WO1988005780A1

WO1988005780A1 - 14-fluorodaunorubicin derivatives

Info

Publication number: WO1988005780A1
Application number: PCT/JP1988/000075
Authority: WO
Inventors: Shiro Terashima; Fuyuhiko Matsuda; Teruyo Matsumoto; Michiyo Suzuki; Masako Ohsaki; Kaoru Yamada
Original assignee: Sagami Chemical Research Center
Priority date: 1987-01-30
Filing date: 1988-01-29
Publication date: 1988-08-11
Also published as: JPS63188694A; JPH06797B2

Abstract

14-Fluorodaunorubicin derivatives represented by general formula (I), (wherein R1 represents a hydrogen atom or a trifluoroacetyl group) and their salts. These compounds have an excellent oncostatic activity.

Description

Akira Takada

1 4-full-age rhodaunorubicin derivative

The present invention has the general formula

Trick

Minute

(Wherein, Mel R ¹ is a hydrogen atom or Bokurijutsufunorusai Roasechiru group _0> - relates to a salt of a full year old Rodaunorubishin derivatives and their - 1 4 represented by.

Further, the present invention relates to an intermediate which is important for producing the Ί4-full-year-old rhodaunorubicin derivative of the general formula (I), wherein the Ί4-full-year-old rhodaunorubicin derivative represented by the general formula (I) of the present invention is provided. Has use as an anticancer agent. The development of superior anticancer drugs is a strong social demand and an urgent matter. Anthracycline derivatives typified by adriamycin occupy an important position in medicine as anticancer drugs due to their strong anticancer activity. Numerous anthracycline derivatives have been developed. However, these derivatives are still unsatisfactory for use in the actual treatment of cancer in terms of the relationship between anticancer activity and side effects such as hair loss and myocardial toxicity. Accordingly, there is a strong demand for the development of novel antracycline analogs that exhibit superior characteristic anticancer activity.

Disclosure of the invention

Against this background, the present inventors have searched for a novel anthracycline analog having excellent anticancer activity, and as a result, have found the compound of the present invention and completed the present invention.

That is, the present invention provides a Ί4-full-age rhodaunorubicin derivative represented by the general formula (I). Further, the present invention provides a compound of the general formula (11), which is an important synthetic intermediate when synthesizing the general formula (e)

(Wherein R ² and R ³ together with the carbon atom to which they are attached form a cyclic or acyclic acetal group, or R ² and ¹ ^ ³ together represent an oxygen atom R ⁴ represents a hydrogen atom or a hydroxyl group.>

2-(2-full-year roethyl)-2,5, Ί 2-trihydroxy-7-methoxy-Ί, 2, 3, 4-tetrahydronaphthacene-6, Ί ジ-dione derivative To provide BEST MODE FOR CARRYING OUT THE INVENTION

The novel Ί4-full-age rhodaunorubicin derivative represented by the general formula (I) can be produced according to the following reaction formula.

CH T O 〇 OH Phase I

Second step

(4th step)

[No.

NHCOCF3

HO

(Step 6

Wherein R ² and R ³ together with the carbon atom to which they are attached form a cyclic or acyclic acetal group, or R ² and R ³ together represent an oxygen atom .

R ^J represents an acyl group. 〉

The steps will be described below in order. [No.

In this step, the (R) -2-acetyl-2,5, Ί2-trihydroxy-7-methoxy--, 2,3,4-tetrayl compound represented by the formula (I) is used. Hydronaphthacene-6, Ί Ί-Dimethyl (7-de-xydaunomycinone) is reacted with a brominating agent, and the 2-bromoacetyl form obtained as a reaction product is represented by the general formula

Μ-F (VI).

(Wherein Μ represents a quaternary ammonium or a metal atom.) By reacting with a fluoride represented by the formula (R) −2− (2−full-year lower acetyl)> -2, 5, Ί 2-Trihydroxy-7-Methoxy-1, 2, 3, 3-4-Tetrahydronaphthacene-6, 1 Ί-Dione (7 才キシ-Ί 4-Full ages Rodaunomycinone).

(R) -2-Acetyl-2,5, Ί2-trihydroxy-7-methoxy-2,3,4-tetratetranaphthacene represented by the formula (I), which is a raw material of the present invention. -6,

11-dione (7-doxydaunomycinone) is a commercially available daunorubicin hydrochloride produced by actinomycetes (Streptomyces peucet ius) produced by hydrogenolysis (Arcamone, et al., Tetrahedron Lett., 31, 3349). (1968)>.

The brominating agent used for the bromination of the compound (ΠΙ) includes bromine, pyridinium bromide perpromide, and bromide. Methyl ammonium repromide and the like can be exemplified. The reaction is desirably carried out in a solvent. As the reaction solvent, ether solvents such as tetrahydrofuran, dioxane and dioxolan are preferably used. The reaction proceeds smoothly at 0-5 ° C.

Examples of the fluoride represented by the above formula (VI) include quaternary ammonium salts such as tetrabutylammonium fluoride and tetraethylammonium fluoride, and lithium fluoride and sodium fluoride. , Potassium fluoride, cesium fluoride, silver fluoride and the like. In addition, when a fluoride is reacted with the 2-bromoacetyl compound obtained by bromination of the compound (m), the desired product can be obtained in good yield by coexisting with an inorganic acid or an organic acid or a salt thereof. it can.

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, Organic acids such as trifluromethanesulfonic acid can be exemplified, and salts of these acids include ammonium salts formed from bases such as pyridin, tributylamine, triethylamine and trimethylamine. . This reaction is preferably carried out in a solvent. Examples of the solvent include ether solvents such as tetrahydrofuran, dioxane, dioxolane, diglyme, dimethyl sulfoxide,, N-dimethylformamide, acetate Non-protonic solvents such as trill are preferred. The reaction is 0 ~ "! Run.

[Second process]

In this step, (R) -2- (2-fluoroacetyl) -2,5, ， 2-trihydroxy-7-methoxy2,3,3 of the above formula (la) obtained in the first step. 4-tert-hydronaphthacene-6, a 2-year-old (7-de-hydroxy--14-full-year-old rhodanomycinone) protecting the carbonyl group at the 2-position in the form of an acetal group The acetalization reaction is carried out, for example, by reacting trialkoxymethane in the presence of trimethylsilyl triflate, such as trimethoxy methane or trimethoxy. Examples include riethoxymethane, tripropoxymethane, etc. This step is desirably performed in a solvent, such as an alcoholic solvent such as methanol, ethanol, or propanol, methylene chloride, Ί, 2,2-dichloroethane. For example, a halogenated hydrocarbon solvent such as liquid form, carbon tetrachloride or the like, an ether solvent such as tetrahydrofuran or dioxane, or a mixed solvent thereof is used. proceed.

The acyclic acetal derivative obtained here can be obtained by using a diol such as ethylene glycol, trimethylene glycol, 2,2-dimethylpropane-1,3-diol in the presence of an acid catalyst in the presence of an acid catalyst. By performing the exchange reaction, a cyclic acetal derivative can be efficiently derived. Acid catalysts used in the acetal exchange reaction include: Examples thereof include sulfonic acids such as ruenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, and trifluromethanesulfonic acid, and inorganic acids such as sulfuric acid and hydrochloric acid.

The acetal exchange reaction can also be achieved by using various silyl disilyl compounds in the presence of trimethylsilyl triflate. Examples of the diol used include disilyl derivatives of the above diyls, namely, ,, 2-bis (trimethylsilyl thioxy) ethane, Ί, 3-bis (trimethylsilyl thioxy) propane, and 2,2-dimethyl- 1,3-bis (trimethylsilyl) -propane can be exemplified.

As the reaction solvent, a halogenated hydrocarbon solvent such as methylene chloride, Ί, 2-dichloroethane, chloroform and carbon tetrachloride, or an aromatic hydrocarbon solvent such as benzene, toluene and xylene is preferably used. The reaction proceeds smoothly from Ο to 100.

[Third process]

In this step, the 4-position of the compound represented by the general formula (Eb) is brominated, the obtained bromide is converted into a hydroxide ぺ, and the acetal group is removed. (2S, 4S) -2-(2-full roacetyl) -2,4,5, Ί2-tetrahydroxy-7,6-methoxy 2,3,4-tetrahydronaphthacene -6, 11-Di-sixene (14-Full-stained rhodaunomycinone) Bromination is carried out in methylene chloride, black form, Ί, 2-dichloromethane In halogen-based solvents such as loroethane and carbon tetrachloride, bromine,

N-Bromocooctamic acid imide, N-promoacetoamide, Ί, 3-dipromo-5,5-dimethylhydantoin or the like is used as a brominating agent. The reaction proceeds smoothly at O 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 an alkaline aqueous solution of Ο.ΊΊ. The reaction proceeds smoothly at 0-5 CTC. Examples of the aqueous aluminum solution include aqueous solutions of sodium hydroxide, potassium hydroxide, barium hydroxide and the like.

Deprotection of Asetaru is Te Bok Rahidorofuran, di old hexa emissions, 1, 2 - in a solvent such as dimethyl Bok Kishimetan can _¾ be carried out under acidic conditions. Hydrochloric acid, sulfuric acid and the like are preferably used as the acid used in the acidic condition. The reaction is carried out between room temperature and 100 ° C.

(4th process)

This step is for producing a -glycoside represented by the general formula (V) by reacting the compound represented by the formula (Ic) with a daunosamine derivative (W). The reaction can be performed in the presence of trimethylsilyl triflate according to the method described in -94990 [Step 5]

This step is for deprotecting the bis-glycoside represented by the general formula (V) obtained in the fourth step to produce a compound represented by the above formula (la). The deprotection in this step can be performed under a dilute alkaline condition using sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or the like in a solvent such as methanol or tetrahydrofuran acetone. The reaction proceeds smoothly from 0 ° C to room temperature.

[Sixth process]

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 (Eb>).

The deprotection in this step can be performed in a dilute alkaline aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate or the like at around room temperature.

The 14-full-age rhodaunorubicin of the formula (Ib) can be produced as a stable salt by treating it with an organic or organic acid. Salts are preferred. Examples of such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, or acetic acid, propionic acid, maleic acid, palmitic acid, citric acid, succinic acid, tartaric acid, and malic acid. And organic acids such as fumaric acid, glutamic acid, pantothenic acid, laurylsulfonic acid, methanesulfonic acid, and naphthalenesulfonic acid.

The usefulness of the 4- 4-year-old rhodaunorubicin derivative obtained as described above as a carcinostatic agent was confirmed by performing a malignant tumor cell growth inhibition test. The test was performed using mouse lymphocytic leukemia cells (P388) according to a standard method. I asked.

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 meanings of the abbreviations in the examples are as follows.

T H F: Tetrahydrofuran

P N B z: p-nitrobenzoyl group

Reference example

152 mg (0.269 mmol) of daunorubicin hydrochloride was dissolved in 3 OmJH of methanol, and 165 mg of 5% Pd-parium sulfate was added, followed by hydrogenolysis at the highest temperature for 2 hours. After diluting the reaction mixture 酢 with ethyl acetate, the catalyst is filtered off, the filtrate is dried over anhydrous sodium sulfate washed with water, and the solvent is distilled off under reduced pressure. Purified using benzene-ethyl acetate 5: Ί), 104 mg (100%) of (R) -7-derivative xidaunonomycinone was obtained as a red solid, which was further purified from benzene. Recrystallization gave a pure product. mp 22δ to 230 ° C.

(Literature: F. Arcamone, et al., J. Am. Chem. Soc., 86,

5334 (1964), 229-231).

[] ^ + 85 ° (C = 0. “Πδ, black mouth form”) (Literature value: same as above, [h] Sat ³ + 91. (c-0.11, black mouth form>).

NMR (CDCi3): δ = 1.88 to 2.12 (2H, m),

2.42 (3H, S), 2.73 to 3.35 (4H, fll), 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 (KB ">: 3520, 1715, 1615, 1585cm _1.

Example 1 (1st step)

CH ₃ 0 OH

(R) -7-Dessert Kishidaunomycinone 21.0mg

0.0549 mmol>, a mixture of 0.7 mg (0.0804 marl ol) of pyridinium promide perpromide and 4 m of THF were stirred at room temperature for 0.5 hours. The reaction mixture was diluted with ethyl acetate, washed successively with 〇% brine and saturated brine, and then dried over anhydrous sodium sulfate. Dried on the stream. The solvent was distilled off under reduced pressure to obtain crude 7-dexoxy-Ί4-promodaunomycinone as a red powder. This was suspended in 4 mils of THF, and 30.9 mg (0.179 mmol) of p-toluenesulfonic anhydride and 0.29 (0.29 mmol!) Of a 1 M solution of tetrafluoroammonium fluoride in HF were sequentially added, and the mixture was added at room temperature for 30 minutes. After stirring, the mixture was heated under reflux. One hour later, 0.04 mil (0.04 mmo!) Of tetrabutylammonium fluoride was added, and the mixture was ripened and refluxed for another 20 minutes.After cooling, the reaction mixture was poured into 50% saline and acetic acid was added. The extract was washed successively with water and saturated saline 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). And benzene-ethyl acetate (Ί0: Ί → 5: Ί)) to give (R> -7-dexoxy-Ί4-fluoraudanomycinone 12.1 mg (55%) as a red powder. A part of this was recrystallized from toluene to obtain a dark red needle-like crystal, which was used as a sample for analysis.

mp 253-257 ° C.

[] ^ 19 ° (C = 0.052, dioxane).

N R (C D C I Q): δ = 1.95 to 2.20 (2H, m),

2.92 (1H, S>, 2.85 ~ 3.40 (4H, m), 4.12 (3H, s), 5.46 (2H 5 d, J = 47Hz), 7.43 (1H, dd, J = 8 and 1HZ), 7.79 (1Η , ΐ, J = 8HZ), 8.05 (1H, dd, J = 8 and 1Hz), 13.37 (1H, S), 13.79 (1H, S). IR (KB ">": 3500, 1740, 1615, 1590cm-1

MS (m / e): Class [M +], 382, 339.

Elementary analysis: as C ₂₁ H ₁₇ F_〇 ₇

Calculated: C, 63.00; H, 4.28%.

Analytical value: C, 62.70; H, 4.27%.

Example 2 (2nd step)

〇 OH

(R) -7-Dexyloxy-Ί4-Full-age rhodaunomycinone 71.5 mg (0.179 mmol) is suspended in methylene chloride 2Ίmi, and methyl orthoformate O mJ? (3.66miiiol), trimethylsilyl triflate -Hexane Ί M solution 0.04 mil (0.04 mmol was added and the mixture was stirred under water cooling for 30 minutes and at room temperature for 2 hours. The reaction mixture was poured into saturated sodium bicarbonate water and extracted with methylene chloride. The solvent was evaporated under reduced pressure, and the red residue was subjected to column chromatography (silica gel, benzene-ethyl acetate).

20: 1〉 and purified using (R)-2-(2-full l-1, 1-dimethyl oxethyl)-2, 5, 5, 12-trimethyl oxi-7-methoxy 2, 3, 4-Tetrahydrona 73,6 mg (92%) of phthacene-6, Ί-diamine was obtained as a red powder.

m p 242.5 to Z44 ° C

MR (CDCI 3) δ = 1.5 to 2.32 (2H, m), 2.52 (1H.S) 2.67 to 3.34 (4H, m), 3.55 (3H, S) 3.58 (3H.S), 4.10 (3H, s) _{>, 4.62 (2H s d,} J = 47Hz), 7.39 (1H, dd, J = 8 and 1HZ), 7.77 (1H, t , J = 8Hz ", 8.04 (1H, dd, J = 8 and 1 Hz}, 13.54 (1H, S), 13.88 (1H 5 S).

IR (KB ">": 3450, 1615, 1585cm- ¹⁾ .

MS (m / e): 446 ( ⁺ ), 107.

Example 3 (2nd step)

(R) -7-deoxy-14-full-age rhodaunomycinone 16.5mg (0.0412mmol), methylene chloride 5.0mJU methyl orthoformate 0.09 (0.823mmol), 1,2-bis (trimethylsilyl-yloxy) ethane 1.0 A mixture of m £ (4.08mmol) To the mixture was added 0.015 mJl (0.015 mmol) of a trimethylsilyl triflate-hexane キサン M solution, and the mixture was stirred under ice cooling for 30 minutes and at room temperature for 21.5 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting red residue was purified using column chromatography (silica gel, benzene-ethyl acetate 10: 1) to give (R> -2-(2-fluoromethylmethyl). -Ί, 3-才才-2-yl)-2, 5, Ί 2-trihydroxy-7-methoxy-1, 2, 3, 3, 4-tetrahydridnaphthacene-6, 1 16.1 mg (88%) of 1-dione were obtained as a red solid ₍ mp 259-264. C.

NMR (CDCI3): δ = 1.58 to 2.24 (2H, m),

2.04 (1H, S>, 2.73 to 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 (ΙΗ, ΐ, J = 8HZ), 8.06 (1H, dd, J = 8 and 1HZ), 13.52 (1H, S), 13.88 (1H, s).

IR (KB ">: 3520, 3450, 1615, 1595cm _1.

MS (m / e): 444 [M ⁺ ), 105. Example 4 Example 3

C

(R)-2-(2-full-year-Ί, Ί-dimethyl)-2, 5, Ί 2-trihydric □ xi-7-methoxy-1, 2, 3, 4- Tetrahydronaphthacene-6, dione

To a mixture of 33.3 mg (0.0746 mmol), black-mouthed form 3.3 · ηΰ, carbon tetrachloride 2.4 mi ?, and water 2.5I, add 0.30 mi (0.041 mmol) of bromine-carbon tetrachloride 0.14 、 solution, and irradiate with a 60 W tungsten lamp. After heating and refluxing on an oil bath at 60 ° G. Ί After 5 minutes, 0.47 (0.063 mmol) of a bromine solution was further added in 5 portions at 5 minute intervals, and the reaction was further performed for 2 hours. 0.15 (0.375 mmol) of a 0% aqueous sodium hydroxide solution was added at C, and the mixture was stirred at the same temperature for 10 minutes and at room temperature for 15 minutes, and 1 M hydrochloric acid Q.4mJi was added to the reaction mixture. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Dissolved in 3.5ra, added 0.35 mL of concentrated hydrochloric acid and stirred at room temperature for about 6 hours Diluted the reaction mixture with water and extracted with chloroform. . The extract water, saturated The solvent was washed successively with 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, benzene-ethyl acetate Ί0: 1 → 5: 1) to obtain (+)-14-full-age rhodaunomycinone (52%) as a red powder.

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

mp 213-218 ° C.

[(X) ^ 20 + 179 ° (C = h.106, dioxane).

NMR (CDCI3): 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 to 3.49 (lH, m), 4.13 (3H, S), 4.66 (1H, S), 5.34 to 5,51 (1H, m),

5.59 (2H, d, J = 48Hz), 7.46 (1H, dd, J = 8 ぴ 1HZ), 7.83 (1H, t, J = 8HZ), 8.09 (1H, dd, J = 8 and 1 Hz), 13.25 (1H, s), 14.01 (1H, S).

IR (KB "): 3450, 1740, 1615, 1590cnT 1.

MS (m / e): 416 (M ⁺ ), 398, 380, 337.

Elemental analysis value: C ₂ lHi7F〇 ₈ ♦ As 0.5H ₂₀

Calculated: C, 59.30; H, 4.27%.

Analytical value: C, 59.12; H, 3.98%. Example 5_ [third step]

(R)-2-(2-Fully-aged methyl -Ί, 3 -Dimethyl oxolan-2 -yl>-2,5, Ί2 -Trihydroxy-7 -Methoxy 2,3,4- Tetrahydronaphthacene-6, Ί 1 -diene 16. img (0, 0362 mmol), chloroform form 3.3 m, carbon tetrachloride 2.4 m, water 2.5ιη 混合 mixture of bromine-carbon tetrachloride 0.U ΜSolution 0.40Ι (0.054 mmol) was added in four portions, and the mixture was ripened and refluxed for 1.5 hours under irradiation with a 6 OW tungsten lamp.After cooling, at 0, Ί0% aqueous sodium hydroxide solution 0.075 mJl (0.188 The mixture was stirred at room temperature for 10 minutes and stirred at room temperature for Ί5 minutes.The reaction mixture was neutralized with 0.2 M hydrochloric acid (0.2 m) and treated in the same manner as in Example 4 to obtain a red residue. Was.

This was then dissolved in 3 mi of THF, and 6 mi of concentrated hydrochloric acid was added, followed by ripening and reflux for 5 hours. After the cold S3, the mixture was treated in the same manner as in Example 4, and the residue was separated and purified using column chromatography (silica gel, benzene-ethyl acetate {0: 1 → 5:}) to give (+)-4- 3.2 mg (21%) of fluorodaunomycinone was obtained as a red powder. The NMR spectrum of this was obtained in Example 4.

Example 6 (4th step and 5th step)

2,3,6-Trilide Acetate 4-Di-0-P-Nitrite Benzoyl-3-Triflumelate Loacet Amide--L-Lixohexopyranose 40.7 mg (0.0752 mmol), Moreki Yuraichi To a mixture of Cias 4A 267 mg and methylene chloride 4.0 mJK ether 3.2 mil was added trimethylsilyl triflate 0.04 mi) (0.207 mmol) at —4 CTC under an argon atmosphere, and the mixture was stirred under ice-cooling for 25 minutes. Then, the reaction solution was cooled to 3 ° C, and 7 mi of THF solution of 19.5 mg (0.0468 mmo!) Of (+)-Ί4-full-age rhodaunomycinone was added dropwise. The reaction was carried out for 6 hours at C. The reaction mixture was poured into a mixed solution of saturated aqueous sodium hydrogen carbonate and Ityl acetate, and extracted with ethyl acetate. The extract was washed with water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude glycoside. This was dissolved in methylene chloride (2iiiJl), and methanol 40IRJU 0.1M aqueous sodium hydroxide solution 0.75 was sequentially added thereto, followed by stirring under ice cooling for 20 minutes. After neutralization with 〇% acetic acid, it was diluted with water and extracted with ethyl acetate. The extract was washed successively with water and saturated saline, 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, pore-form → chloroform-acetate). Separate and purified in step 30) Ί) to obtain 27.2 mg (91%) of (+)-3′-N-trifluoroacetyl-4-fluorofluoraunorubicin as a red powder.

mp 161.5-164.

[] ²⁰ + 185 ° (c = 0.108, dioxane).

NMR (CDCI I): δ = 1.33 (3Η, d, J = 6Hz),

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 to 4.40 (2H, m), 4 2 (3H, s), 4.41 (1H, s), 5.36 (1H, t, J = 5 Hz), 5.54 (2H, d, J = 48 Hz), 5.50 to 5.67 (1H, m), 6.66 ( 1H, brd, J = 8Hz>, 7.45 (1H, d, J = 8Hz) _Λ -7.83 (1H, t, J = 8HZ), 8.08 (1H, d, J = 8Hz), 13.29 (1H, S>, 14.05 (1H, S).

IR (KB ">": 3500, 3450, 1740, 1720, 1615, 1590 cm. MS (m / e): 641 (M +), 41 "6, 398, 380, 337.

Elemental analysis: C29H ₂ jF ₄

Calculated value: C, 54.30; Η, 4.24; Ν, 2.18% Analytical value: C, 54.21; 第, 4.45; Ν, 1.98% Example 7 [Sixth step]

(+)-3'-N-Trifluroyl-Acetyl-Ί4-Full-flooded daunorubicin (19.2 mg, 0.0299 mmol) was suspended in 0.77 mJi of THF, and a 0.05 M aqueous sodium hydroxide solution 3.0 (ΐ The mixture was stirred for 5 minutes at room temperature and for 4 minutes at room temperature.The reaction mixture was adjusted to 9 with hydrochloric acid and extracted with chloroform.The extract was washed with water and washed with anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to about 2 mJH, 0.25 M hydrochloric acid-methanol solution 0.6 mJJ was added, and then about 2 OmJ3 ether was added. To precipitate a precipitate. The supernatant was removed by decantation and further triturated with ether to obtain (+)

-1-Fluorodaunorubicin hydrochloride & .6 mg (49) was obtained as a red powder. -m p 209 (decorap).

[] 20 + 176 ^β (C-0.091, methanol).

_{NMR ((CD 3) 2 SO} ): δ = 1.16 (3H, d, J = 6.5

HZ), 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 = U, 1, and 5,3Hz), 2.21 (1 ^, (1 ^ = 14.1)

HZ), 2.89 (1H, d ₅ J = 18.3HZ), 3.09 (1H, d, J = 18.3HZ), 3.57 (1H, rd, J = 6.1Hz),

4.00 (3H, S), 4.17 (IH.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, (id, J = 47.2 and 17.6Hz)), 5.64 (1HJd, J = 47.2 and 17.6HZ) 5.63 (1H, S), 7.6 to 7.70 (1Η, ΐη), 7.86 (3H, brs), 7.90 ~ 7.97 (2H, m), 13.26 (1H, s), 14.05 (1H, S) ₀

IR (KB "): 3450, 1735, 1615, 1590cm _1.

Test example (cancer cell growth inhibitory effect)

The lymphocytic leukemia cell cultures (P388) of a mouse, R PM I of Ί 0% fetal calf serum-containing - in addition to the 1 640 culture solution, the culture cell number was 5 X Ί 0 ⁴ pieces ZmJH this adjustment, the present invention New Ί 4- Rusai rhodaunorubicin derivative was added to a predetermined concentration, and the cells were cultured at 37 ° C for 2 days. A Coulter counter, by counting the number of adherent cells from growth inhibition rate to the control group, shows the results obtained 50% cell growth inhibitory concentration IC ₅₀ to the Ί table.

Table 1 IV .4 _ Fluorodaunorubicin derivatives

₅ () on cultured mouse lymphocytic leukemia cells (P388)

Compound ¹ 50

(g / mi)

(+)-4-Full-year-old rhodaunorubicin 1.5X 10 ' ⁴ hydrochloride

(+) - 3 '- N - Bok Riffle old Roasechi 1.9X 0 ^"3 Le - 1 4 - Full old Rodaunorubishin

Claims

Range of request

1. General formula

(In the formula, R ¹ represents a hydrogen atom or a triacetyl group.)

14-full-year-old rhodaunorubicin derivative represented by the formula:

2 General formula

(Wherein R ² and R ³ together with the carbon atom to which they are attached form a cyclic or acyclic acetal group, or R ² and ¹ "^ ³ together form an oxygen atom R ⁴ represents a hydrogen atom or a hydroxyl group.) An intermediate for synthesizing a 14-full-age rhodaunorubicin derivative according to claim 2, which is represented by).