JP2005220037A - NAPHTHOQUINONE DERIVATIVE COMPOUND OR ITS PHARMACEUTICALLY PERMISSIBLE SALT AND Cdc25 PHOSPHATASE INHIBITOR AND ANTITUMOR AGENT CONTAINING THE SAME AS ACTIVE INGREDIENT - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a naphthoquinone derivative compound or its pharmaceutically permissible salt having high inhibitory activity against Cdc25 phosphatase and a Cdc25 phosphatase inhibitor and an antitumor agent containing the same as an active ingredient. <P>SOLUTION: The naphthoquinone derivative compound represented by general formula (I) (R<SB>1</SB>and R<SB>2</SB>are each an alkoxy group; R<SB>3</SB>is a hydrogen atom; R<SB>4</SB>is an alkoxyalkyl group) or its pharmaceutically permissible salt has high inhibitory activity against Cdc25 phosphatase. Consequently, a substance containing the naphthoquinone derivative compound or its pharmaceutically permissible salt as an active ingredient is considered to be useful as a Cdc25 phosphatase inhibitor and an antitumor agent. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a naphthoquinone derivative compound or a pharmacologically acceptable salt thereof, and a Cdc25 phosphatase inhibitor and an antitumor agent containing them as active ingredients.

Inhibitors to Cdc25 phosphatase such as Cdc25A and Cdc25B expressed in various tumors are considered to be useful as antitumor agents. Conventionally, several naphthoquinone analogs are known as inhibitors for Cdc25A (see, for example, Non-Patent Documents 1 and 2).
Bioorg. Med. Chem. Lett. 1998, 8 (18), 2507-10 J. Antibiot. 1999, 52,256-262

However, since naphthoquinone analogs known so far have low inhibitory activity, development of naphthoquinone derivative compounds having higher inhibitory activity has been demanded.
Therefore, an object of the present invention is to provide a naphthoquinone derivative compound having high inhibitory activity against Cdc25 phosphatase or a pharmacologically acceptable salt thereof, and a Cdc25 phosphatase inhibitor and an antitumor agent containing them as active ingredients. And

In order to solve the above problems, the present inventors have general formula (II)

(Wherein R ₁ and R ₂ are a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group, and R ₃ is a hydrogen atom, an alkyl group, a hydroxyalkyl group, or a halogen atom). As an example of the naphthoquinone derivative compound represented, the formula (A)

The effects of Cdc25A on the enzyme activity were investigated using the compounds shown in (1). As a result, it was found that the compound represented by the formula (A) highly inhibits the activity of Cdc25 phosphatase.

In addition, the general formula (III)

(Wherein R ₁ and R ₂ are a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group, and R ₃ is a hydrogen atom, an alkyl group, a hydroxyalkyl group, or a halogen atom). As an example of the naphthoquinone derivative compound represented, the formula (B)

As a result of investigating the effect of Cdc25A on the enzyme activity using the compound shown in (2), the compound shown in formula (B) is highly inhibited in the activity of Cdc25 phosphatase as in the compound shown in formula (A). It became clear.

Similarly, the general formula (IV)

(Wherein, R ₁ and R ₂ are a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group.) As an example of a naphthoquinone derivative compound represented by formula (C)

And formula (D)

Each of the compounds shown in Table 2 was used to examine the effect on the enzyme activity of Cdc25A. The compound shown in Formula (C) highly inhibited the activity of Cdc25 phosphatase, and the compound shown in Formula (D) was substrate-specific. It was found that the activity of Cdc25 phosphatase was highly inhibited.

Similarly, the general formula (VI)

(Wherein R ₂ is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group, and R ₅ and R ₆ are a hydrogen atom or an alkyl group). As formula (E)

The effects of Cdc25A on the enzyme activity were investigated using the compounds shown in (1). As a result, it was found that the compound represented by the formula (E) highly inhibits the activity of Cdc25 phosphatase in a substrate-specific manner.

Similarly, the general formula (VII)

(Wherein R ₁ and R ₂ are a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group, and R ₇ is a hydrogen atom or an alkyl group). As an example, the formula (F)

As a result of investigating the effect on the enzyme activity of Cdc25A using each of the compounds shown in the above, it was found that the compound shown in Formula (F) highly inhibits the activity of Cdc25 phosphatase in a substrate-specific manner. Thus, the present inventors have completed the present invention.

That is, the naphthoquinone derivative compound or pharmacologically acceptable salt thereof according to the present invention is represented by the following general formula (I).

In the formula, R ₁ is, for example, a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group; R ₂ is, for example, a hydroxyl group, an acyloxy group, or an alkoxyl group; and R ₃ Is, for example, a hydrogen atom, a hydroxyalkyl group, or a halogen atom, and R ₄ is, for example, an acyl group, a hydroxyalkyl group, a hydroxyalkenyl group, a carboxyl group, an alkoxycarbonyl group, an alkoxyalkyl group, an alkoxyalkenyl group, a phenoxy Alkyl group, phenoxyalkenyl group, carboxyalkenyl group, alkoxycarbonylalkenyl group, acyloxyalkenyl group, hydroxyalkyloxirane alkyl group, alkoxyalkyloxiranealkyl group, dihydroxyalkyl group, hydroxy An alkoxyalkyl group, an oxirane group, or a 2-dimethane-1,3-dioxane-4-alkyl group. In addition, it is preferable that the naphthoquinone derivative compound or pharmacologically acceptable salt thereof according to the present invention does not form a ring with R ₃ and R ₄ .

In addition, the naphthoquinone derivative compound or a pharmacologically acceptable salt thereof according to the present invention is represented by the following general formula (II).

In the formula, R ₁ is, for example, a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group; R ₂ is, for example, a hydroxyl group, an acyloxy group, or an alkoxyl group; and R ₃ Is, for example, a hydrogen atom, a hydroxyalkyl group, or a halogen atom. The naphthoquinone derivative compound may be the following formula (A).

Furthermore, the naphthoquinone derivative compound or pharmacologically acceptable salt thereof according to the present invention is represented by the following general formula (III).

In the formula, R ₁ is, for example, a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group; R ₂ is, for example, a hydroxyl group, an acyloxy group, or an alkoxyl group; and R ₃ Is, for example, a hydrogen atom, a hydroxyalkyl group, or a halogen atom. The naphthoquinone derivative compound may be the following formula (B).

The naphthoquinone derivative compound or a pharmacologically acceptable salt thereof according to the present invention is represented by the following general formula (IV).

In the formula, R ₁ is, for example, a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group, and R ₂ is, for example, a hydroxyl group, an acyloxy group, or an alkoxyl group. The naphthoquinone derivative compound may be represented by the following formula (C) or the following formula (D).

Furthermore, the naphthoquinone derivative compound according to the present invention or a pharmacologically acceptable salt thereof is represented by the following general formula (V).

In the formula, R ₂ is, for example, a hydroxyl group, an acyloxy group, or an alkoxyl group, R ₃ is, for example, a hydrogen atom, a hydroxyalkyl group, or a halogen atom, and R ₄ is, for example, an acyl group. , Hydroxyalkyl group, hydroxyalkenyl group, carboxyl group, alkoxycarbonyl group, alkoxyalkyl group, alkoxyalkenyl group, phenoxyalkyl group, phenoxyalkenyl group, carboxyalkenyl group, alkoxycarbonylalkenyl group, acyloxyalkenyl group, hydroxyalkyloxirane alkyl group An alkoxyalkyloxirane alkyl group, a dihydroxyalkyl group, a hydroxyalkoxyalkyl group, an oxirane group, or a 2-dimethane-1,3-dioxane-4-alkyl group, R ₅ and R ₆ are, for example, a hydrogen atom or an alkyl group. In addition, it is preferable that the naphthoquinone derivative compound or pharmacologically acceptable salt thereof according to the present invention does not form a ring with R ₃ and R ₄ .

Further, the naphthoquinone derivative compound or a pharmacologically acceptable salt thereof according to the present invention is represented by the following general formula (VI).

In the formula, R ₂ is, for example, a hydroxyl group, an acyloxy group, or an alkoxyl group, and R ₅ and R ₆ are, for example, a hydrogen atom or an alkyl group. The naphthoquinone derivative compound may be the following formula (E).

Furthermore, the naphthoquinone derivative compound or pharmacologically acceptable salt thereof according to the present invention is represented by the following general formula (VII).

In the formula, R ₁ is, for example, a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group, and R ₂ is, for example, a hydroxyl group, an acyloxy group, or an alkoxyl group, and R ₇ Is, for example, a hydrogen atom or an alkyl group. The naphthoquinone derivative compound may be the following formula (F).

  The Cdc25 phosphatase inhibitor according to the present invention is characterized by containing the above-mentioned naphthoquinone derivative compound or a pharmacologically acceptable salt thereof as an active ingredient.

  Furthermore, the antitumor agent according to the present invention contains the above-mentioned naphthoquinone derivative compound or a pharmacologically acceptable salt thereof as an active ingredient.

  According to the present invention, it is possible to provide a naphthoquinone derivative compound having high inhibitory activity against Cdc25 phosphatase or a pharmacologically acceptable salt thereof, and a Cdc25 phosphatase inhibitor and an antitumor agent containing these as active ingredients. .

  Hereinafter, embodiments of the present invention completed based on the above findings will be described in detail with reference to examples. Unless otherwise stated in the embodiments and examples, J. Sambrook, EF Fritsch & T. Maniatis (Ed.), Molecular cloning, a laboratory manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2001); FM Ausubel, R. Brent, RE Kingston, DD Moore, JG Seidman, JA Smith, K. Struhl (Ed.), Standard Protocols in Molecular Biology, John Wiley & Sons Ltd. The method described in the protocol collection, or a modified or modified method thereof is used. In addition, when using commercially available reagent kits and measuring devices, unless otherwise explained, protocols attached to them are used.

  The objects, features, advantages, and ideas of the present invention will be apparent to those skilled in the art from the description of the present specification, and those skilled in the art can easily reproduce the present invention from the description of the present specification. it can. The embodiments and specific examples of the invention described below show preferred embodiments of the present invention, and are shown for illustration or explanation. It is not limited. It will be apparent to those skilled in the art that various modifications and variations can be made based on the description of the present specification within the spirit and scope of the present invention disclosed herein.

=== Pharmacological Action of Naphthoquinone Derivative Compound According to the Present Invention ===
As described above, substances having Cdc25 phosphatase inhibitory activity are considered to be useful as antitumor agents. Therefore, the present inventors investigated whether compounds represented by the following formulas (A) to (F) inhibit the enzyme activity of Cdc25A.

As a result, it was revealed that the compounds represented by formula (A), formula (B), and formula (C) have excellent inhibitory activity (IC ₅₀ = 10 μg / ml or less) against Cdc25A phosphatase. . Furthermore, the compound represented by the formula (E) was found to inhibit the enzyme activity of Cdc25A against OMFP (3-O-methylfluorescein phosphate (Cdc25 substrate): 3-O-methylfluorescein phosphate). The compounds represented by D) and Formula (F) were found to inhibit the enzyme activity of Cdc25A against pNPP (p-nitrophenyl phosphate (substrate of Cdc25): p-nitrophenyl phosphate).

  From the above, the naphthoquinone derivative compound represented by the general formula (I) having a structure similar to the compounds represented by the formula (A), the formula (B), the formula (C), and the formula (D), The naphthoquinone derivative compounds represented by formula (II), general formula (III), and general formula (IV) are considered to have Cdc25 phosphatase inhibitory activity.

Similarly, the naphthoquinone derivative compound represented by the general formula (V) having a structure similar to that of the compound represented by the formula (E), particularly the naphthoquinone derivative compound represented by the general formula (VI), also has Cdc25 phosphatase inhibitory activity. It is thought that it has.
Furthermore, the naphthoquinone derivative compound represented by the general formula (VII) having a structure similar to that of the compound represented by the formula (F) is also considered to have Cdc25 phosphatase inhibitory activity.

  Therefore, since the naphthoquinone derivative compounds represented by the general formula (I), the general formula (V), and the general formula (VII) have Cdc25 phosphatase inhibitory activity, the general formula (I), the general formula (V ) And pharmacologically acceptable salts of naphthoquinone derivative compounds represented by the general formula (VII) can also be said to have Cdc25 phosphatase inhibitory activity, and these naphthoquinone derivative compounds and their pharmacology Pharmaceutically acceptable salts are considered useful as antitumor agents.

=== Method for Producing Naphthoquinone Derivative Compound According to the Present Invention ===
An example of the method for producing a naphthoquinone derivative compound according to the present invention will be described based on the following five reaction process formulas ([Chemical Formula 25] to [Chemical Formula 29]).

<Step 1a: Production of Compound 3>
Compound 2 is dissolved in anhydrous tetrahydrofuran, and sodium hydride is added under ice cooling. After stirring at room temperature, compound 1 dissolved in anhydrous tetrahydrofuran is added under ice cooling, and the mixture is further stirred at room temperature. After adding a saturated aqueous solution of ammonium chloride in an ice bath, dilute with ethyl acetate and wash with saturated brine. The organic layer is dehydrated with anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, the residue obtained is dissolved in ether, and water and trifluoroacetic acid are successively added under ice cooling. After 4.5 hours, Compound 3 can be obtained by purifying the crude product obtained by concentrating the solvent under reduced pressure by chromatography.

<Step 2a: Production of Compound 4>
Compound 3 is dissolved in acetic anhydride, potassium acetate is added at room temperature, and the mixture is heated to reflux. Thereafter, the solvent is distilled off under reduced pressure by azeotropic distillation with toluene, and the resulting residue is diluted with ethyl acetate and washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine. Further, the aqueous layer is washed with ethyl acetate, and then the organic layers are combined and dehydrated with anhydrous sodium sulfate. Compound 4 can be obtained by purifying the crude product obtained by concentrating the solvent under reduced pressure by chromatography.

<Step 3a: Production of Compound 5>
Compound 4 was dissolved in ethanol, and potassium carbonate was added at 0 ° C. After stirring at room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was diluted with ethyl acetate and washed with saturated brine. Compound 5 can be obtained by dehydrating the organic layer with anhydrous sodium sulfate and purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 4a: Production of Compound 6>
Compound 5 is dissolved in anhydrous tetrahydrofuran, and lithium aluminum hydride is added under ice cooling. After stirring at room temperature, saturated aqueous ammonium chloride solution is added under ice-cooling, and the mixture is diluted with ethyl acetate and washed with saturated brine. Compound 6 can be obtained by dehydrating the organic layer with anhydrous sodium sulfate and purifying the crude product obtained by concentrating the solvent under reduced pressure by chromatography.

<Step 5a: Production of compound 7>
Compound 6 is dissolved in dimethylformamide and sodium hydride and methyl iodide are added at 0 ° C. After stirring, a saturated aqueous ammonium chloride solution was added under ice cooling, and the reaction mixture was diluted with ethyl acetate. After washing this with saturated saline, the organic layer is dehydrated with anhydrous sodium sulfate, and the crude product obtained by distilling off the solvent under reduced pressure is purified by chromatography to give compound 7.

<Step 6a: Production of Compound 8>
Compound 7 is dissolved in dichloromethane, and water, t-butyl alcohol and DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone are sequentially added at 0 ° C. After stirring, the reaction solution is diluted with chloroform. The organic layer was washed with saturated brine, the aqueous layer was further washed with chloroform, and the organic layers were combined and dehydrated with anhydrous sodium sulfate. The crude product obtained in this manner can be purified by chromatography to give compound 8 (compound represented by formula (A)).

<Step 7a: Production of Compound 9>
Compound 6 is dissolved in dimethylformamide and potassium carbonate and methyl iodide are added at 0 ° C. After stirring, the reaction solution is diluted with ethyl acetate. The organic layer is washed with saturated brine, and the aqueous layer is further washed with ethyl acetate. The organic layers are combined and dried over anhydrous sodium sulfate. Compound 9 can be obtained by purifying the crude product obtained by concentrating the solvent under reduced pressure by chromatography.

<Step 8a: Production of Compound 10>
Compound 9 is dissolved in toluene, and dimethyl sulfoxide, triethylamine, and sulfur trioxide pyridine complex (SO ₃ .Pyr) are sequentially added at room temperature. Thereafter, the reaction solution is diluted with ethyl acetate, and a saturated aqueous ammonium chloride solution is added under ice cooling. The organic layer is washed with saturated brine, and the aqueous layer is further washed with ethyl acetate. The organic layers are combined and dehydrated with anhydrous sodium sulfate. Compound 10 can be obtained by purifying the crude product obtained by concentrating the solvent under reduced pressure by chromatography.

<Step 9a: Production of Compound 11>
After adding dimethyl sulfoxide to sodium hydride and stirring at room temperature, the reaction solution is diluted with anhydrous tetrahydrofuran. Then, trimethylsulfonium iodide dissolved in dimethyl sulfoxide is added at 0 ° C., and then compound 10 dissolved in anhydrous tetrahydrofuran is further added and stirred. The reaction mixture is diluted with ethyl acetate and washed with saturated aqueous ammonium chloride. Compound 11 can be obtained by dehydrating the organic layer with anhydrous sodium sulfate and purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 10a: Production of Compound 12>
Zinc bromide is heated to reflux in benzene, and compound 11 dissolved in benzene is added to the mixture. After the reaction, the reaction solution is returned to room temperature, diluted with ethyl acetate, and washed with water and saturated brine. The organic layer is dehydrated with anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain a crude product of aldehyde.

  Dissolve ethyl diethylphosphonoacetate in anhydrous tetrahydrofuran, add sodium hydride under ice cooling, and stir at room temperature. Thereafter, aldehyde dissolved in anhydrous tetrahydrofuran is added at −78 ° C. and stirred. After the reaction, a saturated aqueous solution of ammonium chloride is added to the reaction solution and diluted with ethyl acetate. The organic layer is washed with saturated brine, and the aqueous layer is further washed with ethyl acetate. The organic layers are combined and dried over anhydrous sodium sulfate. Compound 12 can be obtained by purifying the crude product obtained by concentrating the solvent under reduced pressure by chromatography.

<Step 11a: Production of Compound 13>
Compound 12 is dissolved in anhydrous tetrahydrofuran, and diisobutylaluminum hydride is added dropwise at -78 ° C. After completion of the dropwise addition, the mixture is stirred, and 4M hydrochloric acid is added to return to 0 ° C. The reaction mixture is diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. Compound 13 can be obtained by dehydrating the organic layer with anhydrous sodium sulfate and purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 12a: Production of Compound 14>
After adding dichloromethane and tetraisopropyl orthotitanate to Molecular Sieves 4A and stirring, L-(+)-diisopropyl tartrate dissolved in dichloromethane is added dropwise at -25 ° C. Further, compound 13 dissolved in dichloromethane at −20 ° C. is added. After stirring at −20 ° C., t-butyl hydroperoxide is added dropwise at the same temperature. After further stirring at −20 ° C., 10% L-(+)-tartaric acid aqueous solution is added and stirred under ice cooling. The reaction mixture is diluted with ethyl acetate and washed with saturated brine. The organic layer is dehydrated with anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, the residue obtained is dissolved in diethyl ether, and 1M aqueous sodium hydroxide solution is added in an ice bath. After stirring at room temperature, the reaction is diluted with diethyl ether. The organic layer is washed with saturated brine, dehydrated with anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to purify a crude product obtained by chromatography, whereby compound 14 can be obtained.

<Step 13a: Production of Compound 15>
Compound 14 is dissolved in anhydrous tetrahydrofuran, and Red-Al (65 wt%, toluene solution) is added dropwise at -78 ° C. After completion of the dropwise addition, the mixture is stirred, and a saturated aqueous ammonium chloride solution is added to return to 0 ° C. The reaction mixture is diluted with ethyl acetate and washed with water and saturated brine. Compound 15 can be obtained by dehydrating the organic layer with anhydrous sodium sulfate and purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 14a: Production of Compound 16>
To compound 15, 2,2-dimethoxypropane and (±) -camphor-10-sulfonic acid are added and stirred at room temperature. The reaction mixture is diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layers are combined and dried over anhydrous sodium sulfate. Compound 16 can be obtained by purifying the crude product obtained by concentrating the solvent under reduced pressure by chromatography.

<Step 15a: Production of Compound 17>
Compound 16 is dissolved in 1,4-dioxane, and water and DDQ are added in an ice bath. After stirring at room temperature, the reaction mixture is diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer is dehydrated with anhydrous sodium sulfate, and the crude product obtained by concentrating the solvent under reduced pressure is purified by chromatography, whereby compound 17 (compound represented by formula (B)) can be obtained.

<Step 16a: Production of Compound 18>
Compound 6 is dissolved in anhydrous tetrahydrofuran and hydrobromic acid perbromide pyridine complex (Pyr · HBr ₃ ) is added at 0 ° C. After stirring, a saturated aqueous sodium thiosulfate solution is added, and the reaction solution is diluted with ethyl acetate. This is washed with saturated saline. Compound 18 can be obtained by dehydrating the organic layer with anhydrous sodium sulfate and purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 17a: Production of Compound 19>
Compound 18 is dissolved in dichloromethane, and dimethyl sulfoxide, triethylamine, and sulfur trioxide pyridine complex (SO ₃ .Pyr) are sequentially added at room temperature. The reaction solution is diluted with chloroform, and a saturated aqueous ammonium chloride solution is added under ice cooling. The organic layer is washed with saturated brine, and the aqueous layer is further washed with chloroform. The organic layers are combined and dehydrated with anhydrous sodium sulfate. Compound 19 can be obtained by purifying the crude product obtained by concentrating the solvent under reduced pressure by chromatography.

<Step 18a: Production of Compound 20>
Compound 19 is dissolved in dimethylformamide and potassium carbonate and methyl iodide are added at 0 ° C. After stirring at room temperature, the reaction is diluted with ethyl acetate. The organic layer is washed with saturated brine, and the aqueous layer is further washed with ethyl acetate. The organic layers are combined and dried over anhydrous sodium sulfate. Compound 20 can be obtained by purifying the crude product obtained by concentrating the solvent under reduced pressure by chromatography.

<Step 19a: Production of Compound 21>
After adding dimethyl sulfoxide to sodium hydride and stirring at room temperature, the reaction solution is diluted with anhydrous tetrahydrofuran. Thereafter, trimethylsulfonium iodide dissolved in dimethyl sulfoxide is added at 0 ° C., and then compound 20 dissolved in dimethyl sulfoxide is further added and stirred. The reaction mixture is diluted with ethyl acetate and washed with saturated aqueous ammonium chloride. Compound 21 can be obtained by dehydrating the organic layer with anhydrous sodium sulfate and purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 20a: Production of Compound 22>
In benzene, zinc bromide is heated to reflux, and compound 21 dissolved in benzene is added to the mixture. The reaction solution is returned to room temperature, diluted with ethyl acetate, and washed with water and saturated brine. The organic layer is dehydrated with anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain a crude product of aldehyde.

  Dissolve ethyl diethylphosphonoacetate in anhydrous tetrahydrofuran, add sodium hydride under ice cooling, and stir at room temperature. Thereafter, aldehyde dissolved in anhydrous tetrahydrofuran is added at −78 ° C. and stirred. Saturated aqueous ammonium chloride solution is added to the reaction solution and diluted with ethyl acetate. The organic layer is washed with saturated brine, and the aqueous layer is further washed with ethyl acetate. The organic layers are combined and dried over anhydrous sodium sulfate. Compound 22 can be obtained by purifying the crude product obtained by concentrating the solvent under reduced pressure by chromatography.

<Step 21a: Production of Compound 23>
Compound 22 is dissolved in anhydrous tetrahydrofuran, and diisobutylaluminum hydride is added dropwise at -78 ° C. After completion of the dropwise addition, the mixture is stirred, and 4M hydrochloric acid is added to return to 0 ° C. The reaction mixture is diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. Compound 23 can be obtained by dehydrating the organic layer with anhydrous sodium sulfate and purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 22a: Production of Compound 24>
Compound 23 is dissolved in dimethylformamide, imidazole and t-butyldimethylsilyl chloride are sequentially added at 0 ° C. and stirred. The reaction mixture is diluted with ethyl acetate, washed with saturated brine, and the organic layer is dried over anhydrous sodium sulfate. Compound 24 can be obtained by purifying the crude product obtained by concentrating the solvent under reduced pressure by chromatography.

<Step 23a: Production of compound 25>
Compound 24 is dissolved in anhydrous tetrahydrofuran, and n-butyllithium (1.57 M, hexane solution) is added dropwise at -78 ° C. Add more n-valeraldehyde and stir. Saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, the temperature is returned to 0 ° C., diluted with ethyl acetate, and washed with saturated brine. The organic layer is dehydrated with anhydrous sodium sulfate, and the solvent is concentrated under reduced pressure to obtain a crude secondary alcohol product.

  The secondary alcohol is dissolved in anhydrous tetrahydrofuran and tetra-n-butylammonium fluoride is added at 0 ° C. After stirring at room temperature, the reaction is diluted with ethyl acetate. After washing with water and saturated brine, the organic layer is dehydrated with anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to purify the crude product by chromatography, whereby compound 25 can be obtained.

<Step 24a: Production of Compound 26>
Compound 25 is dissolved in dichloromethane, and water, t-butyl alcohol, and DDQ are sequentially added at 0 ° C. After stirring, the reaction solution is diluted with chloroform, and a saturated aqueous sodium hydrogen carbonate solution is added. The organic layer is washed with saturated brine, and the aqueous layer is further washed with chloroform. The organic layers are combined and dehydrated with anhydrous sodium sulfate. Compound 26 (compound represented by formula (C)) can be obtained by purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 25a: Production of compound 27>
Compound 25 is dissolved in dichloromethane and pyridine and acetic anhydride are added in an ice bath. After stirring at room temperature, Compound 27 can be obtained by purifying the residue obtained by distilling off the solvent under reduced pressure by toluene azeotropy by chromatography.

<Step 26a: Production of Compound 28>
Compound 27 is dissolved in dichloromethane, and water, t-butyl alcohol, and DDQ are sequentially added at 0 ° C. After stirring, the reaction solution is diluted with chloroform, and a saturated aqueous sodium hydrogen carbonate solution is added. The organic layer is washed with saturated brine, and the aqueous layer is further washed with chloroform. The organic layers are combined and dehydrated with anhydrous sodium sulfate. Compound 28 can be obtained by purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 27a: Production of compound 29>
Boron tribromide (1M, dichloromethane solution) is dissolved in dichloromethane, and compound 28 dissolved in dichloromethane is added at −78 ° C. and stirred. The reaction mixture is diluted with chloroform, washed with water and saturated brine, and the organic layer is dried over anhydrous sodium sulfate. Compound 29 can be obtained by purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 28a: Production of compound 30>
Compound 29 is dissolved in anhydrous tetrahydrofuran and methylamine (40 wt%, methanol solution) is added in an ice bath. After stirring at the same temperature, compound 30 can be obtained by purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 29a: Production of compound 31>
Compound 30 is dissolved in methanol and potassium carbonate is added in an ice bath. After stirring at room temperature, the reaction mixture is diluted with ethyl acetate and washed with water and saturated brine. The organic layer is dehydrated with anhydrous sodium sulfate, and the crude product obtained by distilling off the solvent under reduced pressure is purified by chromatography, whereby compound 31 (compound represented by formula (E)) can be obtained.

<Step 30a: Production of Compound 32>
Compound 29 is dissolved in methanol and potassium carbonate is added in an ice bath. After stirring at room temperature, the reaction mixture is diluted with ethyl acetate and washed with water and saturated brine. The organic layer is dehydrated with anhydrous sodium sulfate, and the crude product obtained by distilling off the solvent under reduced pressure is purified by chromatography, whereby compound 32 (compound represented by formula (D)) can be obtained.

<Step 31a: Production of Compound 33>
Compound 26b is dissolved in dichloromethane, manganese dioxide is added and stirred, and then the residue of manganese is separated by filtration through celite, and the celite is washed with chloroform and methanol. A crude product of aldehyde can be obtained by distilling off the washed filtrate under reduced pressure.

  The aldehyde is dissolved in methanol and trimethylsilyldiazomethane (hexane solution) is added at room temperature. After stirring, the solvent can be distilled off under reduced pressure, and the resulting residue can be purified by chromatography to give compound 33.

<Step 32a: Production of Compound 34>
Compound 33 is dissolved in dichloromethane, and boron tribromide (dichloromethane solution) is added thereto at −78 ° C., followed by stirring. The reaction mixture is diluted with chloroform, washed with water and saturated brine, and the organic layer is dried over anhydrous sodium sulfate. Compound 34 (compound represented by formula (F)) can be obtained by purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

  In addition, in the above, it was decided to describe a method for producing some naphthoquinone derivative compounds according to the present invention, but by appropriately combining the above-mentioned steps 1a to 32a or appropriately changing the substance to be used, Other naphthoquinone derivative compounds can be produced. In addition, a pharmacologically acceptable salt of the naphthoquinone derivative compound according to the present invention, for example, an organic salt such as a quaternary ammonium salt or a metal salt such as an alkali metal can be produced by a conventional method.

Hereinafter, it demonstrates in detail using an Example. In Examples, nuclear magnetic resonance spectra ( ¹ H-NMR and ¹³ C-NMR) were measured using JNM GX-400 and EX-270 (manufactured by JEOL). The infrared absorption spectrum was measured using Model A-202 (manufactured by JASCO).

 Silica gel thin layer chromatography used kieselgel 60F254 silica gel (Merck) and colored with phosphomolybdenum sulfate. Silica gel column chromatography used silica gel 60N (manufactured by Kanto Chemical). Each reaction was performed in argon unless otherwise specified.

<Production of (3E) -4- (5-benzyloxy-2,3-dimethoxyphenyl) -3-ethoxycarbonylbut-3-enoic acid>
According to literature (Iinuma, M .; Tanaka, T .; Matsuura, S. Chem. Pharm. Bull. 1984, 32, 2296-2300), Baeyer-Villiger oxidation on Aldrich 5-bromoverataldehyde, Benzylation, nitrile introduction and reduction were carried out to obtain (5-benzyloxy-2,3-dimethoxy-phenyl) formaldehyde (Compound 1b in FIG. 1). Furthermore, using ethyl diethylphosphonoacetate as a raw material, according to the method of literature (Owton, WM; Gallagher, PT; Juan-Montesinos, A. Synth. Commun. 1993, 23, 2119-2125.), 2-diethoxyphosphono- t-Butylethyl succinate (compound 2b in FIG. 1) was obtained.

Compound 2b (20.3 g) was dissolved in anhydrous tetrahydrofuran (70 mL), and sodium hydride (1.53 g) was added under ice cooling. After stirring at room temperature for 2 hours, the above compound 1b (8.19 g) dissolved in anhydrous tetrahydrofuran (25 mL) was added under ice cooling, and the mixture was further stirred at room temperature for 3 hours. After adding a saturated aqueous ammonium chloride solution in an ice bath, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with saturated brine (50 mL). The organic layer was dehydrated with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ether (20 mL), and water (20 mL) and trifluoroacetic acid (60 mL) were successively added under ice-cooling. After 4.5 hours, the solvent was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give (3E) -4- (5-benzyloxy-2 , 3-Dimethoxyphenyl) -3-ethoxycarbonylbut-3-enoic acid (compound 3b in FIG. 1) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 1.35 (t, 3H, J = 7.2 Hz), 3.46 (s, 2H), 3.72 (s, 3H), 3.84 (s, 3H), 4.31 (q, 2H, J = 7.2 Hz), 5.04 (s, 2H), 6.51 (s, 1H), 6.62 (s, 1H), 7.32-7.43 (complex, 5H), 7.97 (s, 1H).
¹³ CNMR (67.80 MHz, CDCl ₃ ) δ 14.2, 34.1, 55.8, 61.3, 61.4, 70.3, 72.3, 102.2, 104.7, 126.6, 127.2, 127.9, 128.5, 128.7, 136.5, 138.4, 141.5, 153.4, 154.8, 167.1, 176.6.
IR (film) 1710, 1591, 1485 cm ^-1 .

<Production of ethyl 4-acetoxy-5-benzyloxy-7,8-dimethoxynaphthalene-2-carboxylate>
Compound 3b (10.0 g) obtained in Example 1 was dissolved in acetic anhydride (190 mL), potassium acetate (2.50 g) was added at room temperature, and the mixture was heated to reflux. After 30 minutes, the solvent was distilled off under reduced pressure by azeotropy with toluene, and the resulting residue was diluted with ethyl acetate (300 mL) and washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine (50 mL each). did. The aqueous layer was further washed with ethyl acetate (100 mL), and then the organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give ethyl 4-acetoxy-5-benzyloxy-7,8- as colorless plate crystals. Dimethoxynaphthalene-2-carboxylate (Compound 4b in FIG. 1; 9.81 g, 92%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 1.42 (t, 3H, J = 7.2 Hz), 1.66 (s, 3H), 3.95 (s, 3H), 3.97 (s, 3H), 4.42 (q, 2H, J = 7.2 Hz), 5.10 (s, 2H), 6.85 (s, 1H), 7.39-7.51 (complex, 6H), 8.73 (s, 1H).
¹³ CNMR (67.80 MHz, CDCl ₃ ) δ 14.4, 20.3, 57.0, 61.2, 61.5, 71.7, 100.2, 116.6, 116.8, 122.5, 128.3, 128.5, 128.7, 128.8, 131.0, 135.7, 137.8, 146.7, 148.7, 151.1, 165.7, 170.0.
IR (disk) 1757, 1714, 1604 cm ^-1 .
mp 156-157 ° C (hexane-EtOAc)

<Production of ethyl 5-benzyloxy-4-hydroxy-7,8-dimethoxynaphthalene-2-carboxylate>
Compound 4b (3.76 g) obtained in Example 2 was dissolved in ethanol (80 mL), and potassium carbonate (12.7 g) was added at 0 ° C. After stirring at room temperature for 18 hours, the solvent was distilled off under reduced pressure, and the resulting residue was diluted with ethyl acetate (100 mL) and washed with saturated brine (30 mL). The organic layer was dehydrated with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give ethyl 5-benzyloxy-4- Hydroxy-7,8-dimethoxynaphthalene-2-carboxylate (Compound 5b in FIG. 1; 2.92 g, 86%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 1.42 (t, 3H, J = 7.3 Hz), 3.94 (s, 3H), 3.95 (s, 3H), 4.41 (q, 2H, J = 7.3 Hz), 5.26 ( s, 2H), 6.78 (s, 1H), 7.27 (s, 1H), 7.43-7.50 (complex, 5H), 8.30 (s, 1H), 9.29 (s, 1H).
¹³ CNMR (67.80 MHz, CDCl ₃ ) δ 14.4, 57.2, 61.1, 61.3, 72.3, 98.7, 107.9, 112.9, 115.0, 127.9, 128.9, 129.0, 129.8, 130.9, 134.6, 138.1, 138.6, 143.0, 148.2, 151.6, 154.6, 166.5, 183.6.
IR (disk) 3395, 2977, 2945, 2848, 1698, 1613 cm ^-1 .
mp 115-116 ° C (hexane-EtOAc)

<Production of 8-benzyloxy-3-hydroxymethyl-5,6-dimethoxynaphthol>
Compound 5b (295 mg) obtained in Example 3 was dissolved in anhydrous tetrahydrofuran (3 mL), and lithium aluminum hydride (44.2 mg) was added under ice cooling. After stirring at room temperature for 1 hour, saturated aqueous ammonium chloride solution was added under ice-cooling, and the mixture was diluted with ethyl acetate (50 mL) and washed with saturated brine (10 mL). The organic layer was dehydrated with anhydrous sodium sulfate, and the crude product obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 8-benzyloxy-3-hydroxymethyl. -5,6-dimethoxynaphthol (Compound 6b in FIG. 1; 162 mg, 61%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 3.89 (s, 3H), 3.94 (s, 3H), 4.74 (s, 2H), 5.24 (s, 2H), 6.66 (s, 1H), 6.72 (s, 1H ), 7.39-7.50 (complex, 6H), 9.25 (s, 1H).
¹³ CNMR (67.80 MHz, CDCl ₃ ) δ 57.1, 61.0, 65.5, 72.1, 72.3, 96.5, 107.4, 109.6, 110.6, 127.9, 128.8, 129.0, 131.5, 134.9, 137.6, 137.7, 141.1, 148.0, 151.8, 154.7.
IR (disk) 3386, 2941, 2844, 1635, 1616 cm ^-1 .
mp 131-132 ° C (hexane-EtOAc)

<Production of 4-benzyloxy-1,2,5-trimethoxy-7-methoxymethylnaphthalene>
Compound 6b (159 mg) obtained in Example 4 was dissolved in dimethylformamide (3 mL), and sodium hydride (121 mg) and methyl iodide (0.18 mL) were added at 0 ° C. After stirring for 1.5 hours, saturated aqueous ammonium chloride solution was added under ice-cooling, and the reaction mixture was diluted with ethyl acetate (20 mL). After washing this with saturated saline (5 mL), the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 5: 1 to 1: 1) to give 4-benzyloxy-1,2,5-trimethoxy-7-methoxymethylnaphthalene (compound 7b in FIG. 1; 111 mg, 65%) as colorless needles. It was.
¹ HNMR (270 MHz, CDCl ₃ ) δ 3.45 (s, 3H), 3.94 (s, 6H), 3.97 (s, 3H), 4.60 (s, 2H), 5.17 (s, 2H), 6.75 (s, 1H ), 6.78 (s, 1H), 7.35 (d, 1H, J = 7.6 Hz), 7.40 (t, 2H, J = 7.6 Hz), 7.59 (d, 2H, J = 7.6 Hz), 7.65 (s, 1H ).

<Production of 2,5-dimethoxy-7-methoxymethylnaphthalene-1,4-dione>
Compound 7b (78.4 mg) obtained in Example 5 was dissolved in dichloromethane (2 mL), and water (1 mL), t-butyl alcohol (1 mL), and DDQ (135 mg) were sequentially added at 0 ° C. It was. After stirring for 2 hours, the reaction solution was diluted with chloroform (20 mL), and saturated aqueous sodium hydrogen carbonate solution (15 mL) was added. The organic layer was washed with saturated brine (10 mL), and the aqueous layer was further washed with chloroform (10 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 1), and 2,5-dimethoxy-7-methoxymethylnaphthalene-1,4-dione ( Compound 8b (compound A) in FIG. 1; 47.1 mg, 84%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 3.46 (s, 3H), 3.86 (s, 3H), 4.01 (s, 3H), 4.54 (s, 2H), 6.07 (s, 1H), 7.34 (s, 1H ), 7.69 (s, 1H).

<Production of (5-benzyloxy-4,7,8-trimethoxy-2-naphthyl) -methane-1-ol>
Compound 6b (120 mg) obtained in Example 4 was dissolved in dimethylformamide (3 mL), and potassium carbonate (383 mg) and methyl iodide (0.2 mL) were added at 0 ° C. After stirring for 10 hours, the reaction solution was diluted with ethyl acetate (25 mL). The organic layer was washed with saturated brine (10 mL), and the aqueous layer was further washed with ethyl acetate (10 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give (5-benzyloxy-4,7,8-trimethoxy-2-naphthyl)- Methane-1-ol (Compound 9b in FIG. 2; 53.4 mg, 43%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 3.90 (s, 3H), 3.91 (s, 3H), 3.93 (s, 3H), 4.77 (s, 2H), 5.13 (s, 2H), 6.70 (s, 1H ), 6.72 (s, 1H), 7.34 (d, 1H, J = 7.0 Hz), 7.41 (t, 2H, J = 7.0 Hz), 7.56 (s, 1H), 7.60 (complex, 2H).

<Production of 5-benzyloxy-4,7,8-trimethoxynaphthalene-2-carbaldehyde>
Compound 9b (147 mg) obtained in Example 7 was dissolved in toluene (2 mL) and dimethyl sulfoxide (0.6 mL), triethylamine (0.3 mL), sulfur trioxide pyridine complex (SO ₃ · Pyr) was dissolved at room temperature. (133 mg) was added sequentially. After 1.5 hours, the reaction mixture was diluted with ethyl acetate (50 mL), and saturated aqueous ammonium chloride solution (30 mL) was added under ice-cooling. The organic layer was washed with saturated brine (10 mL), and the aqueous layer was further washed with ethyl acetate (20 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 5-benzyloxy-4,7,8-trimethoxynaphthalene-2-carbaldehyde. (Compound 10b in FIG. 2; 146 mg, 100%) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ 3.97 (s, 3H), 3.98 (s, 3H), 3.99 (s, 3H), 5.17 (s, 2H), 6.90 (s, 1H), 7.14 (s, 1H ), 7.36 (d, 1H, J = 7.2 Hz), 7.42 (t, 2H, J = 7.2 Hz), 7.57 (d, 2H, J = 7.2 Hz), 8.21 (s, 1H), 10.08 (s, 1H ).

<Production of 4-benzyloxy-1,2,5-trimethoxy-7-oxiran-2-ylnaphthalene>
Dimethyl sulfoxide (3 mL) was added to sodium hydride (124 mg) and stirred at room temperature for 4 hours, and then the reaction mixture was diluted with anhydrous tetrahydrofuran (7 mL). Thereafter, trimethylsulfonium iodide (728 mg) dissolved in dimethylsulfoxide (4 mL) was added at 0 ° C., and further 35 minutes later, compound 10b (253 mg) dissolved in anhydrous tetrahydrofuran (9 mL) was added. And stirred for 20 minutes. The reaction solution was diluted with ethyl acetate (30 mL), and then washed with a saturated aqueous ammonium chloride solution (30 mL). The organic layer was dehydrated with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 4-benzyloxy-1,2 , 5-trimethoxy-7-oxirane-2-ylnaphthalene (compound 11b in FIG. 2; 266 mg) was quantitatively obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 2.92 (dd, 1H, J = 2.4, 5.4 Hz), 3.21 (dd, 1H, J = 4.0, 5.4 Hz), 3.91 (s, 3H), 3.94 (s, 3H ), 3.95 (s, 3H), 4.02 (dd, 1H, J = 2.4, 4.0 Hz), 5.15 (s, 2H), 6.52 (s, 1H), 6.73 (s, 1H), 7.34 (d, 1H, J = 7.0 Hz), 7.41 (t, 2H, J = 7.0 Hz), 7.57 (d, 2H, J = 7.0 Hz), 7.69 (s, 1H).

<Production of ethyl (2E) -4- [5-benzyloxy-4,7,8-trimethoxy (2-naphthyl)] but-2-enoate>
Zinc bromide (135 mg) in benzene (2 mL) was heated to reflux for 10 minutes, and compound 11b (148 mg) dissolved in benzene (4 mL) was added to the mixture. After 25 minutes, the reaction solution was returned to room temperature, diluted with ethyl acetate (20 mL), and washed with water and saturated brine (15 mL each). The organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of aldehyde.
Ethyl diethylphosphonoacetate (0.2 mL) was dissolved in anhydrous tetrahydrofuran (1 mL), sodium hydride (41.3 mg) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hr. Thereafter, aldehyde dissolved in anhydrous tetrahydrofuran (3 mL) was added at −78 ° C., and the mixture was stirred for 20 minutes. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture, and the mixture was diluted with ethyl acetate (20 mL). The organic layer was washed with saturated brine (10 mL), and the aqueous layer was further washed with ethyl acetate (10 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1), and ethyl (2E) -4- [5-benzyloxy-4,7,8- Trimethoxy (2-naphthyl)] but-2-enoate (compound 12b in FIG. 2; 101 mg, 57%) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ 1.27 (t, 3H, J = 7.2 Hz), 3.64 (d, 2H, J = 6.4 Hz), 3.90 (s, 3H), 3.93 (s, 3H), 3.94 ( s, 3H), 4.18 (q, 2H, J = 7.2 Hz), 5.15 (s, 2H), 5.87 (d, 1H, J = 15 Hz), 6.52 (s, 1H), 6.71 (s, 1H), 7.18 (dt, 1H, J = 6.4, 15 Hz), 7.34 (d, 1H, J = 7.2 Hz), 7.42 (t, 2H, J = 7.2 Hz), 7.49 (s, 1H), 7.57 (d, 2H , J = 7.2 Hz).

<Production of 7-((2E) -4-oxybut-2-enyl) -4-benzyloxy-1,2,5-trimethoxynaphthalene>
Compound 12b (36.0 mg) obtained in Example 10 was dissolved in anhydrous tetrahydrofuran (1 mL), and diisobutylaluminum hydride (1.01 M, toluene solution, 0.4 mL) was added dropwise at -78 ° C. After completion of the dropwise addition, the mixture was stirred for 20 minutes, and 4M hydrochloric acid (10 mL) was added to return to 0 ° C. The reaction mixture was diluted with ethyl acetate (20 mL), and washed with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (5 mL). The organic layer was dehydrated with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel thin layer chromatography (hexane: ethyl acetate = 1: 1) to give 7-((2E)- 4-Oxybut-2-enyl) -4-benzyloxy-1,2,5-trimethoxynaphthalene (Compound 13b in FIG. 2; 28.7 mg, 88%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 3.51 (d, 2H, J = 6.5 Hz), 3.90 (s, 3H), 3.93 (s, 3H), 3.94 (s, 3H), 4.16 (complex, 2H), 5.15 (s, 2H), 5.78 (dt, 1H, J = 5.7, 15 Hz), 5.94 (dt, 1H, J = 6.5, 15 Hz), 6.57 (s, 1H), 6.69 (s, 1H), 7.34 (d, 1H, J = 6.8 Hz), 7.41 (t, 2H, J = 6.8 Hz), 7.48 (s, 1H), 7.57 (d, 2H, J = 6.8 Hz).

<7-{[(3S, 2R) -3- (oxymethyl) oxiran-2-yl] methyl} -4-benzyloxy-1,2,5-trimethoxynaphthalene>
To molecular sieves 4A (powder, 102 mg), dichloromethane (1 mL) and tetraisopropyl orthotitanate (215 μL) were added, stirred for 10 minutes, and then dissolved in dichloromethane (1 mL) at −25 ° C. +)-Diisopropyl tartrate (0.25 mL) was added dropwise. After further 10 minutes, compound 13b (28.7 mg) dissolved in dichloromethane (3 mL) at −20 ° C. was added. After stirring at −20 ° C. for 15 minutes, t-butyl hydroperoxide (0.7 mL) was added dropwise at the same temperature. After further stirring at −20 ° C. for 1 hour, 10% L-(+)-tartaric acid aqueous solution (3 mL) was added under ice cooling, and the mixture was stirred for 1.5 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated brine (5 mL). The organic layer was dehydrated with anhydrous sodium sulfate, the residue obtained by evaporating the solvent under reduced pressure was dissolved in diethyl ether (2 mL), and 1M aqueous sodium hydroxide solution (4 mL) was added in an ice bath. After stirring at room temperature for 2 hours, the reaction solution was diluted with diethyl ether (10 mL). The organic layer was washed with saturated brine (5 mL), dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was subjected to silica gel thin layer chromatography (hexane: ethyl acetate = 1: 2). ) And 7-{[(3S, 2R) -3- (oxymethyl) oxiran-2-yl] methyl} -4-benzyloxy-1,2,5-trimethoxynaphthalene (in FIG. 2) Compound 14b (25.3 mg, 85%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 3.02 (d, 2H, J = 5.7 Hz), 3.08 (m, 1H), 3.29 (m. 1H), 3.66 (m, 1H), 3.91 (m, 1H), 3.91 (s, 3H), 3.94 (s, 6H), 5.15 (s, 2H), 6.63 (s, 1H), 6.71 (s, 1H), 7.34 (d, 1H, J = 7.0 Hz), 7.41 (t , 2H, J = 7.0 Hz), 7.52 (s, 1H), 7.57 (d, 2H, J = 7.0 Hz).

<Production of (3R) -4- (5-hydroxy-4,7,8-trimethoxy (2-naphthyl)) butane-1,3-diol>
Compound 14b (14.0 mg) obtained in Example 12 was dissolved in anhydrous tetrahydrofuran (3 mL), and Red-Al (65 wt%, toluene solution, 0.2 mL) was added dropwise at -78 ° C. After completion of the dropwise addition, the mixture was stirred for 4 hours, and a saturated aqueous ammonium chloride solution (15 mL) was added to return to 0 ° C. The reaction mixture was diluted with ethyl acetate (20 mL), and washed with water (10 mL) and saturated brine (5 mL). The organic layer was dehydrated with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel thin layer chromatography (ethyl acetate) to obtain (3R) -4- (5-hydroxy-4, 7,8-trimethoxy (2-naphthyl)) butane-1,3-diol (Compound 15b in FIG. 2 (8.1 mg, 74%) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ 1.82 (copmplex, 2H), 2.89 (complex, 2H), 3.88 (s, 3H), 3.90 (complex, 2H), 3.93 (s, 3H), 4.04 (s, 3H ), 4.18 (m, 1H), 6.52 (s, 1H), 6.64 (s, 1H), 7.47 (s, 1H), 9.15 (s, 1H).

<Production of 6-[((4R) -2,2-dimethyl (1,3-dioxan-4-yl)) methyl] 3,4,8-trimethoxynaphthol>
2,2-Dimethoxypropane (1 mL) and (±) -camphor-10-sulfonic acid (10 mg) were added to compound 15b (8.1 mg) obtained in Example 13, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (5 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentrating the solvent under reduced pressure was purified by silica gel thin layer chromatography (hexane: ethyl acetate = 1: 1) to give 6-[((4R) -2,2-dimethyl (1,3- Dioxane-4-yl)) methyl] 3,4,8-trimethoxynaphthol (Compound 16b in FIG. 2; 8.7 mg, 96%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 1.43 (s, 3H), 1.47 (s, 3H), 1.70 (copmplex, 2H), 2.76 (dd, 1H, J = 6.2, 14 Hz), 2.98 (dd, 1H , J = 6.2, 14 Hz), 3.86 (s, 3H), 3.90 (complex, 2H), 3.93 (s, 3H), 4.04 (s, 3H), 4.16 (m, 1H), 6.58 (s, 1H) , 6.63 (s, 1H), 7.46 (s, 1H), 9.17 (s, 1H).

<Production of 7-[((4R) -2,2-dimethyl (1,3-dioxane-4-yl)) methyl] -2,5-dimethoxynaphthalene-1,4-dione>
Compound 16b (8.7 mg) obtained in Example 14 was dissolved in 1,4-dioxane (0.8 mL), and water (0.2 mL) and DDQ (27.5 mg) were added in an ice bath. After stirring at room temperature for 15 minutes, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine (each 5 mL). The organic layer was dehydrated with anhydrous sodium sulfate, and the crude product obtained by concentrating the solvent under reduced pressure was purified by silica gel thin layer chromatography (chloroform: ethyl acetate = 1/2) to give 7-[((4R)- 2,2-Dimethyl (1,3-dioxane-4-yl)) methyl] -2,5-dimethoxynaphthalene-1,4-dione (Compound 17b (Compound B) in FIG. 2; 7.4 mg, 89%) Got.
¹ HNMR (270 MHz, CDCl ₃ ) δ 1.38 (s, 3H), 1.42 (s, 3H), 1.64 (copmplex, 2H), 2.79 (dd, 1H, J = 6.0, 14 Hz), 2.91 (dd, 1H , J = 6.0, 14 Hz), 3.86 (s, 3H), 3.90 (complex, 2H), 3.99 (s, 3H), 4.13 (m, 1H), 6.07 (s, 1H), 7.23 (s, 1H) , 7.64 (s, 1H).

<Production of 8-benzyloxy-2-bromo-3-hydroxymethyl-5,6-dimethoxynaphthol>
Compound 6b (2.42 g) obtained in Example 4 was dissolved in anhydrous tetrahydrofuran (50 mL), and hydrobromic acid perbromide pyridine complex (Pyr · HBr ₃ ) (2.52 g) was added at 0 ° C. After stirring for 1 hour, saturated aqueous sodium thiosulfate solution (30 mL) was added, and the reaction mixture was diluted with ethyl acetate (100 mL). This was washed with saturated brine (20 mL). The organic layer was dehydrated with anhydrous sodium sulfate, and the crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 8- Benzyloxy-2-bromo-3-hydroxymethyl-5,6-dimethoxynaphthol (Compound 18b in FIG. 3; 2.60 g, 87%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 2.25 (br, 1H), 3.90 (s, 3H), 3.97 (s, 3H), 4.85 (s, 2H), 5.26 (s, 2H), 6.74 (s, 1H ), 7.44-7.47 (complex, 5H), 7.65 (s, 1H), 9.99 (s, 1H).
¹³ CNMR (67.80 MHz, DMSO-d ₆ ) δ 56.7, 56.9, 60.4, 63.1, 63.8, 71.4, 97.7, 99.6, 101.4, 109.5, 128.3, 128.5, 128.7, 128.9, 135.5, 136.0, 140.1, 148.2, 149.7, 150.1.
IR (disk) 3504, 3354, 3056, 2972, 2940, 2881, 2360, 1612 cm ^-1 .
mp 165 ° C dec. (hexane-EtOAc)

<Production of 5-benzyloxy-3-bromo-4-hydroxy-7,8-dimethoxynaphthalene-2-carbaldehyde>
Compound 18b (1.35 g) obtained in Example 16 was dissolved in dichloromethane (10 mL), and dimethyl sulfoxide (9 mL), triethylamine (2.7 mL), sulfur trioxide pyridine complex (SO ₃ · Pyr) was dissolved at room temperature. (1.51 g) was added sequentially. After 20 minutes, the reaction mixture was diluted with chloroform (200 mL), and saturated aqueous ammonium chloride solution (50 mL) was added under ice cooling. The organic layer was washed with saturated brine (30 mL), and the aqueous layer was further washed with chloroform (100 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform) to give 5-benzyloxy-3-bromo-4-hydroxy-7,8-dimethoxynaphthalene-2 as yellow needles. Carbaldehyde (compound 19b in FIG. 3; 1.24 g, 93%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 3.92 (s, 3H), 3.97 (s, 3H), 5.27 (s, 2H), 6.85 (s, 1H), 7.44-7.47 (complex, 5H), 8.17 (s , 1H), 10.09 (s, 1H), 10.48 (s, 1H).
¹³ CNMR (67.80 MHz, CDCl ₃ ) δ 57.1, 61.5, 72.6, 99.6, 99.8, 103.1, 116.2, 116.3, 128.2, 129.1, 129.2, 131.9, 134.0, 134.3, 148.7, 150.6, 151.6, 151.7, 192.3.
IR (disk) 3303, 2950, 1703, 1606 cm ^-1 .
mp 174 ℃ dec. (hexane-EtOAc)

<Production of 5-benzyloxy-3-bromo-4,7,8-trimethoxynaphthalene-2-carbaldehyde>
Compound 19b (449 mg) obtained in Example 17 was dissolved in dimethylformamide (10 mL), and potassium carbonate (463 mg) and methyl iodide (0.3 mL) were added at 0 ° C. After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (10 mL), and the aqueous layer was further washed with ethyl acetate (30 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 5-benzyloxy-3-bromo-4,7,8 as yellow plate crystals. -Trimethoxynaphthalene-2-carbaldehyde (Compound 20b in FIG. 3; 437 mg, 94%) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ 3.80 (s, 3H), 3.95 (s, 3H), 3.96 (s, 3H), 5.20 (s, 2H), 6.91 (s, 1H), 7.38 (d, 1H , J = 7.2 Hz), 7.43 (t, 2H, J = 7.2 Hz), 7.56 (d, 2H, J = 7.2 Hz), 8.50 (s, 1H), 10.50 (s, 1H).
¹³ CNMR (100.40 MHz, CDCl ₃ ) δ 56.9, 61.5, 61.9, 62.0, 62.1, 72.8, 100.5, 103.3, 113.8, 119.6, 121.4, 127.7, 128.1, 128.6, 129.9, 131.5, 136.3, 138.9, 149.0, 151.0, 154.1, 192.2.
IR (disk) 2943, 2848, 1687, 1612, 1577 cm ^-1 .
mp 129-130 ° C (hexane-EtOAc)

<Production of 8-benzyloxy-2-bromo-1,5,6-trimethoxy-3-oxirane-2-ylnaphthalene>
Dimethyl sulfoxide (5 mL) was added to sodium hydride (517 mg), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with anhydrous tetrahydrofuran (50 mL). Thereafter, trimethylsulfonium iodide (2.75 g) dissolved in dimethyl sulfoxide (10 mL) was added at 0 ° C., and further 40 minutes later, Compound 20 (1.89 g) dissolved in dimethyl sulfoxide (25 mL) was added. And stirred for 45 minutes. The reaction solution was diluted with ethyl acetate (50 mL) and then washed with a saturated aqueous ammonium chloride solution (30 mL). The organic layer was dehydrated with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 8- Benzyloxy-2-bromo-1,5,6-trimethoxy-3-oxiran-2-ylnaphthalene (Compound 21b in FIG. 3; 1.77 g, 92%) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ 2.72 (dd, 1H, J = 2.8, 6.0 Hz), 3.25 (dd, 1H, J = 4.0, 6.0 Hz), 3.78 (s, 3H), 3.89 (s, 3H ), 3.95 (s, 3H), 4.26 (dd, 1H, J = 2.8, 4.0 Hz), 5.18 (s, 2H), 6.78 (s, 1H), 7.37 (d, 1H, J = 7.2 Hz), 7.43 (t, 2H, J = 7.2 Hz), 7.56 (d, 2H, J = 7.2 Hz), 7.79 (s, 1H).
¹³ CNMR (100.40 MHz, CDCl ₃ ) δ 51.1, 52.9, 56.9, 61.2, 61.9, 72.6, 100.4, 100.5, 113.5, 114.4, 116.7, 127.7, 128.0, 128.5, 130.8, 136.1, 136.6, 137.3, 143.9, 148.6, 151.1, 153.2.
IR (disk) 2931, 2858, 1612, 1593, 1574 cm ^-1 .
mp 133-134 ° C (hexane-EtOAc)

<Production of ethyl (2E) -4- [5-benzyloxy-3-bromo-4,7,8-trimethoxy (2-naphthyl)] but-2-enoate>
Zinc bromide (708 mg) in benzene (17 mL) was heated to reflux for 40 minutes, and compound 21b (468 mg) dissolved in benzene (10 mL) was added to the mixture. After 20 minutes, the reaction solution was returned to room temperature, diluted with ethyl acetate (30 mL), and washed with water and saturated brine (20 mL each). The organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of aldehyde.
Ethyl diethylphosphonoacetate (1.1 mL) was dissolved in anhydrous tetrahydrofuran (10 mL), sodium hydride (216 mg) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hr. Thereafter, an aldehyde dissolved in anhydrous tetrahydrofuran (10 mL) was added at −78 ° C., and the mixture was stirred for 25 minutes. Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was diluted with ethyl acetate (30 mL). The organic layer was washed with saturated brine (10 mL), and the aqueous layer was further washed with ethyl acetate (20 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give ethyl (2E) -4- [5-benzyloxy-3-bromo-4, 7,8-trimethoxy (2-naphthyl)] but-2-enoate (Compound 22b in FIG. 3; 462 mg, 85%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 1.27 (t, 3H, J = 7.0 Hz), 3.77 (s, 3H), 3.82 (d, 2H, J = 6.2 Hz), 3.90 (s, 3H), 3.95 ( s, 3H), 4.18 (q, 2H, J = 7.0 Hz), 5.18 (s, 2H), 5.81 (d, 1H, J = 16 Hz), 7.18 (dt, 1H, J = 6.2, 16 Hz), 7.36 (d, 1H, J = 7.2 Hz), 7.42 (t, 2H, J = 7.2 Hz), 7.56 (d, 2H, J = 7.2 Hz), 7.74 (s, 1H).
¹³ CNMR (67.80 MHz, CDCl ₃ ) δ 14.3, 39.5, 56.8, 60.2, 61.1, 61.8, 72.5, 100.1, 116.1, 116.3, 118.4, 122.7, 127.6, 127.9, 128.4, 130.3, 130.5, 136.4, 136.5, 136.7, 140.1, 145.7, 148.4, 151.0, 153.7, 166.2.
IR (film) 2937, 2846, 1716, 1614, 1591, 1573 cm ^-1 .

<Production of (2E) -4- [5-benzyloxy-3-bromo-4,7,8-trimethoxy (2-naphthyl)] but-2-en-1-ol>
Compound 22b (147 mg) obtained in Example 20 was dissolved in anhydrous tetrahydrofuran (3 mL), and diisobutylaluminum hydride (1.01 M, toluene solution, 1.5 mL) was added dropwise at -78 ° C. After completion of the dropwise addition, the mixture was stirred for 35 minutes, and 4M hydrochloric acid (10 mL) was added to return to 0 ° C. The reaction mixture was diluted with ethyl acetate (20 mL), and washed with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (5 mL). The organic layer was dehydrated with anhydrous sodium sulfate, and the crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give pale yellow plate crystals (2E ) -4- [5-Benzyloxy-3-bromo-4,7,8-trimethoxy (2-naphthyl)] but-2-en-1-ol (compound 23b in FIG. 3; 125 mg, 93%) Got.
¹ HNMR (270 MHz, CDCl ₃ ) δ 1.82 (br, 1H), 3.66 (d, 2H, J = 6.2 Hz), 3.77 (s, 3H), 3.90 (s, 3H), 3.94 (s, 3H), 4.13 (q, 2H, J = 5.4 Hz), 5.17 (s, 2H), 5.75 (dt, 1H, J = 5.4, 16 Hz), 5.95 (dt, 1H, J = 6.2, 16 Hz), 6.74 (s , 1H), 7.37 (d, 1H, J = 7.2 Hz), 7.42 (t, 2H, J = 7.2 Hz), 7.56 (d, 2H, J = 7.2 Hz), 7.73 (s, 1H).
¹³ CNMR (67.80 MHz, CDCl ₃ ) δ 39.6, 56.8, 61.1, 61.7, 63.4, 63.5, 72.5, 99.8, 115.8, 116.6, 117.7, 127.6, 127.8, 128.3, 129.5, 129.6, 130.5, 131.0, 131.1, 136.7, 138.5, 148.2, 151.0, 153.3.
IR (disk) 3521, 2902, 2860, 1614, 1589, 1574 cm ^-1 .
mp 104-105 ° C (hexane-EtOAc)

<1-{(2E) -4- [5-Benzyloxy-3-bromo-4,7,8-trimethoxy (2-naphthyl)] but-2-enyloxy} -1,1,2,2-tetramethyl -1-Production of Silapropane>
Compound 23b (125 mg) obtained in Example 21 was dissolved in dimethylformamide (3 mL), and imidazole (180 mg) and t-butyldimethylsilyl chloride (215 mg) were sequentially added at 0 ° C. for 15 minutes. Stir. The reaction mixture was diluted with ethyl acetate (15 mL), washed with saturated brine (10 mL), and the organic layer was dried over anhydrous sodium sulfate. The crude product obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 1-{(2E) -4- [5-benzyloxy-3-bromo- 4,7,8-trimethoxy (2-naphthyl)] but-2-enyloxy} -1,1,2,2-tetramethyl-1-silapropane (Compound 24b in FIG. 3; 149 mg, 96%) It was.
¹ HNMR (400 MHz, CDCl ₃ ) δ 0.07 (s, 6H), 0.90 (s, 9H), 3.65 (d, 2H, J = 6.8 Hz), 3.76 (s, 3H), 3.89 (s, 3H), 3.94 (s, 3H), 4.19 (q, 2H, J = 5.2 Hz), 5.18 (s, 2H), 5.67 (dt, 1H, J = 5.2, 15 Hz), 5.93 (dt, 1H, J = 6.8, 15 Hz), 6.74 (s, 1H), 7.36 (d, 1H, J = 7.2 Hz), 7.42 (t, 2H, J = 7.2 Hz), 7.56 (d, 2H, J = 7.2 Hz), 7.73 (s , 1H).
¹³ CNMR (100.40 MHz, CDCl ₃ ) δ -5.0, 18.5, 25.7, 26.0, 39.6, 56.9, 61.3, 61.7, 63.7, 72.6, 99.9, 115.9, 116.8, 117.7, 127.6, 127.7, 127.9, 128.5, 130.6, 131.6 , 135.3, 136.8, 137.0, 139.0, 148.2, 151.1.
IR (film) 2931, 2894, 2854, 1614, 1591, 1576 cm ^-1 .

<Production of (2E) -4- [5-benzyloxy-3-hydroxypentyl-4,7,8-trimethoxy (2-naphthyl)] but-2-en-1-ol>
Compound 24b (1.06 g) obtained in Example 22 was dissolved in anhydrous tetrahydrofuran (30 mL), and n-butyllithium (1.57 M, hexane solution, 3.4 mL) was added dropwise at −78 ° C. Further, n-valeraldehyde (1.0 mL) was added and stirred for 10 minutes. Saturated aqueous sodium hydrogen carbonate solution (15 mL) was added to the reaction solution, the temperature was returned to 0 ° C., diluted with ethyl acetate (30 mL), and washed with saturated brine (10 mL). The organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain a crude secondary alcohol product.
The secondary alcohol was dissolved in anhydrous tetrahydrofuran (20 mL), and tetra n-butylammonium fluoride (1.0 M, tetrahydrofuran solution, 9.0 mL) was added at 0 ° C. After stirring at room temperature for 1.5 hours, the reaction mixture was diluted with ethyl acetate (30 mL). After washing with water (10 mL) and saturated brine (5 mL), the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (hexane: ethyl acetate). = 3: 1) and purified by (2E) -4- [5-benzyloxy-3-hydroxypentyl-4,7,8-trimethoxy (2-naphthyl)] but-2-en-1-ol ( Compound 25b in FIG. 3; 693 mg, 80%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 0.92 (t, 3H, J = 6.2 Hz), 1.37-1.39 (complex, 2H), 1.63-1.80 (complex, 2H), 1.92-2.04 (complex, 2H), 3.57 (d, 2H, J = 5.4 Hz), 3.80 (s, 3H), 3.90 (s, 3H), 3.93 (s, 3H), 4.09 (d, 2H, J = 5.6 Hz), 4.99 (m, 1H) , 5.15 (d, 2H, J = 12 Hz), 5.64 (dt, 1H, J = 5.6, 15 Hz), 5.91 (dt, 1H, J = 5.4, 15 Hz), 6.73 (s, 1H), 7.36 ( d, 1H, J = 7.2 Hz), 7.41 (t, 2H, J = 7.2 Hz), 7.53 (d, 2H, J = 7.2 Hz), 7.65 (s, 1H).
¹³ CNMR (67.80 MHz, CDCl ₃ ) δ 14.2, 22.8, 29.2, 36.6, 39.0, 50.3, 56.9, 61.1, 63.4, 64.0, 71.1, 72.9, 100.3, 113.7, 115.1, 118.2, 127.4, 127.8, 128.4, 130.7, 131.0, 131.2, 136.8, 136.9, 137.0, 147.9, 151.1, 154.8, 163.6.
IR (film) 3408, 2933, 2858, 1620, 1574 cm ^-1 .

<Production of 7-((2E) -4-hydroxybut-2-enyl) -6-hydroxypentyl-2,5-dimethoxynaphthalene-1,4-dione>
Compound 25b (28.7 mg) obtained in Example 23 was dissolved in dichloromethane (2 mL), and water (1 mL), t-butyl alcohol (1 mL) and DDQ (43.4 mg) were sequentially added at 0 ° C. It was. After stirring for 45 minutes, the reaction solution was diluted with chloroform (20 mL), and saturated aqueous sodium hydrogen carbonate solution (10 mL) was added. The organic layer was washed with saturated brine (10 mL), and the aqueous layer was further washed with chloroform (20 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (ethyl acetate) to obtain 7-((2E) -4-hydroxybut-2-enyl) -6-hydroxypentyl-2. , 5-dimethoxynaphthalene-1,4-dione (Compound 26b (Compound C) in FIG. 3; 17.2 mg, 77%) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ 0.89 (t, 3H, J = 7.2 Hz), 1.24-1.40 (complex, 2H), 1.57-1.72 (complex, 2H), 1.88-1.97 (complex, 2H), 3.52 (d, 2H, J = 6.0 Hz), 3.86 (s, 3H), 3.92 (s, 3H), 4.09 (d, 2H, J = 5.4 Hz), 4.95 (m, 1H), 5.63 (dt, 1H, J = 5.6, 15 Hz), 5.81 (dt, 1H, J = 6.0, 15 Hz), 6.06 (s, 1H), 7.74 (s, 1H).
¹³ CNMR (100.40 MHz, CDCl ₃ ) δ 14.1, 22.6, 28.8, 36.4, 37.7, 56.3, 63.1, 63.4, 70.6, 111.7, 121.7, 125.2, 128.7, 131.7, 131.9, 144.2, 144.6, 158.7, 159.1, 179.7, 183.8.
IR (film) 3434, 2933, 1644, 1620, 1581 cm ^-1 .

<Production of (2E) -4- [5-benzyloxy-3-hydroxypentyl-4,7,8-trimethoxy (2-naphthyl)] but-2-enyl acetate>
Compound 25b (111 mg) obtained in Example 23 was dissolved in dichloromethane (5 mL), and pyridine (36 μL) and acetic anhydride (15 μL) were added in an ice bath. After stirring at room temperature for 2 days, the solvent was distilled off under reduced pressure by azeotropic distillation with toluene, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to give (2E) -4- [5-benzyloxy-3 -Hydroxypentyl-4,7,8-trimethoxy (2-naphthyl)] but-2-enyl acetate (compound 27b in FIG. 4; 70.5 mg, 58%) and unreacted compound 25b (38.2 mg, 34% )
¹ HNMR (400 MHz, CDCl ₃ ) δ 0.93 (t, 3H, J = 6.8 Hz), 1.34-1.44, (complex, 4H), 1.63-1.83 (complex, 2H), 2.04 (s, 3H), 3.62 ( d, 2H, J = 6.4 Hz), 3.80 (s, 3H), 3.90 (s, 3H), 3.94 (s, 3H), 4.55 (d, 2H, J = 6.4 Hz), 5.01 (m, 1H), 5.12 (d, 1H, J = 11 Hz), 5.19 (d, 1H, J = 11 Hz), 5.61 (dt, 1H, J = 6.4, 15 Hz), 6.01 (dt, 1H, J = 6.0, 15 Hz ), 6.74 (s, 1H), 7.36 (d, 1H, J = 7.2 Hz), 7.42 (t, 2H, J = 7.2 Hz), 7.53 (d, 2H, J = 7.2 Hz), 7.66 (s, 1H )
¹³ CNMR (100.40 MHz, CDCl ₃ ) δ 14.2, 21.0, 22.7, 29.2, 36.4, 38.9, 56.9, 61.0, 63.9, 64.8, 70.9, 72.8, 100.2, 115.0, 118.3, 125.4, 127.4, 127.8, 128.2, 128.4, 130.9, 131.2, 134.2, 136.6, 136.8, 137.0, 147.9, 151.1, 154.8, 170.6.
IR (film) 3480, 2933, 2857, 1739, 1620, 1573 cm ^-1

<Production of (2E) -4- [3-hydroxypentyl-4,7-dimethoxy-5,8-dioxo (2-naphthyl)] but-2-enyl acetate>
Compound 27b (60.4 mg) obtained in Example 25 was dissolved in dichloromethane (4 mL), and water (2 mL), t-butyl alcohol (2 mL), and DDQ (83.4 mg) were sequentially added at 0 ° C. It was. After stirring for 20 minutes, the reaction solution was diluted with chloroform (20 mL), and saturated aqueous sodium hydrogen carbonate solution (15 mL) was added. The organic layer was washed with saturated brine (10 mL), and the aqueous layer was further washed with chloroform (10 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate), and (2E) -4- [3-hydroxypentyl-4,7-dimethoxy-5,8-dioxo ( 2-Naphthyl)] but-2-enyl acetate (compound 28b in FIG. 4; 37.4 mg, 78%) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ 0.90 (t, 3H, J = 7.2 Hz), 1.28-1.37, (complex, 4H), 1.57-1.68 (complex, 2H), 2.03 (s, 3H), 3.56 ( d, 2H, J = 6.4 Hz), 3.85 (s, 3H), 3.91 (s, 3H), 4.51 (d, 2H, J = 6.0 Hz), 4.94 (m, 1H), 5.58 (dt, 1H, J = 6.4, 15 Hz), 5.88 (dt, 1H, J = 6.0, 15 Hz), 6.06 (s, 1H), 7.74 (s, 1H)
¹³ CNMR (100.40 MHz, CDCl ₃ ) δ 14.1, 20.9, 22.6, 28.8, 36.3, 37.7, 56.3, 63.4, 64.4, 70.5, 111.7, 125.1, 126.6, 126.8, 127.4, 128.4, 131.7, 132.1, 144.3, 158.7, 170.6. 179.6, 183.7.
IR (film) 3502, 2935, 1737, 1683, 1648, 1619 cm ^-1

<Production of (2E) -4- [4-hydroxy-3-hydroxypentyl-7-methoxy-5,8-dioxo (2-naphthyl)] but-2-enyl acetate>
Boron tribromide (1M, dichloromethane solution, 0.22 mL) was dissolved in dichloromethane (5 mL), compound 28b (83.2 mg) dissolved in dichloromethane (3.5 mL) was added at −78 ° C., and the mixture was stirred for 25 minutes. . The reaction mixture was diluted with chloroform (15 mL), washed with water and saturated brine (each 10 mL), and the organic layer was dried over anhydrous sodium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel thin layer chromatography (hexane: ethyl acetate = 1: 2) to give (2E) -4- [4-hydroxy-3-hydroxypentyl-7. -Methoxy-5,8-dioxo (2-naphthyl)] but-2-enyl acetate (compound 29b in FIG. 4; 23.7 mg, 29%) and unreacted compound 28b (11.2 mg, 13%) were obtained. .
¹ HNMR (270 MHz, CDCl ₃ ) δ 0.90 (t, 3H, J = 6.8 Hz), 1.33-1.42 (complex, 4H), 1.50-1.76 (complex, 2H), 2.05 (s, 3H), 3.50 (d , 2H, J = 5.8 Hz), 3.92 (s, 3H), 4.52 (d, 2H, J = 6.2 Hz), 4.86 (m, 1H), 5.59 (dt, 1H, J = 5.8, 15 Hz), 5.87 (dt, 1H, J = 6.2, 15 Hz), 6.07 (s, 1H), 7.48 (s, 1H), 13.11 (s, 1H)
¹³ CNMR (67.80 MHz, CDCl ₃ ) δ 14.1, 21.0, 22.7, 28.6, 36.3, 36.4, 49.2, 49.3, 56.7, 64.4, 70.6, 109.3, 121.7, 126.8, 129.0, 131.6, 138.4, 144.4, 159.5, 161.0, 190.7, 206.5.
IR (film) 3534, 2956, 1739, 1683, 1625 cm ^-1

<Production of (2E) -4- [4-hydroxy-3-hydroxypentyl-7-methylamino-5,8-dioxo (2-naphthyl)] but-2-enyl acetate>
Compound 29b (23.7 mg) obtained in Example 27 was dissolved in anhydrous tetrahydrofuran (2 mL), and methylamine (40 wt%, methanol solution, 20 μL) was added in an ice bath. After stirring at the same temperature for 45 minutes, the crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (hexane: ethyl acetate = 1: 2) to give (2E) -4- [4 -Hydroxy-3-hydroxypentyl-7-methylamino-5,8-dioxo (2-naphthyl)] but-2-enyl acetate (compound 30b in FIG. 4; 19.1 mg, 81%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 0.90 (t, 3H, J = 6.8 Hz), 1.25-1.43 (complex, 4H), 1.54-1.76 (complex, 2H), 2.05 (s, 3H), 2.94 (d , 3H, J = 5.4 Hz), 3.46 (d, 2H, J = 6.2 Hz), 4.53 (d, 2H, J = 5.9 Hz), 4.82 (m, 1H), 5.58-5.64 (m, 2H), 5.87 (dt, 1H, J = 6.2, 15 Hz), 6.17 (m, 1H), 7.39 (s, 1H), 14.09 (s, 1H)
¹³ CNMR (67.80 MHz, CDCl ₃ ) δ 14.2, 21.0, 22.7, 28.6, 29.3, 36.2, 36.3, 49.2, 64.5, 70.9, 99.2, 121.0, 126.5, 128.4, 131.9, 139.1, 142.3, 149.6, 159.7, 170.6, 180.4, 188.8.
IR (film) 3357, 2956, 1737, 1616 cm ^-1

<Production of 7-((2E) -4-hydroxybut-2-enyl) -5-hydroxy-6-hydroxypentyl-2-methylaminonaphthalene-1,4-dione>
Compound 30b (19.1 mg) obtained in Example 28 was dissolved in methanol (3 mL), and potassium carbonate (35.2 mg) was added in an ice bath. After stirring at room temperature for 40 minutes, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water and saturated brine (each 10 mL). The organic layer was dehydrated with anhydrous sodium sulfate, and the crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (ethyl acetate) to give 7-((2E) -4-hydroxybuta-2 -Ethyl) -5-hydroxy-6-hydroxypentyl-2-methylaminonaphthalene-1,4-dione (Compound 31b (Compound E) in FIG. 4; 18.0 mg) was quantitatively obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 0.90 (t, 3H, J = 6.8 Hz), 1.25-1.39 (complex, 4H), 1.49-1.78 (complex, 2H), 2.94 (d, 3H, J = 5.4 Hz ), 3.43 (complex, 2H), 4.11 (d, 2H, J = 5.2 Hz), 4.84 (m, 1H), 5.57 (s, 1H), 5.65 (dt, 1H, J = 5.2, 15 Hz), 5.81 (dt, 1H, J = 5.9, 15 Hz), 6.17 (s, 1H), 7.38 (s, 1H), 14.07 (s, 1H)
¹³ CNMR (67.80 MHz, CDCl ₃ ) δ 14.2, 21.5, 22.7, 28.6, 29.3, 36.2, 36.3, 49.3, 49.4, 63.2, 70.9, 99.2, 121.0, 128.6, 131.8, 139.0, 149.6, 159.7, 188.8, 208.0.
IR (film) 3357, 2929, 1614 cm ^-1

<Production of 7-((2E) -4-hydroxybut-2-enyl) -5-hydroxy-6-hydroxypentyl-2-methoxynaphthalene-1,4-dione>
Compound 29b (3.2 mg) obtained in Example 27 was dissolved in methanol (0.5 mL), and potassium carbonate (14.1 mg) was added in an ice bath. After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with water and saturated brine (5 mL each). The organic layer was dehydrated with anhydrous sodium sulfate, and the crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (ethyl acetate) to give 7-((2E) -4-hydroxybuta-2 -Enyl) -5-hydroxy-6-hydroxypentyl-2-methoxynaphthalene-1,4-dione (Compound 32b (Compound D) in FIG. 4; 2.0 mg, 69%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 0.91 (t, 3H, J = 7.2 Hz), 1.40 (complex, 4H), 1.70 (m, 1H), 2.08 (m, 1H), 3.49 (d, 2H, J = 5.1 Hz), 3.92 (s, 3H), 4.12 (complex, 2H), 4.89 (m, 1H), 5.66 (dt, 1H, J = 4.0, 15 Hz), 5.83 (dt, 1H, J = 6.8, 15 Hz), 6.08 (s, 1H), 7.50 (s, 1H), 13.12 (s, 1H).

<Production of methyl 2-((1R, 3R) -1-butyl-7,10-dimethoxy-6,9-dioxobenzo [2,1-g] isochroman-3-yl) acetate>
Compound 26b (84.0 mg) obtained in Example 24 was dissolved in dichloromethane (5 mL), manganese dioxide (872 mg) was added, and the mixture was stirred at 40 ° C. for 3.5 hours. The residue of manganese was filtered through Celite. The celite was washed with chloroform and methanol. The filtrate was distilled off under reduced pressure to obtain a crude product of aldehyde.
The aldehyde was dissolved in methanol (3 mL), and trimethylsilyldiazomethane (2.0 M, hexane solution, 0.8 mL) was added at room temperature. After stirring for 2 hours, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (hexane: ethyl acetate = 1: 1) to give methyl 2-((1R, 3R) -1-butyl- 7,10-dimethoxy-6,9-dioxobenzo [2,1-g] isochroman-3-yl) acetate (Compound 33b in FIG. 5; 30.7 mg, 34%) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ 0.82 (t, 3H, J = 6.8 Hz), 1.13-1.52 (complex, 4H), 1.67-1.84 (m, 1H), 2.02-2.08 (m, 1H), 2.56 -2.81 (complex, 4H), 3.71 (s, 3H), 3.85 (s, 3H), 3.89 (s, 3H), 3.91-3.97 (m, 1H), 4.37 (m, 1H), 4.82 (m, 1H ), 6.05 (s, 1H), 7.68 (s, 1H)
¹³ CNMR (100.40 MHz, CDCl ₃ ) δ 14.1, 22.6, 27.2, 32.4, 35.7, 40,5, 51.8, 56.2, 61.7, 63.1, 69.4, 74.7, 111.7, 123.6, 140.8, 142.4, 156.3, 157.3, 158.7, 171.2, 179.9, 183.9.
IR (film) 2954, 2859, 1739, 1683, 1648, 1619, 1589 cm ^-1 .

<Production of methyl 2-((1R, 3R) -1-butyl-10-hydroxy-7-methoxy-6,9-dioxobenzo [2,1-g] isochroman-3-yl) acetate>
Compound 33b (4.7 mg) obtained in Example 31 was dissolved in dichloromethane (1 mL), boron tribromide (1M, dichloromethane solution, 0.1 mL) was added at −78 ° C., and the mixture was stirred for 20 minutes. The reaction mixture was diluted with chloroform (10 mL), washed with water and saturated brine (5 mL each), and the organic layer was dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (hexane: ethyl acetate = 1: 1) to give methyl 2-((1R, 3R) -1-butyl-10-hydroxy. -7-methoxy-6,9-dioxobenzo [2,1-g] isochroman-3-yl) acetate (Compound 34b (Compound F) in FIG. 5; 1.9 mg, 41%) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ 0.92 (t, 3H, J = 6.8 Hz), 1.25-1.58 (complex, 4H), 1.74-1.76 (m, 1H), 1.92-1.98 (m, 1H), 2.58 -2.78 (complex, 4H), 3.74 (s, 3H), 3.91 (s, 3H), 3.91-3.97 (m, 1H), 4.38 (m, 1H), 6.06 (s, 1H), 7.41 (s, 1H ), 12.6 (s, 1H).

<Preparation of GST-cdc25A>
PGEX-2T-hcdc25A was prepared by incorporating the cDNA of human cdc25A (hcdc25A) into pGEX-2T (Amersham Biosciences), a GST fusion protein expression vector. Escherichia coli BL21 strain transformed with this plasmid was cultured at 37 ° C. until OD ₆₀₀ = 0.6 to 0.8, and 0.1 mM isopropyl-1-thio-β-D-thiogalactopyranoside (IPTG) (Stratagene) ) Was added to induce GST-Cdc25A protein expression. After further culturing at 37 ° C. for 4 hours, the cells were collected and solubilized solution (MT-PBS (150 mM NaCl, 20 mM Na ₂ HPO ₄ , 4 mM NaH ₂ PO ₄ ), 0.1% Triton X-100, 10 μg / mL leupeptin And suspended in 1 mM phenylmethylsulfonyl fluoride (PMSF). The suspended Escherichia coli was disrupted with an ultrasonic crusher, and then a soluble fraction was obtained by centrifugation. Glutathione agarose (SIGMA) equilibrated with MT-PBS was added to this soluble fraction, and GST-Cdc25A was adsorbed at 4 ° C. for 1 hour. Glutathione agarose was collected by centrifugation, washed 4 times with MT-PBS, and then stirred with eluate (50 mM Tris-HCl (pH 8.0), 20 mM reduced glutathione) at 4 ° C. for 1 hour to give GST-Cdc25A. Was eluted. Thereafter, the supernatant was collected by centrifugation and used as an enzyme (Cdc25A) in the following examples.

<Cdc25A phosphatase assay>
Example 6, Example 15, Example 24, Example 29, Example 30, and Compound 32 (Compounds A, B, C, D, E, and F) obtained with respect to the enzyme activity of Cdc25A The inhibitory effect was examined. In this example, as a substrate for Cdc25A, 3-O-methylfluorescein phosphate (OMFP (manufactured by SIGMA)) and 4-nitrophenyl phosphate (4-nitrophenyl phosphate; pNPP (manufactured by SIGMA)) And were used.

<When using an OMFP>
30 μl (15 μg) of enzyme (Cdc25A) and 1 μl of compound at each concentration (compounds A, B, C, D, E, F, and Na ₃ VO ₄ (used as a phosphatase inhibitor positive control)) assay buffer (50 mM Tris Suspended in 60 μl of HCl (pH 7.5) and preincubated for 15 minutes at room temperature. Thereto was added 10 μl of a substrate (final concentration: 25 μM OMFP) and reacted at room temperature for 30 minutes. Thereafter, the amount of 3-O-methylfluorescein produced (excitation wavelength 355 nm, absorption wavelength 538 nm) was measured using Fluoroskan Ascent (manufactured by Labsystem), and the inhibitory activity of the compound on the enzyme (Cdc25A) was evaluated. The inhibition activity was evaluated by calculating the inhibition rate (%).

<When pNPP is used>
30 μl (30 μg) of enzyme (Cdc25A) and 1 μl of each concentration of compound (compounds A, B, C, D, E, F, and Na ₃ VO ₄ ) in 60 μl of assay buffer (50 mM Tris-HCl (pH 7.5)) And preincubated for 15 minutes at room temperature. Thereto was added 10 μl of substrate (5 mM pNPP) and reacted at 37 ° C. for 60 minutes. Thereafter, the absorbance at a wavelength of 405 nm was measured using MICRO PLATE READER (manufactured by TOSOH) to evaluate the inhibitory activity of the compound on the enzyme (Cdc25A). The inhibition activity was evaluated by calculating the inhibition rate (%).

The results are shown in Table 1. As shown in Table 1, compounds A, B, and C showed inhibitory activity against the enzyme (Cdc25A) when each substrate was used, and compounds A and B were found to have particularly excellent inhibitory activity. It was also found that compounds D, E, and F show inhibitory activity against Cdc25 when a specific substrate (OMFP or pNPP) is used.

1 is a view showing a production process of Compound A. FIG. 2 is a diagram showing a production process of compound B. FIG. 1 is a view showing a production process of Compound C. FIG. It is a figure which shows the manufacturing process of the compounds E and D. 1 is a diagram illustrating a production process of Compound F. FIG.

Claims (14)

A naphthoquinone derivative compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof.

(Wherein R ₁ is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group, R ₂ is a hydroxyl group, an acyloxy group, or an alkoxyl group, and R ₃ is a hydrogen atom, a hydroxyalkyl group. Or R ₄ is an acyl group, hydroxyalkyl group, hydroxyalkenyl group, carboxyl group, alkoxycarbonyl group, alkoxyalkyl group, alkoxyalkenyl group, phenoxyalkyl group, phenoxyalkenyl group, carboxyalkenyl group, alkoxycarbonyl Alkenyl group, acyloxyalkenyl group, hydroxyalkyloxirane alkyl group, alkoxyalkyloxirane alkyl group, dihydroxyalkyl group, hydroxyalkoxyalkyl group, oxirane group, or 2-di (Methane-1,3-dioxane-4-alkyl group, and R ₃ and R ₄ do not form a ring.) A naphthoquinone derivative compound represented by the following general formula (II) or a pharmacologically acceptable salt thereof.

(Wherein R ₁ is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group, R ₂ is a hydroxyl group, an acyloxy group, or an alkoxyl group, and R ₃ is a hydrogen atom, a hydroxyalkyl group. Or a halogen atom.) A naphthoquinone derivative compound represented by the following general formula (III) or a pharmacologically acceptable salt thereof.

(Wherein R ₁ is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group, R ₂ is a hydroxyl group, an acyloxy group, or an alkoxyl group, and R ₃ is a hydrogen atom, a hydroxyalkyl group. Or a halogen atom.) A naphthoquinone derivative compound represented by the following general formula (IV) or a pharmacologically acceptable salt thereof.

(In the formula, R ₁ is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group, and R ₂ is a hydroxyl group, an acyloxy group, or an alkoxyl group.) A naphthoquinone derivative compound represented by the following general formula (V) or a pharmacologically acceptable salt thereof.

Wherein R ₂ is a hydroxyl group, an acyloxy group, or an alkoxyl group, R ₃ is a hydrogen atom, a hydroxyalkyl group, or a halogen atom, and R ₄ is an acyl group, a hydroxyalkyl group, a hydroxyalkenyl group, a carboxyl group Group, alkoxycarbonyl group, alkoxyalkyl group, alkoxyalkenyl group, phenoxyalkyl group, phenoxyalkenyl group, carboxyalkenyl group, alkoxycarbonylalkenyl group, acyloxyalkenyl group, hydroxyalkyloxiranealkyl group, alkoxyalkyloxiranealkyl group, dihydroxyalkyl group , hydroxyalkoxy group, an oxirane group, or a 2-Jimetan-1,3-dioxane-4-alkyl group, _{R 5} and _{R 6} are a hydrogen atom or an alkyl group der , It does not constitute a circular with _{R 3} and _{R 4.)} A naphthoquinone derivative compound represented by the following general formula (VI) or a pharmacologically acceptable salt thereof.

(In the formula, R ₂ is a hydroxyl group, an acyloxy group, or an alkoxyl group, and R ₅ and R ₆ are a hydrogen atom or an alkyl group.) A naphthoquinone derivative compound represented by the following general formula (VII) or a pharmacologically acceptable salt thereof.

(In the formula, R ₁ is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group; R ₂ is a hydroxyl group, an acyloxy group, or an alkoxyl group; and R ₇ is a hydrogen atom or an alkyl group. is there.) The naphthoquinone derivative compound or a pharmacologically acceptable salt thereof according to claim 2, wherein the compound is represented by the following formula (A).

The naphthoquinone derivative compound or a pharmacologically acceptable salt thereof according to claim 3, wherein the compound is represented by the following formula (B).

The naphthoquinone derivative compound or a pharmacologically acceptable salt thereof according to claim 4, wherein the compound is represented by the following formula (C) or the following formula (D).

The naphthoquinone derivative compound or a pharmacologically acceptable salt thereof according to claim 6, wherein the compound is represented by the following formula (E).

The naphthoquinone derivative compound or a pharmacologically acceptable salt thereof according to claim 7, wherein the compound is represented by the following formula (F).

  The Cdc25 phosphatase inhibitor which contains the naphthoquinone derivative compound in any one of Claims 1-12, or its pharmacologically acceptable salt as an active ingredient. The antitumor agent which contains the naphthoquinone derivative compound in any one of Claims 1-12, or its pharmacologically acceptable salt as an active ingredient.

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