JPH0586787B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention provides novel 6-(1,4
-dimethoxy-5,8-dioxonaphthalene-2
-yl)-3,4,5,6-tetrahydro-2H-
Concerning pyran derivatives. [Prior Art] There is a strong demand from society for the development of excellent anticancer drugs, and various anticancer drugs occupy important positions in medicine. Generally, the anticancer activity of a compound is largely dependent on its chemical structure, and therefore, it is extremely likely that a compound that can be put to practical use as an excellent anticancer agent will be found among those having a structure different from known ones. [Problems to be solved by the present invention] The purpose of the present invention is to develop a novel 6-
An object of the present invention is to provide (1,4-dimethoxy-5,8-dioxonaphthalen-2-yl)-3,4,5,6-tetrahydro-2H-pyran derivatives. [Means for solving the problems] The present invention is based on the general formula

^A novel 6-(1,4-dimethoxy-5,8-
dioxonaphthalen-2-yl)-3,4,5,
It is a 6-tetrahydro-2H-pyran derivative. 6-(1,4-
Dimethoxy-5,8-dioxonaphthalene-2-
yl)-3,4,5,6-tetrahydro-2H-pyran derivative can be produced according to the following reaction formula.

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[First step]

This step involves hexane-
1 represented by the above formula () in the 2-one derivative,
By adding lithium salt of 4,5,8-tetramethoxynaphthalene, 2-
This is to produce hexanol derivatives. 6-t-Butyldimethylsilyloxy-4-(N-methoxycarbonyl-N
-Methyl)amino-3,5-dimethoxymethyloxy-hexan-2-one () is a compound that can be synthesized by known methods [M. Kawasaki, et al.
al., Tetrahedron Lett., 26, 2693 (1985)]. The addition reaction in this step is preferably carried out in a solvent, and for example, ether solvents such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, and dioxane can be used. The reaction proceeds smoothly at -78°C to 50°C. [Second step] This step is based on the formula () obtained in the first step.
The 1,5-hexanediol derivative represented by the formula (V) is produced by removing the t-butyldimethylsilyl group of the 2-hexanol derivative represented by the formula (V). When removing the protecting group in this step, use a desilylating agent such as tetrabutylammonium
Fluoride, hydrofluoric acid, acetic acid, etc. can be used. This step is preferably carried out in a solvent; for example, ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, and dioxane, and halogenated hydrocarbon solvents such as chloroform and dichloromethane can be used. . The reaction proceeds smoothly at a temperature of 0°C to 100°C. [Third Step] This step is based on the formula (V) obtained in the second step.
The 1,5-hexanediol derivative represented by is oxidized to produce 6-(1,4,
5,8-tetramethoxynaphthalen-2-yl)
-3,4,5,6-tetrahydro-2-pyranone derivatives are produced. In the oxidation of this step, for example, dimethyl sulfoxide/oxalyl chloride/triethylamine mixed oxidizing agent, dimethyl sulfoxide/trifluoroacetic anhydride/triethylamine mixed oxidizing agent, pyridinium chlorochromate, etc. can be used. . It is desirable to carry out this step in a solvent, and for example, a halogenated hydrocarbon solvent such as chloroform, dichloromethane, dichloroethane, etc. can be used. The reaction proceeds smoothly at a temperature of -60°C to 50°C. [Fourth step] This step is based on the formula () obtained in the third step.
6-(1,4,5,8-tetramethoxynaphthalen-2-yl)-3,4,5,6-
The tetrahydro-2-pyranone derivative is reduced to produce 6-(1,4,5,8-tetramethoxynaphthalen-2-yl)-3,4,
A 5,6-tetrahydro-2H-pyran derivative is produced. In the reduction in this step, for example, diisobutylaluminum hydride, tri-t-butoxyaluminum lithium hydride, etc. can be used as a reducing agent. It is desirable to carry out this step in a solvent, and for example, ether solvents such as diethyl ether, tetrahydrofuran, and 1,2-dimethoxyethane, and hydrocarbon solvents such as toluene and hexane can be used. The reaction proceeds smoothly at a temperature of -78°C to 0°C. [Fifth step] This step is based on the formula () obtained in the fourth step.
6-(1,4,5,8-tetramethoxynaphthalen-2-yl)-3,4,5,6-
6-(1,4,5,8-tetramethoxynaphthalen-2-yl)-3,4, represented by the above general formula (), is obtained by introducing a hydroxyl protecting group into the 2-position hydroxyl group of a tetrahydro-2H-pyran derivative. A 5,6-tetrahydro-2H-pyran derivative is produced. As the hydroxyl protecting group used in this step,
Methyl group, t-butyl group, allyl group, 2,2,2
- Alkyl groups such as trichloroethyl group, benzyl group, p-methoxybenzyl group, arylmethyl group, trimethylsilyl group, triethylsilyl group, isopropyldimethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, etc. Alkoxymethyl groups such as trialkylsilyl group, methoxymethyl group, 2-methoxyethoxymethyl group, benzyloxymethyl group, 2-trimethylsilylethoxymethyl group, 2,2,2-trichloroethoxymethyl group, methylthiomethyl group, Examples include alkyl and arylthiomethyl groups such as a ruthiomethyl group. These protecting groups can be prepared using methods known to those skilled in the art (CBReese,
“Protective Groups in Organic Chemistry”
ed.by JFWMc Omie, Plenum Press,
London and New York, 1973, pp95-144; T.
W. Greene, “Protective Groups in Organic
Chemistry”, John Wiley & Sons, New
York, 1981, pp10-86; Takeshi Oishi, Yugoka, 36,
715 (1978). ) can be introduced by When introducing an alkoxymethyl group as a protecting group for the hydroxyl group in the general formula (), 6-( 1,4,5,8-
Tetramethoxynaphthalen-2-yl)-3,4,
5,6-tetrahydro-2H-pyran derivatives can be produced. Examples of alkoxymethyl halides used in alkoxymethylation include methoxymethyl chloride, methoxymethyl bromide, 2-methoxyethoxymethyl chloride, benzyloxymethyl chloride, 2-trimethylsilylethoxymethyl chloride, and 2,2,2-isochloride. -trichloroethoxymethyl and the like. Although this step can be carried out without a solvent, it can also be carried out by adding an ether solvent such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, or dioxane. The reaction proceeds smoothly at room temperature to 80°C. [Sixth step] This step is performed to obtain the 6-(1,4,5,8-tetramethoxynaphthalen-2-yl)-3,4,5, represented by the general formula () obtained in the fifth step.
6-tetrahydro-2H-pyran derivative is reduced to produce 6-(1,4,5,
8-tetramethoxynaphthalen-2-yl)-3,
A 4,5,6-tetrahydro-2H-pyran derivative is produced. In the reduction in this step, for example, lithium aluminum hydroxide, lithium borohydride, etc. can be used as a reducing agent. This step is preferably carried out in a solvent, and for example, ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, and dioxane can be used. The reaction proceeds smoothly at a temperature of 0°C to 80°C. [Seventh step] This step is performed to obtain the 6-(1,4,5,8-tetramethoxynaphthalen-2-yl)-3,4,5, represented by the general formula () obtained in the sixth step.
oxidizing a 6-tetrahydro-2H-pyran derivative,
6-(1,4-dimethoxy-5,8-dioxonaphthalen-2-yl)-3,4,5,6-tetrahydro-2H-pyran derivative represented by the general formula (I) is produced. be. Cerium ammonium nitrate can be selected as the oxidizing agent. This step is preferably carried out in a solvent, and for example, alcoholic solvents such as methanol, ethanol, and propanol, and polar solvents such as acetonitrile, dimethylformamide, and dimethylacetamide can be used. The reaction proceeds smoothly at a temperature of -50°C to 50°C. 6-(1,4-dimethoxy-5,8-dioxonaphthalen-2-yl)-3,4,5,6 represented by the general formula (I) obtained as above.
The usefulness of the -tetrahydro-2H-pyran derivative as an anticancer agent was confirmed by conducting a malignant tumor cell growth inhibition test. Tested on mouse lymphocytic leukemia cells (p388)
was carried out according to the conventional method, and the inhibition rate was determined. The present invention will be explained in detail below using Reference Examples, Examples, and Test Examples.

[Chemical formula] Dissolve 1.74 g (7.0 mmol) of 1,4,5,8-tetramethoxynaphthalene (mp167-169°C) in 180 ml of anhydrous tetrahydrofuran, and add n-butyllithium hexane solution (1.27 molar concentration) while stirring at 0°C. ) 5.51 ml (7.0 mmol) was added, and stirring was continued at that temperature for 20 minutes. (-)-(3R, 4S,
5S)-6-t-butyldimethylsilyloxy-
3,5-dimethoxymethyloxy-4-(N-methoxycarbonyl-N-methyl)amino-2-hexanone [Tetrahedron Lett., 26, 2693 (1985)
15 ml of a solution of 2.13 g (4.9 mmol) of anhydrous tetrahydrofuran was added dropwise at 0° C. over 30 seconds. Stirring was further continued at that temperature for 3 minutes. followed by 100 ml of saturated ammonium chloride aqueous solution.
was added to stop the reaction. After adding 200 ml of toluene and stirring, the organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was passed through a silica gel column (n
-hexane/ethyl acetate = 3) followed by chloroform/ethyl acetate = 3), (-)-(2R, 3R,
4S, 5S)-6-t-butyldimethylsilyloxy-3,5-dimethoxymethyloxy-4-(N-
Methoxycarbonyl-N-methyl)amino-2-
(1,4,5,8-tetramethoxynaphthalene-
2-yl)-2-hexanol 1.90 g (57% yield)
was obtained as a pale yellow caramel. [α] ²⁰ _D −35.5°C (c=1.00 chloroform) Mass spectrum m/e685 (M ⁺ ). NMR (CDCl ₃ ) δ (ppm): 0.03, 0.05 (6H, 2s,
Si( _CH3 ) ₂ ), 0.86, 0.90(9H, 2s, SiC
(CH ₃ ) ₃ ), 1.76 (3H, s, 3H ₁ ), 3.02 (3H, s,
NCH ₃ ), 3.10, 3.29, 3.33, 3.37, 3.55, 3.64,
3.70, 3.81, 3.84, 3.86, 3.89, (21H, Lis,
70CH ₃ ), 2.9−5.0 (10H, m, OH, OCH ₂ ×
3, H ₃ , H ₄ , H ₅ ), 6.84 (2H, s, ArH),
7.00 (1H, s, ArH). IR (neat): 3450 (OH), 1690 (CO), 1600 (Ar) cm ^-1 . Elemental analysis value: Calculated value as C ₃₃ H ₅₅ NO ₁₁ Si: C: 57.79, H: 8.08, N: 2.04%. Analytical values: C: 57.76, H: 7.93, N: 1.99%.

[Chemical formula] (-)-(2R,3R,4S,5S)-6-t-butyldimethylsilyloxy-3,5-dimethoxymethyloxy-4-(N-methoxycarbonyl-N-
Dissolve 1.50 g (2.19 mmol) of amino-2-(1,4,5,8-tetramethoxynaphthalen-2-yl)-2-hexanol in 50 ml of anhydrous tetrahydrofuran and add tetrabutylammonium under stirring at 15-25°C. = 5.0 ml (5.0 mmol) of a solution of fluoride in tetrahydrofuran (1 molar concentration) was added, and stirring was continued at that temperature for 1 hour. After distilling off the solvent, the residue was passed through a silica gel column (ethyl acetate) to give (-)-(2S, 3S, 4R, 5R)-3-(N-methoxycarbonyl-N-methyl)amino-2,4-dimethoxymethyloxy. -5-(1,4,5,8-tetramethoxynaphthalen-2-yl)-1,5-
1.22 g (98% yield) of hexanediol was obtained as a colorless caramel. [α] ²⁰ _D −31.4°C (c=1.25 chloroform) Mass spectrum m/e571 (M ⁺ ). NMR (CDCl ₃ ) δ (ppm): 1.73 (3H, s, 3H ₆ ),
2.96 (3H, s, NCH ₃ ), 3.2−4.1 (28H, m,
_7CH3 , _2H1 , _H2 , _H3 , _H4 , 20H), 4.4−5.0
(4H, m, OCH ₂ O×2), 6.81 (2H, s,
ArH), 7.05, 7.22 (1H, 2s, ArH). IR (neat): 3450 (OH), 1680 (CO), 1600 (Ar) cm ^-1 .

[Chemical formula] Dissolve 0.38 g (3.0 mmol) of oxalyl chloride in 25 ml of anhydrous dichloromethane, add 5 ml of an anhydrous dichloromethane solution of 0.55 g (7.0 mmol) of dimethyl sulfoxide while stirring at -60℃, and stir at that temperature for 2 minutes. did. (-)-(2S, 3S, 4R, 5R)-3
-(N-methoxycarbonyl-N-methyl)amino-2,4-dimethoxymethyloxy-5-(1,
4,5,8-tetramethoxynaphthalen-2-yl)-1,5-hexanediol 0.90g
(1.57 mmol) in anhydrous dichloromethane, stirred at -60°C for 20 minutes, and then added dropwise 1.52 g (15.0 mmol) of triethylamine at this temperature.
The reaction temperature was increased to 0°C over 20 minutes. The reaction was stopped by adding 100 ml of saturated ammonium chloride aqueous solution and 100 ml of ethyl acetate. The organic layer was separated, washed with saturated brine (20 ml x 2), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/
(3S,4R,5R,6R)-4-(N-methoxycarbonyl-N-methyl)amino-3,5-dimethoxymethyloxy-6- Methyl-6-(1,4,5,
8-tetramethoxynaphthalen-2-yl)-3,
4,5,6-tetrahydro-2-pyranone was obtained as a colorless caramel. Mass spectrum: m/e567 (M ⁺ ). NMR (CDCl ₃ ) δ (ppm): 2.04 (3H, s, 6-
CH ₃ ), 2.97 (3H, s, NCH ₃ ), 3.20, 3.36
(6H, 2s, OCH ₃ × 2), 3.66, 3.70, 3.86,
3.90, 3.92 (15H, 5s, ArOCH ₃ × 4,
CO ₂ CH ₃ ), 4.56 (2H, dd, J = 7Hz, 8Hz,
OCH ₂ O), 4.92 (2H, dd, J = 36Hz, 7Hz,
CCH ₂ O), 6.84 (2H, s, ArH), 7.00 (1H,
s, ArH). IR (neat): 1740 (CO), 1695 (CO), 1600 (Ar), 1025 (-O-) cm ^-1 .

[Chemical formula] (3S,4R,5R,6R)-4-(N-methoxycarbonyl-N-methyl)amino-3,5-dimethoxymethyloxy-6-methyl-6-(1,4,5,
8-tetramethoxynaphthalen-2-yl)-3,
4,5,6-tetrahydro-2-pyranone 435mg
(0.77 mmol) in 30 ml of anhydrous toluene and −78
0.92 ml of a hexane solution of diisobutylaluminum pidolide (1.0 molar) with stirring at °C.
(0.92 mmol) was added dropwise and stirred at this temperature for 20 minutes. The reaction was stopped by adding 0.5 ml of methanol, and 100 ml of saturated ammonium chloride aqueous solution was added, followed by extraction with ethyl acetate (30 ml x 2). The organic layers were combined, washed with saturated brine (20 ml x 2), dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Dissolve the residue in 30ml of methanol and 2.0g of anhydrous potassium carbonate.
After heating and refluxing for 30 minutes, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. This product was purified by silica gel column chromatography (ethyl acetate/hexane = 2) to form (+)-(3S, 4R, 5R, 6R).
-2-hydroxy-4-(N-methoxycarbonyl-N-methyl)amino-3,5-dimethoxymethyloxy-6-methyl-6-(1,4,5,8
-tetramethoxynaphthalen-2-yl)-3,
4,5,6-tetrahydro-2H-pyran 354 mg
(82% yield) was obtained as a pale yellow caramel. [α] ²⁰ _D +12.1°C (c = 1.05 chloroform) mass spectrum m/e569 (M ⁺ ). NMR (CDCl ₃ ) δ (ppm): 1.83, 1.91 (3H, 2s,
6-CH ₃ ), 2.96, 2.99, (3H, 2s, NCH ₃ ),
3.28 (3H, s, OCH ₃ ), 3.37 (3H, s,
OCH ₃ ), 3.4−4.3 (19H, m, OCH ₃ ×4,
CO ₂ CH ₃ , OH, H ₃ , H ₄ , H ₅ ), 4.4−4.9 (5H,
m, OCH ₃ × 2, H ₂ ), 6.80 (2H, s, ArH),
7.72 (1H, s, ArH). IR (neat): 3450 (OH), 1690 (CO), 1600 (Ar), 1070, 1030 (-O-) cm ^-1 .

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[Formula] (+)-(3S,4R,5R,6R)-2-hydroxy-4-(N-methoxycarbonyl-N-methyl)
Amino-3,5-dimethoxymethyloxy-6-
Dissolve 350 mg (0.62 mmol) of methyl-6-(1,4,5,8-tetramethoxynaphthalen-2-yl)-3,4,5,6-tetrahydro-2H-pyran in 5.0 ml of anhydrous tetrahydrofuran, and diisopropylethylamine. After adding 4.44 g (34 mmol) of chloromethyl methyl ether and 3.18 g (30 mmol), the mixture was heated under reflux for 3 hours. Subsequently, 2 ml of triethylamine and 3 ml of methanol were added while stirring under ice cooling, and after the mixture was left at this temperature for 15 minutes, 80 ml of ethyl acetate was added.
The organic layer was washed successively with cold 3NHCl water, saturated sodium bicarbonate water, and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane = 2) to give (-)-(3S,4R,5R,6R)-4-(N-
methoxycarbonyl-N-methyl)amino-2,
3,5-trimethoxymethyloxy-6-methyl-6-(1,4,5,8-tetramethoxynaphthalen-2-yl)3,4,5,6-tetrahydro-2H-pyran 343 mg (91% yield) %) was obtained as colorless crystals. mp115−116℃. [α] ²⁰ _D −16.2°C (c=1.10 chloroform) mass spectrum m/e613 (M ⁺ ). NMR (CDCl ₃ ) δ (ppm): 1.82 (3H, s, 6-
CH ₃ ), 2.96, 3.00 (3H, 2s, NCH ₃ ), 3.23,
3.28, 3.40 (9H, 3s, OCH ₃ × 3), 3.5−4.3
(17H, m, OCH ₃ × 5, H ₃ , H ₅ ,), 4.3−5.3
(7H, m, OCH ₂ O×3, H ₂ ), 6.82 (2H, s,
ArH), 7.74 (1H, s, ArH). IR (KBr): 1700 (CO), 1600 (Ar), 1020 (-O-) cm ^-1 . Elemental analysis values: Calculated values as C ₂₉ H ₄₃ NO ₁₃ : C: 56.76, H: 7.06, N: 2.28%. Analytical values: C: 56.63, H: 7.17, N: 2.21%.

[Chemical formula] (-)-(3S,4R,5R,6R)-4-(N-methoxycarbonyl-N-methyl)amino-2,3,5
-trimethoxymethyloxy-6-methyl-6-
(1,4,5,8-tetramethoxynaphthalene-
2-yl)-3,4,5,6-tetrahydro-2H
−730 mg (1.19 mmol) of pyran in 40 ml of anhydrous ether
182 mg of lithium aluminum hydride dissolved in
(4.8 mmol) was added, and after heating under reflux for 1 hour, 1 ml of methanol was added to stop the reaction. ethyl acetate 100
ml and add this organic layer to saturated saline solution (20ml x 3)
After washing with and drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane = 2) to give (-)-(3S,4R,5R,6R)-4-dimethylamino-2,3,5-trimethoxymethyloxy-6-
641 mg (95% yield) of methyl-6-(1,4,5,8.tetramethoxynaphthalen-2-yl)-3,4,5,6-tetrahydro-2H-pyran was obtained as colorless crystals. mp109−110℃. [α] ²⁰ _D 0 (C = 1.08 chloroform) α] ²⁰ ₄₃₅ −10.3°C (c = 1.08 chloroform) Mass spectrum m/e: 569 (M ⁺ ). NMR (CDCl ₃ ) δ (ppm): 1.84 (3H, s, 6-
CH ₃ ), 2.53 (6H, s, N(CH ₃ ) ₂ ), 3.02 (1H,
t, J = 8.7Hz, H ₄ ), 3.35 (6H, s, OCH ₃ ×
2), 3.38 (3H, s, OCH ₃ ), 3.71, 3.84,
3.90, 3.92 (12H, 4s, ArOCH ₃ × 4), 3.5−4.2
(2H, m, H ₃ , H ₅ ), 4.6−5.3 (7H, m,
OCH ₂ O×3, H ₂ ), 6.80 (2H, s, ArH),
7.70 (1H, s, ArH). IR (KBr): 1600 (Ar), 1070, 1040, 1020 (-O-) cm ^-1 . Elemental analysis value _{: C28H43NO11} Calculated _value : C: 59.04, H: 7.61, N: 2.46%. Analytical values: C: 58.86, H: 7.57, N: 2.40%.

[Formula] (-)-(3S,4R,5R,6R)-4-dimethylamino-2,3,5-trimethoxymethyloxy-
6-Methyl-6-(1,4,5,8-tetramethoxynaphthalen-2-yl)-3,4,5,6-
Tetrahydro-2H-pyran 300mg (0.53mmol)
was dissolved in 8 ml of ethanol, 3 ml of an aqueous solution of 1.80 g (3.28 mmol) of ceric ammonium nitrate was added at -40°C, and the temperature was raised. After stirring at 0°C for 10 minutes, 20 ml of ethyl acetate and 20 ml of water were added, and while stirring vigorously, saturated sodium bicarbonate solution was added dropwise to adjust the pH of the aqueous layer to 8. After separating the organic layer and washing with saturated saline (10 ml),
Back-extracted with 0.5NHCl water (20ml x 2), adjusted to pH=8 with saturated sodium bicarbonate water, and extracted again with ethyl acetate (20ml x 2).
2). After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (ethyl acetate).
(3S,4R,5R,6R)-6-(1,4-
Dimethoxy-5,8-dioxonaphthalene-2-
yl)-4-dimethylamino-2,3,5-trimethoxymethyloxy-6-methyl-3,4,
5,6-tetrahydro-2H-pyran 59 mg (21%
Yield) was obtained as a yellow caramel. Mass spectrometry m/e: 539 (M ⁺ ). NMR (CDCl ₃ ) δ (ppm): 1.81 (3H, s, 6-
CH ₃ ), 2.48 (6H, s, N(CH ₃ ) ₂ ), 2.83 (1H,
t, J = 6Hz, H ₄ ), 3.23, 3.39, 3.40 (9H,
3s, OCH ₃ × 3), 3.82, 3.99 (6H, 2s,
ArOCH ₃ × 2), 4.27 (1H, d, J = 6Hz,
H ₅ ), 4.5−5.2 (7H, m, OCH ₂ O×3,

[Formula]), 6.76 (2H, s, ArH), 8.04 (1H, s, ArH). IR (neat): 1660 (CO), 1040, 1020 (C-O-C) cm ^-1 . Test example (cancer cell growth inhibition effect) Mouse lymphocytic leukemia cells (p388) were added to RPMI-1640 culture medium containing 10% fetal calf serum, the number of cultured cells was adjusted to 5 x ¹⁰⁴ cells/1ml, and this The novel 6-(1,4-dimethoxy-5,8-dioxonaphthalen-2-yl)-3,4,5,6-tetrahydro-2H-pyran derivative (I) of the invention is added to a predetermined concentration. and cultured at 37°C for 2 days.
The number of floating cells was counted using a Coulter counter, and the 50% cell growth inhibition concentration IC ₅₀ was determined from the growth inhibition rate relative to the control group. The results are shown in Table 1.

【table】

Claims (1)

[Claims] 1 6-(1,4-dimethoxy-5,8
-dioxonaphthalen-2-yl)-3,4,5,
6-tetrahydro-2H-pyran derivative (in the formula,
R ¹ is a hydroxyl protecting group. ).