JPH0631299B2 - 14-Fluoro-4-demethoxydaunorubicin 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-fluoro-4-demethoxydaunorubicin derivative and a salt thereof.

14-Fluoro-4 represented by the general formula (I) of the present invention
-Demethoxydaunorubicin derivatives have use as anti-cancer agents.

[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 so far. 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, the development of a novel anthracycline analog showing more excellent characteristic anticancer activity is strongly desired.

[Problems to be solved by the invention]

Against the above background, as a result of the present inventors searching 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]

Novel 14-fluoro-represented by the general formula (I)
The 4-demethoxydaunorubicin derivative can be produced according to the following reaction.

(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-1,2,3,4-tetrahydronaphthacene-6,11-dione [7-deoxy-4-demethoxydaunomycinone) (II) The 2-bromoacetyl derivative obtained by reacting with a brominating agent is a fluoride represented by the general formula MF- (VIII) (wherein M represents a quaternary ammonium or a metal atom). By reacting with
(R) -2- (2-fluoroacetyl) -2,5,12-trihydroxy-represented by the general formula (III)
1,2,3,4-tetrahydronaphthacene-6,11-
It is intended to produce dione (7-deoxy-14-fluoro-4-demethoxydaunomycinone).

(R) -2-acetyl-2,5,12-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11 represented by the general formula (II), which is a raw material of the present invention, is used.
-Dione is an optical resolution of (±) -2-acetyl-2,5,12-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione with an optically active acetal (K. Tamoto, et al., Tetrah
edron, 40 , 4617 (1984). Or (R) -2,5,12-trihydroxy-1,2,
3,4-tetrahydronaphthacene-6,11-dione-
Conversion from 2-carboxylic acids (Y. Kimura, et.
al. , Bull. Chem. Soc. Jpn. , 5
9 , 415 (1986). reference. ) Etc. can be easily synthesized.

Examples of the brominating agent used for bromination of II include bromine, pyridinium bromide perbromide, phenyltrimethylammonium tribromide and the like. The reaction is desirably carried out in a solvent, and as the reaction solvent, an ether solvent such as tetrahydrofuran, dioxane or dioxolane is preferably used. The reaction proceeds smoothly at 0 ° C to 50 ° C.

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. Further, when the 2-bromoacetyl derivative obtained by bromination of II is reacted with a fluoride, an objective compound can be obtained in good yield by coexisting an inorganic or organic acid or a salt thereof. Examples of usable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, or acetic acid, propionic acid, maleic acid,
Organic acids such as succinic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid can be exemplified, and salts of these acids include bases such as pyridine, tributylamine, triethylamine, and trimethylamine. The ammonium salt etc. which are formed can be illustrated. This reaction is desirably carried out in a solvent, and as the solvent, ether solvents such as tetrahydrofuran, dioxane, dioxolane, diglyme, etc., and aprotic solvents such as dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile and the like are preferable. The reaction is 0 ℃ -1
It proceeds smoothly at 00 ° C.

[Second Step] In this step, (R) -2- (2-fluoroacetyl) -2,5,12-trihydroxy-1, obtained in the first step,
Protect the carbonyl group at the 2-position of 2,3,4-tetrahydronaphthacene-6,11-dione (7-deoxy-14-fluoro-4-demethoxydaunomycinone) (III) 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. This step is preferably carried out in a solvent, such as an alcohol solvent such as methanol, ethanol or propanol, methylene chloride, 1,
A halogenated hydrocarbon solvent such as 2-dichloroethane, chloroform or carbon tetrachloride, an ether solvent such as tetrahydrofuran or 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. 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 0 ° C to 100 ° C.

[Third Step] In this step, the compound represented by the general formula (IV) is brominated at the 4-position to convert the obtained bromide into a hydroxide.
By removing the acetal group, (2S, 4S) -2- (2-fluoroacetyl) -2, represented by the general formula (V),
It is intended to produce 5,4,12-tetrahydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione (14-fluoro-4-demethoxydaunomycinone).

Bromination is performed by using bromine, N-bromosuccinimide, N-bromoacetamide, 1,3-dibromo-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 0.1-1.0 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-fluoro-4-demethoxydaunorubicin 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 and maleic acid. , Palmitic acid, citric acid, succinic acid, tartaric acid, malic acid,
Examples thereof include organic acids such as fumaric acid, glutamic acid, pantothenic acid, laurylsulfonic acid, methanesulfonic acid, and naphthalenesulfonic acid.

The 14-fluoro-4-demethoxydaunorubicin derivative obtained as described above was confirmed to be useful as an anticancer agent by conducting a malignant tumor cell growth inhibition test. As the reagent, mouse lymphocytic leukemia cells (P388) were used.
It was carried out according to a conventional method and the inhibition rate was obtained.

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 PPTS: Pyridinium p-toluenesulfonate Reference Example 1 204 mg (0.578 mmol) of (R) -7-deoxy-4-demethoxydaunomycinone was dissolved in 20 ml of THF, and 242 mg of pyridinium bromide perbromide was dissolved.
(0.756 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, 50% brine,
The organic layer was washed successively with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give crude 7-deoxy-
14-Bromo-4-demethoxydaunomycinone was obtained as an orange powder. Suspend this in 40 ml of THF,
310 mg of anhydrous p-toluenesulfonic acid (1.80 mmo
l), tetrabutylammonium fluoride-THF1
2.9 ml (2.90 mmol) of M solution was sequentially added, and the mixture was stirred at room temperature for 30 minutes, and then heated under reflux. After 1 hour, 0.6 ml of tetrabutylammonium fluoride was added, and the mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was poured into 50% saline and extracted with ethyl acetate. The extract was washed successively with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 239 mg of a red residue obtained was purified by column chromatography (silica gel, benzene-ethyl acetate 20: 1), and then (R) -7-deoxy-14-fluoro-4-de 149 mg (69%) of methoxydaunomycinone was obtained as a vermilion powder. A part of this was recrystallized from toluene to give red needle crystals, which were used as a sample for analysis.

mp. 251-255 ° C. ▲ [α] ²⁰ _D ▼ -34.8 ° (c 0.058, dioxane). NMR (CDCl ₃ ): δ = 1.78 to 2.22 (2
H, m), 2.80 (1H, s), 2.85 to 3.28.
(4H, m), 5.44 (2H, d, J = 47Hz),
7.73 to 7.96 (2H, m), 8.26 to 8.52
(2H, m), 13.50 (2H, s).

IR (KBr): 3510, 1735, 1625, 15
90 cm ^-1 .

MS (m / e): 370 [M ⁺ ], 352, 309.

Elemental analysis: H ₂₀ H ₁₅ FO ₆ Calculated: C, 64.87; H, 4.08 %.

Analytical value: C, 64.78; H, 4.17%.

Reference example 2 (R) -7-deoxy-4-demethoxydaunomycin 10.7 mg (0.0304 mmol) was dissolved in THF 1 ml, and pyridinium bromide perbromide 13.5 mg was dissolved.
(0.0422 mmol) was added and the mixture was reacted at room temperature for 2.5 hours. Crude 7-deoxy-14-bromo-4-demethoxydaunomycinone obtained by treating in the same manner as in Reference Example 1 was dissolved in 2 ml of THF, and 24.3 mg of PPTS (0.
0967 mmol), tetrabutylammonium fluoride-1M THF solution 0.18 ml (0.18 mmo
1) were sequentially added, and the mixture was heated under reflux for 30 minutes at room temperature and then for 1 hour. The same treatment as in Reference Example 1 was performed, and the obtained residue was purified by column chromatography (silica gel, benzene-ethyl acetate 20: 1) to give (R) -7-deoxy-.
14-Fluoro-4-demethoxydaunomycinone 6.
Obtained 1 mg (54%) as a red solid. NM of this thing
The R spectrum was identical to that obtained in Reference Example 1.

Reference example 3 337 mg (0.909 mmol) of (R) -7-deoxy-14-fluoro-4-demethoxydaunomycinone was suspended in 67 ml of methylene chloride, and methyl orthoformate2.
0 ml (18.3 mmol), trimethylsilyl triflate-hexane 1M solution 0.18 ml (0.18 mm
ol) 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. The solvent was evaporated under reduced pressure, and 368 mg of a red solid residue was purified by column chromatography (silica gel, benzene-ethyl acetate 100: 1),
(R) -2- (2-Fluoro-1,1-dimethoxyethyl) -2,5,12-trihydroxy-1,2,3,4
-Tetrahydronaphthacene-6,11-dione 331 mg
(88%) was obtained as a red powder.

mp. 206.5-209.5 ° C. NMR (CDCl ₃ ): δ = 1.62 to 2.37 (2
H, m), 22.53 (1H, s), 2.60 to 3.3.
0 (4H, m), 3.56 (3H, s), 3.60 (3
H, s), 4.62 (2H, d, J = 47Hz), 7.
72 to 7.95 (2H, m), 8.22 to 8.57 (2
H, m), 13.53 (1H, s), 13.58 (1
H, s).

IR (KBr): 3600, 3470, 1620, 15
85 cm ^-1 .

MS (m / e): 416 [M ⁺ ], 107.

Reference example 4 4.5 mg of (R) -7-deoxy-14-fluoro-4-demethoxydaunomycinone (0.0122 mmo)
l), methyl orthoformate 0.12 ml, THF 1 ml,
A catalytic amount of trimethylsilyl triflate was added to a mixture of 0.5 ml of methanol, and the mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 2 minutes.
Stir for 2 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give crude (R) -2-
(2-fluoro-1,1-dimethoxyethyl) -2,
5,12-Trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione was obtained. This product was dissolved in benzene, ethylene glycol and a catalytic amount of camphorsulfonic acid were added, and the mixture was heated under reflux for 18 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 residue was purified by column chromatography (silica gel, benzene-ethyl acetate 20: 1) to give (R)-
2- (2-fluoromethyl-1,3-dioxolane-2
-Yl) -2,5,12-trihydroxy-1,2,
4.9 mg (97%) of 3,4-tetrahydronaphthacene-6,11-dione was obtained as an orange solid.

mp. 218-221.5 ° C.

NMR (CDCl ₃ ): δ = 1.60 to 2.48 (2
H, m), 2.06 (1H, s), 2.55 to 3.33
(4H, m), 4.02 to 4.45 (4H, m), 4.
75 (2H, d, J = 48Hz), 7.65 to 8.00
(2H, m), 8.24-8.57 (2H, m), 1
3.51 (1H, s), 13.54 (1H, s).

IR (KBr): 3460, 1620, 1590 cm ^-1 .

MS (m / e): 414 [M ⁺ ], 105.

Reference example 5 (R) -2- (2-Fluoro-1,1-dimethoxyethyl) -2,5,12-trihydroxy-1,2,3,4
-Tetrahydronaphthacene-6,11-dione 301 mg
(0.722 mmol), chloroform 30 ml, carbon tetrachloride 15 ml, and water 22.5 ml were mixed with bromine-carbon tetrachloride 0.067M solution 5.8 ml, and heated under reflux on a 60 ° C. oil bath under white light irradiation. went. After 15 minutes, 1.7 ml of another bromine solution was added, and then every 5 minutes 1.65 m
A total of 14.1 ml (0.939 mmol) was added four times for each l, and the reaction was carried out for 2 hours. After cooling, 1.5 ml (3.75 mmol) of 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at 0 ° C. for 10 minutes and further at room temperature for 25 minutes. The reaction mixture was neutralized by adding 3.8 ml of 1M hydrochloric acid and then 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 dissolved in 30 ml of THF, 6 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 16.5 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 evaporated under reduced pressure, and the residue was subjected to column chromatography (silica gel, benzene-ethyl acetate 20:
Separation and purification using (1 → 10: 1), (+)-14-
Fluoro-4-demethoxydaunomycinone 171mg
(61%) was obtained as a vermilion powder. This was recrystallized from benzene and a benzene-hexane mixed solvent to obtain a sample for analysis.

mp. 129.5-132 ° C.

▲ [α] ²⁰ _D ▼ + 162 ° (c 0.111, dioxane).

NMR (CDCl ₃ ): δ = 2.23 (1H, dd, J
= 14 and 5 Hz), 2.42 (1H, dt, J = 1)
4 and 2 Hz), 3.04 (1H, d, J = 19H
z), 3.27 (1H, dd, J = 19 and 2H
z), 3.36 (1H, t, J = 3Hz), 4.63
(1H, s), 5.33 to 5.48 (1H, m), 5.
57 (2H, d, J = 48Hz), 7.75 to 8.02
(2H, m), 8.25 to 8.53 (2H, m), 1
3.25 (1H, s), 13.57 (1H, s).

IR (KBr): 3450, 1735, 1620, 15
85 cm ^-1 .

MS (m / e): 386 [M ⁺ ], 368, 350, 3
07.

Elemental analysis: Calculated as _{C 20 H 15 FO 7: C} , 62.18: H, 3.91%.

Analytical value: C, 62.18; H, 3.92%.

Reference example 6 (R) -2- (2-Fluoromethyl-1,3-dioxolan-2-yl) -2,5,12-trihydroxy-
1,2,3,4-tetrahydronaphthacene-6,11-
To a mixture of 4.9 mg (0.0118 m-mol) of dione, 1 ml of chloroform, 0.5 ml of carbon tetrachloride and 0.8 ml of water, 0.23 m of a bromine-0.067M carbon tetrachloride solution.
1 (0.0153 mmol) was added in 4 portions, and 60
The mixture was heated under reflux for 70 minutes under irradiation with a W tungsten lamp. After cooling, 10% sodium hydroxide aqueous solution 0.03 at 0 ° C
ml (0.075 mmol) was added, and the mixture was stirred at the same temperature for 15 minutes and further at room temperature for 10 minutes. After neutralizing with 1M hydrochloric acid, the mixture 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 red residue obtained was then dissolved in 1 ml of THF, 2 ml of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 16.5 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 evaporated under reduced pressure, and the residue was separated and purified by column chromatography (silica gel, benzene-ethyl acetate 20: 1 → 10: 1),
0.6 mg (13%) of (+)-14-fluoro-4-demethoxydaunomycinone was obtained as a vermilion powder. The NMR spectrum of this product coincided with that obtained in Reference Example 5.

Example 1 2,3,6-Trideoxy-1,4-di-O-p-nitrobenzoyl-3-trifluoroacetamide-α-L
-Lixohexopyranose 108 mg (0.199 mmo
1), molecular sieves 4A (803 mg), methylene chloride (10 ml), and ether (8 ml) were added to a mixture of trimethylsilyl triflate (0.1%) at -40 ° C under an argon atmosphere.
08 ml (0.414 mmol) was added, and the mixture was cooled with ice to 40
Stir for minutes. The reaction is then cooled to -20 ° C,
(+)-14-Fluoro-4-demethoxydaunomycinone 43.4 mg (0.112 mmol) in THF solution 6
ml was added dropwise, and the mixture was reacted at -10 to -15 ° C for 5.5 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.
This product was then dissolved in 100 ml of methanol, 2.0 ml of 0.1 M aqueous sodium hydroxide solution was added under ice cooling, and the mixture was stirred at the same temperature for 20 minutes. 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, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a red residue. Separation and purification using column chromatography (silica gel, chloroform → chloroform-acetone 30: 1),
(+)-3'-N-trifluoroacetyl-14-fluoro-4-demethoxydaunorubicin 62.6 mg (91
%) As an orange powder.

mp. 161 to 163.5 ° C. [α] ²⁰ _D ▼ + 173 ° (c 0.133, dioxane).

NMR (CDCl ₃ ): δ = 1.33 (3H, d, J =
6 Hz), 1.65 to 2.20 (2 H, m), 2.27
(1H, dd, J = 15 and 5 Hz), 2.40 (1
H, dt, J = 15 and 2 Hz), 3.12 (1H,
d, J = 19 Hz), 3.37 (1H, dd, J = 19)
And 2 Hz), 3.71 (1H, dd, J = 9 and 3 Hz), 4.06 to 4.40 (2H, m), 4.44.
(1H, s), 5.37 (1H, t, J = 4Hz),
5.57 (2H, d, J = 48Hz), 5.58 (1
H, d, J = 3Hz), 6.71 (1H, d, J = 9H)
z), 7.78 to 8.03 (2H, m), 8.30 to
8.54 (2H, m), 13.36 (1H, s), 1
3.67 (1H, s).

IR (KBr): 3450, 1740, 1720, 16
25,1590 cm ^-1 .

MS (m / e): 611 [M ⁺ ], 386, 368, 3
50,307.

Elemental _{analysis: C 28 H 25 F 4 NO} 10 · 0.75H 2 O Calculated: C, 53.81; H, 4.27 ; N, 2.24
%.

Analytical values: C, 53.78; H, 4.18; N, 2.36.
%.

Example 2 (+)-3'-N-trifluoroacetyl-14-fluoro-4-demethoxydaunorubicin 22.9 mg (0.
0375 mmol) in 0.45 ml of THF,
3.8 ml of 0.05 M sodium hydroxide aqueous solution was added, and the mixture was stirred 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. The solvent was concentrated under reduced pressure to about 2 ml, 0.75 ml of a 0.25M hydrochloric acid-methanol solution was added, and then about 30 ml of ether was added to precipitate a precipitate. The supernatant was decanted and further triturated with ether to give 4.8 mg (23%) of (+)-14-fluoro-4-demethoxydaunorubicin hydrochloride as an orange powder.

mp. 231-235 ° C.

▲ [α] ²⁰ _D ▼ (c 0.082, methanol).

NMR ((CD ₃ ) ₂ SO): δ = 1.17 (3H,
d, J = 6.6 Hz), 1.69 (1H, dd, J = 1)
2.5 and 4.1 Hz), 1.89 (1H, dt, J
= 12.5 and 3.3 Hz), 2.15 (1H, d
d, J = 14.1 and 5.4 Hz), 2.23 (1
H, d, J = 14.1 Hz), 2.94 (1H, d, J
= 18.4 Hz), 3.12 (1H, d, J = 18.4)
Hz), 3.56 (1H, brd, J = 6.0 Hz),
4.17 (1H, q, J = 6.6Hz), 4.99 (1
H, dd, J = 5.4 and 3.0 Hz), 5.31
(1H, brd, J = 3.3Hz), 5.46 (1H,
d, J = 6.0 Hz, 5.58 (1H, dd, J = 4)
7.3 and 17.5 Hz), 5.62 (1H, dd,
J = 47.3 and 17.5 Hz), 5.66 (1H,
s), 7.97 to 8.04 (2H, m), 8.27 to
8.34 (2H, m).

IR (KBr): 3450, 1740, 1625, 15
90 cm ^-1 .

Test Example (Cancer Cell Proliferation Inhibitory Action) Mouse lymphocytic leukemia cultured cells (P388)
% Fetal calf serum-containing RPMI-1640 culture solution, and the number of cultured cells is adjusted to 5 × 10 ⁴ cells / ml so that the novel 14-fluoro-4-demethoxydaunorubicin derivative of the present invention has 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 IC50 was calculated from the growth inhibition rate relative to the control group.

Claims (1)

[Claims] 1. A general formula (In the formula, R ¹ is a hydrogen atom or a trifluoroacetyl group.) A 14-fluoro-4-demethoxydaunorubicin derivative and a salt thereof.