NL8502303A - ANTHRACYCLINE GLYCOSIDES. - Google Patents

Description

ï ^ Ί 853079 / vdV / cd

Short designation: Anthracycline glycosides.

The invention relates to anthracyclines glycosides, to processes for their preparation and to pharmaceutical compositions containing these glycosides.

The invention provides anthracycline glycosides of the general formula I of the formula sheet, wherein R represents a hydrogen atom or a hydroxy group and X represents a hydrogen atom or a trifluoroacetyl group; and further provides their pharmaceutically tolerable acid addition salts.

The anthracycline glycosides of formula I can be prepared according to the invention by a process comprising condensing 1-hydroxy-4-demethoxy-11-des-oxydaunomycinone (formula II) with 1-chloro-N, 0-di (trifluoroacetic acid). tyl) -daunosamine in the presence of silver trifluoromethane sulfonate, removal of the O-trifluoroacetyl group by methanolysis, optionally removing the N-trifluoroacetyl group by mild alkaline hydrolysis and optionally bromination of the obtained daunorubicin compound (I: R = H, X H or COCF3) and treating the obtained 14-bromo compound with aqueous sodium formate.

Condensation of the racemic anthracyclinone of formula II gives an easily separable mixture of protects the anthracycline Q »glycosides 7S, 9S and 7R, 9R using the method of US Patent 4107323. The bromination and the sodium formate treatment is carried out according to the method described in U.S. Patent 3,803,124.

1-Hydroxy-4-demethoxy-11-deoxy-daunomycinone of formula II is a new anthracyclinone and two synthetic routes have been developed to obtain this compound. They are illustrated in the following reaction schemes A and B. The scheme shown in reaction scheme A gives both the anthracyclinone of formula II and 6,7-dideoxoxarminomycinone 14, a known compound (see British Patent 8415754); on the other hand, the scheme shown in reaction scheme B gives only the anthracyclinone of formula II. Both pathways rely on the nucleophilic attack of 2-lithium-1,4,5-trimethoxynaphthalene 6, precursor to the C and D rings of the tetracycline, on the ester $ 502 * 30 carbonyl group of a cyclohexene compound, precursor to the A and B rings.

In the first synthetic route, cis 1,2-dimethoxy-carbonyl-4-acetylcyclohexene-1 (see S. Penco et al. Hetero-5 cycles 2_1, 21 (1984)) is converted to 3_, a region chemical mixture of the monoester of p-nitrophenol. The p-nitrophenyl ester is necessary for the coupling reaction with 6 O; the reaction between 6 and 1 gives n.1. only traces of the coupling product while the same reaction used with the new ester 4 gives the IQ compound 7 in a yield of about 50% and the attack takes place on the p-nitrophenyl ester. In the second synthetic route, trans-1,2-dimethoxycarbonyl 4-ethylidene-cyclohexene JL £ is converted into the central intermediate £ -lactone 20 which is coupled with (5 in a regional chemical fashion to form 20). (The attack takes place only on the ester carbonyl group).

Reaction scheme A will now be described in more detail. Compound 1 is hydrolyzed with dilute alkali to form the corresponding monoester 2, 20 as a region chemical mixture. This is treated with p-nitrophenol and DCCI to form compound _3. The carbonyl protection is then carried out with ethylene glycol and pyridinium p-toluenesulfonate to form 4k. The coupling reaction between 3-lithium-1,4,5-trimethoxynaphthalene, obtained from the known 3-bromo compound -5 (see Barber, H.).

Rapoport, J.Org.Chem.44, 2153 (1979)) and compound £ provides compound Ί_. After decetalization and catalytic reduction of the double bond, compound 8 is obtained. The benzylcarbonyl group reduction is performed with a pyridine: borane complex in trifluoroacetic acid while simultaneously reducing the aliphatic keto group to a secondary alcohol group. Hydrolysis of the ester to the corresponding acid gives compound 9 which is converted into the tetracyclic system 10 by treatment with trifluoroacetic anhydride and trifluoro-acetic acid. Oxidation of the alcohol with a triethylamine: sulfur trioxide complex gives the corresponding ketone 11 which is converted into the anthraquinone 12 through oxidative demethylation with aluminum trichloride. The introduction of the 9-hydroxy group is effected under enol acetate formation, epoxidation and basic hydrolysis to obtain a mixture of (+) - 1-hydroxy-4-demethoxy-7,11- dide oxydaunomicinone 13 and (+) 4-demethyl-6,7-dide oxydaunomycinone which are easily separated by silica gel chromatography. Finally, the 7-hydroxy group is introduced by benzyl bromination followed by solvolysis.

According to reaction scheme B, the acidic permanganate oxidation of compound II gives the Oc-hydroxyketone as a stereochemical mixture which is treated with p-toluenesulfonic acid and refluxed toluene to give a mixture of Y-lactone 17 and S- lactone ^ 8. Lacton 18, after silica gel separation, is treated with sodium borohydride on an alumina support to form the alcohol 19.

After protecting the alcohol as the tetrahydropyranyl ether, the resulting compound is coupled with the lithium salt 6 in a region chemical manner to form 21 which is converted to the tetracyclinone of formula II according to the steps already described in scheme A.

The anthracyclinone glycosides: of formula I have anti-tumor properties and, therefore, the invention also provides a pharmaceutical composition containing an anthracycline glycoside of formula I or a pharmaceutically compatible salt thereof together with a pharmaceutically tolerable diluent or carrier.

The invention is illustrated by the following examples.

Example 1: Preparation of (+) 1-hydroxy-4-demethoxy-11-des-oxydaunomycion (II) (Scheme A) a) Preparation of intermediate 2.

440 ml of water and 220 ml of 1N aqueous sodium hydroxide solution were added to a solution of 35 g (0.145 M) of compound 11 in 880 ml of methanol. The solution was stirred at room temperature for 2.5 hours and then neutralized with 1N hydrochloric acid. The methanol was removed by evaporation and the aqueous solution adjusted to pH 8. The unreacted starting material was extracted with ethyl acetate. The solution was acidified to pH 3 with 1N hydrochloric acid and extraction with ethyl acetate gave 31 g of 2 (94% yield) as an oil.

MS: m / e 226 (M +) 40 IR (film): 1730, 1700, 1660 cm-1 1 H NMR (60 MHz, CDClq / S): 2.33 (s, COCH-,), 2.55- 2.95 8332303 ___

• V

-4- (m, 0! 2-C = CH + gi2), 3.00-3.30 (m, HOCOOi, CH3OCOCH), and 3.67 and 3.70 (2 s, 6H, COOCH ^), 6.90 (m, CH = C), 10.4 (s, COOH).

b) Preparation of intermediate 3.

A cooled solution of 28.33 g (0.137 M) DCCI in 150 ml anhydrous tetrahydrofuran was added dropwise at 0 ° C to a solution of 31 g (0.137 M) of compound 2 and 19 g (0.137 M) p-nitrophenol in 200 ml anhydrous tetrahydrofuran. The mixture was allowed to stand at 0 ° C for 2 hours and then at room temperature overnight. DCU was filtered off, the solvent removed in vacuo and the residue dissolved in ethyl acetate. The solution was washed with aqueous sodium bicarbonate solution and aqueous sodium chloride solution. It was then dried over anhydrous sodium sulfate and evaporated to dryness. The crude material was chromatographed on silica gel to obtain 35 g of compound 3 (73% yield) as an oil.

MS: m / e 347 (M +) IR (film): 1730, 1660 cm -1 1 1 H NMR (60 MHz, CDCl 3,,): 2.30 and 2.33 (2s, 6H, COCH 3), 2, 55-2.95 (m, CH2C = CH-CH2), 3.00-3.30 (m, CH3OCOCH, 02N-Ph-OCOCH), 3.70 and 3.73 & 2s, 6H, COCH3), 6, 90 (m, CH = C), 7.27 (d, aromatic protons), 8.27 (d, aromatic protons).

c) Preparation of intermediate 4.

50 ml of ethylene glycol and 3.5 g (14mM) p-toluenesulfonic acid pyridine salt were added to a solution of 35 g (0.1 M) of compound 3 ^ in 450 ml anhydrous benzene. The solution was refluxed for 18 hours using a Dean-Stark apparatus. The reaction mixture was cooled, diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The solvent was removed by evaporation, and after chromatography on silica gel, 31.3 g (80% yield) of compound _4 as an oil were obtained MS: m / e 391 (M +) 35 IR (film): 1730 cm -1 1 H-NMR (60 MHz, CDCl3.6): inter alia 1.50 (s, CH3 + C) 3.75 (s, CH3OCO), 3.9 (s, OCH2-CH2O), 5.93 (m, CH = C ), 7.27 (d, 2 aromatic protons), 8.27 (d, 2 aromatic protons).

d) Preparation of intermediate 7.

850 2 3 0 3 -5- *>

A solution of 107 mM n-butyl lithium in 300 ml anhydrous tetrahydrofuran was added by means of a needle, under nitrogen pressure at -78 ° C, to a solution of 21.3 g (71.68 mM) compound> in 250 ml anhydrous tetra-5 hydrofuran. After standing for 5 minutes, the lithium salt formed (> was converted in the same way into the solution of 24.3 g (62.3 mM) of compound £ in 240 ml anhydrous tetrahydrofuran. After 1 hour at -78 ° C, the reaction mixture quenched with acetic acid and the solvent removed in vacuo The residue was dissolved in ethyl acetate, the solution washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent removed in vacuo After chromatography on silica gel, 10.57 g (47% yield) of compound 7_.

15 MS: m / e 470 (M +) IR (film): 1730, 1660 cm-1 1 H NMR (60 MHz, CDCl 3, S): inter alia 1.45 (s, CH 3 C), 3.63-4, 06 (m, 16H), 5.86 (m, CH = C), 6.9-8.4 (m, 4H).

e) Preparation of intermediate 8.

A solution of 10.57 g (22.5 mM) of compound 7. in 600 ml of methanol and 1 ml of 1N hydrochloric acid was evaporated in vacuo.

The residue was dissolved in diethyl ether. The solution was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent 25 was removed in vacuo. After dissolving in 250 ml of methanol, the crude material was hydrogenated in the presence of 1.5 g of 10 wt% palladium on carbon at room temperature and atmospheric pressure. The catalyst was filtered off and the methanol removed by evaporation to give 8.78 g (91% yield-30) of compound £ as an oil.

MS: m / e 428 (M +) IR (film): 1730, 1710, 1660 cm-1 1 H-NMR (60 MHz, CDC13, £): inter alia 2.20 (s, COCH3), 3.7-4 0.05 (m, 12H), 6.9-7.85 (m, 4H).

F) Preparation of intermediate 9.

8.7 ml Pyridine: borane complex was added dropwise with stirring and under a nitrogen atmosphere to a solution of 8.78 g (20.5 mM) of compound Q in 100 ml of trifluoroacetic acid, which was cooled to -10 ° C. After standing at room temperature for 2 hours, the solvent was removed in vacuo. 60 ml From 8'0 2 30 3

* V

-6- a 4M aqueous sodium hydroxide solution was added and the mixture heated to 70 ° C until complete dissolution. After cooling, the pH was adjusted to 4 with 1N hydrochloric acid. The precipitate formed was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate and the solvent evaporated to give 7.6 g (93% yield) of compound SL MS: m / e 402 (M +) IR (CHCl 3): 3450, 1700 cm -1 of 1 H-NMR (60 MHz, CDCl3, S): inter alia 1.23; (d, J = 4Hz, CH3-CH), 103.8 (s, 0CH3), 3.83 (s, OCH3), 3.97 (s , OCH3), 6.5 (s, 1H), 7.1-8.4 (m, 3H).

g) Preparation of intermediate 10.

7.17 g (17.8 mM) of compound 9_ were treated with 54 ml of trifluoroacetic acid of hydride and 27 ml of trifluoroacetic acid for 2 hours at 0 ° C. The solution, diluted with ethyl acetate and water, was neutralized with solid sodium bicarbonate. The organic phase was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The crude material was treated with 230 ml of methanol in the presence of 4 g of sodium methylate at room temperature for 3 hours. It was then neutralized with 1N hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The residue obtained by evaporation was chromatographed on silica gel to obtain 3.62 g (53% yield) of compound 10o.

MS: m / e 384 (M +) IR (KBr): 3450, 1680 cm-1 301 H-NMR (60 MHz, CDCl 3, £): inter alia 1.23 (d, J = 4 Hz, CH-CH 3), 3 .80 (s, OCH3), 3.93 (s, OCH3), 4.00 (s, OCH3), 6.9-8.00 (m, 3H).

h) Preparation of intermediate 11.

6.82 g (37.7 mM) triethylamine: sulfur trioxide complex in 20 ml dimethyl sulfoxide was added at room temperature with stirring to a solution of 3.62 g (9.42 mM) of compound 10 in 20 ml dimethyl sulfoxide and 13 ml (94, 2 mM) triethylamine. After 1 hour, the pH was adjusted to 3 with 1N hydrochloric acid, and the solution was left for an additional 30 min. The reaction mixture was poured into 400 ml of water and extracted with ethyl acetate. The organic phase was washed with 1N hydrochloric acid, saturated 8502 303 -7% saturated aqueous sodium carbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate. The solvent was evaporated to give 3.57 g (99 %) yield of compound ^.

5 MS: m / e 382 (M +) IR (KBr): 1710, 1680 cm @ -1 H NMR (60 MHz, CDCl3.6): inter alia 2.38 (s, COCH3), 3.8 (s, 0CH3), 3.93 (s, OCH3), 4.00 (s, OCH3), 6.9-8.00 (m, 3H).

i) Preparation of intermediate 12.

IQ 3.57 g (9.34 mM) of compound 11 was dissolved in 70 ml of nitrobenzene. 9.5 g of aluminum trichloride was added and the mixture was allowed to stand at 70 ° C for 3 hours. The reaction mixture was poured into a saturated aqueous solution of oxalic acid and extracted with dichloromethane. The organic layer 15 was washed with water and dried over anhydrous sodium sulfate. The residue, obtained by evaporation of the solvent, was chromatographed on silica gel to obtain 1.55 g (49% yield) of compound 1-2.

MS: m / e 336 (M +) 20 IR (KBr): 2940, 1710, 1670, 1625 cm-1 1 H NMR (60 MHz, CDCl 3, S): inter alia 2.35 (s, COCH-j), 7.30-7.83 (m, 4H), 12.70 (s, OH), 13.10 (s, OH).

1) Preparation of racemic intermediates 13 and 14.

A solution of 1.5 g (4.5 mM) of compound L2 in 32 ml of carbon tetrachloride, 16.8 ml of acetic anhydride and 1 drop of perchloric acid was allowed to stand at room temperature for 15 hours. 0.340 g of sodium bicarbonate was added and the mixture was stirred for 10 min. The solid was filtered off and the filtrate evaporated to a syrup, diluted with dichloromethane, washed with a cold aqueous sodium bicarbonate solution and concentrated in vacuo. The residue was dissolved in 20 ml of dichloromethane and treated with 0.9 g of m-chloroperbenzoic acid in the presence of .28 ml of a 5% aqueous disodium monosolvent hydro-orthophosphate. After standing at room temperature for 3 hours, the phases were separated and the organic layer was washed with a dilute aqueous sodium sulfite solution and with an aqueous sodium bicarbonate solution. The solvent was removed by evaporation. The residue was suspended in a mixture of 30 ml of tetrahydrofuran, 24 ml of water and 11 ml of a 1.5 N aqueous sodium hydroxide solution. After 1 hour at room temperature 8502303 * -8-, the suspension was adjusted to pH 4 with 4N hydrochloric acid and extracted with dichloromethane. The organic layer was evaporated to dryness after chromatography on silica gel 0.19 g of compound 13 and 0.54 g of compound 14 (see F. Angelucci 5 et al, J.Chem.Soc.Chem.Commun 530, 1984).

Physical data of compound 13. melting point = 221-222 ° C UV (MeOH) Kmax: 229, 259, 292, 432 nm IR (KBr): 3465, 1705, 1680, 1605, 1580 cnf1 10HRMS calc. /C^H^Og.+•/: 352.0947 (found: 352.0941) 1 H NMR (200 MHz, CDCl 3,): 2.2-1.9 (m, 2H, 8-H), 2 .36 (s, COCH3), 2.81 & dd, J = 17.0, 2.3 Hz, 10-Heq), 3.2-2.8 (m, 7-H), 3.32 (d, J = 17.0Hz, 10-Ha. 3.69 (s, 9-OH), 7.29 (dd, J = 8.3, 1.2 Hz, Λ 1-H, 2-H), 7, 58 (s, 11-H), 7.67 (dd, J = 8.3, 7.5 Hz, 3H), 157.83 (dd, J = 7.5, 1.2 Hz, 4H), 12 .68 (s, 1 = 0H), 13.10 (s, 6-OH).

m) A suspension of 0.158 g (0.45 mM) of compound JL3 in 25 ml of benzene, 2.9 ml of ethylene glycol and 29 mg of p-toluenesulfonic acid was refluxed in a Dean-Stark apparatus for 1.5 hours. The reaction mixture was cooled, washed with 20% sodium bicarbonate aqueous solution and water and evaporated to dryness. The resulting ketal was dissolved in 70 ml of dichloromethane and at room temperature, treated with 2.9 ml of a 0.195 M solution of bromine in dichloromethane in the presence of 99 mg of AIBN and 13.5 ml of water. After 1.5 hours, the two phases were separated, the organic layer washed with saturated aqueous sodium bicarbonate solution and aqueous sodium chloride solution and the solvent removed in vacuo. The residue was stirred with 1.8 ml of a 90% aqueous TFA solution at 0 ° C for 45 min. The mixture was extracted with dichloromethane, washed with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated in vacuo.

The crude product was chromatographed on silica gel to obtain 60 mg (36% yield) of the racemic compound of formula II.

Melting point: 209-210 ° C

UV (MeOH)> unax: 228, 256, 290, 432 nm IR (Ch 2 Cl 2): 3420, 1705, 1660, 1625, 1605 cm -1 HRMS calc. /C20H1607.+/: 368.0896 (found: 368.0896) 1 H NMR (200 MHz, CDCl 3, S): 2.20 (dd, J = 14.6, 4.8 Hz, 8-Hax), 402.35 (ddd, J = 14.6, 2.3, 1.9 Hz, 8-Heq), 2.41 (s, COCH3), 3.01 (dd, J = 18.0, 2.3 Hz, 10-Heq), 3.28 (d, J = 18.0Hz, 10-Hax), 8502303 __ ψ Λ -9- 3.62 (d, 7-ΟΗ), 4.57 (s, 9- ΟΗ), 5.35 (ddd, J = 5.0, 4.8, 1.9 Hz, 7Η), 7.33 (dd, J = 8.2, 1.2 Hz, 2-H), 7 .66 (s, 11-H), 7.70 (dd, J = 8.2, 7.5 Hz, 3-H), 7.84 (dd, J = 7.5, 1.2 Hz, 4 -H), 12.60 (s, 0-0H, 13.33 (s, 6-OH).

Example 2; Preparation of (+) 1-hydroxy-4-demethoxy-11-des-oxydaunomicinone (II) - (Scheme B).

a) Preparation of intermediate 18.

23 g of potassium permanganate dissolved in 115 ml of water and 575 ml of acetone were added dropwise with vigorous stirring at 10 room temperature to a solution of 23 g (100 raM) of compound 6 in 600 ml of acetone, 70 ml of water and 14 ml of acetic acid. After 1 hour, a solution was obtained by mixing 11.5 g of sodium nitrite, 23 ml of concentrated sulfuric acid and 207 ml of water. The brown precipitate was filtered off. The colorless solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give 25 g of a product in the form of a stereoisomer mixture of Orhydroxyketones. The product was dissolved in 350 ml of toluene and refluxed in a Dean-Stark apparatus in the presence of 1.5 g of p-toluenesulfonic acid. After 4 hours, the solution was cooled and washed with a saturated aqueous sodium bicarbonate solution. The solution was dried over anhydrous sodium sulfate and the solvent removed in vacuo. After chromatography on silica gel, 9 g (36% yield) of compound 17 and 6 g (24% yield) of compound 1-8 were obtained. Connection physical data 18.

30 melting point: 62-63 ° C MS: m / e 226 (M +) IR (KBr): 1760, 1730, 1710 cm-1 1 H NMR (60 MHz, CDCl3, 6): 1.8-2.8 ( m, 5H), 2.33 (s, COCH3), 2.8-3.3 (m, 3H), 3.7 (s, COOCH3).

B) Preparation of intermediate 19.

0.226 g (1 mM) of compound 18 in 3 ml of tetrahydrofuran was added to 1.5 g of sodium borohydride on alumina in 4.5 ml of tetrahydrofuran with stirring at room temperature. After 15 minutes, the solid was filtered off 8502 303 ψ -10- and washed several times with etrahydrofuran. The solvent was removed in vacuo to yield 0.19 g (84% yield) of compound 19 ^ as a stereoisomer mixture (2 products 1: 1).

5 MS: m / e 228 (M +) IR (film): 1760, 1740 cm -1 1 H NMR (CDCl 3, 200 MHz, 5): 1.18, 1.19 (2 d, J = 6.7 Hz ), 6H, CH3-CH), 1.5-2.3 (m, 12H, 3-CH2, 5-CH2, 6-CH2), 2.9-3.1 (2 s, 6H, COOCH3), 3.87, 3.88 (2 q, 2H, J = 6.7, CH-CH 3).

C) Preparation of intermediate 20.

A solution of 0.58 g (2.5 mM) of compound 19, 0.315 g of dihydropyran and 0.062 g of pyridinium p-toluenesulfonate in 17 ml of dichloromethane was allowed to stand at room temperature for 4 hours. After washing with a saturated aqueous solution of sodium chloride, the product was purified by silica gel chromatography to obtain 0.57 g (73% yield) of compound 20 as a stereoisomer mixture (4 products 1: 1: 1: 1).

MS: m / e 312 (M +) 20 IR (film): 1760, 1740 cm-1 1 H NMR (CDCl 3, 200 MHz, 6): 1.1-1.3 (4 d, J = 6.5 Hz , 12H, CH3-CH), 1.4-2.5 (m, 48H, 3-CH2, 5-CH2, 6-CH2, 2'-CH2, 3'-CH2, 4'-CH2), 2, 9-3.1 (m, 8H, 1-CH, 2-CH), 3.4-4.0 (m, 12H, CH-CH3, 5'-CH2), 3.72 (s, 12H, COOCH3 ), 4.72 (m, 4H, 1'-H).

D) Preparation of intermediate 21.

0.58 g (1.95 mM) 3-Bromo-1,4,5-trimethoxynaphthalene in 5 ml anhydrous tetrahydrofuran cooled to -78 ° C was added dropwise to a solution of 1.8 ml (2.14 mM n-butyl lithium in 8 ml of tetrahydrofuran. After standing for 5 minutes, the lithium compound formed was added to a solution of 0.53 g (1.77 mM) of compound 20 in 8 ml of tetrahydrofuran cooled to -78 ° C. After 30 min, the reaction was stopped with acetic acid until the solution was acidic. The solution was diluted with dichloromethane and washed with water. After silica gel column chromatography, 0.52 g (59% yield) of compound 21 was obtained as a diastereoisomer mixture (4 products 1: 1: 1: 1).

MS: m / e 498 (M +) IR (CHCl 3): 1750, 1670 cm-1 40 1 H NMR (CDCl., 200 MHz, S): 1.1-1.3 (4d, J = 6.5 Hz , 12H, CH-- 85 0 2 3 0 at 1 μ -11-CH), 1.5-2.4 (m, 48H, 3-CH2, 5-CH2, 6-CH2, 2-CH2, 3 ' -CH2, 4'-CH2) 2.8-3.1 (m, 8H, 1-CH, 2-CH), 3.76, 3.96, 4.03 (s, 36H, 4 "-OCH3, 8i, -OCH3, 5 "-OCH3), 3.5-4.3 (m, 12H, CH-CH-j, 5'-CH2), 4.7-4.8 (m, 4H, l'- H), 6.86 (4s, 4H, 7 "-H), 6.98 (d, J = 1.7 Hz, 5H, 3" -H), 7.48 (t, J = 2.7 Hz, 4H, 2 "-H), 7.88 (d, J = 2.7 Hz, 4H, 1" -H).

Example 3.

Preparation of 1-hydroxy-4-demethoxy-11-deoxy-N-trifluoroacetyl-daunorubicin (I: R = H, X = COCF3).

60 mg (0.16 mM) of 1-hydroxy-4-demethoxy-11-deoxy-daunomycinone II was dissolved in 60 ml of dichloromethane. A solution of 145 mg (0.4 mM) 1-chloro-N, 0-di (trifluoroacetyl) -daunosamine in 4 ml anhydrous dichloromethane was added at 15 ° C to the first solution, followed by a solution of 80 mg (0 .3 mM) silver trifluoromethanesulfonate in 4 ml anhydrous diethyl ether. After 20 minutes, sym-collidine was added and the reaction mixture was left to stand for 20 minutes. A saturated sodium bicarbonate solution was added and then stirred for 30 min. The two phases were separated and the organic layer washed with water and dried over anhydrous sodium sulfate.

The residue, obtained by evaporation of the solvent, was suspended in 60 ml of methanol and stored at 4 ° C overnight.

After filtering off the unreacted compound of formula II (40 mg was recovered), the filtrate was chromatographed on silica gel to give the title compound (5 mg 7S, 9S and 5 mg 7R, 9R).

MS: m / e 594 (M +) UV (MeOH) kmax: 228, 258, 290, 434 nm C.D.ï Δε231 nm = +8.33, Δ £ 290 nm = -1.78.

301H-NMR (200 MHz, CDCl3),): 2.1-1.8 (m, 2'CH2), 2.14 (dd, J = 14.5,4.1Hz, 8-Hax), 2.35 (ddd, J = 14.5, 2.1, 1.9 Hz, 8-Heg), 2.39 (s, COCH3), 3.11 (dd, J = 18.0, 1.9 Hz, 10 -Heq), 3.28 (d, J = 18.0 Hz, 10ax-H), 3.7-3.6 (m, 4'-H), 4.3-4.1 (m, 3 ' -H), 4.26 (s, 9-OH), 4.26 (m, 5'-H), 5.28 (dd, J = 4.1, 2.1 Hz, 7-H), 5 .47 35 (d, J = 3.4 Hz, 1'-H), 6.64 (br, NHCOCF3), 7.33 (d, J = 8.2 Hz, 2H), 7.66 (s, 11-H), 7.73 (d, J = 7.5 Hz, 3-H), 12.56 (s, 1-OH), 13.32 (s, 6-OH).

Example 4.

Preparation of 1-hydroxy-4-demethoxy-11-deoxy-daunorubicin-8502303 -12-, * hydrochloride (I: R = X = H).

10 ml of an aqueous 1.0 N sodium hydroxide solution was added to 6 mg of 7S, 9S-1-hydroxy-4-demethoxy-11-deoxy-N-trifluoroacetyldaunorubicin in 2 ml of acetone under nitrogen at 0 ° C. After stirring at 0 ° C for 2 hours, the pH was lowered to 4.5 and the neutral products were extracted with dichloromethane. The acidic water layer was adjusted to pH 8.5 and extracted with dichloromethane. The organic solution was evaporated to a small volume and treated with a few drops of a methanolic hydrogen chloride solution. The product was precipitated by adding diethyl ether. After filtration, 4 mg of the title compound was obtained. MS (FD): m / e 498 (MH +) UV (MeOH) ^ max: 228, 258, 290, 432 nm 15 High pressure liquid chromatography (column RP8 10 μ (25 x 0.4 cm), wavelength 254 nm, eluent 65 / 35 v / v mixture of a buffered solution (prepared with 0.025 MK ^ PO ^ adjusted to pH 4 with H ^ PO ^) and CH ^ CN, elution rate 2 ml / min.)

Rt = 8.02.

20Rf (thin layer chromatography on Statocrom: eluent dichloromethane: methanol: acetic acid: water 80: 20: 7: 3 by volume) = 0.44 1 H NMR (200 MHz, dg-DMSO, 6): inter alia 1.16 ( d, J = 6.6 Hz, CH-j), 1.6-1.7 (m, 2'-Heg), 1.8-1.9 (m, 2'-Hax), 2.1- 2.3 (m, 258-H), 2.23 (s, COCH3), 3.02-3.17 (qAB, J = 18.0 Hz, 10-H), 4.13 (q wide, J = 6.6, <2Hz, 5'H), 5.02 (m, 7-H), 5.27 (d, J = 3.2 Hz, 1'-H), 5.40 (br, 4 1 -OH), 5.56 (s, 9-OH), 7.40 (dd, J = 7.5, 2.0 Hz, 3-H), 7.58 (s, 11-H), 7 .9-7.6 (m, 4-H, 2-H).

Example 5.

Preparation of 1-hydroxy-4-demethoxy-11-deoxy-doxorubicin (I: R = OH, X = H).

Proceeding according to the method described in US patent 3803124 starting from 1-hydroxy-4-demethoxy-11-deoxy-daunorubicin prepared according to example 4, the title compound was isolated as the hydrochloride.

- Conclusions - 8502303

Claims (8)

An anthracycline glycoside of the general formula I of the formula sheet, wherein R represents a hydrogen atom or a hydroxy group and X represents a hydrogen atom or a trifluoroacetyl group; or a pharmaceutically acceptable acid addition salt of such an anthracycline glycoside. 2. 1-Hydroxy-4-demethoxy-11-deoxy-N-trifluoroacetyl-daunorbicin. 3. 1-Hydroxy-4-demethoxy-11-deoxy-daunoribicin. 4. l-Hydroxy-4-demethoxy-l1-deoxy-N-trifluoroacetyΙ-ΙΟ doxorubicin. 5. 1-Hydroxy-4-demethoxy-11-deoxy-doxorubicin. 6. {+) 1-Hydroxy-4-demethoxy-11-deoxy-daunomycinone. Process for the preparation of an anthracycline-15 glycoside according to claim 1, characterized in that (+) - 1-hydroxy-4-demethoxy-11-deoxy-daunomycinone is condensed with 1-chloro-N, 0-di ( trifluoroacetyl) -daunosamine in the presence of silver trifluoromethanesulfonate, the o-trifluoroacetyl group is removed by methanolysis, separating the desired 7S, 9S-N-trifluoro-20 acetyl <Vglycoside on a silica gel column from its diastereomeric 7R, 9R derivative trifluoroacetyl by mild alkaline hydrolysis, and optionally brominate the resulting daunorubicin compounds (I: R = H, X = H, or COF 3) and treat the resulting 14-bromo compound with aqueous sodium formate. Pharmaceutical composition containing an anthracycline glycoside according to any one of claims 1 to 5 or a pharmaceutically tolerated acid addition salt of such an anthracycline glycoside together with a pharmaceutically tolerable diluent or carrier. 6502 303