GB2164335A - Anthracycline glycosides - Google Patents

Abstract

Anthracycline glycosides I <IMAGE> (R=H or OH, X=H or COCF3) are prepared by condensing 1-hydroxy-4-demethoxy-11-deoxy-daunomycinone with a protected derivative of daunosamine and have antitumour properties. The above precursor (+/-) 1-hydroxy-4-demethoxy-11-deoxy-daunomycinone has the formula:- <IMAGE>

Description

SPECIFICATION Anthracycline glycosides The invention relates to anthracycline glycosides, to methods for their preparation and to pharmaceutical compositions containing them.

The invention provides anthracycline glycosides having the general formula I

wherein R represents a hydrogen atom or a hydroxy group and X represents a hydrogen atom or a trifluoracetyl group; and further provides their pharmaceutically acceptable acid addition salts.

The anthracycline glycosides I may be prepared according to the invention by a process comprising condensing 1 -hydroxy-4-demethoxy-1 1 -deoxydaunomycinone II

with 1-chloro-N,O-di(trifluoroacetyl)-daunosamine in the presence of silver trifluoromethanesulphonate, removing the O-trifluoroacetyl group by methanolysis, optionally removing the N-trifluoroacetyl group by mild alkaline hydrolysis, and optionally brominating the resultant daunorubicin derivative (I: R=H, X=H or COCK3) and treating the resultant 14-bromo-derivative with aqueous sodium formate.

The condensation of the racemic anthracyclinone II gives an easily separable mixture of protected anthracycline o-glycosides 7S,9S and 7R,9R following the method described in US Patent Specification No.

4107323. The bromination and sodium formate treatment is carried out in accordance with the method described in US Patent Specification No. 3803124.

1 -Hydroxy-4-demethoxy-1 1 -deoxy-daunomycinone II is a new anthracyclinone, and two synthetic routes have been developed in order to obtain it. They are illustrated in the following Reaction Schemes A and B. That set forth in Reaction Scheme A gives both the anthracyclinone II and 6,7-dideoxycarminomycinone 14, a known compound (see British Patent Specification No. 8415754); that set forth in Reaction Scheme B, on the contrary, gives only the anthracyclinone II. Both routes are based on the nucleophilic attack of 2-lithio-1,4,5-trimethoxy-naphthalene 6, precursor of the C and D rings of the tetracycle, on the ester carbonyl group of a cyclohexane derivative, precursor of the A and B rings.

In the first synthetic route cis 1,2-dimethoxycarbonyl-4-acetyl cyclohexene 1 [see S Penco et al. Heterocycles 21, 21, (1984)] is converted to 3, a regiochemical mixture of the monoester of p-nitrophenol. The pnitrophenyl ester is necessary for the coupling reaction with 6: indeed, while the reaction between 6 and 1 afforded only traces of the coupling product, the same reaction using the new ester 4 affords 7 in about 50% yield and the attack occurs on the p-nitrophenyl ester. In the second synthetic route, trans 1,2-dimethoxycarbonyl-4-ethylidene-cyclohexene 16 is converted to the key intermediate 3-lactone 20 which is coupled with 6 in a regiochemical fashion to give 21 (the attack is exclusively on the ester carbonyl group).

Scheme A

Scheme 8

The Reaction Scheme A is now described in more detail. Compound 1 is hydrolyzed with dilute alkali to give the corresponding monoester 2, as a regiochemical mixture. This is treated with p-nitrophenol and DCCI to give compound 3. Then the carbonyl protection is effected with ethylene glycol and pyridinium p-toluene-sulphonate to give 4. The coupling reaction between 3-lithio-1,4,5-trimethoxynaphthalene 6, obtained from the known 3-bromo-derivative 5 [see Barber, H, Rapoport, J Org Chem 44, 2153 (1979)] and compound 4 affords compound 7. After deketalisation and catalytic reduction of the double bond, compound 8 is obtained. The benzylic carbonyl group reduction is performed with a pyridine:borane complex in trifluoroacetic acid with the simultaneous reduction of the aliphatic keto group to a secondary alcohol.Hydrolysis of the ester to the corresponding acid gives compound 9 which is transformed to the tetracyclic system 10 by treatment with trifluoroacetic anhydride and trifluoroacetic acid. Oxidation of the alcohol with a triethylamine: sulphur trioxide complex gives the corresponding ketone 11 which is converted to the anthraquinone 12 via oxidative demethylation with aluminium trichioride. The introduction of the 9-hydroxy group is accomplished with enol acetate formation, epoxidation, and basic hydrolysis to give a mixture of (+) 1-hydroxy-4-demethoxy-7,11-dideoxydaunomycinone 13 and (t) 4-demethyl-6,7-dideoxydaunomycinone 14 which are easily separated by silica gel chromatography.Finally the introduction of the 7-hydroxy group is performed by benzylic bromination followed by solvolysis.

Alternatively, following the Reaction Scheme B, the acidic permanganate oxidation of compound 16 gives the hydroxy ketone as a stereochemical mixture which is treated with p-toluenesulphonic acid and toluene under reflux to give a mixture of y-lactone 17 and b-lactone 18. Lactone 18, after silica gel separation, is treated with alumina supported sodium borohydride to give the alcohol 19. After protection of the alcohol as the tetrahydropyranyl ether, the compound 20 obtained is coupled with the lithium salt 6 in a regiochemical fashion to give 21 which is transformed to the anthracyclinone II following the steps already described for Scheme A.

The anthracyclinone glycosides I have antitumour properties, and accordingly the invention further provides a pharmaceutical composition comprising an anthracycline glycoside i or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.

The invention is illustrated by the following Examples.

Example 1 Preparation of (t) 1-Hydroxy-4-demethoxy- 1 1-deoxydaunomycinone (II) Scheme A a) Preparation of intermediate 2 440 ml of water and 220 ml of 1 N aqueous sodium hydroxide solution were added to a solution of 35 g (0.145M) of compound 1 in 880 ml of methanol. The solution was stirred for 2 1/2 hours at room temperature and then neutralized with 1N hydrochloric acid. The methanol was evaporated off, and the aqueous solution was 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 afforded 31 g of 2 (94% yield) as an oil.

MS . mle 226 (M+) IR (film): 1730, 1700, 1660 cm-5 1H-NMR (60 MHz, CDCI3, b): 2.33 (s, COCH3), 2.55-2.95 (m, CH2-C=CH-CH2), 3.00-3.30 (m, HOCOCH, CH3OCOCH), and 3.67 and 3.70 (2 s, 6H, COOCH3), 6.90 (m, CH=C), 10.4 (s, COOH).

b) Preparation of intermediate 3 A chilled solution of 28.33 g (0.137M) of DCCI in 150 ml of anhydrous tetrahydrofuran was added dropwise at OCto a solution of 31 g (0.137M) of compound 2 and 19 g (0.137M) of p-nitrophenol in 200 ml of an hydros tetrahydrofuran. The mixture stood at 0oC for 2 hours and then overnight at room temperature. DCU was filtered, the solvent was removed in vacuo and the residue was 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 sulphate and evaporated to dryness. The crude material was chromatographed on Kieselgel affording 35 g of compound 3 (73% yield) as an oil.

MS: mle 347 (M-) IR (film): 1730, 1660 cm rH-NMR (60 MHz, CDCI3, b): 2.30 and 2.33 (2s, 6H, COCH3), 2.55-2.95 (m, CH2C=CH-CH2), 3.00-3.30 (m, CH3OCOCH, O2N-Ph-OCOCH), 3.70 and 3.73 (2s, 6H, COOCH3), 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) of p-toluenesulphonic acid-pyridinium salt were added to a solution of 35 g (0.1 M) of compound 3 in 450ml of 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 an hydros sodium sulphate. The solvent was evaporated off to give, after chromatography on Kieselgel, 31.3 g (80% yield) of compound 4 as an oil.

MS: m/e 391 (M-) IR (film): 1730 cm 1H-NMR (60 MHz, CDCl3,5): 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 A solution of 107 mM of n-butyllithium in 300 ml of anhydrous tetrahydrofuran was added through a double ended needle, under nitrogen pressure at -78 C, to a solution of 21.3 g (71.68 mM) of compound 5 in 240 ml of anhydrous tetrahydrofuran. After standing for 5 minutes, the formed lithium salt 6 was transferred in the same manner to a solution of 24.3 g (62.3 mM) of compound 4 in 240 ml of anhydrous tetrahydrofuran. After 1 hour at -78 C the reaction mixture was quenched with acetic acid and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, the solution was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulphate, and the solvent was removed in vacuo. After chromatography on Kieselgel, 10.57 g (47% yield) of compound 7 was obtained.

MS: m/e 470 (M+) IR (film): 1730, 1660 cm 1 H-NMR (60 MHz, CDCl3, 8): inter alia 1.45 (s, CH3-C), 3.63-4.06 (m, 16H), 5.86 (m, CH=C), 6.9-8.4 (m, 4H).

el 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 solution of sodium bicarbonate and dried over anhydrous sodium sulphate. The solvent 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% by weight palladium-on-carbon at room temperature and atmospheric pressure. The catalyst was filtered off and the methanol was evaporated off affording 8.78 g (91% yield) of compound 8 as an oil.

MS: mle 428 (M') IR (film): 1730, 1710, 1660 cm H-NMR (60 MHz, CDCI3, b): inter alia 2.20 (s, COCH3), 3.7-4.05 (m, 12H), 6.9-7.85 (m, 4H) Preparation of intermediate 9 8.7 ml of pyridine:borane complex was added dropwise under stirring and under a nitrogen atmosphere to a solution of 8.78 g (20.5 mM) of compound 8 in 100 ml of trifluoroacetic acid, cooled to -10 C.

After standing for 2 hours at room temperature, the solvent was removed in vacuo. 60 ml of 4M aqueous sodium hydroxide solution was added and the mixture was warmed at 700C until complete dissolution After cooling, the pH was adjusted to 4 with 1N hydrochloric acid. The precipitate which formed was extracted with ethyl acetate. The solution was dried over an hydros sodium sulphate and the solvent was evaporated off to give 7.6 g (93% yield) of compound 9.

MS:m/e 402 (M+) IR (CHCl3): 3450, 1700 cm-1 1H-NMR (60 MHz, CDCl318): inter alia 1.23 (d,J=4Hz CH3-CH), 3.8 (s, OCH3), 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 was treated at 0 C with 54 ml of trifluoroacetic anhydride and 27 ml of trifluoroacetic acid for 2 hours. The solution, diluted with ethyl acetate and water, was neutralized with solid sodium bicarbonate. The organic phase was washed with brine and dried over anhydrous sodium sulphate. The solvent was removed in vacuo. The crude material was treated with 230 ml of methanol in the presence of 4 g of sodium methoxide at room temperature for 3 hours. It was then neutralized with 1 N 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 sulphate. The residue, obtained by evaporation, was chromatographed on Kieselgel to give 3.62 g (53% yield) of compound 10.

MS: m/e 384 (M+) IR (KBr): 3450, 1680 cm l 1H-NMR (60 MHz, CDCI3, 5): inter alia 1.23 (d, J=4Hz, CH-CH3), 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) of triethylamine:sulphur trioxide complex in 20 ml of dimethylsulphoxide was added at room temperature under stirring to a solution of 3.62 g (9.42 mM) of compound 10 in 20 ml of dimethylsulphoxide and 13 ml (94.2 mM) of triethylamine. After 1 hour, the pH was adjusted to 3 with 1 N hydrochloric acid, and the solution was left to stand 30 minutes longer. The reaction mixture was poured into 400 ml of water and extracted with ethyl acetate. The organic phase was washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulphate. The solvent was removed by evaporation to afford 3.57 g (99% yield) of compound 11.

MS: m/e 382 (M') IR (KBr): 1710, 1680 cm 1 H-NMR (60 MHz, CDCI3, b): inter alia 2.38 (s, COUCH3), 3.8 (s,OCH3), 3.93 (s, OCH3), 4.00 (s, OCH3), 6.9-8.00 (m, 3H).

i) Preparation of intermediate 12 3.57 g (9.34 mM) of compound 11 was dissolved in 70 ml of nitrobenzene. 9.5 g of aluminium trichloride was added and the mixture was left 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 was washed with water and dried over anhydrous sodium sulphate. The residue, obtained by evaporation off of the solvent, was chromatographed on Kieselgel to give 1.55 g (49% yield) of compound 12.

MS: mle 336 (M- IR (KBr): 2940, 1710, 1670, 1625 cm 'H-NMR (60 MHz, CDCI3, b): inter alia 2.35 (s, COCH3), 7.30 -7.83 (m, 4H), 12.70 (s, OH), 13.10 (s, OH).

I) Preparation of racemic intermediates 13 and 14 A solution of 1.5 g (4.5 mM) of compound 12 in 32 ml of carbon tetrachloride, 16.8 ml of acetic anhydride and 1 drop of perchloric acid was left to stand at room temperature for 15 hours. 0.340 g of sodium bicarbonate was added and the mixture was stirred for 10 minutes. The solid was removed by filtration, and the filtrate was evaporated to a syrup, diluted with dichloromethane, washed with 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 5% aqueous disodium monohydrogen orthophosphate.After standing for 3 hours at room temperature, the phases were separated and the organic layer was washed with a dilute aqueous solution of sodium sulphite and with an aqueous solution of sodium bicarbonate. The solvent was eliminated by evaporation. The residue was suspended in a mixture of 30 ml of tetrahydrofuran, 24 ml of water and 11 ml of 1.5N aqueous sodium hydroxide solution. After 1 hour at room temperature the suspension was adjusted to pH 4, with 4N hydrochloric acid and extracted with dichloromethane. The organic layer was evaporated to dryness to give, after chromatography on Kieselgel, 0.19 g of compound 13 and 0.54 g of compound 14 (see F Angelucci et al, J Chem Soc Chem Commun 530, 1984).

Physical data for compound 13 m.p.= 221-222"C UV (MeOH) A max: 229, 259, 292, 432 nm IR (KBr): 3465, 1705, 1680, 1605, 1580 cm 1 HRMS calc. [C2oHl606.-]: 352.0947 (Found: 352.0941) aH-NMR (200 MHz, CDCI3, b): 2.2-1.9 (m, 2H, 8-H), 2.36 (s,COCH3), 2.81 (dd, J=17.0, 2.3Hz 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, 1.2Hz, 1-H, 2-H), 7.58 (s, 11-H), 7.67 (dd,J=8.3,7.5Hz, 3H), 7.83 (dd, J=7.5, 1.2Hz, 4H), 12.68 (s,1-OH), 13.10 (s, 6-OH).

m) A suspension of 0.158 g (0.45 mM) of compound 13 in 25 ml of benzene, 2.9 ml of ethylene glycol and 29 mg of p-toluenesulphonic acid was refluxed for 1.5 hours in a Dean-Stark apparatus. The reaction mixture was cooled, washed with aqueous sodium bicarbonate solution and water, and evaporated to dryness. The ketal obtained was dissolved in 70 ml of dichloromethane and treated, at room temperature, 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 was washed with saturated aqueous sodium bicarbonate solution and aqueous sodium chloride solution, and the solvent was removed in vacuo. The residue was stirred with 1.8 ml of 90% aqueous TFA at 0QC for 45 minutes, and then 30 ml of ice/water was added.The mixture was extracted with dichloromethane, washed with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulphate and evaporated in vacuo.

The crude product was chromatographed on Kieselgel to give 60 mg (36% yield) of the racemic compound (II).

mp.209-21 0 C UV (MeOH) À max: 228, 256, 290, 432 nm IR (CH2CI2): 3420, 1705, 1660, 1625, 1605 cm HRMS cacl. [C20H1607.-]: 368.0896 (Found: 368.0896) 1H-NMR (200 MHz, CDCI3, ô): 2.20 (dd, J=14.6, 4.8Hz, 8-Hax), 2.35 (ddd,J=14.6, 2.3, 1.9Hz, 8-Heq), 2.41 (s, COUCH,), 3.01 (dd,J=18.0, 2.3Hz, 10-Heq), 3.28 (d, J=18.0Hz, 10-Hax), 3.62 (d,7-OH), 4.57 (s, 9-OH), 5.35 (ddd, J=5.0, 4.8, 1.9Hz, 7H),7.33 (dd, J-8.2, 1.2Hz, 2-H), 7.66 (s, 11-H), 7.70 (dd,J=8.2, 7.5Hz, 3-H), 7.84 (dd, J=7.5, 1.2Hz, 4-H), 12.60 (s,1-OH, 13.33 (s, 6-OH).

Example 2 Preparation of(tl 1-Hydroxy-4-demethoxy- 1 1-deoxydaunomycinone (11) Scheme B a) Preparation of intermediate 18 23 g of potassium permanganate dissolved in 115 ml of water and 575 ml of acetone was added dropwise under vigorous stirring at room temperature to a solution of 23 g (100 mM) of compound 16 in 600 ml of acetone, 70 ml of water and 14 ml of acetic acid. After 1 hour, a solution made by mixing 11.5 g of sodium nitrite, 23 ml of concentrated sulphuric acid and 207 ml of water was added. The brown precipitate was filtered off. The colourless 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 sulphate.The solvent was removed in vacuo giving 25 g of product, a stereoisomeric mixture of hydroxy ketones. The product was dissolved in 450 ml of toluene and refluxed in a Dean-Stark apparatus in presence of 1.5 g of p-toluenesulphonic acid. After 4 hours the solution was cooled and washed with saturated aqueous sodium bicarbonate solution. The solution was dried over an hydros sodium sulphate and the solvent was removed in vacuo. After chromatography on Kieselgel, 9 g (36% yield) of compound 17 and 6 g (24% yield) of compound 18 were obtained.

Physical data for compound 18 m.p. 62-63"C MS: m/e 226 (M+) IR (KBr): 1760, 1730, 1710 cm--1 rH-NMR (60 MHz, CDCI3, 8): 1.8-2.8 (m, 5H), 2.33 (s, COUCH3), 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 supported on aluminium oxide in 4.5 ml of tetrahydrofuran under stirring at room temperature. After 15 minutes the solid was filtered off and washed several times with tetrahydrofuran. The solvent was removed in vacuo to give 0.19 g (83% yield) of compound 19 as a stereoisomeric mixture (2 products 1:1).

MS: m/e 228 (M+) IR (film): 1760, 1740 cm 1 1H-NMR (CDCl3, 200 MHz, 6): 1.18, (2 d, J=6.7Hz, 6H, CH3-CH), 1.5-2.3 (m, 12H, 3-CH2, 5-CH2, 6-CH2), 2.9-3.1 (2s, 6H, COOCH3), 3.87, 3.88 (2 q, 2H, J=6.7, CH-CH3).

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 ptoluenesulphonate in 17 ml of dichloromethane was left to stand for 4 hours at room temperature. After washing with a saturated aqueous solution of sodium chloride the product was purified by chromatography on Kieselgel to give 0.57 g (73% yield) of compound 20 as a stereoisomeric mixture (4 products 1:1:1:1).

MS: m/e 312 (M4) IR (film) 1760, 1740 cm 1 lH-NMR (CDCl3, 200 MHz, b): 1.1-1.3 (4 d, J=6.5Hz, 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) of 3-bromo-1,4,54rimethoxynaphthalene in 5 ml of anhydrous tetrahydrofuran cooled at -78"C was added dropwise to a solution of 1.8 ml (2.14 mM) of n-butyllithium in 8 ml of tetrahydrofuran. After standing for 5 minutes, the formed lithio-derivative was added to a solution of 0.53 g (1.77 mM) of compound 20 in 8 ml of tetrahydrofuran cooled at -78 C. After 30 minutes the reaction was quenched with acetic acid until the solution was acid. 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 diastereoisomeric mixture (4 products 1:1:1:1).

MS: mie 498 (M-) IR (CHCI3): 1750, 1670 cm H-NMR (CDCl3, 200 MHz, b): 1.1-1.3 (4d, J=6.5Hz, 12H, CH3-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, 8"-OCH3, 5"-OCH3), 3.54.3 (m, 12H, CH-CK2, 5'-CH2), 4.7-4.8 (m, 4H, 1'-H), 6.86 (4s, 4H, 7"-H), 6.98 (d, J=1.7Hz, 4H, 3"-H), 7.48 (t, J=2.7Hz, 4H, 2"-H), 7.88 (d, J=2.7Hz, 4H, 1"-H) Example 3 Preparation of l-hydroxy-4-demethoxy- 1 1-deoxy-N-trifluoroacetyl-daunorubicin rI:: R=H, X= COCF 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) of 1-chloro-N,O-di(trifluoroacetyl)-daunosamine in 4 ml of anhydrous dichloromethane was added to the first solution at 15"C, followed by a solution of 80 mg (0.3 mM) of silver trifluoromethane sulphonate in 4 ml of anhydrous diethyl ether. After 20 minutes symcollidine was added and the reaction mixture was left for an additional 20 minutes. A saturated aqueous sodium bicarbonate solution was added and the stirring was continued for 30 minutes. The two phases were separated, and the organic layer washed with water and dried over anhydrous sodium sulphate.

The residue, obtained by evaporating off the solvent, was suspended in 60 ml of methanol and kept overnight at 4oC. After filtration of the unreacted 11 (40 mg recovered), the filtrate was chromatographed on Kieselgel giving the title compound (5 mg of 7S,9S and 5 mg of 7R,9R).

MS:mZe 594 (M ) UV (MeOH) A max: 206, 228, 258, 290, 434 nm C.D.: At231 nm = +8.33, AF290 nm = -1.78.

'H-NMR (200 MHz, CDCI3, b): 2.1-1.8 (m, 2'CH2), 2.14 (dd, J=14.5,4.1Hz, 8-Hax), 2.35 (ddd, J=14.5, 2.1,1.9Hz, 8-Heq), 2.39 (s, COUCH2), 3.11 (dd, J=18.0, 1;9Hz, 10-Heq), 3.28 (d,J=18.0Hz, 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 (d, J=3.4Hz, 1'-H), 6.64 (br, NHCOCF3), 7.33 (d,J=8.2Hz, 2-H), 7.66 (s, 11-H), 7.73 (d, J=7.5Hz, 3-H), 12.56 (s, 1-OH), 13.32 (s.

6-OH) Example 4 Preparation of 1-hydroxy-4demethoxy-11-deoxy-daunorubicin hydrochloride (I: R=X=H) 10 ml of aqueous 0.1N sodium hydroxide solution was added to 6 mg of 7S,9S-1-hydroxy-4-demethoxy-11-deoxy-N-trifluoroacetyl-daunorubicin in 2 ml of acetone under nitrogen at 0 C. After stirring at 0CC for 2 hours the pH was lowered to 4.5 and neutral products were extracted with dichloromethane.

The acid water layer was adjusted to pH 8.5 and extracted with dichloromethane. The organic solution was reduced to a small volume, and treated with a few drops of methanolic hydrogen chloride. The product was precipitated by addition of diethyl ether. After filtration, 4 mg of the title compound was obtained.

MS (F.D):m/e 498 (MH+) UV. (MeOH) Xmax: 228, 258, 290, 432 nm HPLC (column RP8 10 > (25 x 0.4 cm), wavelength 254 nm, eluent is a 65!35 v/v mixture of a buffered solution (prepared with 0.025 M KH2PO4 adjusted to pH 4 with H3PO4) and CH3 CN, speed of elution 2 ml/ minute) Rt = 8.02.

Rf (TLC on Statocrom: eiuent dichloromethane:methanol:acetic acid:water 80:20:7:3 by volume) = 0.44 rH-NMR (200 MHz, d6-DMSO, b): inter alia 1.16 (d, J=6.6 Hz,CH3), 1.6-1.7 (m, 2'-Heq), 1.8-1.9 (m, 2'-H ax), 2.1-2.3 (m, 8-H), 2.23 (s, COUCH2), 3.02-3.17 (qAB, J=18.0 Hz,10-H), 4.13 (q broad, J=6.6, < 2Hz, 5'-H), 5.02 (m, 7-H), 5.27 (d, J=3.2Hz, 1'-H), 5.40 (br, 4'-OH), 5.56 (s, 9-OH), 7.40 (dd, J=7.5, 2.0Hz, 3-H), 7.58 (s, 11-H), 7.9-7.6 (m, 4-H, 2-H).

Example5 Preparation of l-Hydroxy-4-demethoxy- 1 1-deoxy-doxorubicin (I: R= OH, X=HJ Following the process described in United States Specification No. 3803124 and using as starting material 1-hydroxy-4-demethoxy-11-deoxydaunorubicin prepared according to Example 4, the title compound was isolated as hydrochloride.

Claims (9)

1. An anthracycline glycoside having the general formula I

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-1 1 -deoxy-N-trifluoroacetyl-daunorubicin.

3. 1 -Hydroxy-4-demethoxy-1 1 -deoxy-daunorubicin.

4. 1 -Hydroxy-4-demethoxy-1 -deoxy-N-trifl uoroacetyl-doxoru bicin.

5. 1 -Hydroxy-4-demethoxy-1 1 -deoxy-doxorubicin.

6. (t) 1 -Hydroxy-4-demethoxy-1 1 -deoxy-daunomycinone.

7. A process for the preparation of an anthracycline glycoside according to claim 1, the process comprising condensing (+) -hydroxy-4-demethoxy-1 1 -deoxy-daunomycinone with 1-chloro-N,O- di(trifluoroacetyl)-daunosamine in the presence of silver trifluoromethane-sulphonate, removing the 0trifluoroacetyl group by methanolysis, separating on a silica gel column the wanted 7S,9S-N-trifluoroace tyl-o-glycoside from its diastereomeric 7R,9R derivative, optionally removing the N-trifluoroacetyl group by mild alkaline hydrolysis, and optionally brominating the resultant daunorubicin derivatives (i: : R=H, X=H or COIF3) and treating the resultant 14-bromo-derivative with aqueous sodium formate.

8. A process according to claim 7, the process being substantially as described herein with reference to Example 3, Examples 3 and 4 or Examples 3 to 5.

9. A pharmaceutical composition comprising an anthracycline glycoside according to any of claims 1 to 5 or a pharmaceutically acceptable acid addition salt of such an anthracycline glycoside in admixture with a pharmaceutically acceptable diluent or carrier.