JPH06797B2 - 14-fluorodaunorubicin derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] (In the formula, R ¹ is a hydrogen atom or a trifluoroacetyl group.) The present invention relates to a 14-fluorodaunorubicin derivative and a salt thereof.

The 14-fluorodaunorubicin derivative represented by the general formula (I) of the present invention has a use as an anticancer agent.

[Conventional technology]

The development of excellent anticancer agents is a strong demand of society and an urgent matter. Anthracycline derivatives represented by adriamycin occupy an important position in medicine as an anticancer agent due to their strong antitumor activity, and many anthracycline derivatives have been developed up to now. However, these derivatives are still unsatisfactory for use in the actual treatment of cancer in relation to anticancer activity and side effects such as hair loss and myocardial toxicity. From this fact, there is a strong demand for the development of novel anthracycline derivatives which exhibit more excellent characteristic anticancer activity.

[Problems to be solved by the invention]

Against the above background, the present inventors have searched for a novel anthracycline analog having excellent antitumor activity,
The compound of the present invention was discovered and the present invention was completed.

[Means for solving problems]

The novel 14-fluorodaunorubicin derivative represented by the general formula (I) can be produced according to the following reaction formula.

(In the formula, R ² and R ³ together with the carbon atom to be bonded represent a cyclic or acyclic acetal group, and R ⁴ represents an acyl group.) [Step 1] ) -2-Acetyl-2,5,12-trihydroxy-7-methoxy-1,2,3,4-tetrahydronaphthacene-6,11-dione (7-deoxydaunomycinone) (II) and bromine The 2-bromoacetyl derivative obtained by reacting the agent with the reaction product is a fluoride represented by the general formula MF- (VIII) (wherein M represents a quaternary ammonium or a metal atom). By reacting,
(R) -2- (2-fluoroacetyl) -2,5,12-trihydroxy-7 represented by the general formula (III).
-Methoxy-1,2,3,4-tetrahydronaphthacene-6,11-dione (7-deoxy-14-fluorodaunomycinone) is produced.

(R) -2-acetyl-2,5,12-trihydroxy-7-methoxy-1,2,3,4-tetrahydronaphthacene-6, represented by the general formula (II), which is a raw material of the present invention, 11-dione (7-deoxydaunomycinone) is subjected to hydrogenolysis reaction of commercially available daunorubicin hydrochloride produced by Streptomyces peucetius (F. Arcamone, et al., Tetrah).
edron Lett. , 30 , 3349 (196
8). It is a compound that can be easily obtained by

Examples of the brominating agent used for bromination of compound (II) include
Examples thereof include bromine, pyridinium bromide perbromide, phenyltrimethylammonium tribromide and the like. It is desirable to carry out the reaction in a solvent, and as the reaction solvent,
Ether solvents such as tetrahydrofuran, dioxane and dioxolane are preferably used. Reaction is 0 to 50
Proceed smoothly at ℃.

Examples of the fluoride represented by the general formula (VIII) include quaternary ammonium salts such as tetrabutylammonium fluoride and tetraethylammonium fluoride, and lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, and fluoride. Examples thereof include silver. In addition, the compound (I
When the 2-bromoacetyl derivative obtained by the bromination of I) is reacted with a fluoride, an objective compound can be obtained in good yield by allowing an inorganic or organic acid or its salt to coexist.

Examples of usable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or acetic acid, propionic acid, maleic acid, succinic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfone. Examples thereof include organic acids such as acids, and examples of salts with these acids include ammonium salts formed from bases such as pyridine, tributylamine, tretylamine, and chrymethylamine. This reaction is preferably carried out in a solvent, which may be tetrahydrofuran, dioxane,
Ether-based solvents such as dioxolane and diglyme, and aprotic solvents such as dimethyl sulfoxide, N, N-dimethylformamide and acetonitrile are preferable. The reaction proceeds smoothly at 0 ° C to 100 ° C.

[Second Step] In this step, (R) -2- (2-fluoroacetyl) -2,5,12-trihydroxy-7-obtained in the first step
Methoxy-1,2,3,4-tetrahydronaphthacene-
The carbonyl group at the 2-position of 6,11-dione (7-deoxy-14-fluorodaunomycinone) (III) is protected in the form of an acetal group to obtain an acetal body (IV). The acetalization reaction is carried out, for example, by reacting trialkoxymethane in the presence of trimethylsilyl triflate. Examples of trialkoxymethanes include trimethoxymethane, triethoxymethane, and tripropoxymethane. It is desirable to carry out this step in a solvent, such as an alcohol solvent such as methanol, ethanol or propanol, methylene chloride, 1, 2
-A halogenated hydrocarbon solvent such as dichloroethane, chloroform, carbon tetrachloride, an ether solvent such as tetrahydrofuran, dioxane, or a mixed solvent thereof is used. The reaction proceeds smoothly at 0 ° C to room temperature.

In addition, the acyclic acetal derivative obtained here undergoes an acetal exchange reaction in the presence of an acid catalyst using a diol such as ethylene glycol, trimethylene glycol, and 2,2-dimethylpropane-1,3-diol. By carrying out, it is possible to efficiently lead to a cyclic acetal derivative. Examples of the acid catalyst used in the acetal exchange reaction include sulfonic acids such as p-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 disilyl compounds of various diols in the presence of trimethylsilyl triflate. The diol used is a disilyl derivative of the above diols, that is, 1,2
Examples include -bis (trimethylsilyloxy) ethane, 1,3-bis (trimethylsilyloxy) propane, and 2,2-dimethyl-1,3-bis (trimethylsilyloxy) 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. Reaction is 0 ℃
Proceed smoothly at ~ 100 ° C.

[Third step] In this step, the 4-position of the compound represented by the general formula (IV) is brominated, and the obtained bromide is exchanged with hydroxide.
By removing the acetal group, (2S, 4S) -2- (2-fluoroacetyl) -2, represented by the general formula (V),
4,5,12-tetrahydroxy-7-methoxy-1,
2,3,4-tetrahydronaphthacene-6,11-dione (14-fluorodaunomycinone) is produced.

Bromination is carried out by using bromine, N-bromosuccinimide, N-bromoacetamide, 1,3-dibroo-5,5-dimethylhydantoin in a halogen-based solvent such as methylene chloride, chloroform, 1,2-dichloroethane or carbon tetrachloride. Is used as a brominating agent. The reaction is 0 ° C to 100
Proceed smoothly at ℃.

The reaction of substituting the bromide with the hydroxyl group is carried out by treating the reaction solution of the bromination reaction with a 0.1 to 1.0 M aqueous alkaline solution. The reaction proceeds smoothly at 0 ° C to 50 ° C. Examples of the alkaline aqueous solution include aqueous solutions of sodium hydroxide, potassium hydroxide, barium hydroxide and the like.

Deprotection of the acetal can be carried out in a solvent such as tetrahydrofuran, dioxane, 1,2-dimethoxymethane or the like under acidic conditions. As the acid used under acidic conditions, hydrochloric acid, sulfuric acid and the like are preferably used. The reaction is performed at room temperature to 100 ° C.

[Step 4] In this step, the compound represented by the general formula (V) is reacted with the daunosamine derivative (VI) to produce the α-glycoside represented by the general formula (VII). In this step, the reaction can be carried out in the presence of trimethylsilyl triflate according to the method disclosed in JP-A-60-94990.

[Fifth Step] In this step, the α-glycoside represented by the general formula (VII) obtained in the fourth step is deprotected to obtain the above formula (Ia).
To produce a compound represented by.

Deprotection in this step can be carried out under a dilute alkaline condition with sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or the like in a solvent such as methanol or tetrahydrofuran or acetone. The reaction proceeds smoothly at 0 ° C to room temperature.

[Sixth Step] In this step, the glycoside represented by the formula (Ia) obtained in the fifth step is further deprotected to produce a compound represented by the formula (Ib).

Deprotection in this step is sodium hydroxide, potassium hydroxide,
It can be carried out near room temperature in a dilute alkaline aqueous solution such as sodium carbonate.

The 14-14-fluorodaunorubicin of the formula (Ib) can be prepared as a stable salt by treating with an inorganic or organic acid. The salt is preferably a salt with a pharmaceutically acceptable acid, and examples of such an acid include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, or acetic acid, propionic acid, maleic acid, palmitin. Examples thereof include acids, citric acid, succinic acid, tartaric acid, malic acid, fumaric acid, glutamic acid, pantothenic acid, laurylsulfonic acid, methanesulfonic acid, naphthalenesulfonic acid and other organic acids.

The 14-14-fluorodaunorubicin derivative obtained as described above was confirmed to be useful as an anticancer agent by conducting a malignant tumor cell growth inhibition test. As a reagent, mouse lymphocytic leukemia cells (P388) were used, and the inhibition rate was determined according to a conventional method.

Hereinafter, the present invention will be described in detail with reference to Reference Examples, Examples and Test Examples, but the present invention is not limited thereto.

The abbreviations used in the examples have the following meanings.

THF: tetrahydrofuran pNBz: p-nitrobenzoyl group 152 mg (0.269 m-mol) of daunorubicin hydrochloride was dissolved in 30 ml of methanol, and 5% Pd-barium sulfate 1 was added.
65 mg was added and hydrogenolysis was performed at room temperature for 2 hours. The reaction mixture was diluted 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 evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, benzene-ethyl acetate 5: 1) to give (R) -7-deoxydow. Nomaishinone 1
04 mg (100%) was obtained as a red solid. This product was recrystallized from benzene to obtain a pure product.

mp 228-230 ° C. (Reference value: F. Arcamone, et al., J.
Am. Chem. Soc. , 86 , 5334 (196
4), 229-231 ° C). [Α] ²⁰ _D + 85 ° (c = 0.118, chloroform). (Reference value: same as above, [α] ^{20 ± 3} _D + 91 ° (c = 0.11,
Chloroform)). NMR (CDCl ₃ ): δ = 1.88 to 2.12 (2H, m),
2.42 (3H, s), 2.73 to 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 = 8Hz), 8.05
(1H, dd, J = 8 and 1Hz), 13.45 (1H,
s), 13.85 (1H, s). IR (KBr): 3520, 1715, 1615, 15
85 cm ^-1 . (R) -7-deoxydaunomycinone 21.0 mg (0.0549
mmol) pyridinium bromide perbromide 25.7
A mixture of mg (0.0804 mmol) and 4 ml of THF at room temperature 3.
Stir for 5 hours. The reaction mixture was diluted with ethyl acetate, 5
The extract was washed successively with 0% saline and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give crude 7
-Deoxy-14-bromodaunomycinone was obtained as a red powder. This product was suspended in 4 ml of THF, and anhydrous p-
Toluenesulfonic acid 30.9 mg (0.179 mmol), tetrabutylammonium fluoride-THF 1M solution 0.29 ml (0.
(29 mmol) was sequentially added, and the mixture was stirred at room temperature for 30 minutes and then heated under reflux. After 1 hour, 0.04 ml (0.04 mmol) of tetrabutylammonium fluoride was added, and the mixture was further heated and refluxed for 20 minutes. After cooling, the reaction mixture was poured into 50% saline 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 1
0: 1 → 5: 1) and purified (R) -7-deoxy-14-fluorodaunomycinone 12.1 mg (55%)
Was obtained as a red powder.

A part of this product was recrystallized from toluene to obtain dark red needle crystals, which were used as a sample for analysis.

mp 253-257 ° C. ▲ [α] ²⁰ _D ▼ -19 ° (c = 0.052, dioxane). NMR (CDCl ₃ ): δ = 1.95 to 2.20 (2H, m),
2.92 (1H, s), 2.85 to 3.40 (4H, m), 4.12 (3
H, s), 5.46 (2H, d, J = 47Hz), 7.43 (1
H, dd, J = 8 and 1 Hz), 7.79 (1H, t, J = 8)
Hz), 8.05 (1H, dd, J = 8 and 1Hz), 13.37
(1H, s), 13.79 (1H, s). IR (KBr): 3520, 1740, 1615, 15
90 cm ^-1 . MS (m / e): 400 [M ⁺ ], 382, 339. Elemental analysis: Calculated as _{^{C 21 H 17 FO 7: C}} , 63.00; H, 4.28%. Analytical value: C, 62.70; H, 4.27%. (R) -7-dioxy-14-14-fluorodaunomycinone 71.5 mg (0.179 mmol) was added to methylene chloride 21 m.
suspended in l, methyl orthoformate 0.4 ml (3.66 mmol),
Trimethylsilyl triflate-hexane 1M solution 0.04
ml (0.04 mmol) was added, and the mixture was stirred under ice cooling for 30 minutes and at room temperature for 2 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the red residue was purified by column chromatography (silica gel, benzene-ethyl acetate 20: 1), (R) -2- (2fluoro-1,1-dimethoxyethyl) -2. , 5,12-Trihydroxy-7-methoxy-1,2,3,4-tetrahydronaphthacene-6,11
73.6 mg (92%) of dione was obtained as a red powder.

mp 242.5-244 ° C. NMP (CDCl ₃ ): δ = 1.57 to 2.32 (2H, m),
2.52 (1H, s), 2.67 to 3.34 (4H, m), 3.55 (3
H, 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 (1
H, dd, J = 8 and 1 Hz), 13.54 (1H, s), 13.
88 (1H, s). IR (KBr): 3450, 1615, 1585 cm ^-1 . MS (m / e): 446 [M ⁺ ], 107. (R) -7-Dioxy-14-14-fluorodaunomycinone 16.5 mg (0.0412 mmol), methylene chloride 5.0 m
l, methyl orthoformate 0.09 ml (0.823 mmol), 1,2
-Bis (trimethylsilyloxy) ethane 1.0 ml (4.08
mmol) to a mixture of trimethylsilyl triflate-
0.015 ml (0.015 mmol) of 1M hexane solution was added, and the mixture was stirred for 30 minutes under ice cooling and at room temperature for 21.5 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained red residue was purified by 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,
16.3 mg (88%) of 2,3,4-tetrahydronaphthacene-6,11-dione was obtained as a red solid.

mp 259-264 ° C. NMR (CDCl ₃ ): δ = 1.58 to 2.24 (2H, m),
2.04 (1H, s), 2.73 to 3.35 (4H, m), 4.10 (3
H, s), 4.03 to 4.37 (4H, m), 4.75 (2H, d,
J = 48Hz), 7.40 (1H, d, J = 8Hz), 7.78 (1
H, t, J = 8Hz), 8.06 (1H, dd, J = 8 and 1)
Hz), 13.52 (1H, s), 13.88 (1H, s). IR (KBr): 3520, 3450, 1615, 15
95 cm ^-1 . MS (m / e): 444 [M ⁺ ], 105. (R) -2- (2-Fluoro-1,1-dimethoxyethyl) -2,5,12-trihydroxy-7-methoxy-
1,2,3,4-tetrahydronaphthacene-6,11-
Dione 33.3mg (0.0746mmol), chloroform 3.3m
0.30 ml (0.041 mmol) of a bromine-carbon tetrachloride 0.14 M solution was added to a mixture of 1, carbon tetrachloride (2.4 ml) and water (2.5 ml).
The mixture was heated under reflux on a 60 ° C. oil bath under irradiation with a 0 W tungsten lamp. After 15 minutes, 0.47 ml of bromine solution (0.063 mm
ol) was added 5 times at 5 minute intervals and the reaction was continued for 2 hours. After cooling, 0.15 ml (0.375 mmol) of 10% aqueous sodium hydroxide solution was added at 0 ° C.
And stirred for 15 minutes at room temperature. 1M hydrochloric acid was added to the reaction mixture.
It was neutralized by adding 4 ml 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 red residue obtained was then dissolved in 3.5 ml of THF, 0.35 ml of concentrated hydrochloric acid was added, and the mixture was 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 subjected to column chromatography (silica gel,
Separation and purification using benzene-ethyl acetate 10: 1 → 5: 1) gives (+)-14-fluorodaunomycinone 1
6.1 mg (52%) was obtained as a red powder.

This was recrystallized from benzene and a mixed solvent of benzene and hexane to obtain a sample for analysis.

mp 213-218 ° C. ▲ [α] ²⁰ _D ▼ + 179 ° (c = 0.106, dioxane). NMR (CDCl ₃ ): δ = 2.22 (1H, dd, J = 1)
5 and 5 Hz), 2.44 (1H, dt, J = 15 and 2)
Hz), 3.05 (1H, d, J = 19Hz), 3.27 (1H, d
d, J = 19 and 2 Hz), 3.29 to 3.49 (1H, m),
4.13 (3H, s), 4.66 (1H, s), 5.34 to 5.51 (1
H, m), 5.59 (2H, d, J = 48Hz), 7.46 (1
H, dd, J = 8 and 1 Hz), 7.83 (1H, t, J = 8)
Hz), 8.09 (1H, dd, J = 8 and 1Hz), 13,25
(1H, s), 14.01 (1H, s). IR (KBr): 3450, 1740, 1615, 15
90 cm ^-1 MS (m / e): 416 [M ⁺ ], 398, 380, 3
37. Elemental _{analysis: C 21 H 17 FO 8 ·} 0.5H 2 O Calculated: C, 59.30; H, 4.27 %. Analytical value: C, 59.12; H, 3.98%. (R) -2- (2-Fluoromethyl-1,3-dioxolan-2-yl) -2,5,12-trihydroxy-7
Bromine-carbon tetrachloride 0.14 M in a mixture of -methoxy-1,2,3,4-tetrahydronaphthacene-6,11-dione 16.1 mg (0.0362 mmol), chloroform 3.3 ml, carbon tetrachloride 2.4 ml, water 2.5 ml. 0.40 ml (0.054 mmol) of solution was added in 4 batches and irradiated with 60 W tungsten lamp 1.
The mixture was heated under reflux for 5 hours. After cooling, add 0.075 ml (0.188 mmol) of 10% sodium hydroxide aqueous 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, the same treatment as in Reference Example 5 was carried out to obtain a red residue.

This product was then dissolved in 3 ml of THF, 6 ml of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 15 hours. After cooling, the mixture was treated in the same manner as in Reference Example 5, and the residue was separated and purified using column chromatography (silica gel, benzene-ethyl acetate 10: 1 → 5: 1) to give (+)-14-fluorodaunomycinone. 3.2 mg (21%) was obtained as a red powder.

The NMR spectrum of this product coincided with that obtained in Reference Example 5.

2,3,6-Trideoxy-1,4-di-O-p-nitrobenzoyl-3-trifluoroacetamide-α-L
-Lixohexopyranose 40.7 mg (0.0752 mmol),
Molecular sieves 4A 267 mg, methylene chloride 4.0 m
l, a mixture of ether 3.2 ml, under an argon atmosphere, -4
Trimethylsilyl triflate 0.04ml (0.207
mmol) was added and the mixture was stirred for 25 minutes under ice cooling. Then, the reaction solution was cooled to −30 ° C., and (+)-14-fluorodaunomycinone 19.5 mg (0.0468 mmol) in THF solution 7
ml was added dropwise and the reaction was carried out at -7 to -15 ° C for 6 hours.
The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate-ethyl acetate and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude glycoside. Dissolve this in 2 ml of methylene chloride, 40 ml of methanol, 0.1M
Sequentially add 0.75 ml of sodium hydroxide aqueous solution and under ice cooling 20
Stir for minutes. After neutralizing with 10% acetic acid, dilute with water,
It was extracted with ethyl acetate. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained red residue was separated and purified by column chromatography (silica gel, chloroform → chloroform-acetone 30: 1) and (+)-3′-M-trifluoroacetyl-14-. 27.2 mg (91%) of 14-fluorodaunorubicin was obtained as a red powder.

mp 161.5-164 ° C. ▲ [α] ²⁰ _D ▼ + 185 ° (c = 0.108, dioxane). NMR (CDCl ₃ ): δ = 1.33 (3H, d, J = 6H
z), 1.65 to 2.55 (4H, m), 3.09 (1H, d, J =
19Hz, 3.32 (1H, d, J = 19Hz), 3.55 to 3.80
(1H, m), 3.95-4.40 (2H, m), 4.12 (3H,
s), 4.41 (1H, s), 5.36 (1H, t, J = 5H
z), 5.54 (2H, d, J = 48Hz), 5.50-5.67 (1
H, m), 6.66 (1H, brd, J = 8Hz), 7.45 (1
H, d, J = 8Hz), 7.83 (1H, t, J = 8Hz), 8.
08 (1H, d, J = 8Hz), 13.29 (1H, s), 14.05
(1H, s). IR (KBr): 3500, 3450, 1740, 17
20, 1615, 1590 cm ^-1 MS (m / e): 641 [M ⁺ ], 416, 398, 3
80,337. Elemental analysis value: Calculated as C ₂₉ H ₂₇ F ₄ NO ₁₁ : C, 54.30; H, 4.24; N, 2.18% Analytical value: C, 54.21; H, 4.45; N, 1.98% (+)-3'-N-Trifluoroacetyl-14-14
-Fluorodaunorubicin 19.2 mg (0.0299 mmol) was suspended in THF 0.77 ml and 0.05 M sodium hydroxide aqueous solution was added.
3.0 ml 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 with 1M hydrochloric acid and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. Concentrate the solvent under reduced pressure to about 2 ml,
About 20m after adding 0.6ml of 0.25M hydrochloric acid-methanol solution
l of ether was added to precipitate a precipitate. The supernatant was decanted and further triturated with ether to give 8.6 mg (49%) of (+)-14-14-fluorodaunorubicin hydrochloride as a red powder.

mp 209 ° C (decomp). ▲ [α] ²⁰ _D ▼ + 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 (1H,
dd, J = 14.1 and 5.3 Hz), 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 = 6.1H
z), 4.00 (3H, s), 4.17 (1H, q, J = 6.5H
z), 4.98 (1H, dd, J = 5.3 and 2.9Hz), 5.31
(1H, d, J = 3.2Hz), 5.47 (1H, d, J = 6.1H
z), 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 to 7.70 (1H, m), 7.86 (3H, br
s), 7.90 to 7.97 (2H, m), 13.26 (1H, s), 1
4.05 (1H, s). IR (KBr): 3450, 1735, 1615m, 1
590 cm ^-1 test example (cancer cell growth inhibitory effect) 10 cells of cultured lymphocytic leukemia cells (P388) of mouse were used.
% RPM fetal bovine serum-containing RPMI-1640 medium,
The number of cultured cells was adjusted to 5 × 10 ⁴ cells / ml, and the novel 14-14-fluorodaunorubicin derivative of the present invention was added thereto to a predetermined concentration, followed by culturing at 37 ° C. for 2 days. Using a Coulter Counter, the number of floating cells was counted, and from the growth inhibition rate for the control group, 50% cell growth inhibition concentration I
The results of determining C ₅₀ are shown in Table 1.

Claims (1)

[Claims] 1. A general formula (In the formula, R ¹ is a hydrogen atom or a trifluoroacetyl group.) A 14-fluorodaunorubicin derivative and a salt thereof.