JPH0544937B2 - - Google Patents

Description

[Detailed description of the invention] [Industrial field of application] The present invention relates to the general formula (In the formula, R ¹ represents a hydrogen atom or a hydroxyl group,
R ² and R ³ together with the carbon atom to which they are bonded form a cyclic or acyclic acetal, or R ² and R ³ together represent an oxygen atom. ) 2-(2-fluoroethyl)-2,
5,12-trihydroxy-7-methoxy-1,
2,3,4-tetrahydronaphthacene-6,11-
Regarding dione derivatives. 2-(2-
fluoroethyl)-2,5,12-trihydroxy-7-methoxy-1,2,3,4-tetrahydronaphthacene-6,11-dione derivative has excellent anticancer properties due to its glycosylation reaction with daunosamine derivatives. It is an important synthetic intermediate that can lead to active 14-fluorodaunorubicin. [Prior Art] The development of excellent anticancer drugs is a strong demand of society and an urgent matter. Anthracycline derivatives, represented by adriamycin, play an important role in medicine as anticancer agents due to their strong anticancer activity, and a large number of anthracycline derivatives have been developed to date. However, these derivatives are still unsatisfactory for use in actual cancer treatment due to the relationship between anticancer activity and effects such as alopecia and myocardial toxicity.
For this reason, there is a strong desire to develop novel anthracycline analogs that exhibit superior and characteristic anticancer activity. [Problems to be Solved by the Invention] Against the above background, the present inventors searched for novel anthracycline analogues with excellent anticancer activity, and found that 14-fluorodaunorubicin is a powerful anticancer agent. They discovered that it has activity and completed the present invention. [Means for solving the problem] 2-(2-fluoroethyl)-2,5,12-trihydroxy-7 represented by the above general formula ()
-Methoxy-1,2,3,4-tetrahydronaphthacene-6,11-dione derivative can be produced according to the following reaction formula. (In the formula, R ⁴ and R ⁵ combine with the carbon atoms to which they are bonded to form a cyclic or acyclic acetal.) [First step] This step consists of (R)-2-acetyl-2 , 5,12-trihydroxy-7-methoxy-1,2,3,4-tetrahydronaphthacene-6,11-dione (7-deoxydaunomycinone) () was reacted with a brominating agent, and the reaction results were By reacting the 2-bromoacetyl compound obtained as a 2-bromoacetyl compound with a fluoride represented by the general formula M-F-() (wherein, M represents a quaternary ammonium or a metal atom), the 2-bromoacetyl compound obtained as a (R)-2-(2-fluoroacetyl)-2,5,12 represented by a)
-trihydroxy-7-methoxy-1,2,3,
4-tetrahydronaphthacene-6,11-dione (7-deoxy-14-fluorodaunomycinone)
It manufactures. (R)-2-acetyl-2,5,12-trihydroxy-7-methoxy-1,2,3,4-tetrahydronaphthacene-6,11 represented by the general formula () which is a raw material of the present invention -Dione (7-deoxydaunomycinone) is produced by hydrolyzing commercially available daunorubicin hydrochloride produced by Streptomyces peucetius (F.
Arcamone, et al., Tetrahedron Lett., 30 ,
3349 (1968). (see). Examples of the brominating agent used for brominating the compound () include bromine, pyridinium bromide perbromide, and phenyltrimethylammonium tribromide. The reaction is preferably carried out in a solvent, and ether solvents such as tetrahydrofuran, dioxane, and dioxolane are preferably used as the reaction solvent. The reaction temperature is 0℃~50℃
Proceeds smoothly at ℃. Examples of the fluoride represented by the general formula () include quaternary ammonium salts such as tetrabutylammonium fluoride and tetraethylammonium fluoride, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, and fluoride. An example is silver. Moreover, when reacting a fluoride with the 2-bromoacetyl compound obtained by bromination of the compound (), the desired product can be obtained in good yield by allowing an inorganic or organic acid or a salt thereof to coexist. Acids that can be used include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, or acetic acid, propionic acid, maleic acid, succinic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid. Examples include organic acids such as, and salts with these acids include:
Examples include ammonium salts formed from bases such as pyridine, tributylamine, triethylamine, and trimethylamine. This reaction is preferably carried out in a solvent, and suitable solvents include ether solvents such as tetrahydrofuran, dioxane, dioxolane, and diglyme, and aprotic solvents such as dimethyl sulfoxide, N,N-dimethylformamide, and acetonitrile. The reaction proceeds smoothly at 0°C to 100°C. [Second step] In this step, the (R)-2-(2-
fluoroacetyl)-2,5,12-trihydroxy-7-methoxy-1,2,3,4-tetrahydronaphthacene-6,11-dione (7-deoxy-
The carbonyl group at the 2-position of 14-fluorodaunomycinone (a) is protected in the form of an acetal group to obtain an acetal compound (b). The acetalization reaction is carried out, for example, by reacting trialkoxymethane in the presence of trimethylsilyl triflate. Examples of trialkoxymethane include trimethoxymethane, triethoxymethane, and tripropoxymethane.
This step is preferably carried out in a solvent, including alcoholic solvents such as methanol, ethanol, and propanol, halogenated hydrocarbon solvents such as methylene chloride, 1,2-dichloroethane, chloroform, and carbon tetrachloride, and tetrahydrofuran and dioxane. An ether solvent or a mixed solvent thereof is used. The reaction proceeds smoothly at a temperature of 0° C. to room temperature. In addition, the acyclic acetal derivative obtained here is subjected to an acetal exchange reaction in the presence of an acid catalyst using diols such as ethylene glycol, trimethylene glycol, and 2,2-dimethylpropane-1,3-diol. By doing so, it is possible to efficiently lead to a cyclic acetal derivative. The acid catalyst used in the acetal exchange reaction is p-
Examples include sulfonic acids such as toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid and trifluoromethanesulfonic acid, and inorganic acids such as sulfuric acid and hydrochloric acid. The acetal exchange reaction can also be achieved by using disilyls of various diols in the presence of trimethylsilyl triflate. The diols used include the disilyls of the above diols, namely 1,2-bis(trimethylsilyloxy)ethane, 1,3-bis(trimethylsilyloxy)propane, and 2,2-dimethyl-1,3-bis(trimethylsilyloxy). An example is propane. As the reaction solvent, halogenated hydrocarbon solvents such as methylene chloride, 1,2-dichloroethane, chloroform, and carbon tetrachloride, or aromatic hydrocarbon solvents such as benzene, toluene, and xylene are preferably used. The reaction proceeds smoothly at a temperature of 0°C to 100°C. [Third Step] In this step, the 4-position of the compound represented by the general formula (b) is brominated, the obtained bromide is converted to a hydroxide, and the acetal group is further removed to form the compound represented by the general formula (c). (2S, 4S)−2−(2
-fluoroacetyl)-2,4,5,12-tetrahydroxy-7-methoxy-1,2,3,4-tetrahydronaphthacene-6,11-dione (14-fluorodaunomycinone). It is. For bromination, methylene chloride, chloroform, 1,
In a halogenated solvent such as 2-dichloroethane or carbon tetrachloride, bromine, N-bromosuccinimide, N
-bromoacetamide, 1,3-dibromo-5,
This is carried out using a brominating agent such as 5-dimethylhydantoin. The reaction proceeds smoothly at 0°C to 100°C. The reaction of replacing bromide with a hydroxyl group is carried out by treating the reaction solution of the bromination reaction with a 0.1 to 1.0 M aqueous alkali solution. The reaction proceeds smoothly at 0°C to 50°C. Examples of alkaline aqueous solutions include sodium hydroxide,
Examples include aqueous solutions of potassium hydroxide, barium hydroxide, and the like. Deprotection of the acetal can be performed using tetrahydrofuran,
It can be carried out under acidic conditions in a solvent such as dioxane or 1,2-dimethoxymethane. As the acid used under acidic conditions, hydrochloric acid, sulfuric acid, etc. are preferably used. The reaction takes place between room temperature and 100°C. Hereinafter, the present invention will be explained in detail with reference to Reference Examples, Examples, and Test Examples, but the present invention is not limited thereto. The meanings of the abbreviations in the examples are as follows. THF: Tetrahydrofuran pNB ₂ : p-nitrobenzoyl group Reference example 1 152 mg (0.269 mmol) of daunorubicin hydrochloride was dissolved in 30 ml of methanol, 165 mg of 5% Pd-barium sulfate was added, and hydrolysis was performed at room temperature for 2 hours. After diluting the reaction mixture with ethyl acetate, the catalyst was filtered off and the filtrate was washed with water. The red residue obtained by drying over anhydrous sodium sulfate and distilling off the solvent under reduced pressure was purified using column chromatography (silica gel, benzene-ethyl acetate 5:1) (R).
-7-deoxydaunomycinone 104mg (100%)
was obtained as a red solid. This product was further recrystallized from benzene to obtain a pure product. mp.228-230℃. (Literature value: F.Arcamone, et al., J.Am.Chem.
Soc., 86 , 5334 (1964), 229-231℃). [α] _D ²⁰ +85° (c=0.118, chloroform). (Literature value: same as above, [α] _D ^20±3 +91° (c=0.11, chloroform)). NMR ( _CDCl3 ): δ=1.88-2.12 (2H, m),
2.42 (3H, s), 2.73-3.35 (4H, m), 3.76
(1H, s), 4.12 (3H, s), 7.42 (1H, dd,
J = 8 and 1Hz), 7.78 (1H, t, J = 8
Hz), 8.05 (1H, dd, J=8 and 1Hz), 13.45 (1H, s), 13.85 (1H, s). IR (KBr): 3520, 1715, 1615, 1585cm ^-1 . Example 1 (R)-7-deoxydaunomycinone 21.0mg
A mixture of pyridinium bromide (0.0549 mmol), 25.7 mg (0.0804 mmol) of perbromide, and 4 ml of THF was stirred at room temperature for 3.5 hours. The reaction mixture was diluted with ethyl acetate, washed successively with 50% brine and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain crude 7-deoxy-14-bromodaunomycinone as a red powder. Suspend this in 4 ml of THF, add 30.9 mg (0.179 mmol) of anhydrous p-toluenesulfonic acid, and 0.29 ml of a 1M solution of tetrabutylammonium fluoride in THF.
(0.29 mmol) were added one after another, stirred at room temperature for 30 minutes, and then heated to reflux. After 1 hour, add 0.04 ml (0.04 mmol) of tetrabutylammonium fluoride.
The mixture was further heated under reflux for 20 minutes. After cooling, the reaction mixture was poured into 50% brine and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The red residue obtained by distilling off the solvent under reduced pressure was subjected to column chromatography (silica gel, benzene-ethyl acetate 10:1 →
5:1) to obtain 12.1 mg (55%) of (R)-7-deoxy-14-fluorodaunomycinone as a red powder. A portion of this product was recrystallized from toluene to obtain dark red needle crystals, which were used as a sample for analysis. mp.253-257℃. [α] _D ²⁰ −19° (c=0.052, dioxane). NMR ( _CDCl3 ): δ=1.95-2.20 (2H, m),
2.92 (1H, s), 2.85-3.40 (4H, m), 4.12
(3H, s), 5.46 (2H, d, J=47Hz), 7.43
(1H, dd, J = 8 and 1Hz), 7.79 (1H, t, J = 8Hz), 8.05 (1H, dd, J
=8 and 1Hz), 13.37 (1H, s), 13.79 (1H, s). IR (KBr): 3500, 1740, 1615, 1590 cm ^-1 . MS (m/e) 400 [M ⁺ ], 382, 339. Elemental analysis value: C ₂₁ H ₁₇ FO ₇ Calculated value: C, 63.00; H , 4.28%. Analysis value: C, 62.70; H, 4.27%. Example 2 71.5 mg (0.179 mmol) of (R)-7-deoxy-14-fluorodaunomycinone was suspended in 21 ml of methylene chloride, 0.4 ml (3.66 mmol) of methyl orthoformate,
0.04 ml (0.04 mmol) of a 1M solution of trimethylsilyl triflate in hexane was added, and the mixture was stirred for 30 minutes under ice cooling and for 2 hours at room temperature. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with methylene chloride. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the red residue was subjected to column chromatography (silica gel, benzene-ethyl acetate).
(R)-2-(2-fluoro-1,1-dimethoxyethyl)-2,5,12-
Trihydroxy-7-methoxy-1,2,3,4
-tetrahydronaphthacene-6,11-dione 73.6
mg (92%) was obtained as a red powder. mp.242.5~244℃. NMR ( _CDCl3 ): δ=1.57-2.32 (2H, m),
2.52 (1H, s), 2.67-3.34 (4H, m), 3.55
(3H, s), 3.58 (3H, s), 4.10 (3H, s),
4.62 (2H, d, J = 47Hz), 7.39 (1H, dd, J
= 8 and 1Hz), 7.77 (1H, t, J = 8Hz), 8.04 (1H, dd, J
=8 and 1Hz), 13.54 (1H, s), 13.88 (1H, s). IR (KBr): 3450, 1615, 1585cm ^-1 . MS (m/e) 446 [M ⁺ ], 107. Example 3 (R)-7-deoxy-14-fluorodaunomycinone 16.5 mg (0.0412 mmol), methylene chloride 5.0 ml,
Methyl orthoformate 0.09ml (0.823mmol), 1,2
-bis-(trimethylsilyloxy)ethane 1.0ml
(4.08 mmol) in a mixture of trimethylsilyl triflate-hexane 1M solution 0.015 ml (0.015 mmol)
was added, and the mixture was stirred for 30 minutes under ice-cooling and then at room temperature for 21.5 hours.
The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting red residue was subjected to column chromatography (silica gel, benzene-ethyl acetate).
10:1) to give (R)-2-(2-fluoromethyl-1,3-dioxolan-2-yl)
-2,5,12-trihydroxy-7-methoxy-
1,2,3,4-tetrahydronaphthacene-6,
16.1 mg (88%) of 11-dione was obtained as a red solid. mp.259-264℃. NMR ( _CDCl3 ): δ=1.58-2.24 (2H, m),
2.04 (1H, s), 2.73-3.35 (4H, m), 4.10
(3H, s), 4.03~4.37 (4H, m), 4.75 (2H,
d, J = 48Hz), 7.40 (1H, d, J = 8Hz),
7.78 (1H, t, J = 8Hz), 8.06 (1H, dd, J
=8 and 1Hz), 13.52 (1H, s), 13.88 (1H,
s). IR (KBr): 3520, 3450, 1615, 1595 cm ^-1 . MS (m/e): 444 [M ⁺ ], 105. Example 4 (R)-2-(2-fluoro-1,1-dimethoxyethyl)-2,5,12-trihydroxy-7-methoxy-1,2,3,4-tetrahydronaphthacene-6,11-dione 33.3 mg (0.0746 mmol), 0.30 ml of bromine-carbon tetrachloride 0.14M solution in a mixture of 3.3 ml of chloroform, 2.4 ml of carbon tetrachloride, and 2.5 ml of water.
(0.041 mmol) was added and heated to reflux on a 60°C oil bath under irradiation with a 60W tungsten lamp. After 15 minutes, 0.47 ml (0.063 mmol) of bromine solution was added in 5 portions at 5 minute intervals, and the reaction was continued for a further 2 hours. After cooling, add 10% sodium hydroxide aqueous solution at 0℃
0.15 ml (0.375 mmol) was added and stirred at the same temperature for 10 minutes and at room temperature for 15 minutes. Add 0.4ml of 1M hydrochloric acid to the reaction mixture.
was added to neutralize the mixture, and the mixture was extracted with chloroform. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The red residue obtained by evaporating the solvent under reduced pressure was then dissolved in 3.5 ml of THF and added with concentrated hydrochloric acid.
0.35 ml was added and stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with chloroform. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified using column chromatography (silica gel, benzene-ethyl acetate 10:1 → 5:1) to obtain (+)-14-fluorodaunomycinone.
Obtained 16.1 mg (52%) as a red powder. This product was recrystallized from benzene and a benzene-hexane mixed solvent to obtain a sample for analysis. mp.213-218℃. [α] _D ²⁰ +179° (c=0.106, dioxane). NMR ( _CDCl3 ): δ = 2.22 (1H, dd, J = 15 and 5Hz), 2.44 (1H, dt, J = 15 and 2Hz),
3.05 (1H, d, J = 19Hz), 3.27 (1H, dd, J
= 19 and 2Hz), 3.29-3.49 (1H, m), 4.13
(3H, s), 4.66 (1H, s), 5.34~5.51 (1H,
m), 5.59 (2H, d, J=48Hz), 7.46 (1H,
dd, J = 8 and 1Hz), 7.83 (1H, t, J =
8Hz), 8.09 (1H, dd, J=8 and 1Hz),
13.25 (1H, s), 14.01 (1H, s). IR (KBr): 3450, 1740, 1615, 1590 cm ^-1 . MS (m/e): 416 [M ⁺ ], 398, 380, 337. Elemental analysis value: as C ₂₁ H ₁₇ FO ₈・0.5H ₂ O Calculated value: C, 59.30; H, 4.27%. Analytical value: C, 59.12; H, 3.98%. Example 5 (R)-2-(2-fluoromethyl-1,3-dioxolan-2-yl)-2,5,12-trihydroxy-7-methoxy-1,2,3,4-tetrahydronaphthacene-6, 11-dione 16.1mg
(0.0362mmol), chloroform 3.3ml, carbon tetrachloride
Bromine-carbon tetrachloride in a mixture of 2.4 ml and 2.5 ml water.
0.40 ml (0.054 mmol) of a 0.14M solution was added in four portions, and the mixture was heated under reflux for 1.5 hours under irradiation with a 60W tungsten lamp. After cooling, add 0.075 ml (0.188 mmol) of 10% aqueous sodium hydroxide solution at 0°C.
The mixture was stirred at the same temperature for 10 minutes and at room temperature for 15 minutes. After neutralizing the reaction mixture by adding 0.2 ml of 1M hydrochloric acid, post-treatment was carried out in the same manner as in Example 4 to obtain a red residue. This was then dissolved in 3 ml of THF, and 6 ml of concentrated hydrochloric acid was added.
ml was added and heated under reflux for 15 hours. After cooling, the same treatment as in Example 4 was carried out, and the residue was subjected to column chromatography (silica gel, benzene-ethyl acetate).
10:1→5:1) to separate and purify (+)-
3.2 mg (21%) of 14-fluorodaunomycinone was obtained as a red powder. The NMR spectrum of this product matched that obtained in Example 4. Reference example 2 2,3,6-trideoxy-1,4-di-O-
p-Nitrobenzoyl-3-trifluoroacetamide-α-L-lyxohexopyranose 40.7mg
(0.0752mmol), molecular sieves 4A 267mg,
In a mixture of 4.0 ml of methylene chloride and 3.2 ml of ether,
0.04 ml (0.207 mmol) of trimethylsilyl triflate was added at −40° C. under an argon atmosphere, and the mixture was stirred for 25 minutes under ice cooling. The reaction solution was then cooled to -30°C, and 19.5 mg of (+)-14-fluorodaunomycinone was added.
(0.0468 mmol) of THF solution was added dropwise to -7
The reaction was carried out at ~-15°C for 6 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate-ethyl acetate mixed solution and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude glycoside. Dissolve this in 2 ml of methylene chloride, 40 ml of methanol, and 0.75 ml of 0.1M aqueous sodium hydroxide solution.
were added one after another and stirred for 20 minutes under ice cooling. After neutralizing with 10% acetic acid, it was diluted with water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting red residue was subjected to column chromatography (silica gel, chloroform → chloroform-
Separate and purify with acetone 30:1) to obtain (+)-3'-N
-Trifluoroacetyl-14-fluorodaunorubicin 27.2 mg (91%) was obtained as a red powder. mp.161.5~164℃. [α] _D ²⁰ +185° (c=0.108, dioxane). NMR (CDCl ₃ ): δ=1.33 (3H, d, J=6
Hz), 1.65-2.55 (4H, m), 3.09 (1H, d,
J=19Hz), 3.32 (1H, d, J=19Hz), 3.55
~3.80 (1H, m), 3.95 ~ 4.40 (2H, m), 4.12
(3H, s), 4.41 (1H, s), 5.36 (1H, t,
J=5Hz), 5.54 (2H, d, J=48Hz), 5.50
~5.67 (1H, m), 6.66 (1H, brd, J=8
Hz), 7.45 (1H, d, J=8Hz), 7.831H,
t, J = 8Hz), 8.08 (1H, d, J = 8Hz),
13.29 (1H, s), 14.05 (1H, s). IR (KBr): 3500, 3450, 1740, 1720, 1615, 1590 cm ^-1 . MS (m/e): 641 [M ⁺ ], 416, 398, 380, 337. Elemental analysis value: C ₂₉ H ₂₇ F ₄ Calculated value as NO ₁₁ : C, 54.30; H, 4.24: N, 2.18%. Analytical values: C, 54.21; H, 4.45; N, 1.98%. Reference example 3 (+)-3'-N-trifluoroacetyl-14-
Fluorodaunorubicin 19.2mg (0.0299mmol)
was suspended in 0.77 ml of THF, 3.0 ml of 0.05M aqueous sodium hydroxide solution was added, and the mixture was stirred at 0°C for 15 minutes and at room temperature for 40 minutes. The reaction mixture was adjusted to pH 9 using 1M hydrochloric acid and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was concentrated to about 2 ml under reduced pressure, 0.6 ml of 0.25M hydrochloric acid-methanol solution was added, and then about 20 ml of ether was added to precipitate. The supernatant was removed by decantation and further tritiated with ether to obtain 8.6 mg (49%) of (+)-14-fluorodaunorubicin hydrochloride as a red powder. mp.209℃ (decomp.). [α] _D ²⁰ +176° (c=0.091, methanol). NMR ((CD ₃ ) ₂ SO): δ = 1.16 (3H, d, J = 6.5Hz), 1.68 (1H, dd, J =
12.5 and 3.6Hz), 1.88 (1H, dt, J = 12.5 and
3.2Hz), 2.14 (H, dd, J = 14.1 and 5.3Hz),
2.21 (1H, d, J = 14.1Hz), 2.89 (1H, d,
J = 18.3Hz), 3.09 (1H, d, J = 18.3Hz), 3.57 (1H, brd, J = 6.1Hz), 4.00 (3H, s), 4.17 (1H, q, J = 6.5Hz),
4.98 (1H, dd, J = 5.3 and 2.9Hz), 5.31 (1H,
d, J = 3.2Hz), 5.47 (1H, d, J = 6.1Hz),
5.57 (1H, dd, J = 47.2 and 17.6Hz), 5.64
(1H, dd, J = 47.2 and 17.6Hz), 5.63 (1H,
s), 7.64-7.70 (1H, m), 7.86 (3H, brs),
7.90-7.97 (2H, m), 13.26 (1H, s), 14.05 (1H, s). IR (KBr): 3450, 1735, 1615, 1590 cm ^-1 . Test example (cancer cell growth inhibition effect) Mouse lymphocytic leukemia cultured cells (P388) were
% fetal calf serum-containing RPMI-1640 culture solution, the number of cultured cells was adjusted to 5 x ¹⁰ cells/ml, and the novel 14-fluorodaunorubicin hydrochloride of the present invention was added to a predetermined concentration, The cells were cultured at 37°C for 2 days. Using a Coulter counter, count the number of floating cells and determine the growth inhibition rate compared to the control group.
The results of determining the % cell growth inhibition concentration IC ₅₀ are shown in Table 1. 【table】

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ represents a hydrogen atom or a hydroxyl group,
R ² and R ³ together with the carbon atom to which they are bonded form a cyclic or acyclic acetal, or R ² and R ³ together represent an oxygen atom. ) 2-(2-fluoroethyl)-2,
5,12-trihydroxy-7-methoxy-1,
2,3,4-tetrahydronaphthacene-6,11-
Dione derivative.