl group from the natural amino acid, its enantiomer or racemate.

A β-D-glucopyranosyl group in which two hydroxyl groups together with a protecting group form a 1-lower alkoxy lower alkylidenedioxy group, a benzylidenedioxy group, a phosphinicodioxy group, a carbonyldioxy group, etc. Is the case where, for example, the hydroxyl group at the 4- and 6-position of the β-D-glucopyranosyl group is 1 together with its protecting group.
A lower alkoxy lower alkylidenedioxy group, a benzylidenedioxy group, a phosphinicodioxy group, a β-D-glucopyranosyl group forming a carbonyldioxy group or the like, that is,

[0014]

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[0015] (or wherein, R ⁷ and R ⁸ are one of a hydrogen atom or a lower alkyl group, the other is a lower alkoxy group, or one is hydrogen atom, the other is a phenyl group, or, R ⁷ And R ⁸ together form an oxo group.).

When the two hydroxyl groups of the β-D-glucopyranosyl group together with the protecting group form a 1-lower alkoxy lower alkylidene dioxy group, the 1-lower alkoxy lower alkylidene dioxy group is 1-lower alkoxyethylidene Dioxy groups are preferred, especially 1-
A methoxyethylidenedioxy group, a 1-ethoxyethylidenedioxy group and the like can be suitably used.

Further, in compound (I), which is an active ingredient of the present invention, Y is preferably an alkyl group having 1 to 4 carbon atoms, particularly preferably a methyl group and an ethyl group.

As a specific compound, one or more hydroxyl groups are acylated with Z being a group selected from a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkoxy lower alkanoyl group and a lower alkoxy lower alkoxycarbonyl group. A β-D-glucopyranosyl group or a β-D in which two hydroxyl groups together with its protecting group form a 1-lower alkoxy lower alkylidenedioxy group or a phosphinicodioxy group
-A compound which is a glucopyranosyl group.

More specifically, Z is 2-, 2- and 3-positions wherein Z is a group selected from a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkoxy lower alkanoyl group and a lower alkoxy lower alkoxycarbonyl group.
The 4-, 6- or 6-position hydroxyl group is an optionally acylated β-D-glucopyranosyl group, or the 4- and 6-position hydroxyl group together with its protecting group is a 1-lower alkoxy-lower alkylidene dioxy group or a phosphinicodi group Examples of the compound include a β-D-glucopyranosyl group forming an oxy group.

Among the compounds (I) which are the active ingredients of the present invention, preferred compounds are those in which OX is a hydroxyl group, a lower alkanoyloxy group or a lower alkoxycarbonyloxy group, and Z is a β-D-glucopyranosyl group, O
-(Lower alkanoyl) -β-D-glucopyranosyl group, 2,3-di-O- (lower alkanoyl) -β-D-
Glucopyranosyl group, 4-O- (lower alkoxycarbonyl) -β-D-glucopyranosyl group, 6-O- (lower alkanoyl) -β-D-glucopyranosyl group, 6-O
-(Lower alkoxycarbonyl) -β-D-glucopyranosyl group, 6-O- (lower alkoxy lower alkanoyl) -β-D-glucopyranosyl group, 6-O- (lower alkoxy lower alkoxycarbonyl) -β-D-glucopyranosyl group A 4,6-O- (1-lower alkoxy lower alkylidene) -β-D-glucopyranosyl group or
Examples of the compound include a 4,6-O-phosphinico-β-D-glucopyranosyl group.

Among the compounds (I) which are the active ingredients of the present invention, more preferred compounds are those in which OX is a hydroxyl group or a lower alkanoyloxy group, Z is a β-D-glucopyranosyl group, and 2,3-di-O- ( Lower alkanoyl) -β-
D-glucopyranosyl group, 4-O- (lower alkoxycarbonyl) -β-D-glucopyranosyl group, 6-O-
(Lower alkoxycarbonyl) -β-D-glucopyranosyl group, 4,6-O- (1-lower alkoxy lower alkylidene) -β-D-glucopyranosyl group or 4,6-
Examples of the compound include an O-phosphinico-β-D-glucopyranosyl group.

Among the compounds (I), which are the active ingredients of the present invention, OX is a hydroxyl group, Y is a methyl or ethyl group, Z is a β-D-glucopyranosyl group, and 4-O- ( Lower alkoxycarbonyl)
-Β-D-glucopyranosyl group, 6-O- (lower alkoxycarbonyl) -β-D-glucopyranosyl group, 4,
6-O- (1-lower alkoxy lower alkylidene) -β
Examples of the compound include a -D-glucopyranosyl group and a 4,6-O-phosphinico-β-D-glucopyranosyl group.

Particularly preferred compounds are those wherein Z is β
Examples of the compound include a -D-glucopyranosyl group and a 6-O- (lower alkoxycarbonyl) -β-D-glucopyranosyl group.

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 pharmacologically acceptable salts include alkali metal salts such as sodium salts, mineral salts such as hydrochlorides, and organic acid salts such as tosylate salts.

The propiophenone derivative (I) or a pharmaceutically acceptable salt thereof includes any of its internal salts, solvates and hydrates thereof.

The compound (I) or a pharmaceutically acceptable salt thereof, which is an active ingredient of the present invention, has an excellent urinary glucose increasing effect based on inhibition of renal glucose reabsorption, and is useful as a hypoglycemic drug. is there.

For example, when administered orally to rats, the compound as the active ingredient of the present invention can increase urinary glucose by 180 to 580 times as compared with the case of administration of phlorizin. Further, when administered to a diabetes model, the active ingredient of the present invention can suppress an increase in blood sugar level and also can prevent an increase in hemoglobin A1c level, which is an index reflecting a blood sugar control state.

Further, the active ingredient of the present invention was continuously administered to non-insulin-dependent diabetes model animals for 4 weeks, and it was examined by an oral glucose tolerance test whether or not the glucose metabolism function of the whole body was improved. And insulin secretion deficiency was found to be improved. Insulin sensitivity was also confirmed to be restored by the insulin clamp method. Furthermore, the insulin content in the pancreas was also improved, and it was found to have a protective effect on pancreatic β cells. Furthermore, when the active ingredient of the present invention was administered to a diabetic model animal and the plasma triglyceride level was examined, the active ingredient of the present invention reduced the value.

The compound which is the active ingredient of the present invention comprises
It is characterized by low toxicity, and a weak inhibitory effect of the facilitated-diffusion-type sugar transport carrier on the aglycone moiety generated by hydrolysis in the body.

Therefore, the compound (I), which is an active ingredient of the present invention, can improve diabetes by reducing hyperglycemia, breaking the vicious cycle of glucose toxicity, and improving the glucose metabolism function of the whole body. And diabetes mellitus such as insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus], and / or prevention and treatment of hyperglycemia, in particular, postprandial hyperglycemia.
Furthermore, the active ingredient of the present invention improves insulin resistance, improves hyperinsulinemia, abnormal lipid metabolism (for example,
It can also be used effectively for prevention and treatment of hyperlipidemia such as hypertriglyceridemia.

The active ingredient of the present invention exhibits a hypoglycemic effect even when administered to an insulin-dependent diabetes model, so that it can be used as an adjuvant to insulin in the treatment of insulin-dependent diabetes.

Furthermore, in a diabetic experimental animal, if the hyperglycemic state continues for about 6 months, the amount of albumin in urine increases, and the responsiveness to heat stimulation decreases. These are indicators of renal and neuropathy among the diabetic complications which become problems when diabetes is troubled for a long time. By continuously administering the active ingredient of the present invention to a non-insulin-dependent diabetes model animal, the blood glucose level was controlled, and an increase in urinary albumin level and a decrease in responsiveness to heat stimulation could be suppressed. Furthermore, the active ingredient of the present invention was administered to a diabetic model animal, and creatinine clearance was measured and histopathological examination of the kidney was carried out.The active ingredient of the present invention suppressed reduction in creatinine clearance and suppression of expansion of the mesangial region. did. Therefore, compound (I), which is an active ingredient of the present invention, can be effectively used for the prevention and treatment of diabetic complications such as renal disorder (eg, diabetic nephropathy) and neuropathy.

The compound (I) or a pharmaceutically acceptable salt thereof, which is an active ingredient of the present invention, can be administered orally or parenterally, and a drug 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, sorbite, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, corn starch, potassium phosphate, sorbit, glycine, etc.), lubricants ( Examples thereof include magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrants (potato starch, etc.) and wetting agents (sodium lauryl sulfate, etc.). In the case of oral administration, these pharmaceutical preparations may be solid preparations such as tablets, granules, capsules and powders, or liquid preparations such as solutions, suspensions and emulsions. On the other hand, when administered parenterally, for example, as an injection or infusion using distilled water for injection, physiological saline, aqueous glucose solution,
Alternatively, suppositories and the like can be used.

The dose of the propiophenone derivative (I) or a pharmaceutically acceptable salt thereof, which is the active ingredient of the present invention, varies depending on the method of administration, the age, weight, condition and degree of disease of the patient. The daily dose is
0.05 to 30 mg / kg for oral administration, especially 0.5 to 15 mg / kg, for parenteral administration,
0.005-30mg / kg, especially 0.05-3m
g / kg.

The active ingredient of the present invention, propiophenone derivative (I) or a pharmaceutically acceptable salt thereof is represented by the general formula (II):

[0036]

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(Wherein the symbols have the same meanings as described above). The compound can be produced by reducing the compound, if necessary, to obtain a pharmacologically acceptable salt.

This reduction reaction can be carried out by a conventional method such as reduction with a metal hydride or catalytic reduction. 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 such as methanol, ethanol, or tetrahydrofuran or a mixed solvent thereof).
Sodium tellurium hydride is available from Synthesis
is), page 545 (1978). And in a catalytic reduction [eg, palladium-carbon, platinum-carbon, palladium-carbon, platinum-carbon, organic solvent such as methanol or ethanol, or a mixed solvent of these organic solvents and water] in a catalytic reduction.
Platinum oxide, Raney nickel, etc. Further, in order to prevent the double bond of the benzofuran ring from being reduced, a substance (for example, N, N-dimethylaminopyridine or the like) which can reduce the catalytic ability may be added. And under heating (especially at 10 to 30 ° C.).

The compounds thus obtained, which are the active ingredients of the present invention, can be converted into each other by the following methods or a combination of the following methods.

(1) Of the compound (I) which is an active ingredient of the present invention, the compound represented by the general formula (Ib)

[0041]

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(Wherein R ¹ represents an acyl group, and other symbols have the same meanings as described above). The compound represented by the general formula (Ia)

[0043]

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

(2) Among the compounds (I) which are the active ingredients of the present invention, the compound represented by the general formula (Ic)

[0046]

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(Wherein, R ³ represents an acyl group, and other symbols have the same meanings as described above). The compound represented by the formula (Ia) has a 4-position of the β-D-glucopyranosyl group and The compound represented by the general formula (I-
d)

[0048]

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(In the formula, R ¹¹ O and R ¹² O represent a protected hydroxyl group, and other symbols have the same meanings as described above.)
Can be prepared by acylating the compound represented by, and then removing the protecting groups R ¹¹ and R ²¹ .

(3) Of the compound (I) which is an active ingredient of the present invention, the compound represented by the general formula (Ie)

[0051]

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(Wherein, R ⁴ represents an acyl group, and other symbols have the same meanings as described above). The compound represented by the formula (3) is a hydroxyl group at the 3-position of the β-D-glucopyranosyl group of the compound (Id). A compound of the general formula (If)

[0053]

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(Wherein R ³¹ O represents a protected hydroxyl group and other symbols have the same meanings as described above), and the protecting groups R ¹¹ , R ²¹ and R ³¹ are removed. Can be produced.

Compound (Id) and Compound (If)
In the formula, as the protecting groups R ¹¹ , R ²¹ and R ³¹ for the hydroxyl group of the β-D-glucopyranosyl group, conventional protecting groups can be used. Those which bond to each other to form a benzylidene group or the like can be preferably used. As the protecting group for the 3-position hydroxyl group, a tri-lower alkylsilyl group such as a t-butyldimethylsilyl group or a trimethylsilyl group is preferably used. be able to. Removal of these protecting groups
It can be carried out by a conventional method such as acid treatment, hydrolysis, reduction and the like.

The acylation in the production methods (1) to (3)
The reaction can be carried out by reacting an organic acid (for example, lower alkyl carboxylic acid, lower alkoxy lower alkyl carboxylic acid, benzoic acid, etc.) corresponding to a desired acyl group, a salt thereof or a reactive derivative thereof with a raw material compound.

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 in the presence or absence of a condensing agent (for example, dicyclohexylcarbodiimide or the like). The reaction between the derivative and the starting compound is carried out in a suitable solvent or in the absence of a solvent in the presence or absence of a deoxidizing agent (eg, alkali metal hydroxide, pyridine and the like), from under cooling to under heating (preferably at -10 ° C). ~ 1
00 ° C, especially 0 ° C to 50 ° C).

Examples of the salt of an organic acid include an alkali metal salt such as a sodium salt, a potassium salt and a calcium salt, and an alkaline earth metal salt. 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 lower alkyl carboxylic acids, lower alkoxy lower alkyl carboxylic acids, lower alkoxy carboxylic acids, acid halides such as benzoic acid, acid anhydrides, active esters, active amides and the like. .

As the solvent, any solvent can be used as long as it does not adversely affect the reaction. For example, conventional solvents such as water, esters (eg, ethyl acetate), and halogenated hydrocarbons (eg, dichloromethane); Alternatively, a mixed solvent thereof can be used. Further, an organic base such as pyridine exemplified as the deoxidizing agent can be used as the solvent.

The compound (Ia) is a compound (II)
Among them, it is obtained by reducing a compound in which Z is a β-D-glucopyranosyl group.

Compound (Id) can be obtained by protecting the 4- and 6-position hydroxyl groups of the β-D-glucopyranosyl group of compound (Ia), and compound (If) is obtained by protecting compound (Id) )) By protecting the 3-position hydroxyl group of the β-D-glucopyranosyl group. The protection of the hydroxyl group of the β-D-glucopyranosyl group can be carried out, for example, by following the method shown in Production method (5) described below, the method described in Production Examples, or a conventional method.

In the acylation reaction of the above (1) to (3), when OX of the starting compound is a hydroxyl group, the hydroxyl group may be acylated in some cases. The compound is also included in the compound as the active ingredient of the present invention. If acylation is not appropriate, a suitable solvent (eg, tetrahydrofuran,
Methanol, water, etc.), a base [eg, an alkali metal hydrogencarbonate (eg, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.)]
With an amine (such as t-butylamine)], an acyl group can be removed from the resulting compound.

(4) Of the compound (I) which is the active ingredient of the present invention, the compound represented by the general formula (Ig)

[0065]

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(Wherein R ² represents a lower alkyl group, and other symbols have the same meanings as described above). The compound represented by the general formula (Ih)

[0067]

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(Wherein the symbols have the same meanings as described above) and a compound represented by the general formula (III) R ² OH (III) (wherein the symbols have the same meanings as described above). It can be produced by reacting a compound.

In this reaction, a suitable solvent [for example, dichloromethane and the like. Compound (III) can also be used as a solvent. ], An acid catalyst [arylsulfonic acid (p
Organic acids such as toluenesulfonic acid), lower alkanesulfonic acids (such as methanesulfonic acid), or inorganic acids such as hydrochloric acid or sulfuric acid] in the presence or absence of from cooling to heating (preferably 25 ° C.). ~ 50 ° C, especially 25
C. to 35 C.).

Compound (III) includes methanol,
Alkanol having 1 to 6 carbon atoms having a straight or branched chain such as ethanol, propanol, isopropanol, n-butanol and t-butanol can be used. It is preferably used.

Compound (Ih) may be, for example, (a)
In a suitable solvent (for example, tetrahydrofuran or the like) or in the absence of a solvent, the compound is prepared in the presence or absence of a deacidifier (an organic base such as 2,4,6-collidine or pyridine, or an inorganic base such as sodium hydrogen carbonate). (Ia) is reacted with an aryl halide formate (e.g., p-nitrophenyl halogenoformate) or N, N-carbonyldiimidazole, and then, if necessary, by heating, or (b) a production method described below ( Obtained by following 5).

When an organic base is used as a deoxidizing agent in the method (a), the organic base can be used as a solvent.

The reaction is carried out under cooling to under heating, especially-
It can be carried out at 50C to 60C. When an aryl halogenoformate is used, it is preferable to heat after adding the aryl halogenoformate.
It is preferred to heat to a temperature between 70C and 70C.

(5) Of the compound (I) which is an active ingredient of the present invention, the compound represented by the general formula (Ii)

[0075]

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(In the formula, R ⁵ and R ⁶ are each independently selected from the group consisting of R ⁵ being a hydrogen atom or a lower alkyl group, R ⁶ being a lower alkoxy group, or R ⁵ being a hydrogen atom and R ⁶ being a phenyl group; Alternatively, R ⁵ and R ⁶ together form an oxo group, and the other symbols have the same meaning as described above.) The compound represented by the general formula (IV)

[0077]

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(Wherein A ¹ and A ² represent leaving groups, and other symbols have the same meanings as described above).

In the compound (IV), as the leaving group, an ordinary leaving group which does not affect the reaction can be used, and a halogen atom (for example, a chlorine atom or a bromine atom) or a lower alkoxy group (for example, Methoxy group, ethoxy group) and the like can be suitably used.

In this reaction, a suitable solvent [for example, dichloromethane and the like. Further, the compound (IV) can be used as a solvent by using an excess amount. In an organic solvent (arylsulfonic acid, lower alkanesulfonic acid, etc.), inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a salt of a strong acid and a weak base (pyridinium p-toluenesulfonate, etc.) A base (eg, a tri-lower alkylamine such as triethylamine,
In the presence or absence of pyridine or the like, from heating to cooling (preferably 0 ° C to 50 ° C, particularly 20 ° C to 30 ° C).
C).

(6) Among the compounds (I) which are the active ingredients of the present invention, the compound represented by the general formula (Ij)

[0082]

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(Wherein OX ¹ represents a protected hydroxyl group, and other symbols have the same meanings as described above) and a compound represented by the general formula (Ik)

[0084]

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(The symbols in the formula have the same meanings as described above.)
Can be converted into each other.
That is, compound (Ij) protects compound (Ik) and compound (Ik) converts compound (I-
It can be produced by removing the protecting group X1 from j).

In the case of protecting the compound (Ik), this reaction can be appropriately carried out according to a conventional method. For example, in the case of protecting with an acyl group, the above-mentioned (1) to (1)
It can be carried out in the same manner as in the production method of (3). When protecting with an allyl group, the reaction should be carried out by reacting an allyl halide (allyl bromide or the like) in an appropriate solvent (acetone or the like) in the presence or absence of a deoxidizing agent (potassium carbonate or the like). Can be.

When removing the protecting group X ¹ from the compound (Ij), this reaction can be carried out according to a conventional method depending on the kind of the protecting group. For example, when OX ¹ is a lower alkanoyloxy group or a lower alkoxycarbonyloxy group, it can be carried out by treating with an acid or a base in an appropriate solvent. When OX ¹ is a lower alkoxy lower alkoxy group, it can be carried out by using an acid in a suitable solvent. When OX ¹ is an allyloxy group, it is treated with a palladium catalyst [for example, bis (triphenylphosphine) palladium (II) or the like] in a suitable solvent (for example, acetonitrile) in the presence of ammonium formate or the like. Can be implemented.

(7) Of the compound (I) which is the active ingredient of the present invention, the compound represented by the general formula (I-1)

[0089]

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(Wherein the symbols have the same meanings as described above) are represented by the general formula (Im)

[0091]

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(Wherein R ⁹ and R ¹⁰ are the same or different and each represents a hydroxyl-protecting group, and the other symbols have the same meanings as described above). be able to.

As the protecting groups R ⁹ and R ¹⁰ , conventional protecting groups can be used, and a phenyl group, a lower alkyl group (eg, a methyl group, an ethyl group) and the like are preferable.

The hydrolysis is carried out by a commonly used method, and a solvent (for example, ethers such as dioxane,
A base (eg, an alkali metal hydroxide such as sodium hydroxide,
It is desirable to carry out the reaction in the presence of an alkali metal carbonate such as lithium carbonate) under heating to under cooling (preferably -20 ° C to 50 ° C, particularly 0 ° C to 30 ° C).

When hydrolysis is carried out with a base in this reaction, compound (I-1) can also be isolated as a salt with the base used for the hydrolysis.

Compound (Im) comprises compound (Ia) and compound of general formula (IX)

[0097]

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(Wherein, A ³ represents a leaving group, and other symbols have the same meanings as described above).

In the compound (IX), as the leaving group A ³ , an ordinary leaving group which does not affect the reaction can be used, and a halogen atom (eg, a chlorine atom, a bromine atom) and the like are preferably used. Can be used.

This reaction is carried out in a suitable solvent (eg, dichloromethane, tetrahydrofuran, etc.) or without solvent in the presence or absence of a base (eg, tri-lower alkylamine such as triethylamine, 2,4,6-collidine, etc.). In addition, under cooling from heating (preferably -20 ℃ ~ 50 ℃,
(In particular, 0 ° C to 30 ° C).

The starting compound (II) of the compound which is the active ingredient of the present invention has the general formula (V)

[0102]

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(In the formula, Z ¹ represents a β-D-glucopyranosyl group whose hydroxyl group may be protected, and other symbols have the same meanings as described above) and 5-formylbenzo [b The compound can be produced by condensing furan and, if necessary, protecting the hydroxyl group present in the obtained compound.

When Z ^{1 of the} starting compound (V) is a hydroxyl-protected β-D-glucopyranosyl group,
As the protecting group for the hydroxyl group of the glucopyranosyl group, a conventional protecting group such as a lower alkanoyl group (for example, an acetyl group) can be used.

The condensation reaction between the starting compound (V) and 5-formylbenzo [b] furan can be carried out by a conventional method. For example, a suitable solvent (for example, an organic solvent such as methanol or ethanol or an organic solvent such as The reaction can be carried out in a mixed solvent of a solvent and water) in the presence of a base (for example, an alkali metal hydroxide such as potassium hydroxide) from under cooling to under heating (particularly from 10 ° C to 30 ° C).

When protecting the hydroxyl group in the obtained compound, the protection is carried out according to a conventional method, or the above-mentioned (1) to (5).
It can be carried out by following the method (5) or by combining these methods.

Compound (II) obtained by this reaction
May be purified and used for the reaction, or may be used crude for the reduction reaction.

The starting compound (V) is, for example, a compound represented by the general formula (V)
I)

[0109]

Embedded image

(Wherein the symbols have the same meanings as described above) and 2,3,4,6-tetra-O
-Acetyl-α-D-glucopyranosyl bromide is cooled to under heating in the presence or absence of a quaternary ammonium salt (particularly benzyltri-lower alkylammonium chloride is preferred) in the presence or absence of a base (eg, hydroxylated). Using potassium, potassium carbonate, cadmium carbonate, etc.) in a suitable solvent (eg, chloroform, toluene, acetone, etc.) and, if desired, protecting the 6′-position phenolic hydroxyl group. it can.

More specifically, for example, (i) Journal of Medicinal and Pharmaceutical Chemistry (J. Med. Pharm. Chem.)
m. ), Vol. 5, p. 1045 (1962), and compound (VI) and 2,3,4,6-tetra-
O-acetyl-α-D-glucopyranosyl bromide is reacted in a suitable solvent (for example, aqueous acetone) in the presence of potassium hydroxide and then, if desired, protecting the hydroxyl group or (ii) Hydrate Research (C
arbohydrate research) 70th
Volume, page 313 (1979), compound (VI) and 2,3,4,6-tetra-O-acetyl-α
-D-glucopyranosyl bromide is heated and refluxed in a suitable solvent (for example, aromatic hydrocarbons such as toluene) in the presence of cadmium carbonate, and then, if necessary, protecting the hydroxyl group, or (iii) ) Compound (VI) and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide in a suitable solvent (for example, halogenated hydrocarbons such as chloroform or a small amount of water The reaction can be carried out in the presence of a quaternary ammonium salt (benzyltributylammonium chloride) and an alkali metal carbonate (potassium carbonate), and then, if necessary, protecting the hydroxyl group.

The protection of the phenolic hydroxyl group at the 6'-position can be carried out according to a conventional method.

As the raw material compound (VI), for example, a compound in which Y is a methyl group is described in Journal of Organic Chemistry (J. Org. Chem), Vol.
Or acetylation of orcinol and the resulting orcinol diacetate in a suitable solvent (eg, chlorobenzene) or without solvent in the presence of a Lewis acid (eg, aluminum chloride). To a Fries rearrangement reaction.

The compound (VI) wherein Y is a lower alkyl group having 2 or more carbon atoms can be produced, for example, by the process shown by the following formula.

[0115]

Embedded image

(Wherein Y ¹ represents a lower alkenyl group;
Other symbols have the same meaning as described above. That is, first, 3,5-dimethoxyaniline is added in acetic acid,
After a diazonium salt is formed using sodium nitrite in the presence of hydrochloric acid, potassium iodide is allowed to act to produce dimethoxyiodobenzene. This compound is treated with hydrobromic acid in acetic acid to demethylate it, and then the phenolic hydroxyl group formed is acetylated using acetic anhydride or the like to produce diacetoxyiodobenzene. Thereafter, tributyl lower alkenyl tin is reacted in the presence of a palladium catalyst (for example, bis (triphenylphosphine) palladium (II) dichloride) to produce diacetoxy lower alkenyl benzene represented by the general formula (VII). After subjecting this compound to catalytic reduction, the resulting diacetoxy lower alkylbenzene (VIII) is subjected to a Fries rearrangement reaction in the presence of a Lewis acid such as aluminum chloride to produce compound (VI).

In the present specification, a lower alkyl group is
For example, it means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, and a butyl group, and preferably has 1 to 4 carbon atoms. The lower alkoxy group includes, for example, a methoxy group, an ethoxy group,
It means a linear or branched alkoxy group having 1 to 6 carbon atoms such as a propoxy group and a butoxy group, preferably having 1 carbon atom.
~ 4. The lower alkanoyl group means, for example, an acetyl group, a propionyl group, a butyryl group or the like, a straight or branched alkanoyl group having 2 to 6 carbon atoms,
It preferably has 2 to 4 carbon atoms. The lower alkylidene group means a linear or branched alkylidene group having 1 to 6 carbon atoms, such as a methylene group, an ethylidene group, and an isopropylidene group, and preferably has 1 to 4 carbon atoms.

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

[0119]

Embedded image

Represents the structure represented by

Experimental Example 1 Urinary glucose increasing action in rats (Experimental method) Using the active ingredient of the present invention (the compound described in the following Production Example) or a comparative compound (phlorizin) as a sample, sodium carboxymethylcellulose (CMC) (Nacalai Tesque, Inc.) was used as the sample. 0.5% C
A sample administration solution containing 120 mg of a sample in 12 ml of an aqueous MC sodium solution was prepared. A test solution was orally administered to male SD rats (6 weeks old, 3 to 5 animals per group) (dosage:
100 mg / kg), and 24 hours after administration, the rats were placed in metabolic cages and urine was collected. After measuring the amount of urine, the contaminants were removed by centrifugation, and then the urine sugar concentration was measured with a glucose analyzer (manufactured by 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). Table 1 shows the results. In the group to which only the 0.5% CMC sodium aqueous solution was administered, the amount of urinary sugar was 2.0 mg / 24 hr / 20.
It weighed 0 g.

[0122]

[Table 1]

Experimental Example 2 A 4-week-old female KK-A ^y / Ta mouse was treated with Production Example 2 described below.
The compound described was administered in a diet for 4 weeks (dose: 100 mg)
%), Blood glucose level, hemoglobin A1c level, plasma triglyceride level, plasma insulin level, urinary microalbumin excretion, and creatinine clearance.

The blood glucose level was measured by the glucose oxidase method (New Blood Sugar Test, Boehringer Mannheim),
The hemoglobin A1c value was measured by an affinity column method (glycaffin / GHb, ISOLAB INC.), The plasma triglyceride value was measured by an enzyme method (triglyzyme-V, Eiken), and the plasma insulin value was measured by an ELISA method (ELISA insuli).
n kit, Morinaga).

Urine microalbumin is available from ELISA
The creatinine clearance (Ccr) was measured by the method A (Albuwell-M, Exocell Inc.), and the urine volume (V; ml / hr)
Was measured, and plasma creatinine concentration (Pcr; mg / ml) and urine creatinine concentration (Ucr; mg / ml) were measured by Jaffe '.
After measurement by the method (creatinine-test Wako, Wako Pure Chemical Industries), it was calculated from the following equation.

Ccr = Ucr × V / Pcr The normal control group was female C57BL / 6N of the same age. Table 2 shows the results.

[0127]

[Table 2]

Experimental Example 3 Eight-week-old male C57BL / KSJ-db / db mice were administered the compound described in Production Example 2 in a diet for 12 weeks (dose: 100 mg%), and the change in urinary albumin excretion was observed. Examined. Further, after the administration period, histopathological examination was performed on the kidney.

The urinary albumin was measured by an ELISA method. The histopathological examination of the kidney was performed as follows. After fixing the kidney with methanol-Carnoa fixative,
Paraffin sections were prepared according to a conventional method, stained with hematoxylin and eosin, and stained with PAS, followed by microscopic examination. The expansion of the glomerular mesangial area was scored by the degree of increase in the PAS-positive area. In other words, glomerular epidermis that slightly increases chronically is mild (+), in addition, glomerular part that increases nodularly is moderate (++),
Those with a clear increase in PAS-positive substances throughout the glomerulus and showing glomerular sclerosis were defined as high (+++). Inspection was performed on a total of 100 glomeruli, each with 50 arbitrary glomeruli on the left and right of each individual.

Table 3 shows the results.

[0131]

[Table 3]

In the group to which the active ingredient of the present invention was administered, the increase in urinary albumin excretion was significantly suppressed. In the histopathological examination of the kidney, in the group to which the active ingredient of the present invention was administered, the expansion of the PAS-positive glomerular mesangial region, which was remarkably observed in db / db mice, was significantly suppressed.

[0133]

[Production Example] Production Example 1 2 '-(2,3,4,6-tetra-O-acetyl-β-
D-glucopyranosyloxy) -6′-hydroxy-4 ′
120 g of methyl acetophenone was added to and dissolved in a mixture of 1.2 g of water-cooled ethanol and 240 g of a 50% aqueous potassium hydroxide solution, and 5-formylbenzo [b] furan 4
Add 2.4 g and stir at room temperature overnight under an argon atmosphere. 29.5 g of 4-dimethylaminopyridine and 23.58 g of 10% platinum-carbon are added to the reaction solution, and the mixture is stirred under a normal pressure of hydrogen at room temperature for 4.5 hours. The catalyst is removed by filtration, the filtrate is washed with toluene, acidified with 18% hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The obtained organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated saline, and the washed aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried and concentrated under reduced pressure. Crystallized from ethanol, 3-
82.4 g of (5-benzo [b] furanyl) -2 ′-(β-D-glucopyranosyloxy) -6′-hydroxy-4′-methylpropiophenone are obtained.

Melting point: 152.5-154 ° C. ESI-MS (m / z): 476 [(M + NH ₄ ) ⁺ ] IR (nujol, cm ⁻¹ ): 3560, 3510, 3
_{350,3270,1630 NMR (DMSO-d 6)} δ: 2.24 (3H, s),
3.00 (2H, t, J = 7.4, the unit of the coupling constant J is Hz; the same applies hereinafter), 3.1-3.5 (7H,
m), 3.71 (1H, ddd, J = 2.0, 5.5,
12), 4.59 (1H, t, J = 5.8), 4.98
(1H, d, J = 7.3), 5.05 (1H, d, J =
5.1), 5.12 (1H, d, J = 4.6), 5.2
9 (1H, d, J = 5.1), 6.40 (1H, d, J
= 0.4), 6.54 (1H, s), 6.88 (1H,
dd, J = 0.9, 2.2), 7.22 (1H, dd,
J = 1.8, 8.4), 7.46 (1H, d, J = 8.
6), 7.53 (1H, d, J = 1.5), 7.93
(1H, d, J = 2.2), 11.90 (1H, s).

Production Example 2 (1) 3- (5-benzo [b] furanyl) -2 '-(β
-D-glucopyranosyloxy) -6'-hydroxy-
2.50 g of 4'-methylpropiophenone was added to acetone 2
Dissolve in 0 ml, add potassium carbonate (2.13 g) and allyl bromide (933 mg), and heat to reflux for 6 hours. After cooling,
The reaction solution is poured into ice water and extracted with ethyl acetate. After the organic layer is washed with water and dried, the solvent is distilled off. The obtained residue is purified by silica gel column chromatography (elution solvent: chloroform / methanol) to give 3- (5-benzo [b] furanyl) -2 ′-(β-D-glucopyranosyloxy) -6. 1.63 g of '-allyloxy-4'-methylpropiophenone are obtained.

ESI-MS (m / z): 521 [(M +
Na) ⁺ ], 516 [(M + NH ₄ ) ⁺ ] IR (neat, cm ⁻¹ ): 3019, 1691, 16
09 NMR (DMSO-d ₆ ) δ: 2.28 (3H, s),
2.92-3.02 (2H, m), 3.04-3.32
(6H, m), 3.40-3.50 (1H, m), 3.
66-3.74 (1H, m), 4.50 (2H, dt,
J = 1.5, 5.0), 4.57 (1H, t (b
r)), 4.87 (1H, d, J = 7.7), 5.03
(1H, d, J = 4.8), 5.09 (1H, d (b
r)), 5.16 (1H, ddt, J = 10.4, 1.
7, 1.5 Hz), 5.23 (1H, br), 5.26
(1H, ddt, J = 17.4, 1.7, 1.5),
5.90 (1H, ddt, J = 17.4, 10.4,
5.0), 6.56 (1H, s), 6.66 (1H,
s), 6.88 (1H, dd, J = 0.9, 2.2),
7.18 (1H, dd, J = 1.7, 8.4), 7.4
5 (1H, d, J = 8.4), 7.49 (1H, d, J
= 1.3), 7.93 (1H, d, J = 2.2).

(2) 3- (5-benzo [b] furanyl)
-2 '-(β-D-glucopyranosyloxy) -6'-allyloxy-4'-methylpropiophenone 500 mg
Was dissolved in 5 ml of 2,4,6-collidine, cooled to -40 ° C. with dry ice-acetone, and stirred while stirring.
1 solution is added dropwise. Stir at -40 ° C for 1 hour, then at room temperature for 1.5 hours. Pour the reaction into cold 10% aqueous citric acid and extract with ethyl acetate. After the organic layer is washed with water and dried, the solvent is distilled off. The obtained residue is subjected to silica gel column chromatography (elution solvent: chloroform / methanol).
And purified by 3- (5-benzo [b] furanyl) -2′-
487 mg of (6-O-methoxycarbonyl-β-D-glucopyranosyloxy) -6′-allyloxy-4′-methylpropiophenone are obtained.

ESI-MS (m / z): 579 [(M +
Na) ⁺ ] IR (neat, cm ^-1 ): 3401, 1751, 16
09 NMR (DMSO-d ₆ ) δ: 2.27 (3H, s),
2.92-2.99 (2H, m), 3.02-3.32
(5H, m), 3.57-3.62 (1H, m), 3.
64 (3H, s), 4.13 (1H, dd, J = 6.
8, 11.4), 4.38 (1H, dd, J = 1.7,
11.4), 4.50 (2H, dt, J = 5.0, 1.
5), 4.91 (1H, d, J = 7.7), 5.16
(1H, ddt, J = 10.6, 1.8, 1.5),
5.21 (1H, d, J = 5.0), 5.26 (1H,
ddt, J = 17.4, 1.7, 1.6), 5.35
(2H, d, J = 5.7), 5.89 (1H, ddt,
J = 17.2, 10.6, 4.9), 6.57 (1H,
s), 6.61 (1H, s), 6.87 (1H, dd,
J = 0.9, 2.2), 7.16 (1H, dd, J =
(1.8, 8.4), 7.45 (1H, d, J = 8.
4), 7.47 (1H, s), 7.93 (1H, d, J
= 2.0).

(3) 3- (5-benzo [b] furanyl)
470 mg of -2 '-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy) -6'-allyloxy-4'-methylpropiophenone in 7 ml of acetonitrile
And 17.7 mg of bis (triphenylphosphine) palladium (II) dichloride and 319 of ammonium formate.
Add and heat to reflux overnight. After cooling, the insolubles were removed by filtration, and the filtrate was concentrated, and ethyl acetate and water were added to the residue.
Separate the organic layer. After washing with water and drying, the solvent is distilled off, and the obtained residue is purified by silica gel column chromatography (elution solvent: chloroform / methanol) to give 3-
(5-benzo [b] furanyl) -2 ′-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy)-
6'-hydroxy-4'-methylpropiophenone 370
mg.

ESI-MS (m / z): 539 [(M +
Na) ⁺ ], 534 [(M + NH ₄ ) ⁺ ] IR (nujol, cm ^-1 ): 3200-3500, ¹
_{714 NMR (DMSO-d 6)} δ: 2.23 (3H, s),
2.99 (2H, t, J = 7.4), 3.14-3.4
2 (5H, m), 3.65 (3H, s), 3.63-
3.69 (1H, m), 4.16 (1H, dd, J =
6.6, 11.5), 4.39 (1H, dd, J = 2.
0, 11.5), 5.02 (1H, d, J = 7.5),
5.25 (1H, d, J = 5.0), 5.37 (1H,
d, J = 5.3), 5.39 (1H, d, J = 5.
3), 6.42 (1H, s), 6.50 (1H, s),
6.88 (1H, dd, J = 0.9, 2.2), 7.2
0 (1H, dd, J = 1.7, 8.4), 7.47 (1
H, d, J = 8.4), 7.51 (1H, d, J = 1.
3), 7.93 (1H, d, J = 2.2), 11.80
(1H, s).

Production Example 3-9 (1) In the same manner as in Production Example 2- (2), the compounds shown in Tables 4 to 7 are obtained from the corresponding starting compounds.

[0142]

[Table 4]

[0143]

[Table 5]

[0144]

[Table 6]

[0145]

[Table 7]

(2) The compounds shown in Tables 8 to 11 were obtained in the same manner as in Production Example 2- (3).

[0147]

[Table 8]

[0148]

[Table 9]

[0149]

[Table 10]

[0150]

[Table 11]

Production Example 10 3- (5-benzo [b] furanyl) -2 ′-(β-D-
400 mg of (glucopyranosyloxy) -6'-hydroxy-4'-methylpropiophenone is dissolved in 5 ml of trimethyl orthoacetate, and 22 mg of pyridinium p-toluenesulfonate is added, followed by stirring at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate and poured into a saturated aqueous sodium hydrogen carbonate solution. The organic layer is separated, washed with water, dried, and the solvent is distilled off. The obtained residue was purified by silica gel column chromatography (eluent: chloroform / methanol) to give 3- (5
-Benzo [b] furanyl) -2 '-(4,6-O- (1
-Methoxyethylidene)-[beta] -D-glucopyranosyloxy) -6'-hydroxy-4'-methylpropiophenone (320 mg) is obtained.

ESI-MS (m / z): 537 [(M +
Na) ⁺ ], 515 [(M + H) ⁺ ] IR (nujol, cm ^-1 ): 3423,1631 NMR (DMSO-d ₆ ) δ: 1.40 (3H, s),
2.25 (3H, s), 2.99 (2H, t, J = 7.
5), 3.23 (3H, s), 3.26-3.82 (8
H, m), 5.18 (1H, d, J = 7.7), 5.3
8 (1H, d, J = 5.3), 5.61 (1H, d, J)
= 5.7), 6.41 (1H, s), 6.55 (1H,
s), 6.84 (1H, dd, J = 0.9, 2.2),
7.19 (1H, dd, J = 1.7, 8.4), 7.4
7 (1H, d, J = 8.4), 7.51 (1H, d, J
= 1.3), 7.94 (1H, d, J = 2.2), 1
1.7 (1H, s).

Production Example 11 (1) 3- (5-benzo [b] furanyl) -2 ′-(β
-D-glucopyranosyloxy) -6'-hydroxy-
1.87 g of 4'-methylpropiophenone was suspended in 36 ml of dichloromethane, and 78 mg of p-toluenesulfonic acid and 930 of benzaldehyde dimethyl acetal were suspended at room temperature.
mg and stirred at room temperature for 1.5 hours. The solvent is distilled off, and ethyl acetate and saturated aqueous sodium hydrogen carbonate are added, and the organic layer is separated. The organic layer is washed with water and dried, and the solvent is distilled off. The obtained residue is subjected to silica gel column chromatography (elution solvent:
Purification with chloroform / acetone) gave 3- (5-benzo [b] furanyl) -2 ′-(4,6-O-benzylidene-β-D-glucopyranosyloxy) -6′-hydroxy-4. 2.03 g of '-methylpropiophenone are obtained.

ESI-MS (m / z): 569 [(M +
Na) ⁺ ], 547 [(M + H) ⁺ ] IR (neat, cm ⁻¹ ): 3450, 1631 NMR (DMSO-d ₆ ) δ: 2.09 (3H, s),
3.01 (2H, t, J = 7.4), 3.34-3.4
8 (4H, m), 3.58-3.70 (3H, m),
4.23 (1H, m), 5.22 (1H, d, J = 7.
7), 5.51 (1H, d, J = 4.9), 5.59
(1H, s), 5.64 (1H, d, J = 5.5),
6.42 (1H, s), 6.59 (1H, s), 6.9
0 (1H, dd, J = 0.9, 2.2), 7.22 (1
H, dd, J = 1.8, 8.4), 7.36-7.53
(7H, m), 7.95 (1H, d, J = 2.2), 1
1.80 (1H, s).

(2) 3- (5-benzo [b] furanyl)
1.00 g of -2 '-(4,6-O-benzylidene-β-D-glucopyranosyloxy) -6'-hydroxy-4'-methylpropiophenone was dissolved in 10 ml of N, N-dimethylformamide. , Imidazole 747 mg, t-
827 mg of butyldimethylchlorosilane is added, and the mixture is stirred at room temperature for 13 hours. The reaction solution is poured into ice water and extracted with 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 (eluent: hexane / ethyl acetate) to give 3- (5-benzo [b].
(Furanyl) -2 '-(3-O-t-butyldimethylsilyl-4,6-O-benzylidene-β-D-glucopyranosyloxy) -6'-t-butyldimethylsilyloxy-4'-methyl 1.06 g of propiophenone are obtained.

FAB-MS (m / z): 797 [(M +
Na) ⁺ ] IR (nujol, cm ^-1 ): 3459, 1691, ¹
_{610 NMR (DMSO-d 6)} δ: 0.01 (3H, s),
0.08 (3H, s), 0.18 (6H, s), 0.8
6 (9H, s), 0.89 (9H, s), 2.28 (3
H, s), 2.93-3.02 (2H, m), 3.04.
-3.15 (2H, m), 3.28 (1H, m), 3.
44 (1H, m), 3.62 (2H, m), 3.74
(1H, t, J = 8.8), 4.18 (1H, m),
5.18 (1H, d, J = 7.9), 5.56 (1H,
d, J = 7.0), 5.58 (1H, s), 6.40
(1H, s), 6.71 (1H, s), 6.88 (1
H, dd, J = 0.9, 2.2), 7.17 (1H, d
d, J = 1.8, 8.6), 7.36-7.49 (7
H, m), 7.93 (1H, d, J = 2.2).

(3) 3- (5-benzo [b] furanyl)
-2 '-(3-O-t-butyldimethylsilyl-4,6
1.04 g of —O-benzylidene-β-D-glucopyranosyloxy) -6′-t-butyldimethylsilyloxy-4′-methylpropiophenone in 5.4 ml of pyridine
And 2.7 ml of acetic anhydride is added, followed by stirring at room temperature overnight. Pour the reaction into 10% cold aqueous citric acid and extract with ethyl acetate. The organic layer is washed with water and saturated aqueous sodium bicarbonate, then dried,
The solvent was distilled off and 3- (5-benzo [b] furanyl)-
2 ′-(2-O-acetyl-3-O-t-butyldimethylsilyl-4,6-O-benzylidene-β-D-glucopyranosyloxy) -6′-t-butyldimethylsilyloxy-4 1.09 g of '-methylpropiophenone are obtained.

ESI-MS (m / z): 840 [(M +
Na) ⁺ ] IR (neat, cm ^-1 ): 1753, 1705, 16
09 NMR (DMSO-d ₆ ) δ: -0.04 (3H,
s), 0.00 (3H, s), 0.17 (3H, s),
0.17 (3H, s), 0.78 (9H, s), 0.8
6 (9H, s), 2.02 (3H, s), 2.28 (3
H, s), 2.80-3.02 (4H, m), 3.62.
(1H, t, J = 9.0), 3.70-3.85 (2
H, m), 4.04 (1H, t, J = 9.2), 4.2
9 (1H, dd, J = 3.7, 8.8), 4.93 (1
H, t, J = 9.0), 5.38 (1H, d, J = 8.
1), 5.65 (1H, s), 6.42 (1H, s),
6.65 (1H, s), 6.90 (1H, dd, J =
0.9, 2.2), 7.15 (1H, dd, J = 1.
8, 8.6), 7.37-7.47 (6H, m), 7.
50 (1H, d, J = 8.6), 7.94 (1H, d,
J = 2.2).

(4) 3- (5-benzo [b] furanyl)
-2 '-(2-O-acetyl-3-O-t-butyldimethylsilyl-4,6-O-benzylidene-β-D-glucopyranosyloxy) -6'-t-butyldimethylsilyloxy- 1.07 g of 4'-methylpropiophenone is dissolved in a mixture of 23 ml of tetrahydrofuran and 2.3 ml of acetic acid, 685 mg of tetra-n-butylammonium fluoride is added, and the mixture is stirred at room temperature for 25 minutes. The reaction solution is concentrated, and the obtained residue is dissolved in ethyl acetate and poured into ice water. After the organic layer was washed with water and dried, the solvent was distilled off to give 3- (5
-Benzo [b] furanyl) -2 '-(2-O-acetyl-3-O-t-butyldimethylsilyl-4,6-O-benzylidene-β-D-glucopyranosyloxy) -6'
-Hydroxy-4'-methylpropiophenone 968m
g.

FAB-MS (m / z): 725 [(M +
Na) ⁺ ] IR (neat, cm ^-1 ): 1753, 1634 NMR (DMSO-d ₆ ) δ: -0.05 (3H,
s), 0.00 (3H, s), 0.78 (9H, s),
2.03 (3H, s), 2.24 (3H, s), 2.9
2-2.99 (2H, m), 3.05-3.11 (2
H, m), 3.60 (1H, t, J = 9.1), 3.7
2 (1H, t, J = 9.3), 3.77-3.85 (1
H, m), 4.04 (1H, m), 4.27 (1H, d
d, J = 4.2, 9.2), 4.95 (1H, t, J =
8.5), 5.46 (1H, d, J = 8.1), 5.6
4 (1H, s), 6.42 (1H, s), 6.52 (1
H, s), 6.89 (1H, dd, J = 0.9, 2.H).
2), 7.20 (1H, dd, J = 1.7, 8.3),
7.36-7.46 (5H, m), 7.50 (1H,
d, J = 8.3), 7.51 (1H, m), 7.94
(1H, d, J = 2.2), 10.7 (1H, s).

(5) 3- (5-benzo [b] furanyl)
-2 '-(2-O-acetyl-3-O-t-butyldimethylsilyl-4,6-O-benzylidene-β-D-glucopyranosyloxy) -6'-hydroxy-4'-methylpro Dissolve 958 mg of piophenone in 35 ml of acetic acid,
4 ml of water and 75 mg of p-toluenesulfonic acid were added,
Stir at room temperature for 4 days. The reaction solution is poured into 700 ml of ice water and extracted with 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 (eluent: chloroform / methanol) to give 3- (5-benzo [b] furanyl) -2 ′-(2 −
O-acetyl-β-D-glucopyranosyloxy)-
6'-hydroxy-4'-methylpropiophenone 420
mg.

Melting point: 160 ° C.-(gradual melting) ESI-MS (m / z): 518 [(M + NH ₄ ) ⁺ ] IR (nujol, cm ⁻¹ ): 3100-3510,1
_{752 NMR (DMSO-d 6)} δ: 1.99 (3H, s),
2.22 (3H, s), 2.90-2.97 (2H,
m), 3.03-3.11 (2H, m), 3.21-
3.31 (1H, m), 3.42-3.53 (3H,
m), 3.72 (1H, m), 4.67 (1H, t, J
= 5.6), 4.78 (1H, dd, J = 8.2,9.
5), 5.20 (1H, d, J = 8.1), 5.28
(1H, d, J = 5.3), 5.36 (1H, d, J =
5.5), 6.39 (1H, s), 6.52 (1H,
s), 6.88 (1H, dd, J = 0.9, 2.2),
7.18 (1H, dd, J = 1.7, 8.4), 7.4
7 (1H, d, J = 8.4), 7.50 (1H, d, J
= 1.3), 7.93 (1H, d, J = 2.2), 1
0.86 (1H, s).

Production Example 12 (1) 3- (5-benzo [b] furanyl) -2'-
2.02 g of (4,6-O-benzylidene-β-D-glucopyranosyloxy) -6′-hydroxy-4′-methylpropiophenone was dissolved in 20 ml of pyridine, and 2.27 g of acetic anhydride was added. Stir at room temperature for 4.5 hours. Pour the reaction into 10% cold aqueous citric acid and extract with ethyl acetate. After the organic layer was washed with water and dried, the solvent was distilled off to give 3- (5-
Benzo [b] furanyl) -2 ′-(2,3-di-O-acetyl-4,6-O-benzylidene-β-D-glucopyranosyloxy) -6′-acetoxy-4′-methylpro 2.37 g of piophenone are obtained.

Melting point: 200-203 ° C. ESI-MS (m / z): 690 [(M + NH ₄ ) ⁺ ] IR (nujol, cm ⁻¹ ): 1764,1747,1
_{699,1619 NMR (DMSO-d 6)} δ: 1.94 (3H, s),
2.01 (3H, s), 2.02 (3H, s), 2.3
4 (3H, s), 2.87-3.03 (4H, m),
3.76 (1H, t, J = 9.9), 3.90 (1H,
t, J = 9.4), 3.97 (1H, dd, J = 4.
5,9.9), 4.44 (1H, dd, J = 4.6,1)
0.0), 5.07 (1H, dd, J = 7.9, 8.
1), 5.40 (1H, t, J = 9.4), 5.63
(1H, s), 5.68 (1H, d, J = 7.9),
6.74 (1H, s), 6.91 (1H, dd, J =
0.9, 2.2), 7.00 (1H, s), 7.17
(1H, dd, J = 1.8, 8.6), 7.39 (5
H, s), 7.49 (1H, d, J = 1.3), 7.5
1 (1H, d, J = 8.4), 7.95 (1H, d, J
= 2.2).

(2) 3- (5-benzo [b] furanyl)
-2 '-(2,3-di-O-acetyl-4,6-O-benzylidene-β-D-glucopyranosyloxy) -6'
-Acetoxy-4'-methylpropiophenone 2.04
g was suspended in 60 ml of acetic acid, 6 ml of water and 58 mg of p-toluenesulfonic acid were added, and the mixture was stirred at room temperature for 20 hours.
The reaction solution is poured into 800 ml of ice water, left for 1 hour, and then the precipitated insoluble insoluble matter is collected by filtration. The obtained product is dissolved in ethyl acetate, and the organic layer is washed with saturated aqueous sodium hydrogen carbonate, dried, and the solvent is distilled off. The resulting residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol) to give 3- (5-benzo [b] furanyl) -2 ′-(2,3-di-O-acetyl-β- 1.72 g of (D-glucopyranosyloxy) -6'-acetoxy-4'-methylpropiophenone are obtained.

ESI-MS (m / z): 602 [(M +
NH ₄ ) ⁺ ] IR (nujol, cm ⁻¹ ): 3404, 1751 NMR (DMSO-d ₆ ) δ: 1.87 (3H, s),
2.00 (3H, s), 2.00 (3H, s), 2.3
1 (3H, s), 2.84-3.11 (4H, m),
3.48-3.57 (2H, m), 3.64-3.77
(2H, m), 4.77 (1H, t, J = 5.8),
4.89 (1H, dd, J = 8.1, 9.7), 5.1
0 (1H, t, J = 9.7), 5.50 (1H, d, J
= 8.1), 5.59 (1H, d, J = 5.7), 6.
70 (1H, s), 6.89 (1H, dd, J = 0.
9, 2.2), 7.00 (1H, s), 7.16 (1
H, dd, J = 1.5, 8.5), 7.47-7.50.
(2H, m), 7.94 (1H, d, J = 2.2).

Production Example 13 (1) 3- (5-benzo [b] furanyl) -2'-
671 mg of (2,3-di-O-acetyl-4,6-O-benzylidene-β-D-glucopyranosyloxy) -6′-acetoxy-4′-methylpropiophenone was added to 5 ml of tetrahydrofuran, 5 ml of methanol, Water 0.1m
and mixed with 419 mg of sodium bicarbonate.
Stir for 0 hours. The reaction solution is poured into water and extracted with ethyl acetate. 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 (elution solvent: hexane / ethyl acetate) to give 3- (5-benzo [b] furanyl) -2 ′-(2,3-di-O-acetyl-4). , 6-O-benzylidene-β-D-glucopyranosyloxy) -6′-hydroxy-4′-methylpropiophenone (410 mg).

Melting point: 187-189 ° C. ESI-MS (m / z): 648 [(M + NH ₄ ) ⁺ ] IR (neat, cm ⁻¹ ): 1754, 1633 NMR (DMSO-d ₆ ) δ: 1.97 (3H, s),
2.01 (3H, s), 2.25 (3H, s), 2.9
0-2.98 (2H, m), 3.01-3.09 (2
H, m), 3.76 (1H, t, J = 9.9), 3.8
8 (1H, t, J = 9.4), 3.95 (1H, dd,
J = 4.6, 9.5), 4.32 (1H, dd, J =
4.6, 10.1), 5.05 (1H, dd, J = 7.
9, 9.3), 5.40 (1H, t, J = 9.3),
5.63 (1H, s), 5.63 (1H, d, J = 7.
9), 6.43 (1H, s), 6.53 (1H, s),
6.90 (1H, dd, J = 0.9, 2.2), 7.1
9 (1H, dd, J = 1.7, 8.6), 7.39 (5
H, s), 7.50 (2H, m), 7.95 (1H,
d, J = 2.2), 10.70 (1H, s).

(2) 3- (5-benzo [b] furanyl)
-2 '-(2,3-di-O-acetyl-4,6-O-benzylidene-β-D-glucopyranosyloxy) -6'
-Hydroxy-4'-methylpropiophenone 395m
g was dissolved in 14 ml of acetic acid, 1.4 ml of water and 12 mg of p-toluenesulfonic acid were added, and the mixture was stirred at room temperature for 2 days.
The reaction solution is poured into ice water and left for 1 hour. The precipitated colorless precipitate is collected by filtration, dissolved in ethyl acetate, washed with water, dried, and the solvent is distilled off. The obtained residue is subjected to silica gel column chromatography (elution solvent: chloroform / methanol).
To give 3- (5-benzo [b] furanyl) -2 ′
297 mg of-(2,3-di-O-acetyl-β-D-glucopyranosyloxy) -6′-hydroxy-4′-methylpropiophenone are obtained.

Melting point: 151-153 ° C. ESI-MS (m / z): 560 [(M + NH ₄ ) ⁺ ] IR (nujol, cm ⁻¹ ): 3543,3288,1
_{751,1729 NMR (DMSO-d 6)} δ: 1.91 (3H, s),
1.99 (3H, s), 2.23 (3H, s), 2.8
9-2.96 (2H, m), 3.02-3.09 (2
H, m), 3.46-3.80 (4H, m), 4.75
(1H, t, J = 5.7), 4.88 (1H, dd, J
= 8.0, 9.8), 5.09 (1H, t, J = 9.
4), 5.43 (1H, d, J = 8.0), 5.58
(1H, d, J = 5.7), 6.41 (1H, s),
6.54 (1H, s), 6.88 (1H, dd, J =
0.9, 2.2), 7.17 (1H, dd, J = 1.
8, 8.4), 7.47 (1H, d, J = 8.9),
7.49 (1H, s), 7.94 (1H, d, J = 2.
2), 10.48 (1H, s).

Production Example 14 (1) 3- (5-benzo [b] furanyl) -2'-
(4,6-O-benzylidene-β-D-glucopyranosyloxy) -6′-hydroxy-4′-methylpropiophenone (600 mg) was added to N, N-dimethylacetamide (4 m).
Then, 123 mg of triethylamine is added, and a solution of 115 mg of methyl chloroformate in 2 ml of N, N-dimethylacetamide is added dropwise over 40 minutes under ice-cooling.
Stir at the same temperature for 10 minutes, pour the reaction solution into cold 10% citric acid water, and extract with ethyl acetate. After washing the organic layer with water and drying,
The solvent is distilled off. The obtained residue was purified by silica gel column chromatography (eluent: chloroform / methanol) to give 3- (5-benzo [b] furanyl)-
2 ′-(4,6-O-benzylidene-β-D-glucopyranosyloxy) -6′-methoxycarbonyloxy-
637 mg of 4'-methylpropiophenone are obtained.

ESI-MS (m / z): 622 [(M +
NH ₄ ) ⁺ ] IR (nujol, cm ⁻¹ ): 3383,1762,1
_{689,1618 NMR (DMSO-d 6)} δ: 2.34 (3H, s),
2.92-2.98 (2H, m), 3.05-3.25
(2H, m), 3.33-3.47 (2H, m), 3.
54-3.70 (3H, m), 3.75 (3H, s),
4.22 (1H, m), 5.28 (1H, d, J = 7.
9), 5.51 (1H, d, J = 5.3), 5.57
(1H, s), 5.68 (1H, d, J = 5.9),
6.81 (1H, s), 6.91 (1H, dd, J =
0.9, 2.2), 7.09 (1H, s), 7.19
(1H, dd, J = 1.7, 8.6), 7.37-7.
48 (5H, m), 7.50 (1H, d, J = 8.
6), 7.50 (1H, d, J = 1.7), 7.95
(1H, d, J = 2.2).

(2) 3- (5-benzo [b] furanyl)
618 mg of -2 '-(4,6-O-benzylidene-β-D-glucopyranosyloxy) -6'-methoxycarbonyloxy-4'-methylpropiophenone was added to acetic acid 60
Then, 1.4 ml of water and 19 mg of p-toluenesulfonic acid are added, and the mixture is stirred at room temperature overnight. The reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium hydrogen carbonate and dried, and the solvent is distilled off. The obtained residue is purified by silica gel column chromatography (elution solvent: chloroform / methanol) to give 3- (5-benzo [b] furanyl) -2 ′-(β-D-glucopyranosyloxy)-.
428 mg of 6'-methoxycarbonyloxy-4'-methylpropiophenone are obtained.

ESI-MS (m / z): 534 [(M +
NH ₄ ) ⁺ ] IR (neat, cm ⁻¹ ): 3387, 1765 NMR (DMSO-d ₆ ) δ: 2.32 (3H, s),
2.90-2.98 (2H, m), 3.09-3.50
(7H, m), 3.67-3.74 (1H, m), 3.
74 (3H, s), 4.60 (1H, t, J = 5.
7), 5.04 (1H, d, J = 7.5), 5.08
(1H, d, J = 5.3), 5.15 (1H, d, J =
4.9), 5.37 (1H, d, J = 5.5), 6.7
8 (1H, m), 6.88 (1H, dd, J = 0.9,
2.2), 7.03 (1H, s), 7.19 (1H, d
d, J = 1.8, 8.4), 7.46 (1H, d, J =
8.4), 7.51 (1H, d, J = 1.3), 7.9
3 (1H, d, J = 2.2).

Production Example 15 (1) In the same manner as in Production Example 14- (1), 3- (5-benzo [b] furanyl) -2′-
(4,6-O-benzylidene-β-D-glucopyranosyloxy) -6′-acetoxy-4′-methylpropiophenone is obtained.

ESI-MS (m / z): 606 [(M +
NH ₄ ) ⁺ ] IR (nujol, cm ⁻¹ ): 3367, 1767, ¹
_{690,1617 NMR (DMSO-d 6)} δ: 2.03 (3H, s),
2.33 (3H, s), 2.92-3.00 (2H,
m), 3.05-3.73 (7H, m), 4.17-
4.27 (1H, m), 5.26 (1H, d, J = 7.
7), 5.50 (1H, d, J = 5.3), 5.58
(1H, s), 5.68 (1H, d, J = 5.9),
6.68 (1H, m), 6.91 (1H, dd, J =
0.9, 2.2), 7.05 (1H, s), 7.19
(1H, dd, J = 1.6, 8.6), 7.37-7.
52 (7H, m), 7.95 (1H, d, J = 2.
2).

(2) In the same manner as in Production Example 14- (2),
3- (5-benzo [b] furanyl) -2 ′-(4,6-
O-benzylidene-β-D-glucopyranosyloxy)
-6'-acetoxy-4'-methylpropiophenone to 3- (5-benzo [b] furanyl) -2 '-(β-D-
Glucopyranosyloxy) -6'-acetoxy-4'-methylpropiophenone is obtained.

ESI-MS (m / z): 518 [(M +
NH ₄ ) ⁺ ] IR (neat, cm ⁻¹ ): 3393, 1769, 16
_{91,1618,1198 NMR (DMSO-d 6)} δ: 2.02 (3H, s),
2.30 (3H, s), 2.89-3.02 (2H,
m), 3.06-3.51 (7H, m), 3.67-
3.75 (1H, m), 4.58 (1H, t, J = 5.
7), 5.02 (1H, d, J = 7.3), 5.05
(1H, d, J = 5.1), 5.12 (1H, d, J =
4.8), 5.34 (1H, d, J = 5.5), 6.6
4 (1H, s), 6.88 (1H, dd, J = 0.9,
2.2), 6.99 (1H, s), 7.19 (1H, d
d, J = 1.7, 8.4), 7.47 (1H, d, J =
8.4), 7.51 (1H, d, J = 1.3), 7.9
3 (1H, d, J = 2.0).

Production Example 16 3- (5-benzo [b] furanyl) -2 ′-(β-D-
Glucopyranosyloxy) -6′-hydroxy-4′-methylpropiophenone (500 mg) was dissolved in N, N-dimethylacetamide (3.5 ml).
15 mg, and 282 mg of acetyl chloride were added under ice cooling.
And the mixture is stirred under ice-cooling for 30 minutes and at room temperature overnight. Pour the reaction into 10% cold aqueous citric acid and extract with ethyl acetate. After the organic layer was washed with water and dried, the solvent was distilled off, and silica gel column chromatography (elution solvent: chloroform / chloroform /
Methanol) to give 3- (5-benzo [b] furanyl) -2 ′-(6-O-acetyl-β-D-glucopyranosyloxy) -6′-acetoxy-4′-methylpro- 304 mg of piophenone are obtained.

ESI-MS (m / z): 560 [(M +
NH ₄ ) ⁺ ] IR (neat, cm ⁻¹ ): 3417, 1769, 17
_{40,1695,1618 NMR (DMSO-d 6)} δ: 1.97 (3H, s),
2.02 (3H, s), 2.31 (3H, s), 2.8
8-2.98 (2H, m), 3.04-3.32 (5
H, m), 3.62-3.70 (1H, m), 4.03
(1H, dd, J = 7.2, 14.1), 4.35 (1
H, dd, J = 1.8, 11.7), 5.04 (1H,
d, J = 7.5), 5.25 (1H, d, J = 4.
9), 5.34 (1H, d, J = 5.3), 5.44
(1H, d, J = 5.5), 6.67 (1H, s),
6.88 (1H, dd, J = 0.9, 2.2), 6.9
5 (1H, s), 7.18 (1H, dd, J = 1.8,
8.4), 7.47 (1H, d, J = 8.4), 7.5
0 (1H, d, J = 1.5), 7.94 (1H, d, J)
= 2.2).

Production Example 17 (1) 3- (5-benzo [b] furanyl) -2 ′-(β
-D-glucopyranosyloxy) -6'-hydroxy-
3.0 g of 4'-methylpropiophenone was added to 2,4,6-
Dissolved in 33 ml of collidine, cooled to -40 ° C with dry ice-acetone, and stirred while stirring 1.71 g of 4-nitrophenyl chloroformate in 8.6 m of dichloromethane.
1 solution is added dropwise. 1 hour 30 minutes at -40 ° C, 1 hour at room temperature
After stirring for 3 hours, the mixture is stirred at 53 ° C. for 3 hours. After cooling, the reaction solution is poured into cold 10% hydrochloric acid and extracted with ethyl acetate. 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 (elution solvent: chloroform / acetone) to give 3- (5-benzo [b] furanyl) -2 ′-(4,6-O-carbonyl-
2.16 g of β-D-glucopyranosyloxy) -6′-hydroxy-4′-methylpropiophenone are obtained.

FAB-MS (m / z): 507 [(M +
Na) ⁺ ], 485 [(M + H) ⁺ ] IR (nujol, cm ^-1 ): 3386,1753,1
_{630 NMR (DMSO-d 6)} δ: 2.25 (3H, s),
2.99 (2H, t, J = 7.4), 3.30-3.4
0 (3H, m), 3.64 (1H, m), 4.09-
4.21 (2H, m), 4.26 (1H, dd, J =
9.3, 9.7), 4.49 (1H, dd, J = 5.
3,9.2), 5.26 (1H, d, J = 7.9),
5.80 (1H, d, J = 5.9), 5.86 (1H,
d, J = 5.7), 6.43 (1H, s), 6.55.
(1H, s), 6.89 (1H, dd, J = 0.9,
2.2), 7.19 (1H, dd, J = 1.8, 8.
6), 7.49 (1H, d, J = 8.6), 7.50
(1H, d, J = 1.9), 7.94 (1H, d, J =
2.2), 11.6 (1H, s).

(2) 3- (5-benzo [b] furanyl)
2.13 g of -2 '-(4,6-O-carbonyl-β-D-glucopyranosyloxy) -6'-hydroxy-4'-methylpropiophenone was dissolved in 40 ml of methanol, and p-toluenesulfone was dissolved. Add 84 mg of acid and add 1
Stir for hours. The reaction solution is diluted with ethyl acetate and poured into saturated aqueous sodium hydrogen carbonate. The organic layer is separated, washed with water and dried, and the solvent is distilled off. The obtained residue was purified by silica gel column chromatography (elution solvent: chloroform / acetone).
3- (5-benzo [b] furanyl) -2 '-(4-O-
986 mg of methoxycarbonyl-β-D-glucopyranosyloxy) -6′-hydroxy-4′-methylpropiophenone are obtained.

ESI-MS (m / z): 534 [(M +
NH ₄ ) ⁺ ] IR (neat, cm ⁻¹ ): 3459, 1752, 16
_{31 NMR (DMSO-d 6)} δ: 2.24 (3H, s),
3.00 (2H, t, J = 7.4), 3.32-3.4
5 (4H, m), 3.49-3.60 (2H, m),
3.66-3.73 (1H, m), 3.73 (3H,
s), 4.54 (1H, t, J = 9.6), 4.82.
(1H, t, J = 5.6), 5.12 (1H, d, J =
7.7), 5.52 (1H, d, J = 5.7), 5.6
0 (1H, d, J = 5.7), 6.44 (1H, d, J
= 0.6), 6.56 (1H, d, J = 0.9), 6.
90 (1H, dd, J = 0.9, 2.2), 7.22
(1H, dd, J = 1.7, 8.4), 7.47 (1
H, d, J = 8.4), 7.54 (1H, d, J = 1.
3), 7.93 (1H, d, J = 2.2), 11.8
(1H, s).

Production Example 18 By treating in the same manner as in Production Example 1, 3- (5-benzo [b] furanyl) -2′-
(Β-D-glucopyranosyloxy) -6′-hydroxy-4′-ethylpropiophenone is obtained.

Melting point: 146-18.5 ° C. ESI-MS (m / z): 490 [(M + NH ₄ ) ⁺ ] IR (nujol, cm ⁻¹ ): 3600-3200,1
_{633,1605 NMR (DMSO-d 6)} δ: 1.15 (3H, t, J
= 7.5), 2.55 (2H, q, J = 7.5), 3.
00 (2H, t, J = 7.5), 3.10-3.50
(7H, m), 3.68-3.74 (1H, m), 4.
61 (1H, t, J = 5.5), 4.98 (1H, d,
J = 7.5), 5.06 (1H, d, J = 5.5),
5.14 (1H, d, J = 5.0), 5.31 (1H,
d, J = 5.5), 6.42 (1H, d, J = 1.
5), 6.57 (1H, d, J = 1.5), 6.88
(1H, dd, J = 1.0, 2.0), 7.22 (1
H, dd, J = 2.0, 8.5), 7.46 (1H,
d, J = 8.5), 7.53 (1H, d, J = 2.
0), 7.93 (1H, d, J = 2.0), 11.90
(1H, s).

Production Example 19 (1) 3- (5-benzo [b] furanyl) -2 ′-(β-D-glucopyranosyloxy) -6′- obtained in Production Example 2- (1) Dissolve 300 mg of allyloxy-4'-methylpropiophenone in 3 ml of tetrahydrofuran, add 315 mg of 2,4,6-collidine and 486 mg of diphenylchlorophosphate under ice cooling, and stir at room temperature for 22 hours under an argon atmosphere. The reaction was cooled on ice 1
Pour into 0% aqueous citric acid and extract with ethyl acetate. The obtained organic layer is sequentially washed with water, saturated aqueous sodium hydrogen carbonate and saturated saline, dried, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol) to give 3- (5-benzo [b] furanyl) -2 '-(6-O-diphenylphosphono-β-
D-glucopyranosyloxy) -6′-allyloxy-
327 mg of 4'-methylpropiophenone are obtained.

ESI-MS (m / z): 748 [(M +
NH ₄ ) ⁺ ] IR (nujol, cm ⁻¹ ): 3396, 1698, ¹
_{609 NMR (DMSO-d 6)} δ: 2.17 (3H, s),
2.95 (2H, t, J = 7.5), 3.0-3.3
(5H, m), 3.72 (1H, dt, J = 9.5,
2.5), 4.30 (1H, ddd, J = 5.5,7.
5, 11.5), 4.52 (2H, dt, J = 1.5,
5.0), 4.57 (1H, ddd, J = 3.5,5.
5,11.5), 5.00 (1H, d, J = 7.5),
5.16 (1H, ddt, J = 11.0, 3.5, 1 ..
5), 5.26 (1H, ddt, J = 17.5,3.
5,1.5), 5.3-5.4 (3H, br), 5.8
9 (1H, ddt, J = 17.5, 11.0, 5.
0), 6.55 (1H, s), 6.68 (1H, s),
6.86 (1H, dd, J = 1.0, 2.0), 7.1
−7.2 (7H, m), 7.30 (4H, dt, J =
8.0, 1.5), 7.44 (1H, d, J = 9.
5), 7.45 (1H, d, J = 2.0), 7.92
(1H, d, J = 2.0) (2) 3- (5-benzo [b] furanyl) -2 ′-(6-O-diphenylphosphono-β-D- obtained in (1).
Glucopyranosyloxy) -6'-allyloxy-4'-
308 mg of methyl propiophenone in acetonitrile 3
of ammonium formate and 3 mg of bis (triphenylphosphine) palladium (II) dichloride.
And heated to reflux for 1.5 hours under an argon atmosphere.
The reaction solution is returned to room temperature, poured into ice water and extracted with ethyl acetate. The obtained organic layer is sequentially washed with water and saturated saline, dried, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol) to give 3- (5-benzo [b] furanyl) -2 ′-(6-O-diphenylphosphono-β-D-
246 mg of (glucopyranosyloxy) -6'-hydroxy-4'-methylpropiophenone are obtained.

ESI-MS (m / z): 708 [(M +
NH ₄ ) ⁺ ] IR (nujol, cm ⁻¹ ): 3405, 1630, ¹
600 NMR (DMSO-d ₆ ) δ: 2.13 (3H, s),
2.98 (2H, t, J = 7.0), 3.2-3.5
(5H, m), 3.75-3.85 (1H, m), 4.
3-4.4 (1H, m), 4.55 (1H, ddd, J
= 3.5, 5.5, 11.5), 5.10 (1H, d,
J = 8.0), 5.29 (1H, d, J = 5.0),
5.41 (1H, d, J = 4.5), 5.43 (1H,
d, J = 5.5), 6.39 (1H, d, J = 1.
0), 6.57 (1H, d, J = 1.0), 6.85
(1H, dd, J = 1.0, 2.0), 7.1-7.2
(7H, m), 7.29 (4H, dt, J = 8.0,
2.5), 7.44 (1H, d, J = 9.5), 7.4
9 (1H, d, J = 2.0), 7.92 (1H, d, J)
= 2.0), 11.84 (1H, s) (3) 3- (5-benzo [b] furanyl) -2 '-(6
-O-diphenylphosphono-β-D-glucopyranosyloxy) -6′-hydroxy-4′-methylpropiophenone (764 mg) is dissolved in 1,4-dioxane (33 ml), and a 0.1N sodium hydroxide aqueous solution (33 ml) is dissolved. And stirred at room temperature for 2.5 hours under an argon atmosphere. 60 mg of ammonium chloride is added to the reaction solution, and the solvent is distilled off under reduced pressure. Ethanol is added to the obtained residue, and the insoluble matter is filtered off. Isopropanol was added to the filtrate, and the precipitate was collected by filtration to give 3- (5-benzo [b] furanyl) -2′-.
327 mg of (4,6-O-phosphinico-β-D-glucopyranosyloxy) -6′-hydroxy-4′-methylpropiophenone sodium are obtained.

ESI-MS (m / z): 519 [(M +
Na) ⁺ ] IR (nujol, cm ^-1 ): 3300, 1625, ¹
_{612 NMR (DMSO-d 6)} δ: 2.25 (3H, s),
2.97 (2H, t, J = 7.5), 3.3-3.9
(8H, m), 5.15 (1H, d, J = 7.5),
5.40 (1H, br), 5.55 (1H, br),
6.41 (1H, s), 6.55 (1H, s), 6.9
8 (1H, dd, J = 1.0, 2.0), 7.19 (1
H, dd, J = 1.5, 8.5), 7.49 (1H,
d, J = 8.5), 7.51 (1H, d, J = 1.
5), 7.92 (1H, d, J = 2.0) Reference Example 1 (1) 50 g of orcinol monohydrate was treated with 400 m of pyridine.
, and 133 ml of acetic anhydride was added, followed by stirring at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in 500 ml of ethyl acetate, washed with 10% hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried, and the solvent was distilled off to remove 74 g of orcinol diacetate. obtain.

EI-MS (m / z): 208 (M ⁺ ) NMR (CDCl ₃ ) δ: 2.27 (6H, s), 2.
35 (3H, s), 6.71 (1H, t, J = 1.
8), 6.80 (2H, m).

(2) 19.2 g of aluminum chloride was heated to 90 ° C. in 50 ml of chlorobenzene, and a solution of 10 g of orcinol diacetate in 8 ml of chlorobenzene was added dropwise over 35 minutes. After the dropwise addition, the mixture was stirred at the same temperature for 1 hour, cooled, and the reaction solution was cooled with ice-10% hydrochloric acid (100 ml-
100 ml) and stirred for 30 minutes. Ethyl acetate 10
0 ml was added, the organic layer was separated, washed with water, dried and the solvent was distilled off. 100 ml of hexane was added to the obtained residue, and the mixture was stirred at room temperature for 30 minutes, filtered, and dried to obtain 5.9 g of 2 ′, 6′-dihydroxy-4′-methylacetophenone. Melting point: 146-148 [deg.] C.

Reference Example 2 0.5 g of 2 ', 6'-dihydroxy-4'-methylacetophenone, 2.08 g of cadmium carbonate and toluene 4
Add 0 ml of the mixture to a Dean-Stark distillation tube (Die
Reflux while removing the solvent with n-Stark trap). After removing 10 ml of the solvent, it was cooled to about 80 ° C.
Then 2,3,4,6-tetra-O-acetyl-α-D
Add 2.48 g of glucopyranosyl bromide and reflux overnight. After cooling, chloroform is added for dilution, and insolubles are filtered off. The filtrate was concentrated, and the residue was crystallized from methanol to give 2 ′-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) -6′-hydroxy-4′-. 735 mg of methylacetophenone are obtained.

Melting point: 140-141.5 ° C. ESI-MS (m / z): 514 [(M + NH ₄ ) ⁺ ] IR (nujol, cm ⁻¹ ): 1755, 1725, ¹
_{650 NMR (DMSO-d 6)} δ: 1.96 (3H, s),
2.01 (9H, s), 2.26 (3H, s), 2.3
9 (3H, s), 4.05-4.22 (2H, m),
4.28 (1H, ddd, J = 2.6, 5.7, 9.
9), 5.00 (1H, dd, J = 9.5, 9.9),
5.10 (1H, dd, J = 8.0, 9.6), 5.3
9 (1H, t, J = 9.5), 5.64 (1H, d, J
= 8.1), 6.46 (1H, s), 6.48 (1H,
s), 11.60 (1H, s).

Reference Example 3 414 g of potassium carbonate was suspended in 1.3 l of chloroform, and 29 ml of water was slowly added dropwise thereto. Then
37 g of tributylbenzylammonium chloride and 100 g of 2 ', 6'-dihydroxy-4'-methylacetophenone were added, and 2,3,4,6-tetra-O
-Acetyl-α-D-glucopyranosyl bromide 419
g and stirred at room temperature. After 27 hours, 21 ml of water was added, and the mixture was further stirred for 2.5 hours.
Neutralize by adding approximately 500 ml of hydrochloric acid. 10% more
After adding about 200 ml of hydrochloric acid and 500 ml of water,
Separate the chloroform layer. The organic layer is washed with water and saturated saline and then dried, and the obtained organic layer is concentrated. 400 ml of methanol is added to the residue and concentrated again. When about half of the residue was distilled off, 2 l of methanol was added to the residue, and the mixture was slightly heated and then stirred under ice cooling for 30 minutes. The precipitate is collected by filtration,
After drying under reduced pressure, 2 '-(2,3,4,6-tetra-O
-Acetyl-β-D-glucopyranosyloxy) -6 ′
-Hydroxy-4'-methylacetophenone 239.7
5 g are obtained. Physical properties were the same as those of the compound obtained in Reference Example 2.

Reference Example 4 (1) 1.0 g of 3,5-dimethoxyaniline was added to 3 m of hydrochloric acid
, 2 ml of acetic acid and 5 ml of water, and a solution of 473 mg of sodium nitrite in 5 ml of water is added dropwise over 15 minutes under ice cooling. After 10 minutes, a solution of 1.62 g of potassium iodide in 5 ml of water is added, the mixture is heated to 80 ° C., and stirred for 1 hour. The reaction solution is extracted with diethyl ether, and the extracted layer is washed with water, dried, and then the solvent is distilled off. The residue is purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate), and the obtained solid is recrystallized from ethyl acetate-hexane to give 3,5-dimethoxyiodobenzene (1.05 g). Melting point: 73-74 [deg.] C.

(2) 1.19 g of 3,5-dimethoxyiodobenzene is dissolved in 10 ml of acetic acid, 10 ml of 47% hydrobromic acid is added at room temperature, and the mixture is heated under reflux for 15 hours. The reaction solution is returned to room temperature, dried under reduced pressure, and the residue is dissolved in ethyl acetate. The organic layer was washed with water and dried, and then the solvent was distilled off.
1.06 g of dihydroxyiodobenzene are obtained.

EI-MS (m / z): 236 (M ⁺ ) IR (neat, cm ⁻¹ ): 3325, 1605 NMR (CDCl ₃ ) δ: 5.22 (2H, s), 6.
31 (1H, t, J = 2.5), 6.79 (2H, d,
J = 2.5).

(3) Dissolve 1.02 g of 3,5-dihydroxyiodobenzene in 2.8 ml of pyridine, and add 1.53 g of acetic anhydride at room temperature. After stirring for 1 hour, the reaction solution was
Pour into 0% aqueous citric acid and extract with ethyl acetate. After the organic layer is washed with water and dried, the solvent is distilled off to obtain 1.37 g of 3,5-diacetoxyiodobenzene.

EI-MS (m / z): 320 (M ⁺ ),
278,236 IR (neat, cm ^-1 ): 1771,1586 NMR (CDCl ₃ ) δ: 2.28 (6H, s), 6.
92 (1H, t, J = 2.0), 7.36 (2H, d,
J = 2.0).

(4) 860 mg of 3,5-diacetoxyiodobenzene was dissolved in 4 ml of 1,4-dioxane, and 1.41 g of vinyltributyltin and 20 mg of bis (triphenylphosphine) palladium (II) dichloride were added at room temperature. Heat to reflux for 3 hours. The reaction solution was returned to room temperature, diluted with ethyl acetate, and a 10% aqueous potassium fluoride solution was added.
Stir at room temperature for 30 minutes. After filtering off the insolubles, the mixture is extracted with ethyl acetate. After the organic layer is washed with water and dried, the solvent is distilled off. The obtained residue is purified by silica gel column chromatography to obtain 585 mg of 3,5-diacetoxystyrene.

EI-MS (m / z): 220 (M ⁺ ),
^{178,136 IR (neat, cm -1)} : 1771,1610 NMR (CDCl 3) δ: 2.29 (6H, s), 5.
32 (1H, d, J = 11.0), 5.74 (1H,
d, J = 17.0), 6.65 (1H, dd, J = 1)
1.0, 17.0), 6.82 (1H, t, J = 2.
0), 7.03 (2H, d, J = 2.0).

(5) 3,5-diacetoxystyrene 58
0 mg was dissolved in ethyl acetate 6 ml-ethanol 2 ml, and 10% palladium-carbon (water 51.4%) 50 m
g is used as a catalyst to perform catalytic reduction under normal pressure. After 2 hours, the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to obtain 450 mg of 1,3-diacetoxy-5-ethylbenzene. .

EI-MS (m / z): 222 (M ⁺ ) IR (neat, cm ⁻¹ ): 1771, 1616 NMR (CDCl ₃ ) δ: 1.23 (3H, t, J =
7.5), 2.28 (6H, s), 2.66 (2H,
q, J = 7.5), 6.74 (1H, t, J = 2.
0), 6.82 (2H, d, J = 2.0).

(6) By treating 1,3-diacetoxy-5-ethylbenzene in the same manner as in Reference Example 1- (2), 2 ′, 6′-dihydroxy-4′-ethylacetophenone is obtained. Melting point: 121-123 [deg.] C.

(7) 2 ′, 6′-Dihydroxy-4′-ethylacetophenone was treated in the same manner as in Reference Example 3 to give 2 ′-(2,3,4,6-tetra-O-acetyl-β -D-glucopyranosyloxy) -6'-hydroxy-4'-ethylacetophenone is obtained. Melting point: 125
-127 ° C.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07F 9/6574 C07F 9/6574 Z // C07H 15/203 C07H 15/203 (72) Inventor Mamoru Matsumoto Nara 3-72-15 Chiyogaoka, Nara City, Japan (72) Inventor Tetsu Oku 2083 Niiso, Oji, Toda City, Saitama

Claims (15)

[Claims] 1. A compound of the general formula (I) (In the formula, OX represents an optionally protected hydroxyl group, Y represents a lower alkyl group, and Z represents a β-D-glucopyranosyl group optionally having one or more hydroxyl groups protected.) A pharmaceutical composition comprising a phenone derivative or a pharmaceutically acceptable salt thereof as an active ingredient. 2. Z is a β-D-glucopyranosyl group in which one or more hydroxyl groups may be acylated, or Z is a 1-lower alkoxy lower alkylidene dioxy group or a benzylidene in which two hydroxyl groups together with a protecting group thereof are present. A β-D-glucopyranosyl group forming a dioxy group, a phosphinicodioxy group or a carbonyldioxy group, or one or two hydroxyl groups are acylated, and two hydroxyl groups are 1-
The pharmaceutical composition according to claim 1, which is a β-D-glucopyranosyl group forming a lower alkoxy lower alkylidenedioxy group, a benzylidenedioxy group, a phosphinicodioxy group or a carbonyldioxy group. 3. β-D wherein Z is a group selected from a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkoxy lower alkanoyl group and a lower alkoxy lower alkoxycarbonyl group, wherein one or more hydroxyl groups may be acylated. 3. The β-D-glucopyranosyl group which is a -glucopyranosyl group or two hydroxyl groups together with a protecting group thereof form a 1-lower alkoxy lower alkylidenedioxy group or a phosphinicodioxy group. Pharmaceutical composition. 4. Z is a group selected from a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkoxy lower alkanoyl group and a lower alkoxy lower alkoxycarbonyl group, wherein the 2-, 2-, 3-, 4- or 6-position hydroxyl group is acylated. Β-D-glucopyranosyl group which is optionally substituted, or β-D in which the 4- and 6-position hydroxyl groups together with its protecting group form a 1-lower alkoxy-lower alkylidenedioxy group or a phosphinicodioxy group
The pharmaceutical composition according to claim 3, which is a glucopyranosyl group. 5. OX is a hydroxyl group, a lower alkanoyloxy group or a lower alkoxycarbonyloxy group;
Is a β-D-glucopyranosyl group, 2-O- (lower alkanoyl) -β-D-glucopyranosyl group, 2,3-di-
O- (lower alkanoyl) -β-D-glucopyranosyl group, 4-O- (lower alkoxycarbonyl) -β-D-
Glucopyranosyl group, 6-O- (lower alkanoyl)-
β-D-glucopyranosyl group, 6-O- (lower alkoxycarbonyl) -β-D-glucopyranosyl group, 6-O
-(Lower alkoxy lower alkanoyl) -β-D-glucopyranosyl group, 6-O- (lower alkoxy lower alkoxycarbonyl) -β-D-glucopyranosyl group, 4,
6-O- (1-lower alkoxy lower alkylidene) -β
The pharmaceutical composition according to claim 4, which is a -D-glucopyranosyl group or a 4,6-O-phosphinico-β-D-glucopyranosyl group. 6. OX is a hydroxyl group or a lower alkanoyloxy group, Z is a β-D-glucopyranosyl group, 2,3-di-O- (lower alkanoyl) -β-D-glucopyranosyl group, 4-O- (lower alkoxy) Carbonyl) -β-D
-Glucopyranosyl group, 6-O- (lower alkoxycarbonyl) -β-D-glucopyranosyl group, 4,6-O-
(1-lower alkoxy lower alkylidene) -β-D-glucopyranosyl group or 4,6-O-phosphinico-
The pharmaceutical composition according to claim 5, which is a β-D-glucopyranosyl group. 7. OX is a hydroxyl group, Y is a methyl group or an ethyl group, Z is a β-D-glucopyranosyl group, 4-O- (lower alkoxycarbonyl) -β-D-glucopyranosyl group, 6-O- (lower alkoxy) Carbonyl) -β-D-
The pharmaceutical composition according to claim 6, which is a glucopyranosyl group, 4,6-O- (1-lower alkoxy lower alkylidene) -β-D-glucopyranosyl group or 4,6-O-phosphinico-β-D-glucopyranosyl group. 8. The pharmaceutical composition according to claim 7, wherein Z is a β-D-glucopyranosyl group or a 6-O- (lower alkoxycarbonyl) -β-D-glucopyranosyl group. 9. 3- (5-benzo [b] furanyl)-
A pharmaceutical composition comprising 2 '-(β-D-glucopyranosyloxy) -6'-hydroxy-4'-methylpropiophenone or a pharmaceutically acceptable salt thereof as an active ingredient. 10. A 3- (5-benzo [b] furanyl)-
Pharmaceutical composition comprising 2 '-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy) -6'-hydroxy-4'-methylpropiophenone or a pharmaceutically acceptable salt thereof as an active ingredient object. 11. The method according to claim 1, which is a hypoglycemic drug.
The pharmaceutical composition according to 4, 5, 6, 7, 8, 9 or 10. 12. The method according to claim 1, which is a drug for preventing or treating diabetes.
The pharmaceutical composition of claim 1. 13. The method according to claim 1, which is a prophylactic / therapeutic agent for hyperglycemia.
The pharmaceutical composition of claim 1. 14. The pharmaceutical composition according to claim 11, which is an agent for preventing or treating diabetic complications. 15. The pharmaceutical composition according to claim 14, wherein the diabetic complication is diabetic nephropathy.