JP2795162B2 - Dihydrochalcone derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel dihydrochalcone derivative having a hypoglycemic action and a method for producing the same.

[0002]

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

[0003] In recent years, glucose toxicity theory that hyperglycemia itself is involved in the onset and progress of diabetes.
ry) has been proposed. That is, chronic hyperglycemia causes abnormalities in both insulin secretion and insulin action, which further increases blood glucose and progresses diabetes [Diabetrolog (Diabetolog).
ia) Vol. 28, p. 119 (1985)].

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

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

However, when phlorizin is administered orally, most of it is hydrolyzed to aglycones, phloretin and glucose, and the rate of absorption as phlorizin is small, and the urinary glucose excretion effect is very weak. Further, phloretin, which is an aglycone, is known to strongly inhibit a facilitating diffusion type sugar transporting carrier, and its use over a long period of time may adversely affect various tissues. For that reason, no attempt has been made to use phlorizin as a therapeutic drug for diabetes.

[0007]

DISCLOSURE OF THE INVENTION The present invention provides a novel dihydrochalcone glycoside compound which shows an excellent urinary glucose increasing effect even when administered orally and is useful as a hypoglycemic agent.

[0008]

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

[0009]

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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 Forming a methylene group which may have R ³ and R
⁴ is the same or different and is a hydrogen atom or an acyl group;
R ⁵ represents a hydroxyl group or a lower alkoxy group which may be protected (provided that R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen atoms). And a pharmaceutically acceptable salt thereof.

In the dihydrochalcone derivative [I] of the present invention, the aryl group includes a hydrocarbon aryl group, and the acyl group includes an aliphatic acyl group or an aromatic acyl group.

The above-mentioned hydrocarbon-based aryl group includes a phenyl group which may have a substituent. Examples of the aliphatic acyl group include 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 And an aryloxycarbonyl group.

Further, the phenyl group which may have a substituent includes 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. Examples of the lower alkanoyl group which 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 a lower alkoxy group or a phenyl group. A good lower alkoxycarbonyl group is mentioned. Examples of the arylcarbonyl group include a benzoyl group, and examples of the aryloxycarbonyl group include a phenoxycarbonyl group.

When the optionally substituted lower alkanoyl group is a lower alkanoyl group substituted with a protected amino group, the amino-protecting group may be an amino-protecting group. Any examples include an acyl group such as a lower alkanoyl group such as an acetyl group and a propionyl group or a phenyl lower alkoxycarbonyl group such as a benzyloxycarbonyl group.

The lower alkanoyl group which may have a substituent may be a group obtained by removing a hydroxyl group from a carboxyl group of an α-amino acid, for example, isoleucine,
Examples include natural amino acids such as phenylalanine, valine, alanine, proline, and leucine, and groups obtained by removing a hydroxyl group from one carboxyl group of an enantiomer or a racemate thereof.

In the general formula [I], when R ¹ and R ² are bonded to each other to form a substituted methylene group, the substituent on the methylene group may be a phenyl group, a lower alkanoyloxy group, a lower Preferable examples include an alkoxy group and an oxo group, particularly a phenyl group. Further, the methylene group may be substituted with one or two groups selected from these substituents.

In the general formula [I], when the group represented by OR ⁵ is a protected hydroxyl group, the protecting group may be any one which can be a protecting group for a phenolic hydroxyl group. A lower alkanoyl group such as a propionyl group or a pivaloyl group; a lower alkoxycarbonyl group optionally substituted with a phenyl group such as a benzyloxycarbonyl group or a t-butoxycarbonyl group; a phenoxycarbonyl group; or an acyl group such as a benzoyl group; Or a phenyl lower alkyl group such as a benzyl group.

As specific examples of the dihydrochalcone derivative [I] of the present invention, (1) Ar is a phenyl group which may have a substituent, and OR ⁵ is a hydroxyl group or a lower alkoxy group which may be protected. 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 each represent a hydrogen atom,
A lower alkanoyl group which may have a substituent, a lower alkoxycarbonyl group which may have a substituent, an arylcarbonyl group or an aryloxycarbonyl group (provided that R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen atoms) compounds, or, (2) Ar is a phenyl group which may have a substituent group, is a good hydroxyl group or a lower alkoxy group oR ⁵ is protected, 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 an aryloxycarbonyl group, wherein R ² , R ³ and R ⁴ are the same or Differently, a hydrogen atom, a lower alkanoyl group which may have a substituent, a lower alkoxycarbonyl group which may have a substituent,
Compounds that are an arylcarbonyl group or an aryloxycarbonyl group can 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 a substituent, the substituent of these groups is as described above. Groups similar to those described can be used.

In the compound [I], preferred compounds include (1) a compound represented by the general formula [Ia]:

[0021]

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

[0023]

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

[0025]

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

[0027]

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[0028] ^{(wherein, R 13, R 23, R} 33 and R ⁴³ are the same or different, and display the acyl group, and other symbols equal to the
Meaningful . A compound represented by the general formula [Ie]:

[0029]

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

[0031]

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

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

In the compound [Ie], when R ⁶ is an acyl group, the acyl group may be the group mentioned as a protecting group when OR ⁵ is a protected hydroxyl group. Typically, for example, acetyl group, propionyl group,
A lower alkanoyl group such as a pivaloyl group; a lower alkoxycarbonyl group optionally substituted with a phenyl group such as a benzyloxycarbonyl group or a t-butoxycarbonyl group; a phenoxycarbonyl group; or an acyl group such as a benzoyl group.

Among the compounds [Ia], a more preferred compound is one in which 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. R ⁵ is a hydroxyl group or a lower alkoxy group which may be protected, 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. A lower alkanoyl group which may be substituted with one or two groups selected from a group, a phenyl group and an optionally protected amino group; which may be substituted with a group selected from a lower alkoxy group and a phenyl group A lower alkoxycarbonyl group; a benzoyl group; or a phenoxycarbonyl group That compound, and the like.

Among the compounds [Ib], a more preferred compound is one in which 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. And 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 one or two 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 compound that is a phenoxycarbonyl group.

Among the compounds [Ic], more preferably, 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. 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, a phenyl group, and a lower alkanoyl group optionally substituted with one or two 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 compound that is a phenoxycarbonyl group.

Among the compounds [Id], more preferably, 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. And OR ⁵ is a hydroxyl group or a lower alkoxy group which may be protected, and R ¹³ , R ²³ , R ³³ and R ⁴³ are the same or different and are a hydroxyl group, a lower alkoxy group, a lower alkoxy group. A lower alkoxy group, a carboxyl group, a lower alkanoylamino group, a phenoxy group, a phenyl group, and a lower alkanoyl group which may be substituted with one or two groups selected from an optionally protected amino group; A lower alkoxycarbonyl group which may be substituted with a group selected from a phenyl group; benzo And a phenoxycarbonyl group.

Among the compounds [If], more preferred are compounds wherein 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 a hydroxyl group from a carboxyl group of an α-amino acid, for example, isoleucine,
Examples include natural amino acids such as phenylalanine, valine, alanine, proline and leucine, and groups obtained by removing hydroxyl groups from carboxyl groups of enantiomers or racemates thereof.

Among the above compounds, compounds having a preferable effect on the medicament include those represented by the general formula [Ic], wherein Ar is a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group,
A phenyl group which may be substituted with a group selected from a lower alkanoyloxy group and a lower alkoxycarbonyloxy group, OR ⁵ is a hydroxyl group which may be protected, and R ³¹ and R ⁴¹ are the same or different and each have a hydroxyl group; A lower alkoxy group, a lower alkoxy lower alkoxy group, a benzyloxycarbonylamino group and a compound which is a lower alkanoyl group which may be substituted with a group selected from an amino group, a lower alkoxycarbonyl group, a benzoyl group or a phenoxycarbonyl group. Can be

As a compound more preferable in terms of medicinal effect, in the general formula [Ic], Ar is a phenyl group optionally substituted with a lower alkyl group or a lower alkoxy group, and OR ⁵ is a hydroxyl group or a lower alkanoyl group. Compounds in which the protected hydroxyl group, R ³¹ and R ⁴¹ are a lower alkanoyl group, a lower alkoxy-substituted lower alkanoyl group, an amino-substituted lower alkanoyl group, a lower alkoxycarbonyl group or a phenoxycarbonyl group, and in particular, where Ar is a lower alkoxy group Group-substituted phenyl groups, R ³¹ and R
Compounds in which ⁴¹ is a lower alkoxy-substituted lower alkanoyl group.

The target compound [I] of the present invention can be used for pharmaceutical use in the form of a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts include salts with inorganic acids such as hydrochloric acid and sulfuric acid or acetic acid, salts with organic acids such as methanesulfonic acid or inorganic bases such as sodium and potassium or ammonia and organic bases such as lower alkylamine. Salt.

The objective compound [I] of the present invention and a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and are mixed with an excipient suitable for oral or parenteral administration. And can be used as a pharmaceutical preparation. The pharmaceutical preparation may be a solid preparation such as a tablet, a capsule or a powder, or a liquid preparation such as a solution, a suspension or an emulsion. In the case of parenteral administration, it can be used in the form of injection.

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

Among the desired products [I], (1) the dihydrochalcone derivative represented by the general formula [Ia]

[0047]

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(Wherein the symbols have the same meanings as described above). The compound can be produced by acylating the 6-position hydroxyl group of the glucopyranosyl group.

(2) The dihydrochalcone derivative represented by the general formula [Ib]

[0050]

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(Wherein R ³² and R ⁴² represent hydroxyl-protecting groups, and the 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 the formula It can be produced by removing a group.

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

[0053]

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

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

[0056]

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[However, R ¹⁴ , R ²⁴ , R ³⁴ and R ⁴⁴ represent that at least one of them is a hydrogen atom and the other group is an acyl group, and other symbols are the same as those described above. Meaningful. By acylating the hydroxyl group of the glucopyranosyl group of the compound of formula (I).

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

[0059]

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

[0061]

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

In the acylation reaction of the above (2) and (3), the hydroxyl-protecting group of the compounds [Ig] and [Ih] may be any as long as it can be a hydroxyl-protecting group. protecting groups described in the OR ⁵ may be used. Specifically, an acyl group such as a benzyloxycarbonyl group, a lower alkanoyl group or a lower alkoxycarbonyl group, or a benzylidene group, a lower alkoxy-substituted methylene group or a di-lower alkoxy-substituted methylene group in which R ¹² and R ²² are bonded to each other. Are formed.

In the above acylation reactions (1) to (4), when the group OR ⁵ in the raw material compound is a free hydroxyl group, or when Ar is a hydroxyphenyl group, these are also acylated. In some cases, the product thus obtained is also included in the present object.

The starting compound is acylated by an organic acid corresponding to a desired acyl group (for example, a lower alkyl carboxylic acid optionally having a substituent, a lower alkoxy carboxylic acid optionally having a substituent, (Benzoic acid, phenoxycarboxylic acid, etc.), a salt thereof or a reactive derivative thereof and a starting compound, and the reaction can be carried out. The reaction of the organic acid compound corresponding to the acyl group is carried out in the presence or absence of a condensing agent, and the reaction between the reactive derivative of the acid compound and the starting compound is carried out in the presence or absence of a deoxidizing agent in a solvent. Can be appropriately implemented.

Examples of the salt of the organic acid include alkali metal salts such as sodium salt, potassium salt and calcium salt, and alkaline earth metal salts. Examples of the reactive derivative include a corresponding acid halide, acid anhydride, active ester and the like.

As deoxidizing agents: alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; sodium carbonate;
Alkali metal carbonates such as potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; inorganic bases such as alkali metal hydrides such as sodium hydride and potassium hydride; and tri-lower alkylamines such as triethylamine and diisopropylethylamine Organic bases such as pyridine, aniline and dimethylaminopyridine.

As the condensing agent, a conventional one such as phosphorus oxychloride, thionyl chloride, dicyclohexylcarbodiimide, diethyl cyanophosphate, carbonyldiimidazole and the like can be used.

As the solvent, any solvent can be used as long as it does not adversely affect the reaction, and examples thereof include conventional solvents such as dichloromethane, dimethylformamide, tetrahydrofuran, and acetonitrile.

This reaction is carried out under cooling to under heating, preferably
It can be suitably carried out at -10 ° C to 100 ° C, especially at 0 ° C to 50 ° C.

In the above reaction, all the hydroxyl groups may be acylated by adjusting the difference in the steric environment around the hydroxyl groups of the starting compound or the amount of the organic acid compound, its salt or its reactive derivative. Also, the hydroxyl groups can be relatively selectively acylated. Therefore, compound [Ia] or compound [Id] can be arbitrarily produced using compound [II] as a starting compound.

In the product, R ^{11 to} R ⁴¹ or R ^{11
When 13 to} R ⁴³ are an acyl group having a protected amino group, or when OR ⁵ is a protected hydroxyl group, these protecting groups may be removed as desired. The removal of the protecting group can be appropriately carried out, if necessary, by a conventional method such as hydrolysis, reduction, and acid treatment, depending on the type.

In the production method (5), when R ⁶ is a lower alkyl group, the reactive derivative of the compound [IV] may be a lower alkyl halide or a lower alkyl such as a lower alkyl p-toluenesulfonate or a lower alkylmethanesulfonate. Examples include sulfonates. When R ⁶ is an acyl group, examples thereof include acid halides, acid anhydrides, and active esters.

The reaction of compound [IV] wherein R ⁶ is an acyl group with compound [Ij] can be carried out in the same manner as in production methods (1) to (4).

The reaction of the compound [IV] wherein R ⁶ is a lower alkyl group with the compound [Ij] can be carried out according to a conventional method in a solvent in the presence or absence of a deoxidizing agent. As the solvent and the deoxidizing agent, the solvents and deoxidizing agents shown in the production methods (1) to (4) can be used.

(6) Of the target compound [I], a compound represented by the general formula [I-
f] or the general formula [Ik]

[0077]

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

[0079]

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

[0081]

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

In the compound [III-a], examples of the reactive residue X include a lower alkoxy group and a halogen atom.

The reaction of compound [II] with compound [III-a] or [III-b] can be carried out in a solvent, in the presence of an acid catalyst, or in the presence of a deoxidizing agent. As the acid catalyst, Lewis acids such as zinc chloride, mineral acids such as hydrochloric acid, sulfuric acid and nitric acid, and organic acids such as paratoluenesulfonic acid and methanesulfonic acid can be used. As the deoxidizer,
Inorganic bases such as alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogencarbonate and alkali metal hydride, and organic bases such as tri-lower alkylamine, pyridine and aniline can be mentioned. The reaction is carried out under cooling to heating, especially
It proceeds suitably at 0 ° C to 40 ° C.

As the solvent that can be used in the above reaction, any solvent can be used as long as it does not adversely affect each reaction and can achieve the object, and examples thereof include dichloromethane, tetrahydrofuran, and dioxane.

(7) Further, the target product [I] is represented by the general formula [V
III]

[0087]

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[However, the symbols have the same meaning as described above.] Can be produced by reducing the chalcone derivative of the formula (1).

This reduction reaction can be carried out by a conventional method, such as reduction with a metal hydride, catalytic hydrogen reduction, or the like. For example, the reduction with a metal hydride can be carried out by using a metal hydride in a solvent, and the catalytic hydrogen reduction can be carried out by catalytic reduction in a solvent under a normal pressure hydrogen stream using a catalyst.

Specifically, in the catalytic hydrogen reduction, a conventional catalyst can be used as the catalyst, and for example, a catalyst such as palladium-carbon and platinum oxide can be suitably used.

The reduction with a metal hydride may be any metal hydride that can reduce a double bond, but is preferably one that does not reduce ketones. Is, for example, sodium sodium hydride
n telluride). Sodium telluride hydride is available from Synthesi
s) It can be prepared according to the method described on page 545 (1978).
It is preferred to use molar equivalents, especially 1 to 1.5 molar equivalents.

As the solvent, any solvent can be used as long as it is inert to the reaction. For example, organic solvents such as methanol, ethanol, tetrahydrofuran, ethyl acetate and acetic acid, and mixed solvents of these organic solvents and water can be used. .

The reaction can be carried out under cooling to heating, and is preferably carried out at 10 ° C. to 30 ° C.

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

[0095]

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[However, the symbols have the same meanings as described above.] And reducing the protecting group if desired.

This reduction reaction can be carried out according to a conventional method in the same manner as in the above-mentioned reduction reaction (7) of compound [VIII].

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

[0099]

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(However, OZ ¹ , OZ ² , OZ ³ and OZ
⁴ represents a hydroxyl group which may be protected, and other symbols have the same meanings as described above. An acetophenone derivative represented by the general formula [VII]:

[0101]

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(Where the symbols have the same meanings as described above), and after condensing the aldehyde compound, the protecting group is removed if necessary, and the hydroxyl group is acylated or the compound [III- a) or with the compound [III-b].

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

In the starting compound [VI], OZ ¹ -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, a substituted or unsubstituted phenyl lower alkyl group, and a tri-lower alkylsilyl group. . The removal of the protecting group can be carried out according to the type thereof according to a conventional method such as hydrolysis, reduction, acid treatment, etc., but if the protecting group is a lower alkanoyl group such as an acetyl group, use of an alkali metal hydroxide. Advantageously, the condensation reaction and removal of the protecting group can be performed in one step.

The starting compound [VI] of the present invention is, for example, a compound wherein OZ ^{1 to} OZ ⁴ are acetyloxy groups.
Journal of Medicinal and Pharmaceutical Chemistry (J. Med. Phar
m. Chem. 5), 1054 (1962), for example, 2 ', 6'-dihydroxyacetophenone and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl. It can be produced by reacting bromide in aqueous acetone in the presence of potassium hydroxide.

In the above condensation reaction, when hydroxybenzaldehyde is used as the aldehyde compound [VII], the use of hydroxybenzaldehyde having a protected phenolic hydroxyl group improves the yield of the condensation reaction.

When protecting the phenolic hydroxyl group of the aldehyde compound [VII], any group which can be easily removed according to a conventional method such as hydrolysis, reduction, acid treatment and the like can be used. In particular, it is preferable to use a group that can be reductively removed (such as a substituted or unsubstituted phenyl lower alkyl group such as a benzyl group).

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

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

In the above reaction, when protecting the hydroxyl group of the glucopyranosyl group, any group which can be easily removed by a conventional method such as hydrolysis, reduction, acid treatment and the like can be used as the protecting group.

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

[0112]

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(Wherein 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 to the reaction of i).

Compound [IX] was prepared using the method described in 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 those having 1 to 6 carbon atoms, and the lower alkanoyl groups include those having 2 to 7 carbon atoms. In this specification, “2′-
O- (β-D-glucopyranosyl)-”means“ 2′-
(Β-D-glucopyranosyloxy)-”.

[0116]

【Example】

Example 1 4-methoxy-6′-hydroxy-2′-O-β-D-
2.79 g of glucopyranosyl dihydrochalcone [that is, 4-methoxy-6'-hydroxy-2'-β-D-glucopyranosyloxydihydrochalcone]
The mixture was added to a methylene chloride mixed solution (20-100 ml), and benzaldehyde dimethyl acetal 1.47 was added with stirring.
g, 120 mg of p-toluenesulfonic acid are added, and the mixture is stirred at room temperature for 20 hours. The reaction solution is washed with water, dried and filtered, and the filtrate is concentrated under reduced pressure. Silica gel column chromatography of the residue (solvent: chloroform / methanol)
To give 4-methoxy-6′-hydroxy-2′-O- (4,6-O-benzylidene-β-D-
2.65 g of (glucopyranosyl) dihydrochalcone are obtained as a white powder.

M. p. : 126 to 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), 3.3-3.7 (5H, m), 3.72 (3H,
s), 4.21 (1H, d, J = 4.9 Hz), 5.1.
6 (1H, d, J = 7.8 Hz), 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 (5H, m), 10.85 (1
H, s).

Example 2-8 In the same manner as in Example 1, the first compound
The compounds shown in the table are obtained.

[0119]

[Table 1]

[0120]

[Table 2]

Example 9 (1) 4-methoxy-6'-hydroxy-2'-O-
Dissolve 1.86 g of (4,6-O-benzylidene-β-D-glucopyranosyl) dihydrochalcone in 40 ml of pyridine, add 10 ml of acetic anhydride, react at room temperature for 3 hours, concentrate under reduced pressure, and add isopropyl ether to the residue. In addition, the precipitated powder is collected by filtration, washed and dried to obtain 4
-Methoxy-6'-acetoxy-2'-O- (2,3-
Di-O-acetyl-4,6-O-benzylidene-β-D
2.06 g of -glucopyranosyl) dihydrochalcone are obtained as a white powder.

M. p. 175.5-176.5 ° C FABMS (m / z): 649 (MH ⁺ ).

(2) The above 4-methoxy-6'-acetoxy-2'-O- (2,3-di-O-acetyl-4,6
-O-benzylidene-β-D-glucopyranosyl) dihydrochalcone (1.00 g) is added to an 80% aqueous acetic acid solution (30 ml), and 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'-O-.
820 mg of (2,3-di-O-acetyl-β-D-glucopyranosyl) dihydrochalcone are obtained as a white amorphous powder.

FABMS (m / z): 583 [(M + N
a) ⁺ ] 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).

Example 10 (1) 4-methoxy-6'-acetoxy-2'-O-
(2,3-di-O-acetyl-4,6-O-benzylidene-β-D-glucopyranosyl) dihydrochalcone
05 g, 272 mg of sodium bicarbonate in methanol
Add to tetrahydrofuran mixture (30-100ml)
After stirring at room temperature for 4 hours and at 40 ° C. for 30 minutes, the mixture is concentrated under reduced pressure, and ethyl acetate and water are added to the residue. 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.
After washing and drying, 4-methoxy-6′-hydroxy-2′-O- (2,3-di-O-acetyl-4,6
911 mg of —O-benzylidene-β-D-glucopyranosyl) dihydrochalcone are obtained.

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

(2) The above-mentioned 4-methoxy-6'-hydroxy-2'-O- (2,3-di-O-acetyl-4,6
-O-benzylidene-β-D-glucopyranosyl) dihydrochalcone 900 mg was reacted and treated in the same manner as in Example 9- (2) to give 4-methoxy-6′-hydroxy-2′-O- (2,3- Di-O-acetyl-β-D-
640 mg of (glucopyranosyl) 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 = 7.8 Hz), 5.5
6 (1H, d, J = 5.4 Hz), 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).

Example 11 (1) 4-methoxy-6'-hydroxy-2'-O-
1.045 g of (4,6-O-benzylidene-β-D-glucopyranosyl) dihydrochalcone was added to 20 ml of pyridine.
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 diluted hydrochloric acid are added to the residue, and after stirring, the organic layer is separated, 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. After concentration, ethyl acetate and water are added to the residue, and after stirring, the organic layer is separated. After drying, filtration and concentration, the residue was purified by silica gel column chromatography (solvent: ethyl acetate / n-hexane) to give 4-methoxy-6'-hydroxy-2'-O-.
(2,3-Di-O-butyryl-4,6-O-benzylidene-β-D-glucopyranosyl) dihydrochalcone is obtained as a white powder.

FABMS (m / z): 662 (MH ⁺ ).

(2) The above-mentioned 4-methoxy-6'-hydroxy-2'-O- (2,3-di-O-butyryl-4,6
-O-benzylidene-β-D-glucopyranosyl) dihydrochalcone was added to 50 ml of an 80% aqueous acetic acid solution.
C. for 2 hours, and treated in the same manner as in Example 9- (2) to give 4-methoxy-6'-hydroxy-2'-O
0.54 g of-(2,3-di-O-butyryl-β-D-glucopyranosyl) dihydrochalcone is obtained as a white powder.

M. p. : 126 to 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), 1.3-1.6 (4H, m), 2.1-2.3
(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 = 5.9 Hz), 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 = 5.9 Hz), 6.56 (1H,
d, J = 8.3 Hz), 6.67 (1H, d, J = 8.
3 Hz), 6.83 (2H, d, J = 8.3 Hz),
7.13 (2H, d, J = 8.3 Hz), 7.18 (1
H, t, J = 8.3 Hz), 10.26 (1H, s).

Examples 12 to 51 In the same manner as in Examples 9, 10, and 11, the compounds shown in Tables 2 to 8 are obtained from the corresponding starting compounds.

[0134]

[Table 3]

[0135]

[Table 4]

[0136]

[Table 5]

[0137]

[Table 6]

[0138]

[Table 7]

[0139]

[Table 8]

[0140]

[Table 9]

[0141]

[Table 10]

[0142]

[Table 11]

[0143]

[Table 12]

[0144]

[Table 13]

[0145]

[Table 14]

[0146]

[Table 15]

[0147]

[Table 16]

[0148]

[Table 17]

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

(2) The above 4-methoxy-6'-hydroxy-2'-O- (2,3-di-O-benzyloxyacetyl-4,6-O-benzylidene-β-D-glucopyranosyl) dihydro 0.90 g of chalcone in ethanol 2
Dissolve in 0 ml and 20 ml of acetic acid, add 0.4 g of 10% palladium-carbon, and perform hydrogen reduction overnight under normal pressure stirring.

After filtration, the filtrate is concentrated, and the residue is purified by silica gel column chromatography (solvent: chloroform / methanol) to give 4-methoxy-6'-hydroxy-2'-O- (2,3-diethylbenzene). 460 mg of -O-hydroxyacetyl-β-D-glucopyranosyl) dihydrochalcone are obtained as a white powder. Physical data is ninth
It is as described in the table.

Example 53 4-methoxy-6'-hydroxy-2'-O-β-D-
Glucopyranosyl dihydrochalcone (1.30 g) is dissolved in pyridine (13 ml), and benzoyl chloride (0.90 g) is added dropwise over 30 minutes while stirring on ice. After stirring on ice for 2 hours, the mixture is poured into ice water and extracted 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 0.80 g of 4-methoxy-6′-hydroxy-2′-O- (6-O-benzoyl-β-D-glucopyranosyl) dihydrochalcone. As a colorless amorphous powder. Physical data is as shown in Table 9.

[0153]

[Table 18]

Example 54 4-methoxy-6'-hydroxy-2'-O-β-D-
Glucopyranosyl dihydrochalcone (1.0 g) is dissolved in pyridine (20 ml), and acetic anhydride (5 ml) is added.

After stirring at room temperature for 2 days, the mixture was concentrated, and ethyl acetate and diluted hydrochloric acid were added to the residue. After stirring, the organic layer was separated. After washing with water, drying, filtration and concentration, the residue is subjected to silica gel column chromatography (solvent: chloroform / ethyl acetate).
To give 4-methoxy-6'-acetoxy-2'-O- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) dihydrochalcone 1.2
1 g is obtained as a white powder. Physical data is as shown in Table 10.

Example 55 4-methoxy-6'-hydroxy-2'-O-β-D-
Glucopyranosyl dihydrochalcone (869 mg) is dissolved in pyridine (10 ml), and methoxyacetic acid chloride (1.30 g) is added dropwise with ice cooling and stirring. After reacting at room temperature for 2 hours, the mixture is concentrated under reduced pressure. Ethyl acetate and ice-cold diluted hydrochloric acid are added to the residue, and after stirring, the organic layer is separated. After washing with water, drying, filtering and concentrating,
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 purified by silica gel column chromatography (solvent: chloroform / methanol) to give 4-methoxy-6'-.
Hydroxy-2'-O- (2,3,4,6-tetra-O
-Methoxyacetyl-β-D-glucopyranosyl) dihydrochalcone 882 mg is obtained as a pale yellow oil. Physical data is as shown in Table 10.

[0157]

[Table 19]

[0158] Example 56 4-methoxy-6 ^'- benzyloxycarbonyl ^carboxy-2' -
O- (2,3-di-O-benzyloxycarbonyl-β-
569 mg of (D-glucopyranosyl) dihydrochalcone is dissolved in 5 ml of pyridine, and 278 mg of acetic anhydride is added dropwise at room temperature. 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. After washing with water, drying, filtration and concentration, the residue is dissolved in a mixed solution of ethanol and ethyl acetate (5 ml-5 ml). Hydrogen reduction is performed under normal pressure using 10% palladium-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 -
The 2 ^'-O- (4,6-di -O- acetyl-beta-D-glucopyranosyl) dihydrochalcone 251mg 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.
8 Hz), 5.47 (1H, d, J = 5.7 Hz),
5.58 (1H, d, J = 5.6 Hz), 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).

Examples 57 to 59 In the same manner as in Example 56, the eleventh
The compounds shown in the table are obtained.

[0161]

[Table 20]

[0162]

[Table 21]

[0163] Example 60 4-methoxy-6 ^'- hydroxy ^-2' -O-β-D-
Glucopyranosyl dihydrochalcone (9.22 g) is dissolved in acetone (50 ml), potassium carbonate (14.64 g) is added, and benzyl bromide (4.36 g) is added dropwise with stirring. After stirring at room temperature for 1 hour, the mixture is heated under reflux for 2.5 hours. After diluting the reaction mixture with ethyl acetate and removing potassium carbonate by filtration, washing with water,
After drying, the solvent is distilled off. The residue is purified by silica gel column chromatography (solvent: chloroform / methanol) and then 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 carboxybenzyloxyphenylalanine were dissolved in 30 ml of pyridine, concentrated to 15 ml under reduced pressure, and N, N-bis (2-oxo-3-oxazolidinyl) phosphinic chloride 636 was added.
Add mg. After stirring at room temperature for 24 hours, a 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 give 4
-Methoxy-6'-benzyloxy-2'-O- {6-O
-[N-carbobenzyloxy) -L-phenylalanyl] -β-D-glucopyranosyl dihydrochalcone 4
56 mg 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 (1H, m), 4.
38 (1H, d, J = 10.6 Hz), 4.93 (1
H, d, J = 7.7 Hz), 4.96 (2H, s),
5.04 (2H, s), 5.22 (1H, d, J = 5.
0 Hz), 5.31 (1H, d, J = 3.8 Hz),
5.33 (1H, d, J = 3.6 Hz), 6.74 (2
H, d, J = 8.7 Hz), 6.75 (1H, d, J =
8.5Hz), 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).

[0166] Example 61 4-methoxy-6 ^'- benzyloxy ^-2' -O- {6-
877 mg of O- [N- (carbobenzyloxy) -L-phenylalanyl] -β-D-glucopyranosyl dihydrochalcone is dissolved in a mixed solution of ethanol and tetrahydrofuran (14 ml-6 ml), and 10% palladium-carbon is used as a catalyst. 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' -O- obtain [6-O- (L- phenylalanyl)-beta-D-glucopyranosyl] 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 = 5.4 Hz), 5.42 (1H,
d, J = 5.3 Hz), 6.52 (1H, d, J = 8.
1 Hz), 6.71 (1H, d, J = 8.4 Hz),
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) Examples 62 to 67 The compounds shown in Table 12 are obtained from the corresponding starting compounds in the same manner as in Examples 60 and 61.

[0168]

[Table 22]

[0169]

[Table 23]

[0170]

[Table 24]

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

(2) The compound is dissolved in ethanol solvent at 10
% Palladium-carbon is used as a solvent to perform hydrogen reduction at normal pressure. 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′-O- (2,3,4,4).
6-Tetra-O-acetyl-β-D-glucopyranosyl) dihydrochalcone is obtained. Physical data is in Example 5.
4 is as described.

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

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

Reference Examples 2 to 6 In the same manner as in Reference Example 1, the thirteenth
The compounds shown in the table are obtained.

[0176]

[Table 25]

[0177]

[Table 26]

Reference Example 7 (1) 2'-O- was added to 50 ml of dimethylformamide.
4.82 g of (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) -6′-hydroxyacetophenone and 4.14 g of potassium carbonate were added thereto, and the mixture was stirred.
2.56 g of benzyl bromide is added dropwise and stirred at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure, and ethyl acetate and water are added to the residue. After stirring, the organic layer is separated. After the obtained organic layer is washed with water and dried, the solvent is distilled off. The residue is purified by silica gel column chromatography to obtain 3.2 g of 6′-benzyloxy-2′-O- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) acetophenone.

FABMS (m / z): 595 [(M + Na) ⁺ ].

(2) 6'-benzyloxy-2'-O-
2.9 g of (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) acetophenone and 1.56 g of 4-tetrahydropyranyloxybenzaldehyde are added to 30 ml of ethanol, and a 50% aqueous solution of potassium hydroxide is stirred. Add 3 ml dropwise and stir at room temperature overnight. The solvent is distilled off under reduced pressure, water and diethyl ether are added to the residue, and the mixture is stirred, and the aqueous layer is separated.

The ice-cooled aqueous layer is neutralized with 10% hydrochloric acid and extracted with ethyl acetate. After washing the obtained organic layer with water and drying,
The solvent was distilled off, and the obtained crude product was dissolved in 50 ml of an acetic acid-water-tetrahydrofuran (2: 1: 2) solution, and
After heating at 3 ° C. for 3 hours, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 6′-benzyloxy-2′-O- (β-D-glucopyranosyl) -4-.
1.20 g of hydroxychalcone are obtained.

FABMS (m / z): 531 [(M + Na) ⁺ ].

(3) 6'-benzyloxy-2'-O-
0.79 g of (β-D-glucopyranosyl) -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 with stirring under ice cooling. After stirring at room temperature for 1 hour,
Ethyl acetate and water are added, and after stirring, the organic layer is separated. After 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 give 6′-benzyloxy-4-ethoxycarbonyloxy-2′-.
O- (β-D-glucopyranosyl) chalcone 0.73 g
Get.

FABMS (m / z): 603 [(M + Na) ⁺ ].

(4) 0.70 g of 6'-benzyloxy-4-ethoxycarbonyloxy-2'-O- (β-D-glucopyranosyl) chalcone was dissolved in ethanol, and 1
Catalytic hydrogen reduction is carried out under normal pressure using 0% 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′-O- (β-D-glucopyranosyl) -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 = 7.1 Hz), 4.57 (1H, t,
J = 5.7 Hz), 4.91 (1H, d, J = 7.3H)
z), 5.03 (1H, d, J = 5.3 Hz), 5.1
0 (1H, d, J = 4.7 Hz), 5.27 (1H,
d, J = 5.2 Hz), 6.55 (1H, d, J = 8.
2 Hz), 6.68 (1H, d, J = 8.3 Hz),
7.10 (2H, d, J = 8.6 Hz), 7.24 (1
H, t, J = 8.3 Hz), 7.31 (2H, d, J =
8.6 Hz), 10.94 (1H, s).

[0187]

The dihydrochalcone derivative [I] and the pharmaceutically acceptable salt thereof, which are the object of the present invention, are excellent in blood glucose based on inhibition of glucose reabsorption in the kidney and / or inhibition of glucose absorption in the intestinal tract. Has a descent action. Therefore, the object of the present invention is useful as an agent for preventing and treating diabetes. Furthermore, since the target compound [I] of the present invention and its pharmaceutically acceptable salt are less susceptible to hydrolysis in the intestinal tract, unlike the phlorizin, they have an excellent hypoglycemic effect in both oral and parenteral administration. Show. In addition, the target compound [I] of the present invention has low toxicity, and its hydrolyzate, aglycone, has a feature that the inhibitory effect of the facilitated-diffusion-type sugar transporting carrier is extremely weak, and its safety as a drug. high.

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

Claims (21)

(57) [Claims] 1. A compound of the general formula [I] [However, 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. R ³ and R ⁴ are the same or different and are 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 ² , R ³ and R ⁴ are not simultaneously hydrogen atoms). Or a pharmacologically acceptable salt thereof. 2. The compound 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. The hydrocarbon-based aryl group is a phenyl group which may have a substituent, and the aliphatic acyl group has a lower alkanoyl group or a substituent which may have a substituent. Is also a lower alkoxycarbonyl group,
3. The compound according to claim 2, wherein the aromatic acyl group is an arylcarbonyl group or an aryloxycarbonyl group. 4. A phenyl group which may be substituted with a phenyl group which may have a substituent, is 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 group or a group obtained by removing a hydroxyl group from a carboxyl group of an α-amino acid, and a lower alkoxycarbonyl group which may have a substituent is a lower alkoxy group And lower alkoxycarbonyl optionally substituted with a group selected from phenyl and phenyl Wherein the arylcarbonyl group is a benzoyl group, the aryloxycarbonyl group is a phenoxycarbonyl group, and the optionally substituted methylene group is a phenyl group, a lower alkanoyloxy group, a lower alkoxy group and an oxo group. The compound according to claim 3, which is a methylene group optionally substituted with two groups. 5. A compound of the general formula [Ia] (However, Ar represents an aryl group, R ¹¹ represents an acyl group,
OR ⁵ represents a hydroxyl group or a lower alkoxy group which may be protected. Or a pharmacologically acceptable salt thereof. 6. A compound of 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. Or a pharmacologically acceptable salt thereof. 7. A compound of the general formula [Ic] (However, Ar represents an aryl group, R ³¹ and R ⁴¹ represent the same or different acyl groups, and OR ⁵ represents a hydroxyl group or a lower alkoxy group which may be protected.) Acceptable salts. 8. A compound of the general formula [Id] (However, Ar is an aryl group, R ¹³ , R ²³ , R ³³ and R ⁴³
Is the same or different and represents an acyl group, and OR ⁵ represents an optionally protected hydroxyl group or a lower alkoxy group. Or a pharmacologically acceptable salt thereof. 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. 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 and an amino group which may be protected. A lower alkanoyl group optionally substituted with one or two groups selected from the group consisting of: a lower alkoxy group optionally substituted by a group selected from a lower alkoxy group and a phenyl group; a benzoyl group; a phenoxycarbonyl group; A group obtained by removing a hydroxyl group from a carboxyl group of an α-amino acid. 6. The compound of claim 5, wherein. 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;
Is a hydroxyl group or a lower alkoxy group which may be 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 lower alkanoyl group optionally substituted with one or two groups selected from a phenyl group and an amino group which may be protected; a lower alkoxy optionally substituted with a group selected from a lower alkoxy group and a phenyl group Carbonyl group; benzoyl group; phenoxycarbonyl group; or α-
The compound according to claim 6, which is a group obtained by removing a hydroxyl group from a carboxyl group of an amino acid. 11. 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;
Is a hydroxyl group or a lower alkoxy group which may be protected, 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 lower alkanoyl group optionally substituted with one or two groups selected from a phenyl group and an amino group which may be protected; a lower alkoxy optionally substituted with a group selected from a lower alkoxy group and a phenyl group Carbonyl group; benzoyl group; phenoxycarbonyl group; or α-
The compound according to claim 7, which is a group obtained by removing a hydroxyl group from a carboxyl group of an amino acid. 12. 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;
Is an optionally protected hydroxyl group or lower alkoxy group, wherein R ¹³ , R ²³ , R ³³ and R ⁴³ 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 lower alkanoyl group optionally substituted with one or two groups selected from a phenoxy group, a phenyl group and an amino group which may be protected; a lower alkanoyl group optionally substituted with a group selected from a lower alkoxy group and a phenyl group The compound according to claim 8, which is a lower alkoxycarbonyl group; a benzoyl group; a phenoxycarbonyl group; or a group obtained by removing a hydroxyl group from a carboxyl group of an α-amino acid. 13. 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;
Is an optionally protected hydroxyl group, wherein R ³¹ and R ⁴¹ are the same or different and are substituted with a group selected from a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a benzyloxycarbonylamino group and an amino group. 12. The compound according to claim 11, which is a lower alkanoyl group, a lower alkoxycarbonyl group, a benzoyl group or a phenoxycarbonyl group. 14. Ar is a phenyl group which may be substituted by a lower alkyl group or a lower alkoxy group;
R ⁵ is a hydroxyl group protected by a hydroxyl group or a lower alkanoyl group, R ³¹ and R ⁴¹ are a lower alkanoyl group, a lower alkoxy-substituted lower alkanoyl group, an amino-substituted lower alkanoyl group, a lower alkoxycarbonyl group or a phenoxycarbonyl group. Item 14. The compound according to Item 13. 15. The compound according to claim 14, wherein Ar is a lower alkoxy-substituted phenyl group and R ³¹ and R ⁴¹ are lower alkoxy-substituted lower alkanoyl groups. 16. A compound of the general formula [II] [However, Ar represents an aryl group, and OR ⁵ represents a hydroxyl group or a lower alkoxy group which may be protected. Wherein the compound represented by the general formula [Ia] is acylated. (Wherein R ¹¹ represents an acyl group, and the other symbols have the same meanings as described above). 17. A compound of the general formula [Ig] [However, Ar represents an aryl group, R ³² and R ⁴² represent a hydroxyl-protecting group, and OR ⁵ represents a hydroxyl group or a lower alkoxy group which may be protected. Wherein the compound represented by the general formula [Ib] is acylated to remove the protecting group. (However, R ¹¹ and R ²¹ represent an acyl group, and other symbols have the same meanings as described above.) 18. A compound of the general formula [Ih] [However, Ar represents an aryl group, R ¹² and R ²² represent a hydroxyl-protecting group, and OR ⁵ represents a hydroxyl group or a lower alkoxy group which may be protected. Wherein the compound represented by the general formula [Ic] is acylated to remove the protecting group. (However, R ³¹ and R ⁴¹ represent an acyl group, and the other symbols have the same meanings as described above.) 19. A compound of the general formula [Ii] [However, Ar represents an aryl group, and R ¹⁴ , R ²⁴ , R ³⁴
And R ⁴⁴ is at least one of them one group is a hydrogen atom, the other group is an acyl group, OR ⁵
Represents a hydroxyl group or a lower alkoxy group which may be protected. Wherein the compound represented by the general formula [Id] is acylated. (However, R ¹³ , R ²³ , R ³³ and R ⁴³ are the same or different and each represents an acyl group). 20. The general formula [II] (Where Ar represents an aryl group, and OR ⁵ represents a hydroxyl group or a lower alkoxy group which may be protected) and a compound represented by the general formula [III-a]: (Provided that B ¹ and B ² are the same or different and are each a hydrogen atom,
X represents a phenyl group, a lower alkanoyloxy group or a lower alkoxy group, or B ¹ and B ² form a group represented by ＯO, and X represents a reactive residue. Or a compound represented by the general formula [III-b]: (However, B ³ represents a hydrogen atom, a phenyl group, a lower alkanoyloxy group or a lower alkoxy group). The compound represented by the general formula [I-
f] (Wherein the symbols have the same meanings as described above) or the general formula [Ik] (Wherein the symbols have the same meanings as described above). 21. A compound of the general formula [Ij] [However, Ar is an aryl group, R ¹ is a hydrogen atom or
An acyl group, and 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
R ³ and R ⁴ may be the same or different.
Represents a hydrogen atom or an acyl group (however,
R ¹ , R ² , R ³ and R ⁴ are not simultaneously hydrogen atoms). ]
And a compound represented by the general formula [IV]: (However, R ⁶ represents a lower alkyl group or an acyl group.)
Or a reactive derivative thereof represented by the following general formula [Ie]: (Wherein the symbols have the same meanings as described above).