JPH0827006A - Hypoglycemic agent - Google Patents

Abstract

PURPOSE:To obtain a hypoglycemic agent, capable of manifesting increasing actions on urine sugar and hypoglycemic actions based on inhibition of resorption of glucose in the kidney and useful as a preventing and therapeutic agent for diabetes. CONSTITUTION:This hypoglycemic agent contains a dihydrochalcone derivative of formula I (Ar is an aryl; R<1> and R<2> are each H or an acyl or mutually bound to form methylene which may have a substituent group; R<3> and R<4> are each H or an acyl; OR<5> is OH or a lower alkoxy which may be protected, with the proviso that R<1> to R<4> are not simultaneously H) or its pharmacologically permissible salt, e.g. 4-methoxy-6'-hydroxy-2'-(2,3-di-O-ethoxyacetyl-beta-D- glucopyranosyloxy)dihydrochalcone as an active ingredient. The compound is obtained by reducing a chalcone derivative of formula II. Furthermore, the compound of formula I (R<1> is an acyl and R<2> to R<4> are each H) is prepared by acylating OH group at the 6-position of glucopyranosyl group in a compound of formula III.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a hypoglycemic agent.

[0002]

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

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

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

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

However, when phlorizin is administered orally, most of it is hydrolyzed into aglycone, phloretin and glucose, and the proportion absorbed as phlorizin is small, and the urinary glucose excretion action is very weak. In addition, it is known that phloretin, which is an aglycone, strongly inhibits the facilitative diffusion-type sugar transporter, and for example, it has been reported that intravenous administration of phloretin reduces the glucose concentration in the brain [stroke (Stroke), Vol. 14, p. 388 (1983)], it is thought that use of this for a long period of time may adversely affect various tissues. Perhaps because of this, no attempts have been made to use phlorizin as a therapeutic drug for diabetes. or,
2'-β-D-Glucopyranosyloxy-4,6'-dihydroxydihydrochalcone is also known to inhibit Na ⁺ -glucose cotransporter in the kidney [eg, Biokimica et biophysica].・ Actor (Bioc
him. Biophys. Acta), Vol. 71, No. 6
88 (1963)]. However, nothing is described that the above compound has an action of increasing urinary glucose even after oral administration.

[0007]

DISCLOSURE OF THE INVENTION The present invention provides a dihydrochalcone derivative as an active ingredient which has an excellent urinary sugar increasing activity even when it is orally administered, and the aglycone of which has a markedly weak inhibitory effect on the facilitative diffusion type sugar transport carrier. And a hypoglycemic agent.

[0008]

The present invention has the general formula [I]

[0009]

Embedded image

[Wherein Ar is an aryl group, R ¹ is a hydrogen atom or an acyl group, R ² is a hydrogen atom or an acyl group, or R ¹ and R ² are bonded to each other to form a substituent. It forms a methylene group which may have R ³ and R
⁴ are the same or different and each is a hydrogen atom or an acyl group,
R ⁵ represents an optionally protected hydroxyl group or a lower alkoxy group (provided that R ¹ , R ² , R ³ and R ⁴ are not hydrogen atoms at the same time). ] The present invention relates to a hypoglycemic agent containing a dihydrochalcone derivative and a pharmacologically acceptable salt thereof as an active ingredient.

The dihydrochalcone derivative [I], which is the active ingredient of the present invention, exhibits an excellent hypoglycemic action based on the action of increasing urinary glucose. For example, when the active ingredient [I] of the present invention was administered to rats, the amount of glucose excreted in the urine in 24 hours was about 5-35 times that when phlorizin was administered. Further, when the active ingredient of the present invention was orally administered to glucose-loaded diabetic mice, the rise in blood glucose level was significantly suppressed. Therefore, the hypoglycemic agent of the present invention is useful for treating / preventing diabetes. Such an action of increasing the urinary glucose of the active ingredient [I] of the present invention is considered to be due to inhibition of glucose reabsorption in the kidney, and has a characteristic that conventional hypoglycemic agents do not have.

The dihydrochalcone derivative which is the active ingredient of the present invention has low toxicity and shows high safety as a medicine. For example, 4-methoxy-6'-hydroxy-2 '
1000 mg of-(2,3-di-O-ethoxyacetyl-β-D-glucopyranosyloxy) dihydrochalcone
The rats were orally administered daily for 28 days at a rate of 1 kg / kg, and no deaths were observed even when observed.

Further, aglycone, which is a hydrolyzate of the active ingredient of the present invention, is different from phloretin in that it has a remarkably weak inhibitory effect on sugar uptake. For example, human erythrocyte and D- [3- ³ H] glucose for 1 minute, were examined by measuring the radioactivity of erythrocyte uptake sugar in erythrocytes, if the time sample compound not added was 100, the present invention 2 ', which is the aglycone of the active ingredient of
4,6'-trihydroxydihydrochalcone is 92.7
And 2 ', 6'-dihydroxy-4-methoxydihydrochalcone is 91.0, while phloretin is 1
It was 3.7.

Therefore, the inhibitory effect of the aglycone of the active ingredient of the present invention on glucose uptake in human erythrocytes is significantly smaller than that of phloretin, an aglycone of phlorizin, and even if the active ingredient of the present invention is partially hydrolyzed. The decrease in tissue concentration is considered to be extremely unlikely.

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

Examples of the above hydrocarbon aryl group include a phenyl group which may have a substituent. The aliphatic acyl group includes a lower alkanoyl group which may have a substituent or a lower alkoxycarbonyl group which may have a substituent, and the aromatic acyl group includes an arylcarbonyl group or An aryloxycarbonyl group is mentioned.

Further, the phenyl group which may have a substituent is a phenyl which may be substituted with a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group or a lower alkoxycarbonyloxy group. Examples of the lower alkanoyl group that may have a substituent include a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a carboxyl group, a lower alkanoylamino group, a phenoxy group, a phenyl group and a protected group. 1 selected from good amino groups
A lower alkanoyl group which may be substituted with 2 to 2 groups, and the lower alkoxycarbonyl group which may have a substituent may be substituted with a group selected from a lower alkoxy group and a phenyl group. An example is a good lower alkoxycarbonyl group. Examples of the arylcarbonyl group include a benzoyl group, and examples of the aryloxycarbonyl group include a phenoxycarbonyl group.

When the lower alkanoyl group which may have a substituent is a lower alkanoyl group substituted with a protected amino group, the amino group protecting group may be an amino group protecting group. It may be any group, and examples thereof include lower alkanoyl groups such as acetyl group and propionyl group, and acyl groups such as phenyl lower alkoxycarbonyl group such as benzyloxycarbonyl group.

The lower alkanoyl group which may have a substituent may be a group obtained by removing the hydroxyl group from the carboxyl group of α-amino acid, and examples thereof include isoleucine, phenylalanine, valine, alanine, proline and leucine. A group in which a hydroxyl group is removed from one carboxyl group of a natural amino acid such as and the enantiomer or racemate thereof is raised.

In the dihydrochalcone derivative [I],
When R ¹ and R ² are bonded to each other to form a methylene group having a substituent, the substituent on the methylene group is
A phenyl group, a lower alkanoyloxy group, a lower alkoxy group and an oxo group are preferred, and a phenyl group is particularly preferred. Further, the methylene group may be substituted with 1 to 2 groups selected from these substituents.

Further, in the dihydrochalcone derivative [I], when the group represented by OR ⁵ is a protected hydroxyl group, the protecting group may be any group which can serve as a protecting group for a phenolic hydroxyl group, for example, acetyl. Group, lower alkanoyl group such as propionyl group and pivaloyl group; lower alkoxycarbonyl group optionally substituted by phenyl group such as benzyloxycarbonyl group and t-butoxycarbonyl group; phenoxycarbonyl group; or acyl group such as benzoyl group Etc.

As a specific example of the dihydrochalcone derivative [I] which is the active ingredient of the present invention, (1) Ar is a phenyl group which may have a substituent, and OR ⁵ may be protected. A hydroxyl group or a lower alkoxy group, R ¹
And R ² are both hydrogen atoms or bonded to each other to form a methylene group having a substituent, and R ³ and R ⁴ are the same or different and are a hydrogen atom, a lower alkanoyl group optionally having a substituent, a substituent A lower alkoxycarbonyl group, an arylcarbonyl group or an aryloxycarbonyl group which may have (provided that R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen atoms), or (2) Ar
Is a phenyl group which may have a substituent, and OR ⁵
Is an optionally protected hydroxyl group or a lower alkoxy group, and R ¹ is a lower alkanoyl group which may have a substituent, a lower alkoxycarbonyl group which may have a substituent, an arylcarbonyl group or aryl. An oxycarbonyl group, wherein R ² , R ³ and R ⁴ are the same or different, and a hydrogen atom, a lower alkanoyl group which may have a substituent, a lower alkoxycarbonyl group which may have a substituent, A compound which is an arylcarbonyl group or an aryloxycarbonyl group may be mentioned.

When the phenyl group, methylene group, lower alkanoyl group and / or lower alkoxycarbonyl group of the compounds mentioned in the above (1) and (2) have substituents, the substituents of these groups are as described above. Groups similar to those described can be used.

Other specific examples of the active ingredient [I] of the present invention include (1) the general formula [Ia]

[0025]

[Chemical 6]

(Wherein R ¹¹ represents an acyl group, and other symbols have the same meanings as described above),
(2) General formula [Ib]

[0027]

[Chemical 7]

(Wherein R ²¹ represents an acyl group and other symbols have the same meanings as described above),
(3) General formula [Ic]

[0029]

Embedded image

(Wherein R ³¹ and R ⁴¹ are the same or different and each represents an acyl group, and other symbols have the same meanings as described above), (4) the general formula [Id]

[0031]

[Chemical 9]

(Wherein R ¹³ , R ²³ , R ³³ and R ⁴³ are the same or different and each represents an acyl group, and other symbols have the same meanings as described above), (5) the general formula [ I-
e]

[0033]

[Chemical 10]

(Wherein R ^{1 to} R ⁴ have the same meanings as described above, and R ⁶ represents an acyl group or a lower alkyl group), or (6) the general formula [If].

[0035]

[Chemical 11]

(However, B ¹ and B ² are the same or different and each represents a hydrogen atom, a phenyl group, a lower alkanoyloxy group or a lower alkoxy group, or B ¹ and B ² =
Represents that the group represented by O is formed, and other symbols have the same meanings as described above. ).

In these [Ia] to [Id],
As the acyl group represented by R ^{11 to} R ⁴¹ and R ^{13 to} R ⁴³ ,
An acyl group similar to the acyl group described for the groups represented by R ^{1 to} R ⁴ can be mentioned.

Further, in the compound represented by the general formula [Ie], when R ⁶ is an acyl group, the acyl group may be the group mentioned as the protecting group for OR ^{5 in} the compound [I]. Specifically, for example, lower alkanoyl group such as acetyl group, propionyl group, pivaloyl group; lower alkoxycarbonyl group optionally substituted by phenyl group such as benzyloxycarbonyl group, t-butoxycarbonyl group; phenoxycarbonyl group Or an acyl group such as a benzoyl group.

As a more specific example of the compound [Ia], Ar is substituted with a group selected from a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group and a lower alkoxycarbonyloxy group. Optionally a phenyl group, OR ⁵ is an optionally protected hydroxyl group or a lower alkoxy group, and R ¹¹ is a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a carboxyl group, a lower alkanoylamino group, or a phenoxy group. Group, a phenyl group and a lower alkanoyl group which may be substituted with 1 to 2 groups selected from optionally protected amino groups; may be substituted with a group selected from lower alkoxy groups and phenyl groups Compounds having a lower alkoxycarbonyl group; a benzoyl group; or a phenoxycarbonyl group And the like.

As a more specific example of the compound [Ib], Ar is substituted with a group selected from a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group and a lower alkoxycarbonyloxy group. Optionally a phenyl group, OR ⁵ is an optionally protected hydroxyl group or a lower alkoxy group, and R ¹¹ and R ²¹ are the same or different and are a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a carboxyl group. , A lower alkanoylamino group, a phenoxy group, a phenyl group, and a lower alkanoyl group optionally substituted with 1 to 2 groups selected from an optionally protected amino group; a group selected from a lower alkoxy group and a phenyl group A lower alkoxycarbonyl group which may be substituted with; a benzoyl group; or a phenoxy group Carbonyl is a group compounds.

As a more specific example of the compound [Ic], Ar is substituted with a group selected from a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group and a lower alkoxycarbonyloxy group. Optionally a phenyl group, OR ⁵ is an optionally protected hydroxyl group or a lower alkoxy group, and R ³¹ and R ⁴¹ are the same or different and are a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a carboxyl group. , A lower alkanoylamino group, a phenoxy group, a phenyl group, and a lower alkanoyl group optionally substituted with 1 to 2 groups selected from an optionally protected amino group; a group selected from a lower alkoxy group and a phenyl group A lower alkoxycarbonyl group which may be substituted with; a benzoyl group; or a phenoxy group Carbonyl is a group compounds.

As a more specific example of the compound [Id], Ar is substituted with a group selected from a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group and a lower alkoxycarbonyloxy group. Optionally a phenyl group, OR ⁵ is an optionally protected hydroxyl group or a lower alkoxy group, and R ¹³ and R
²³ , R ³³ and R ⁴³ are the same or different and are selected from a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a carboxyl group, a lower alkanoylamino group, a phenoxy group, a phenyl group and an optionally protected amino group. A lower alkanoyl group optionally substituted with two groups; a lower alkoxycarbonyl group optionally substituted with a group selected from a lower alkoxy group and a phenyl group;
Examples thereof include a compound which is a benzoyl group; or a phenoxycarbonyl group.

More specific examples of the compound [If] include compounds in which B ¹ is a phenyl group and B ² is a hydrogen atom.

In the compounds [Ia] to [Ie], the acyl group may be a group obtained by removing the hydroxyl group from the carboxyl group of α-amino acid, for example, isoleucine,
Examples of the natural amino acid such as phenylalanine, valine, alanine, proline and leucine, and a group obtained by removing a hydroxyl group from the carboxyl group of its antipode or racemate.

Examples of the pharmaceutically effective compound in the active ingredient [I] include compounds in which R ¹ and R ² are the same or different and each is a hydrogen atom or an acyl group, and among them, the compound represented by the general formula [Ia], The compound shown by [Ib] or [Ic] is mentioned.

Among these compounds, compounds having an excellent therapeutic effect include Ar in the general formula [Ia].
Is a lower alkoxy group-substituted phenyl group, and R ¹¹ is a lower alkanoyl group or benzoyl group substituted with an amino group or a lower alkoxy group, a compound of the general formula [I-
b], Ar is a phenyl group, and R ¹¹ and R ²¹
Is a lower alkoxy group-substituted lower alkanoyl group, or in the general formula [Ic], Ar is selected from a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group and a lower alkoxycarbonyloxy group. Is a phenyl group which may be substituted with a group, OR ⁵ is an optionally protected hydroxyl group, and R ³¹ and R ⁴¹ are the same or different and are selected from a lower alkoxy group, a lower alkoxy lower alkoxy group and an amino group. Examples of the compound include a lower alkanoyl group optionally substituted with a group, a lower alkoxycarbonyl group optionally substituted with a lower alkoxy group, a benzoyl group or a phenoxycarbonyl group.

As a compound exhibiting a more excellent therapeutic effect, a compound of the general formula [Ia] wherein Ar is a lower alkoxy group-substituted phenyl group and R ¹¹ is a benzoyl group, or a general formula [Ic] Wherein Ar is a phenyl group which may be substituted with a lower alkyl group or a lower alkoxy group, OR ⁵ is a hydroxyl group or a hydroxyl group protected by a lower alkanoyl group, R ³¹ and R ⁴¹ are a lower alkanoyl group, a lower alkoxy group. Examples thereof include compounds having a substituted lower alkanoyl group, an amino group substituted lower alkanoyl group, a lower alkoxycarbonyl group or a phenoxycarbonyl group, and in particular, in the general formula [Ic], Ar is a lower alkoxy group substituted phenyl group, R ³¹ and R ^41. Is a lower alkanoyl group substituted with a lower alkoxy group.

The dihydrochalcone derivative [I] can be used for the purpose of the present invention in the free form or in the form of its pharmaceutically acceptable salt.

Examples of such salts include mineral acid salts such as hydrochlorides and sulfates, and organic acid salts such as methanesulfonate and acetate.

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

The dosage depends on the method of administration, the age / weight of the patient,
The daily dose is usually 1 to 100 mg / orally in the case of oral administration, though it varies depending on the condition or degree of disease.
kg, especially 5 to 40 mg / kg, in the case of parenteral administration, 0.1 to 50 mg / kg, especially 0.5 to 10
It is preferably mg / kg.

The dihydrochalcone derivative [I], which is the active ingredient of the present invention, can be produced as follows.

(1) The dihydrochalcone derivative represented by the general formula [I] has the general formula [VIII]

[0054]

[Chemical 12]

[However, the symbols have the same meanings as described above. ] It can manufacture by reducing the chalcone derivative shown by these.

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

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

(2) The dihydrochalcone derivative represented by the general formula [Ia] has the general formula [II]

[0059]

[Chemical 13]

It can be produced by acylating the 6-position hydroxyl group of the glucopyranosyl group of the compound represented by (where the symbols have the same meaning as described above).

(3) The dihydrochalcone derivative represented by the general formula [Ib] has the general formula [Ig]

[0062]

Embedded image

(Wherein R ³² and R ⁴² represent a hydroxyl-protecting group, and other symbols have the same meanings as described above), the 4- and 6-position hydroxyl groups of the glucopyranosyl group of the compound represented by acylation are protected by acylation. It can be produced by removing the group.

(4) The dihydrochalcone derivative represented by the general formula [Ic] has the general formula [Ih]

[0065]

[Chemical 15]

(Provided that R ¹² and R ²² represent a hydroxyl-protecting group and other symbols have the same meanings as described above), and the 2- and 3-position hydroxyl groups of the glucopyranosyl group of the compound represented by It can be produced by removing the group.

(5) The dihydrochalcone derivative represented by the general formula [Id] has the general formula [Ii]

[0068]

Embedded image

(Provided that at least one of R ¹⁴ , R ²⁴ , R ³⁴ and R ⁴⁴ is a hydrogen atom and the other group is an acyl group, and other symbols are the same as the above. It has a meaning.) It can manufacture by acylating the hydroxyl group of the glucopyranosyl group of the compound shown by these.

(6) The dihydrochalcone derivative represented by the general formula [Ie] has the general formula [Ij]

[0071]

[Chemical 17]

(Where the symbols have the same meaning as described above) and a compound of the general formula [IV]

[0073]

Embedded image

(Wherein R ⁶ represents a lower alkyl group or an acyl group) or a reactive derivative thereof can be produced.

In the acylation reaction of the above (3) and (4), the hydroxyl group-protecting group of the compounds [Ig] and [Ih] may be any group capable of forming a hydroxyl group-protecting group. An acyl group such as a benzyloxycarbonyl group,
Alternatively, R ¹² and R ²² may be bonded to each other to form a benzylidene group or the like, and the protecting groups described for OR ⁵ may be used.

In the acylation reaction of the above (2) to (5), an organic acid corresponding to a desired acyl group (for example, a lower alkylcarboxylic acid which may have a substituent, a substituent which has a substituent) Lower alkoxycarboxylic acid, etc.), its salt (eg, alkali metal salt such as sodium salt, calcium salt, alkaline earth metal salt) or its reactive derivative (eg, acid halide, acid anhydride, active ester, etc.) It can be carried out by reacting the raw material compounds. The reaction of an organic acid compound corresponding to an acyl group or a salt thereof is carried out according to a conventional method in the presence or absence of a conventional condensing agent (eg, dicyclohexylcarbodiimide etc.), or a reaction between a reactive derivative of an acid compound and a starting compound. Is in the presence or absence of a deoxidizing agent (for example; an alkali metal hydroxide; an alkali metal carbonate; an inorganic base such as alkali metal hydrogen carbonate or a tri-lower alkylamine; an organic base such as pyridine);
Each in a conventional solvent (eg, dichloromethane, dimethylformamide, tetrahydrofuran, etc.) under cooling to
It can be appropriately carried out under heating (particularly 0 ° C to 50 ° C).

In the above reaction, the difference in steric environment around the hydroxyl group of the raw material compound or the amount of the organic acid compound, its salt or its reactive derivative used is adjusted so that the compound [II] to the compound [I- a] or [Id] can be produced arbitrarily.

In the product, R ^{11 to} R ⁴¹ or R
^{When 13 to} R ⁴³ are acyl groups having a protected amino group, or when OR ⁵ is a protected hydroxyl group, these protecting groups may be optionally removed. The removal of the protecting group can be appropriately performed depending on the type.

In the production method (6), the reaction of the compound [IV] in which R ⁶ is an acyl group with the compound [Ij] is the production method (2).
~ (5) can be carried out in the same manner as compound (IV)
Examples of the reactive derivative of (1) include acid halides and acid anhydrides.

The reaction of the compound [IV] in which R ⁶ is a lower alkyl group with the compound [Ij] can be carried out in a solvent in the presence or absence of a deoxidizing agent according to a conventional method.
As the reactive derivative of the compound [IV], a lower alkyl halide or a lower alkyl p-toluenesulfonate,
Examples include lower alkyl sulfonates such as lower alkyl methane sulfonate.

As the solvent and the deoxidizing agent, the production method (2) is used.
The same as those mentioned in (5) can be used.

(7) Of the active ingredients [I], the compounds of the general formula [I]
-F] or general formula [Ik]

[0083]

[Chemical 19]

(B ³ represents a hydrogen atom, a phenyl group, a lower alkanoyloxy group or a lower alkoxy group,
Other symbols have the same meanings as above. The dihydrochalcone derivative represented by the formula) is a compound represented by the general formula [II] and a compound represented by the general formula [III-a]

[0085]

Embedded image

(Wherein X represents a reactive residue, and other symbols have the same meanings as described above) or a compound of the general formula [III-b].

[0087]

[Chemical 21]

(Wherein the symbols have the same meaning as described above), and the compound can be produced.

The reaction of the compound [II] with the compound [III-a] or [III-b] is carried out in a solvent (eg dichloromethane, tetrahydrofuran etc.), with an acid catalyst (eg Lewis acid such as zinc chloride, hydrochloric acid, sulfuric acid etc.). Mineral acid, organic acid such as paratoluenesulfonic acid, methanesulfonic acid, etc.) or a deoxidizing agent (for example, inorganic base such as alkali metal carbonate or alkali metal hydrogen carbonate, or tri-lower alkylamine, pyridine etc.) It can be carried out under cooling to heating (especially 10 ° C. to 40 ° C.) in the presence of the organic base).

The starting compound represented by the general formula [II] is
General formula [V]

[0091]

[Chemical formula 22]

[However, the symbols have the same meanings as described above. ] It can manufacture by reducing the chalcone derivative shown by these, and removing a protecting group if desired.

This reduction reaction can be carried out in the same manner as in the reduction reaction (1) of compound [VIII].

The starting compound represented by the general formula [V] has the general formula [VI]

[0095]

[Chemical formula 23]

(However, OZ ¹ , OZ ² , OZ ³ and OZ
⁴ represents an optionally protected hydroxyl group, and other symbols have the same meanings as described above. ) And an acetophenone derivative represented by the general formula [VII]

[0097]

[Chemical formula 24]

(However, the symbols have the same meanings as described above.) After condensing the aldehyde compound, if necessary, the protecting group is removed and, if desired, the hydroxyl group is acylated or the compound [III- It can be produced by reacting with a] or with a compound [III-b].

In the starting compound [VI], OZ ^{1 to} O
When Z ⁴ is a protected hydroxyl group, examples of the protected hydroxyl group include a hydroxyl group protected by a conventional protecting group such as a lower alkanoyl group. The removal of the protective group can be carried out by a conventional method such as hydrolysis.

The condensation reaction between the acetophenone derivative [VI] and the aldehyde compound [VII] is carried out by a conventional method, for example, in a solvent (organic solvent such as methanol or ethanol or a mixed solvent of these organic solvent and water), a base ( In the presence of alkali metal hydroxide or the like) under cooling to under heating (especially 10
C. to 30.degree. C.).

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

The compound represented by the general formula [Ig] is, for example, a compound of the general formula [If] in which B ¹ is a phenyl group and B is
After protecting the 2- and 3-position hydroxyl groups of the glucopyranosyl group of the compound in which ² is a hydrogen atom, 4 of the glucopyranosyl group is protected.
It can be produced by removing the substituent of the hydroxyl group at the 6-position.

The compound represented by the general formula [Ih] can be prepared, for example, by protecting the hydroxyl groups at the 4th and 6th positions of the glucopyranosyl group of the compound represented by the general formula [Ig], and then protecting the glucopyranosyl groups 2 and 3 It can be produced by removing the protective group for the hydroxyl group.

When protecting the hydroxyl group of the glucopyranosyl group in the above reaction, any protecting group that can be easily removed by a conventional method such as hydrolysis, reduction, acid treatment or the like can be used.

The starting compound [VIII] is obtained by acylating a part or all of the hydroxyl groups of (i) compound [V],
(Ii) reacting compound [V] with compound [III-a] or [III-b], or (iii) above (i)
And (ii) are carried out in any order, or (iv) the general formula [IX]

[0106]

[Chemical 25]

(Where the symbols have the same meanings as described above) and the compound [VI
I] is condensed, and if necessary, the above (i) or (i
It can be produced by subjecting it to the reaction of i).

The compound [IX] is a compound of Journal of Medicinal and Pharmaceutical Chemistry (J. Med. Pharm. Chem.) No. 5
Volume, page 1054 (1962).

In the present invention, the lower alkyl group and the lower alkoxy group include, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t
-Butyl group, methoxy group, ethoxy group, propoxy group,
Isopropoxy group, butoxy group, isobutoxy group, t-
Examples thereof include butoxy group, methylene group, ethylene group, propylene group and the like having 1 to 6 carbon atoms, and particularly preferably those having 1 to 4 carbon atoms. Examples of the lower alkanoyl group include acetyl group, propionyl group, butyryl group, 2
Examples thereof include those having 2 to 7 carbon atoms such as a methylpropionyl group, valeryl group and pivaloyl group, and those having 2 to 5 carbon atoms are particularly preferable.

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

[0111]

[Chemical formula 26]

Represents a structure represented by:

[0113]

[Action]

Experimental Example (Hypoglycemic action in mice) (Experimental method) 6-week-old male ddY mice fasted overnight
Oral administration of sample suspension to 5 animals per group (dose: 100
mg / kg) and immediately after that, glucose is subcutaneously administered (1
g / kg / 5 ml physiological saline). The sample suspension was prepared by suspending the sample in a 0.1% NIKKOL HCO-60 (manufactured by Nippon Chemical Co., Ltd.) aqueous solution. In the control group, 0.1% NIKK was used instead of the sample suspension.
The OL aqueous solution was orally administered. Blood was collected from the tail blood vessel immediately before administration and after a certain time after administration, and the blood glucose level was measured by the glucose oxidase method.

The results are as shown in Table 1.

(Sample Compound) 4-Methoxy-6'-hydroxy-2 '-(2,3-di-O-acetyl-β-D-glucopyranosyloxy) dihydrochalcone (Compound described in Production Example 10) 4-Methoxy-6′-hydroxy-2 ′-(2,3-di-O-ethoxyacetyl-β-D-glucopyranosyloxy) dihydrochalcone (Compound described in Preparation Example 15) 3-Methyl-6 ′ -Hydroxy-2 '-(2,3-di-
O-ethoxyacetyl-β-D-glucopyranosyloxy) dihydrochalcone (Compound described in Production Example 42)

[0116]

[Table 1]

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

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

The results are as shown in Table 2.

[0120]

[Table 2]

As is clear from the above results, the group administered with the dihydrochalcone derivative [I], which is the active ingredient of the present invention, has an increase in urinary sugar by about 5 to 35 times compared to the group treated with phlorizin. I understand.

Production Example 1 2.79 g of 4-methoxy-6'-hydroxy-2'-β-D-glucopyranosyloxydihydrochalcone was added to a dioxane-methylene chloride mixed solution (20-100 ml), and benzaldehyde was stirred. Dimethylacetal (1.47 g) and p-toluenesulfonic acid (120 mg) were added, and the mixture was reacted with stirring at room temperature for 20 hours. The reaction solution is washed with water, dried, filtered, and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform / methanol) to give 4-methoxy-6'-.
Hydroxy-2 '-(4,6-O-benzylidene-β-
D-glucopyranosyloxy) dihydrochalcone 2.6
5 g are obtained as a white powder.

M. p. : 126-130 ° C FABMS (m / z): 545 [(M + Na) ⁺ ] NMR (d ₆ -DMSO) δ: 2.84 (2H, t, J
= 7.6 Hz), 3.19 (2H, t, J = 7.6H)
z), 3.3 to 3.7 (5H, m), 3.72 (3H,
s), 4.21 (1H, d, J = 4.9 Hz), 5.1
6 (1H, d, J = 7.8Hz), 5.48 (1H,
d, J = 5.4 Hz), 5.59 (1H, d, J = 5.
4Hz), 5.60 (1H, s), 6.57 (1H,
d, J = 7.8 Hz), 6.72 (1H, d, J = 8.
3 Hz), 6.84 (2H, ddd, J = 2.0, 2.
9, 8.8 Hz), 7.17 (2H, ddd, J = 2.
0, 2.7, 8.3 Hz), 7.25 (1H, t, J =
8.3 Hz), 7.40 (5 H, m), 10.85 (1
H, s).

Production Example 2-8 In the same manner as in Production Example 1, from the corresponding starting compound to the third
The compounds listed are obtained.

[0125]

[Table 3]

[0126]

[Table 4]

Production Example 9 (1) 4-methoxy-6'-hydroxy-2 '-(4
1.86 g of 6-O-benzylidene-β-D-glucopyranosyloxy) dihydrochalcone was dissolved in 40 ml of pyridine, 10 ml of acetic anhydride was added, and the mixture was reacted at room temperature for 3 hours and then concentrated under reduced pressure, and isopropyl ether was added to the residue. Was added and the precipitated powder was collected by filtration, washed and dried to 4
-Methoxy-6'-acetoxy-2 '-(2,3-di-
2.06 g of O-acetyl-4,6-O-benzylidene-β-D-glucopyranosyloxy) dihydrochalcone is obtained as a white powder.

M. p. 175.5-176.5 <0> C FABMS (m / z): 649 (MH ^<+> ).

(2) The above 4-methoxy-6'-acetoxy-2 '-(2,3-di-O-acetyl-4,6-O
Benzylidene-β-D-glucopyranosyloxy) dihydrochalcone 1.00 g, 80% acetic acid aqueous solution 30 ml
In addition, the mixture is heated and stirred at 70 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: chloroform / methanol) to give 4-methoxy-6′-acetoxy-2 ′-(2.
820 mg of 3-di-O-acetyl-β-D-glucopyranosyloxy) dihydrochalcone are obtained as a white amorphous powder.

FABMS (m / z): 583 [(M + Na) ⁺ ] NMR (d ₆ -DMSO) δ: 1.89 (3H, s),
2.00 (3H, s), 2.06 (3H, s), 2.7
7 (2H, m), 2.88 (2H, m), 3.4-3.
8 (4H, m), 3.71 (3H, s), 4.76 (1
H, t, J = 5.9 Hz), 4.88 (1H, dd, J
= 7.8, 9.8 Hz), 5.11 (1H, dd, J =
9.3, 9.8 Hz), 5.50 (1H, d, J = 7.
8Hz), 5.59 (1H, d, J = 5.9Hz),
6.84 (2H, ddd, J = 2.0, 2.9, 8.3
Hz), 6.88 (1H, d, J = 8.3 Hz), 7.
13 (2H, ddd, J = 2.0, 2.9, 8.3H
z), 7.15 (1H, d, J = 7.8 Hz), 7.4
4 (1H, t, J = 8.3 Hz).

Production Example 10 (1) 4-methoxy-6'-acetoxy-2 '-(2,
3-di-O-acetyl-4,6-O-benzylidene-β
-D-glucopyranosyloxy) dihydrochalcone 1.
05 g and 272 mg of sodium hydrogen carbonate were added to methanol-
Add to the tetrahydrofuran mixture (30-100 ml),
After stirring at room temperature for 4 hours and at 40 ° C for 30 minutes, the mixture is concentrated under reduced pressure, ethyl acetate and water are added to the residue, and after stirring, the organic layer is separated, washed with water and dried. After filtration and concentration of the filtrate, isopropyl ether was added to the residue, and the precipitated white powder was collected by filtration,
By washing and drying, 4-methoxy-6'-hydroxy-2 '-(2,3-di-O-acetyl-4,6-O
911 mg of -benzylidene-β-D-glucopyranosyloxy) dihydrochalcone are obtained.

M. p. 149-151 ° C FABMS (m / z): 607 (MH ⁺ ).

(2) 4-methoxy-6'-hydroxy-2 '-(2,3-di-O-acetyl-4,6-O above)
By reacting 900 mg of -benzylidene-β-D-glucopyranosyloxy) dihydrochalcone and treating in the same manner as in Production Example 9- (2), 4-methoxy-6'-hydroxy-2 '-(2,3- 640 mg of di-O-acetyl-β-D-glucopyranosyloxy) dihydrochalcone are obtained as a white powder.

M. p. 136-138 ° C FABMS (m / z): 541 [(M + Na) ⁺ ] NMR (d ₆ -DMSO) δ: 1.93 (3H, s),
2.00 (3H, s), 2.76 (2H, m), 2.9
0 (2H, m), 3.4 to 3.8 (4H, m), 3.7
1 (3H, s), 4.73 (1H, t, J = 5.6H
z), 4.85 (1H, dd, J = 7.8, 9.8H)
z), 5.09 (1H, dd, J = 8.8, 9.8H
z), 5.35 (1H, d, J = 7.8Hz), 5.5
6 (1H, d, J = 5.4Hz), 6.57 (1H,
d, J = 7.8 Hz), 6.67 (1H, d, J = 8.
3 Hz), 6.83 (2H, ddd, J = 2.0, 2.
9, 8.8 Hz), 7.13 (2H, ddd, J = 2.
4, 2.9, 8.8 Hz), 7.19 (1H, t, J =
8.3 Hz), 10.26 (1 H, s).

Production Example 11 (1) 4-Methoxy-6'-hydroxy-2 '-(4
6-O-benzylidene-β-D-glucopyranosyloxy) dihydrochalcone (1.045 g) and pyridine (20 ml)
And n-butyryl chloride 1.28 under cooling and stirring.
g is added dropwise. After reacting at room temperature for 2 hours, the mixture is concentrated under reduced pressure, ethyl acetate and ice-cooled dilute hydrochloric acid are added to the residue, the organic layer is separated after stirring, washed with water, dried, filtered and concentrated. 20 ml of methanol and 0.84 g of sodium hydrogen carbonate are added to the residue, and the mixture is stirred at 40 ° C. for 4 hours. Concentrate, add ethyl acetate and water to the residue, stir, and separate the organic layer. After drying, filtration, concentration, and purification of the residue by silica gel column chromatography (solvent: ethyl acetate / n-hexane), 4-methoxy-6'-hydroxy-2 '-(2,
3-di-O-butyryl-4,6-O-benzylidene-β
-D-Glucopyranosyloxy) dihydrochalcone is obtained as a white powder.

FABMS (m / z): 662 (MH ⁺ ).

(2) The above 4-methoxy-6'-hydroxy-2 '-(2,3-di-O-butyryl-4,6-O
-Benzylidene-β-D-glucopyranosyloxy) dihydrochalcone was added to 50 ml of 80% acetic acid aqueous solution, and
4-Methoxy-6'-hydroxy-2'- by heating at 0 ° C for 2 hours and treating in the same manner as in Production Example 9- (2).
0.54 g of (2,3-di-O-butyryl-β-D-glucopyranosyloxy) dihydrochalcone is obtained as a white powder.

M. p. : 126-127 ° C FABMS (m / z): 597 [(M + Na) ⁺ ] NMR (d ₆ -DMSO) δ: 0.79 (3H, t, J
= 7.3 Hz), 0.87 (3H, t, J = 7.3H)
z), 1.3 to 1.6 (4H, m), 2.1 to 2.3.
(4H, m), 2.7 to 2.9 (4H, m), 3.5 to
3.7 (4H, m), 3.71 (3H, s), 4.73
(1H, t, J = 5.9Hz), 4.89 (1H, t,
J = 7.8 Hz), 5.12 (1H, t, J = 8.8H)
z), 5.38 (1H, d, J = 7.8 Hz), 5.5
3 (1H, d, J = 5.9Hz), 6.56 (1H,
d, J = 8.3 Hz), 6.67 (1H, d, J = 8.
3Hz), 6.83 (2H, d, J = 8.3Hz),
7.13 (2H, d, J = 8.3Hz), 7.18 (1
H, t, J = 8.3 Hz), 10.26 (1 H, s).

Production Examples 12 to 51 In the same manner as in Production Examples 9, 10, and 11, the compounds shown in Tables 4 to 10 were obtained from the corresponding starting compounds.

[0140]

[Table 5]

[0141]

[Table 6]

[0142]

[Table 7]

[0143]

[Table 8]

[0144]

[Table 9]

[0145]

[Table 10]

[0146]

[Table 11]

[0147]

[Table 12]

[0148]

[Table 13]

[0149]

[Table 14]

[0150]

[Table 15]

[0151]

[Table 16]

[0152]

[Table 17]

[0153]

[Table 18]

[0154]

[Table 19]

Production Example 52 (1) 4-methoxy-6'-hydroxy-2 '-(4
6-O-benzylidene-β-D-glucopyranosyloxy) dihydrochalcone 1.5 g, benzyloxyacetic acid chloride 2.0 g were used in the same manner as in Production Example 11- (1) to give 4
-Methoxy-6'-hydroxy-2 '-(2,3-di-
0.90 g of O-benzyloxyacetyl-4,6-O-benzylidene-β-D-glucopyranosyloxy) dihydrochalcone is obtained as a white powder.

(2) The above 4-methoxy-6'-hydroxy-2 '-(2,3-di-O-benzyloxyacetyl-4,6-O-benzylidene-β-D-glucopyranosyloxy. ) 0.90 g of dihydrochalcone was dissolved in 20 ml of ethanol and 20 ml of acetic acid to prepare 10% palladium-
0.4 g of carbon is added, and hydrogen reduction is performed overnight under normal pressure stirring. After filtration and concentration of the filtrate, the residue is subjected to silica gel column chromatography (solvent: chloroform / methanol).
4-methoxy-6'-hydroxy-2 '-(2,3-di-O-hydroxyacetyl-β-
D-glucopyranosyloxy) dihydrochalcone 460
mg is obtained as a white powder. Physical data are as shown in Table 11.

Production Example 53 1.30 g of 4-methoxy-6'-hydroxy-2'-β-D-glucopyranosyloxydihydrochalcone was dissolved in 13 ml of pyridine, and 0.90 g of benzoyl chloride was stirred under ice-cooling. Add dropwise over 30 minutes. After stirring for 2 hours with ice cooling, pour into ice water and extract with ethyl acetate. The organic layer is washed with water, dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (solvent: chloroform / methanol) to give 4-methoxy-6′-hydroxy-2 ′-(6-O-benzoyl-β-D-glucopyranosyloxy) dihydrochalcone 0. 0.80 g is obtained as a colorless amorphous powder. Physical data are as shown in Table 11.

[0158]

[Table 20]

Production Example 54 4-Methoxy-6'-hydroxy-2'-β-D-glucopyranosyloxydihydrochalcone (1.0 g) was dissolved in pyridine (20 ml), and acetic anhydride (5 ml) was added. After stirring at room temperature for 2 days, the mixture is concentrated, ethyl acetate and dilute hydrochloric acid are added to the residue, and the organic layer is separated after stirring. After washing with water, drying, filtration and concentration, the residue is purified by silica gel column chromatography (solvent: chloroform / ethyl acetate) to give 4-methoxy-6′-acetoxy-2 ′-(2,3,3.
1.21 g of 4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) dihydrochalcone is obtained as a white powder. Physical data are shown in Table 12.

Production Example 55 869 mg of 4-methoxy-6′-hydroxy-2′-β-D-glucopyranosyloxydihydrochalcone was dissolved in 10 ml of pyridine, and 1.30 g of methoxyacetic acid chloride was added dropwise under stirring with ice cooling. To do. After reacting at room temperature for 2 hours, the mixture is concentrated under reduced pressure, ethyl acetate and ice-cooled dilute hydrochloric acid are added to the residue, the mixture is stirred, and the organic layer is separated. After washing with water, drying, filtration and concentration, the residue is dissolved in 20 ml of methanol. After adding 840 mg of sodium hydrogen carbonate and stirring at room temperature for 30 minutes, 100 ml of ethyl acetate is added and the insoluble matter is filtered off. The filtrate is washed with water, dried, filtered, and the filtrate is concentrated. The residue was subjected to silica gel column chromatography (solvent: chloroform /
4-methoxy-6 'by purification with (methanol)
-Hydroxy-2 '-(2,3,4,6-tetra-O-
Methoxyacetyl-β-D-glucopyranosyloxy)
882 mg of dihydrochalcone is obtained as a pale yellow oil. Physical data are shown in Table 12.

[0161]

[Table 21]

[0162] Production Example 56 4-methoxy-6 ^'- benzyloxycarbonyl ^carboxy-2' -
(2,3-di-O-benzyloxycarbonyl-β-D-
Glucopyranosyloxy) dihydrochalcone 569 mg
Was dissolved in 5 ml of pyridine and acetic anhydride 278 mg was added at room temperature.
Is dripped. After reacting at room temperature for 2 hours, the mixture is concentrated under reduced pressure, ethyl acetate is added to the residue, and the mixture is stirred and the organic layer is separated. Washing with water,
After drying, filtration and concentration, the residue is dissolved in an ethanol-ethyl acetate mixed solution (5 ml-5 ml). 10% palladium-
Hydrogen is reduced under atmospheric pressure using carbon as a catalyst. The catalyst was filtered off, the filtrate concentrated under reduced pressure the residue was purified by silica gel column chromatography (solvent: chloroform / methanol) to give 4-methoxy-6 ^'- hydroxy -
251 mg of 2 ^′ -(4,6-di-O-acetyl-β-D-glucopyranosyloxy) dihydrochalcone is obtained as a white amorphous powder.

M. p. : 108-112 ° C FABMS (m / z): 519 [(M + H) ⁺ ] NMR (d ₆ -DMSO) δ: 1.94 (3H, s),
2.05 (3H, s), 2.83 (2H, t, J = 7.
1Hz), 3.18 (2H, m), 3.32 (1H,
m), 3.53 (1H, m), 3.71 (3H, s),
3.90 (1H, m), 3.96 (1H, dd, J =
2.2, 12.4 Hz), 4.09 (1H, dd, J =
5.7, 12.0 Hz), 4.69 (1H, dd, J =
9.5, 9.8 Hz), 5.08 (1H, d, J = 7.
8Hz), 5.47 (1H, d, J = 5.7Hz),
5.58 (1H, d, J = 5.6Hz), 6.57 (1
H, d, J = 8.1 Hz), 6.66 (1H, d, J =
8.1 Hz), 6.82 (2H, ddd, J = 2.1,
3.0, 8.7 Hz), 7.16 (2H, ddd, J =
2.0, 3.0, 8.6 Hz), 7.24 (1H, t,
J = 8.3 Hz), 10.82 (1H, s).

Production Examples 57 to 59 In the same manner as in Production Example 56, 13
The compounds listed are obtained.

[0165]

[Table 22]

[0166]

[Table 23]

[0167] Production Example 60 4-methoxy-6 - a ^{'hydroxy -2'-beta-D-glucopyranosyloxy} dihydrochalcone 9.22g was dissolved in acetone 50 ml, stirring was added potassium carbonate 14.64 g, benzyl 4.36 g of bromide are added dropwise. After stirring at room temperature for 1 hour, the mixture is heated under reflux for 2.5 hours. The reaction mixture is diluted with ethyl acetate, potassium carbonate is filtered off, washed with water, dried and the solvent is distilled off. Silica gel column chromatography of the residue (solvent: chloroform / methanol)
After purification by, the crystals were crystallized from ethyl acetate-isopropyl ether to obtain 8.62 g of a white powdery substance.

525 mg of this product and 359 mg of carbobenzyloxyphenylalanine were dissolved in 30 ml of pyridine and concentrated under reduced pressure to 15 ml, and then N, N-bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride 636.
Add mg. After stirring overnight at room temperature, saturated aqueous sodium hydrogen carbonate solution is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried, filtered, and concentrated under reduced pressure to 4
-Methoxy-6'-benzyloxy-2 '-{6-O-
[N-carbobenzyloxy) -L-phenylalanyl]
456 mg of -β-D-glucopyranosyloxy} dihydrochalcone are obtained as a colorless foam.

FABMS (m / z): 828 [(M + Na) ⁺ ] NMR (d ₆ -DMSO) δ: 2.78 (3H, m),
2.9-3.4 (6H, m), 3.65 (1H, m),
3.68 (3H, s), 4.11 (1H, dd, J =
7.5, 11.8 Hz), 4.29 (1 H, m), 4.
38 (1H, d, J = 10.6Hz), 4.93 (1
H, d, J = 7.7 Hz), 4.96 (2H, s),
5.04 (2H, s), 5.22 (1H, d, J = 5.
0Hz), 5.31 (1H, d, J = 3.8Hz),
5.33 (1H, d, J = 3.6Hz), 6.74 (2
H, d, J = 8.7 Hz), 6.75 (1H, d, J =
8.5 Hz), 6.84 (1H, d, J = 8.5H
z), 7.07 (2H, d, J = 8.6 Hz), 7.2
-7.4 (16H, m), 7.76 (1H, d, J =
8.4 Hz).

[0170] Production Example 61 4-methoxy-6 ^'- benzyloxy ^-2' - {6-O-
877 mg of [N- (carbobenzyloxy) -L-phenylalanyl] -β-D-glucopyranosyloxy} dihydrochalcone was dissolved in an ethanol-tetrahydrofuran mixed solution (14 ml-6 ml) to catalyze 10% palladium-carbon. The catalytic hydrogen reduction is carried out under normal pressure in the presence of a small excess of hydrochloric acid. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was washed with ether to give 4-methoxy-
6 ^{'- hydroxy-2'} - obtaining [6-O-(L-phenylalanyl)-beta-D-glucopyranosyloxy] dihydrochalcone hydrochloride 495mg as a light brown amorphous powder.

FABMS (m / z): 604 [(M + Na) ⁺ ] NMR (d ₆ -DMSO) δ: 2.83 (2H, t, J
= 7.2 Hz), 3.0-3.4 (7H, m), 3.7
0 (1H, m), 3.71 (3H, s), 4.18 (1
H, dd, J = 6.3, 12.3 Hz), 4.30 (1
H, t, J = 6.1 Hz), 4.42 (1H, d, J =
10.9 Hz), 5.01 (1H, d, J = 7.5H
z), 5.35 (1H, d, J = 4.1 Hz), 5.3
8 (1H, d, J = 5.4Hz), 5.42 (1H,
d, J = 5.3 Hz), 6.52 (1H, d, J = 8.
1Hz), 6.71 (1H, d, J = 8.4Hz),
6.82 (2H, ddd, J = 2.1, 3.2, 8.7
Hz), 7.1-7.3 (8H, m), 8.58 (3
H, broad), 10.87 (1H, s) Production Examples 62 to 67 In the same manner as in Production Examples 60 and 61, the compounds shown in Table 14 are obtained from the corresponding starting material compounds.

[0172]

[Table 24]

[0173]

[Table 25]

[0174]

[Table 26]

Production Example 68 (1) 4-Methoxy-6'-hydroxy-2'-β-D
-Glucopyranosyloxychalcone was treated in the same manner as in Production Example 54 to give 4-methoxy-6'-acetoxy-2 '-(2,3,4,6-tetra-O-acetyl-.
β-D-glucopyranosyloxy) chalcone is obtained.

(2) The compound was treated with 10% ethanol in a solvent.
Atmospheric hydrogen reduction is performed using% palladium-carbon as a solvent. The catalyst was removed by filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to give 4-methoxy-6'-acetoxy-2 '-(2,3,4,6-
Tetra-O-acetyl-β-D-glucopyranosyloxy) dihydrochalcone is obtained. Physical data is Production Example 5
4 is as described.

Reference Example 1 6'-hydroxy-2 '-(2,3,4,6-tetra-
O-acetyl-β-D-glucopyranosyloxy) acetophenone 2.41 g, p-anisaldehyde 1.36
To a mixture of g and 25 ml of ethanol, 2.5 ml of 50% aqueous potassium hydroxide solution was added dropwise with stirring, and the mixture was stirred overnight at room temperature. Concentrate under reduced pressure and add 100 ml of water and 5 ether to the residue.
After adding 0 ml and stirring, the aqueous layer is separated. The ice-cooled lower aqueous layer is neutralized with 10% hydrochloric acid, 200 ml of ethyl acetate is added, and after stirring, the organic layer is separated, washed with water, dried and filtered. The filtrate is concentrated under reduced pressure to obtain crude 4-methoxy-6'-hydroxy-2'-β-D-glucopyranosyloxychalcone. Dissolve the compound in 50 ml of ethanol and add 10%
Hydrogen reduction is carried out under atmospheric pressure using palladium-carbon as a catalyst. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: chloroform / methanol) to give 4-methoxy-6'-.
1.02 g of hydroxy-2′-β-D-glucopyranosyloxydihydrochalcone is obtained as a white crystalline powder.

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

Reference Examples 2 to 6 In the same manner as in Reference Example 1, from the corresponding starting material compounds,
The compounds listed are obtained.

[0180]

[Table 27]

[0181]

[Table 28]

Reference Example 7 (1) 2 '-(2,
3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy) -6′-hydroxyacetophenone (4.82 g) and potassium carbonate (4.14 g) were added and the mixture was stirred.
2.56 g of benzyl bromide is added dropwise and stirred at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure, ethyl acetate and water are added to the residue, and after stirring, the organic layer is separated. The obtained organic layer is washed with water and dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography to obtain 3.2 g of 6'-benzyloxy-2 '-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) acetophenone. obtain.

FABMS (m / z): 595 [(M + Na) ⁺ ].

(2) 6'-benzyloxy-2'-
(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy) acetophenone 2.9 g and 4
-Tetrahydropyranyloxybenzaldehyde 1.5
6 g is added to 30 ml of ethanol, 3 ml of 50% aqueous potassium hydroxide solution is added dropwise with stirring, and the mixture is stirred overnight at room temperature.
The solvent is distilled off under reduced pressure, water and diethyl ether are added to the residue, the mixture is stirred, and the aqueous layer is separated. The ice-cooled lower aqueous layer is neutralized with 10% hydrochloric acid and then extracted with ethyl acetate. The obtained organic layer was washed with water and dried, then the solvent was distilled off, and the obtained crude product was added with an acetic acid-water-tetrahydrofuran (2: 1: 2) solution 50 m.
It was dissolved in 1 l, heated at 50 ° C. for 3 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography.
1.20 g of 6'-benzyloxy-2 '-(β-D-glucopyranosyloxy) -4-hydroxychalcone is obtained.

FABMS (m / z): 531 [(M + Na) ⁺ ].

(3) 6'-benzyloxy-2 '-(β
0.79 g of -D-glucopyranosyloxy) -4-hydroxychalcone and 0.19 g of triethylamine are dissolved in 30 ml of dimethylacetamide, and 0.20 g of ethyl chlorocarbonate is added dropwise under stirring with ice cooling. After stirring at room temperature for 1 hour, ethyl acetate and water are added, and after stirring, the organic layer is separated.
The obtained organic layer was washed with water and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 6 ′.
-Benzyloxy-4-ethoxycarbonyloxy-
0.73 g of 2 '-(β-D-glucopyranosyloxy) chalcone is obtained.

FABMS (m / z): 603 [(M + Na) ⁺ ].

(4) 0.70 g of 6'-benzyloxy-4-ethoxycarbonyloxy-2 '-(β-D-glucopyranosyloxy) chalcone was dissolved in ethanol,
Catalytic hydrogen reduction is performed under atmospheric pressure using 10% palladium-carbon as a catalyst. After removing the catalyst by filtration, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 4
0.48 g of -ethoxycarbonyloxy-2 '-(β-D-glucopyranosyloxy) -6'-hydroxydihydrochalcone is obtained.

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

[0190]

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

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

Claims (14)

[Claims] 1. A compound of the general formula [I] [Wherein Ar is an aryl group, R ¹ is a hydrogen atom or an acyl group, R ² is a hydrogen atom or an acyl group, or R ¹ and R ² are bonded to each other to have a substituent. Optionally a methylene group, R ³ and R ⁴ are the same or different and each is a hydrogen atom or an acyl group, and OR ⁵ represents an optionally protected hydroxyl group or a lower alkoxy group (provided that R ¹ , R 4 ² , R ³ and R ⁴ are not simultaneously hydrogen atoms). ] A hypoglycemic agent comprising a dihydrochalcone derivative represented by the above or a pharmacologically acceptable salt thereof as an active ingredient. 2. The hypoglycemic agent according to claim 1, wherein the aryl group is a hydrocarbon aryl group, and the acyl group is an aliphatic acyl group or an aromatic acyl group. 3. A hydrocarbon-based aryl group is a phenyl group which may have a substituent, and an aliphatic acyl group has a lower alkanoyl group which may have a substituent or a substituent. Is also a lower alkoxycarbonyl group,
The hypoglycemic agent according to claim 2, wherein the aromatic acyl group is an arylcarbonyl group or an aryloxycarbonyl group. 4. A phenyl group which may have a substituent, a phenyl group which may be substituted with a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group or a lower alkoxycarbonyloxy group. And a lower alkanoyl group which may have a substituent is a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a carboxyl group, a lower alkanoylamino group, a phenoxy group, a phenyl group and an optionally protected amino group. A lower alkanoyl group which may be substituted with 1 to 2 groups selected from the following, or a group in which a hydroxyl group is removed from the carboxyl group of an α-amino acid, and the lower alkoxycarbonyl group which may have a substituent is lower. Lower alkoxycarl optionally substituted with a group selected from an alkoxy group and a phenyl group The nyl group, the arylcarbonyl group is a benzoyl group, the aryloxycarbonyl group is a phenoxycarbonyl group, and the methylene group which may have a substituent is selected from a phenyl group, a lower alkanoyloxy group, a lower alkoxy group and an oxo group. The hypoglycemic agent according to claim 3, which is a methylene group which may be substituted with 1 to 2 groups. 5. A compound represented by the general formula [Ia]: (However, Ar represents an aryl group, R ¹¹ represents an acyl group,
OR ⁵ represents an optionally protected hydroxyl group or a lower alkoxy group. ) A hypoglycemic agent comprising a dihydrochalcone derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. 6. A compound represented by the general formula [Ib]: (However, Ar represents an aryl group, R ¹¹ represents an acyl group,
R ²¹ represents an acyl group, and OR ⁵ represents an optionally protected hydroxyl group or a lower alkoxy group. ) A hypoglycemic agent comprising a dihydrochalcone derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. 7. A compound represented by the general formula [Ic]: (However, Ar represents an aryl group, R ³¹ and R ⁴¹ are the same or different and represent an acyl group, and OR ⁵ represents a hydroxyl group or a lower alkoxy group which may be protected.) Or its pharmacology. Hypoglycemic agent containing a salt that is chemically acceptable as an active ingredient. 8. Ar is a phenyl group which may be substituted with a group selected from a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group and a lower alkoxycarbonyloxy group, and OR ⁵ is protected. An optionally protected hydroxyl group or a lower alkoxy group, and R ¹¹ is a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a carboxyl group, a lower alkanoylamino group, a phenoxy group, a phenyl group or an optionally protected amino group. A lower alkanoyl group optionally substituted with 1 to 2 groups selected from: a lower alkoxycarbonyl group optionally substituted with a group selected from a lower alkoxy group and a phenyl group; a benzoyl group; a phenoxycarbonyl group; or A group obtained by removing the hydroxyl group from the carboxyl group of α-amino acid. Hypoglycemic agent according to claim 5, wherein. 9. Ar is a phenyl group which may be substituted with a group selected from a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group and a lower alkoxycarbonyloxy group, and OR ⁵ is protected. And R ¹¹ and R ²¹ are the same or different and are a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a carboxyl group, a lower alkanoylamino group, a phenoxy group, a phenyl group and a protected group. A lower alkanoyl group optionally substituted with 1 to 2 groups selected from optionally substituted amino groups; a lower alkoxycarbonyl group optionally substituted with a group selected from a lower alkoxy group and a phenyl group;
The hypoglycemic agent according to claim 6, which is a benzoyl group; a phenoxycarbonyl group; or a group obtained by removing a hydroxyl group from the carboxyl group of an α-amino acid. 10. Ar ⁵ is a phenyl group which may be substituted with a group selected from a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group and a lower alkoxycarbonyloxy group, and OR ⁵
Is an optionally protected hydroxyl group or a lower alkoxy group, and R ³¹ and R ⁴¹ are the same or different and are a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a carboxyl group, a lower alkanoylamino group, a phenoxy group,
Lower alkanoyl group optionally substituted by 1 to 2 groups selected from phenyl group and optionally protected amino group; lower alkoxy optionally substituted by group selected from lower alkoxy group and phenyl group Carbonyl group; benzoyl group; phenoxycarbonyl group; or α-
The hypoglycemic agent according to claim 7, which is a group obtained by removing a hydroxyl group from a carboxyl group of an amino acid. 11. An phenyl group which may be substituted with a group selected from a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group and a lower alkoxycarbonyloxy group, and OR ⁵
Is a hydroxyl group which may be protected, and R ³¹ and R ⁴¹ are the same or different and are optionally substituted with a lower alkoxy group, a lower alkoxy lower alkoxy group and a group selected from an amino group. A lower alkoxycarbonyl group which may be substituted with a group, a benzoyl group or a phenoxycarbonyl group.
The hypoglycemic agent according to 0. 12. Ar is a phenyl group optionally substituted with a lower alkyl group or a lower alkoxy group, and O
R ⁵ is a hydroxyl group or a hydroxyl group protected by a lower alkanoyl group, R ³¹ and R ⁴¹ are a lower alkanoyl group, a lower alkoxy group-substituted lower alkanoyl group, an amino group-substituted lower alkanoyl group, a lower alkoxycarbonyl group or a phenoxycarbonyl group. Item 11. A hypoglycemic agent according to item 11. 13. The hypoglycemic agent according to claim 12, wherein Ar is a phenyl group substituted with a lower alkoxy group, and R ³¹ and R ⁴¹ are lower alkanoyl groups substituted with a lower alkoxy group. 14. The hypoglycemic agent according to claim 1, which is a prophylactic / therapeutic agent for diabetes.