GB2191479A - Antitumor anthracycline glycosides - Google Patents

Description

GB2191479A 1

SPECIFICATION

New antliturnor anthracycline glycosides The invention relates to new synthetic anthracycline glycosides, to methods for their preparation, 5 to pharmaceutical compositions containing them and the use of the giycosides as antitumor agents.

The present invention provides anthracycline glycosides having the general formula (I):

H 11 10 CH 2R egQf' 0 0 'bH OH 0 o 15 M4 je 0 7H) Ho 2 wherein R represents a hydrogen atom or a hydroxy group, and pharmaceutically acceptable acid 20 addition salts thereof.

The invention also provides a compound useful in the preparation of the glycosides of formula (1), of formula (1"):

9H 9 1-1 -bH CH 2 H 25 [01 0 'bH OH 0 -0 Me 0 30 4 H HO 1 COW3 The present invention therefore embraces a new class of anthracyline glycosides of formula 35 (i'):

He CH 2 R la: R=H, X-COW 3 0 0 'bH Ib: R=X-H OH 0 ' 0 Ic: R=OH, X=H 40 Me 0 HX HO 45 wherein R is hydrogen or hydroxy, and pharmaceutically acceptable salts thereof such as the hydrochloride. More particularly, two of the new anthracycline glycosides are:

lb: 4-demethyl-l-hydroxy-6,11-dideoxydaunorubicin (RH) lc: 4-demethyi-l-hydroxy-6,1 1-dideoxydoxorubicin (R=OH) 50 The anthracycline glycosides (1) are prepared by a process starting from a new anthracyclinone 4-demethyl- 1 -hydroxy-6,1 1 -d ideoxydaunomyci none (I]):

0H 0 0 $9 55 OH 0 6H 11 60 coupling it with 1-chloro-N,O-a-(trifluoroacetyi) daunosamine, typically in the presence of silver trifluoromethanesulfonate; and removal of the N,0 protecting groups. The condensation of the racemic anthracylinone (11) gives an easily separable mixture of protected anthracycline a-glyco sides 7S,9S and 711,9R following the method described in US-A-3803124. The resultant glyco- 65 2 GB2191479A 2 side (Jb) is converted to (1c) via bromination and sodium formate treatment in accordance with the method described in US-A-3803124.

Thus, the invention process a process for the preparation of an anthracycline glycoside of formula (1) or a pharmaceutically acceptable salt thereof, which process comprises condensing ( )-4-demethyi-l-hydroxy-6,1 1-dideoxydaunomycinone of formula (11) with 1-chloro-N,O-di(trifluo- 5 roacetyl)-daunosamine so as to form a mixture of 7S: 9S and 7R:9R 4- demethy]- 1 -hydroxy-6,1 1 dideoxy-N,O-di(trifluoroacetyl)et-glycosides; removing the 0trifluoroacetyl group; separating the 7S:9S N-trifluoroacetyl a-glycoside thus obtained from the 7R:9R N- trifluoroacetyl a-glycoside thus obtained; removing the N-trifluoroacetyl group from the 7S: 9S N- trifluoroacetyl a-glycoside so as to obtain a glycoside of formula (1) as defined in claim 1 wherein R represents a hydrogen 10 atom; if desired, converting the said glycoside of formula (1) into a pharmaceutically acceptable salt thereof; if desired, brominating the said glycoside of formula (1) or pharmaceutically acceptable salt thereof and hydrolysing the 14-bromo derivative thus obtained so as to form a glycoside of formula (1) as defined in claim 1 wherein R is a hydroxy group; and, if desired, converting the said glycoside of formula (1) wherein R is a hydroxy group into a pharmaceutically 15 acceptable salt thereof.

Typically, the ( )-4-demethy]-1-hydroxy-6,1 1-dideoxydaunomycinone, dissolved in anhydrous dichloromethane, is reacted at a temperature of WC and under nitrogen with 1-chloro-N,O di(trifluoroacetyi)-daunosamine, in the presence of silver trifluoromethanesuifonate, to give a mix ture of 7S: 9S and 7R: 9R 4-demethyl- 1 -hydroxy-6,1 1 -dideoxy-N,Odi(trifluoroacetyi) a-glycosides; 20 removing the 0-trifluoroacetyl protecting group from the glycosides by overnight treatment with methanol at a temperature of 4'C; separating by chromatography (eluent dichloromethane-metha nol 100: 1 v/v) the so obtained 7R: 9R N-trifluoroacetyl a-glycoside from the desired correspond ing 7S:9S diastereoisomer, which after treatment with acetone at O'C for 1.5 hours gives the desired 4-demethy]-1-hydroxy-6,1 1-dideoxydaunorubicin of formula (1) wherein R represents a 25 hydrogen atom which, by treatment with methanolic hydrogen chloride is isolated as the corre sponding hydrochloride and reacted, if desired, with a chloroform solution of bromine to give the corresponding 14-bromo derivative from which, after a treatment with an aqueous solution of sodium formate, the desired 4-demethyi-l-hydroxy-6,1 1-dideoxydoxorubicin of formula (1) wherein R represents a hydroxy group is obtained and isolated, by treatment with methanolic 30 hydrogen chloride, as the corresponding hydrochloride.

Two synthetic routes have been.devised in order to obtain the new anthracyclinone (11). They are illustrated in the following reaction Schemes A and B. Indeed the formation of the tetracycle is achieved by the condensation, via a Friedel-Crafts acylation (Scheme A) of 1,4,5,8-tetrame- thoxynapthalene (1) and the acid 2, obtained from 1,2-dimethoxycarbonyi-4- acetylcyclohexane 35 (see S. Penco et aL, Tetrahedron 40, 4677, 1984); or alternatively (Scheme B), via nucleophilic attack of 2-lithio-1,4,5,8-tetramethoxynaphthalene (7) on the mono-pnitrophenylester 8, already described in G-A-2164335.

The reaction Scheme A is now described in more detail, Compounds 1 and 2 are condensed in presence of trifluoroacetic acid and trifluoroacetic anhydride to yield 3 as a mixture of 40 regioisomers. 3 is doubly reduced with the complex borane-pyridine and then hydrolysed to the acid that is immediately cyclized to 4 using trifluoroacetic anhydride and trifluoroacetic acid. The benzylic ketone is reduced with sodium borohydride to the alcohol, dehydrated in refluxing benzene in the presence of p-toluene sulfonic acid, oxidized with the complex triethylamine sulphur trioxide in dimethyisulphoxide and finally converted to the anthraquinone 5 via oxidative 45 demethylation with aluminium trichloride. The introduction of the hydroxyl group at C-9 and C-7 of the chromophore is achieved following the procedures already described (see S. Penco et aL, Tetrahedron 40, 4677, 1984).

The present invention also provides pharmaceutical compositions comprising an anthracycline glycoside of formula (1) or a pharmaceutically acceptable salt thereof, together with a pharmaceu- 50 tically acceptable carrier or diluent. The compounds of formula (1) and their salts are useful in methods of treatment of the human or animal body by therapy. They are useful as antitumor agents in administering a therapeutically effective amount to a patient.

3 GB2191479A 3 SCHEME A pm. Ome COOH (CP3C0) 2 0 5 CO 2 Me W 3 COOH 6me 6me 2 10 0Me 0Me:Prr, 0 1) W3-PY 2) oH > ---------------------- > 00 3) (Cr CO) 0, CF COOH CMe CMe 0 3 2 3 3 15 WMeOMe OCOCF3 1)NaBH4 2) H+ > 3) TEA - SO 3 OM. M. 4) A1C1 20 0Me Me 39 02 4 OH 0 1)AC201HC104 2)MCPj3A 0 3) NaOH > 25 4) H+ OH 0 5 OH 1)0k--OH, pTSA 2) NBS 30 > OH 3) AgOAc ----------- > 4) NaOMe, MeOH OH 0 6 35 OH > OH H 0 OH 40 (+) 45 SCHEME B PMe Me 0 2 Me o,2.1 -> 50 Li CO elo 2 Ph 0Me 2 7 55 3 60 The invention is illustrated by the following examples:

4 GB2191479A 4 Example 1

Preparation of intermediate 3 (Scheme A) 1,4,5,8-Tetramethoxynaphthalene 1 (9 0.45, 1.8 mmol) and the acid 2 (9 0. 55, 2.4 mmol) are dissolved in 2 mi of trifluoroacetic acid and trifluoroacetic anhydride (mI 4) is added. The solution is refluxed for 30 h, cooled and poured in a mixture of ice and sat. aq. sodium 5 bicarbonate. After stirring 30', the organic materials are extracted with dichloromethane, washed with water, dried over anhydrous sodium sulphate and concentrated. Purification by flash chro matography (eluant: hexane-ethyl acetate 2: 1) yields 3 (g 0.4, 36% yield).

Example 2 10

Preparation of intermediate 3 (Scheme B) A solution of 2-Br, 1,4,5,8tetramethoxynaphthalene (9 2.4, 7.3 mmol) in anhydrous tetrahydrofuran (40 mi) is cooled to -78'C and pushed by N2 through a plastic tube into a solution of 1.65 Mn-BuLi in hexane (5 mi) in anhydrous tetrahydrofuran (20 mi) cooled at -78'C with vigorous stirring. After addition the solution is pushed dropwise by nitrogen pressure through a 15 plastic tube into the cooled (-78'C) solution of diester 8 (9 2.3, 5.9 mmol) in anhydrous tetrahydrofuran (30 m]) with good stirring. After 30' at -78'C the reaction mixture is quenched with acetic acid (0.5 ml) and the solvent removed---invacuo-. The residue is dissolved in dichloromethane, washed with water and dried to yield, after concentration, a raw material that is dissolved in acetone (150 mi) and treated with 1 N hydrochloric acid (50 mi). 20 After 30' the solution is neutralized with 1 N NaOH, concentrated under vacuum and extracted with ethyl acetate. The organic layer is washed with brine, dried, concentrated and the resulting residue dissolved in methanol (1 1.4), is reduced with 10% Pd-C (mg 120) and hydrogen under normal conditions. After filtration, concentration and purification by flash chromatography, 3 (g 1.6, 60% yield) is obtained. 25 m.p. 144-148'C MS: m/e 458 (M+.) IR (film): 1725, 1705, 1665 cm-1 H-NMR (60 MHz, CDO, & inter alia 2.00 (s, COCHJ, 3.50 (s, OCHJ, 3.65 (s, OCH3), 3.80 (s, OCHJ, 3.85 (s, OCH,), 6.65 (s, 2H, aromatic protons), 6.8 (s, 1H, aromatic proton).

30 Example 3

Preparation of intermediate 4 Compound 3 (g 0.65, 1.44 mmol) is dissolved in trifluoroacetic acid (mi 7), the solution cooled to 0' and the complex boranepyridine (mi 0.6, 5.7 mmol) dropped slowly with stirring. After 60' the solution is concentrated under vacuum, 1 N NaOH is added and the mixture heated to WC 35 for several hours. The mixture is cooled, the neutral phase extracted with ethyl acetate, the aqueous phase acidified with 1 N HCI and the acid extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulphate and concentrated. To the brownish foam (9 0.5) dissolved in trifluoroacetic acid (mi 4) and cooled to O'C, trifluoroacetic anhydride (mi 2) is added. The solution is stirred for 30', concentrated and poured into crushed 40 ice. The organic material is extracted with diethylether, washed with water, sat. aq. sodium bicarbonate, dried and concentrated. Purification by flash chromatography (eluant petroleum eth erethyl acetate 6: 1) yields 4 (9 0.31, 42% overall yield as crystalline powder.

m.p. 138-143'C MS:m/e 510 (M') IR (KBr): 1780, 1680 cm-1 45 H-NMR (60 MHz, CDC13 d): inter alia 1.3 (dd, -CH-CH,), 3.55 (s, OCHJ, 3. 65 (s, OCH3), 3.80 (s, 2 OCH3), 6.6 (d, aromatic protons).

Example 4

Preparation of 4-demethyl- 1-hydroxy-6,7,9, 1 1-tetradeoxydaunomycinone 5 50 Compound 4 (g 1.6, 3.1 mmol) is dissolved in ethanol (mi 20), sodiumborohydride (mg 300, 7.9 mmole) is added and the mixture stirred overnight. The ethanol is evaporated off and the residue, dissolved in ethyl acetate, is poured into cold 0.1 N HCL The organic layer is washed with water, dried and concentrated. The residue, dissolved in benzene (mi 10), is refluxed 40' in presence of a small amount of p-toluenesulphonic acid. After cooling, the solution is washed 55 with sat. aq. sodium bicarbonate, water and concentrated under vacuum. The residue (9 1.13) is dissolved in dimethyisulphoxide (6 m]) and triethylammine (3 mi) and treated at room tempera ture with the complex triethylamine-sulphur trioxide (g 1.03) in dimethyl sulphoxide (3 mi).

After 30' the mixture is poured into 200 m] of water, 0.1 N hydrochloric acid added to reach pH 2 and the organic material extracted with ethylacetate. After several washings with water 60 and brine, the organic layer is dried and concentrated. The residue (g 1) is dissolved in nitrobenzene (mi 10), aluminium trichloride (g 2.4, 18 mmol) added and the mixture kept at 7WC for 20'. The reaction mixture is poured into sat. aq. oxalic acid and extracted with dichlorometh ane.

The organic layer is washed with water and dried over anhydrous sodium sulphate. The 65 GB2191479A 5 residue is chromatographed on kieselgel to give 9 0.5 (52% yield) of 5. m. p. 208-210T MS: m/z 336 (M+.) IR (KBr): 1700, 1635 cm-1 'H-NMR (60 MHz, CDC13 & inter alia 2.28 (s, COCH3), 7.29 (s, H2-H3), 8.04 (s, H,), 8.08 (s, H6), 12.94 (s, Ar-OH) 5 Example 5

Preparation of 4-demethyl- 1-hydroxy-6,7, 1 1-trideoxydaunomycinone 6 Compound 5 (0.26 g, 0.77 mmol), dissolved in a solution of carbon tetrachloride (6 mi), acetic anhydride (3.3 m[) and one drop of perchloric acid, is let to stand at room temperature for 7 h. 10 Sodium bicarbonate (9 0.25) is added together with some toluene and the mixture concentrated under vacuum. Ethyl acetate is added and the mixture is filtered through a cellulose pad, washed with sat. aq. sodium bicarbonate, brine, dried over sodium sulphate and concentrated.

The crude material is dissolved in dichloromethane (mi 10) and metachloroperbenzoic acid (9 0.3) added. After stirring at room temperature for 2 h, diluted aq. sodium metabisulphite is 15 added with stirring. After 30' the organic phase is separated, washed with sat. aq. sodium metabisulphite, sodium bicarbonate and brine. After drying over sodium sulphate and concentra tion under vacuum, the crude product is dissolved in tetrahydrofuran (mi 6) and water (m[ 4) and cooled at O'C. A 10% NaOH solution (mi 2) is dropped slowly and the mixture stirred at 5' for 60' then acidified to pH 3 and the organic material extracted with dichloromethane. After flash 20 chromatography (eluant dichloromethane), product 6 (g 0.22, 42% yield) is obtained.

m.p. 224-226C MS: m/e 352 (M+) IR (KBr): 3440, 1700; 1630 cm-1 H-NMR (200 MHz, CD0, b): 1.9-2.3 (m, 2H, H8), 2.36 (s, COCH3), 2.9-3.6 (m, 4H, H10-H7), 3.80 (s, OH), 7.29 (s, H,-H3), 8.04, 8.12 (2s, H6-H 11), 12.92, 12.93 (2 s, 2H, Ar-OH). 25 Example 6

Preparation of ( ) 4-demethyl- 1-hydroxy-6, 1 1-dideoxydaunomyeinone 11 A suspension of compound 6 (0.26 g, 0.73 mmol) in benzene (60 m[), ethylene glycol (3.5 mi) and p-toluensulphonic acid (9 0.055) is refluxed 50' in a Dean-Stark apparatus. the reaction 30 mixture is cooled, washed with aq. sodium bicarbonate, water and evaporated to dryness. The ketal obtained (9 0.28, 0.7 mmole) is dissolved in carbon tetrachloride (mi 150), N-bromosuccin imide (g 0.165) and azo-bis-isobutyronitrile (9 0.09) are added and the mixture is refluxed under nitrogen using a 250 W lamp. After refluxing 20' the mixture is cooled, concentrated, the residue dissolved in glacial acetic acid (mi 30) and silver acetate (g 0. 44) added. The reaction 35 mixture is let to stand overnight under stirring, filtered and concentrated. The residue is dis solved in 90% aq. trifluoroacetic acid (20 mi), stirred at O'C for 3.5 h then concentrated. Ethyl acetate and sat. aq. sodium bicarbonate are added, the organic layer washed with water, brine, dried over sodium sulphate and concentrated. The raw material is suspended in anhydrous methanol (m] 60), sodium methoxide (9 0.17) is added and the mixture stirred for 90' at room 40 temperature. The reaction solution is acidified with methanolic hydrogen chloride and concen trated to yield a crude product purified by flash chromatography (eluant: dichloromethane-acetone 25: 1). Obtained 11 (9. 0. 135, 50% yield) as an orange powder.

m.p. 132-135'C MS=m/e 368 (M') LIV (MeOH) Anz,=230, 264, 478 nm 45 IR (KBr)=3400, 1700, 1630 cm-1 H-NMR (200 MHz, CDCI.,): 2.3-2.4 (m, 2H, H8), 2.40 (s, COCHJ, 2.98-3.06 (2 s' H10j, 3.29, 3.38 (2 s, H10al 5.01 (m, H7), 7.29 (s, H2-H3), 8.04 (s, H1 1), 8. 41 (s, H6), 12.83 (s, Ar-OM, 12.88 (s, Ar-OM.

50 Example 7

Preparation of 4-demethyl- 1-hydroxy-6, 11 -dideoxy-Ntrifluoroacetyidaunomycin la ( ) 4-demethy]-1-hydroxy-6,1 1-dideoxydaunomycinone 11 (mg 130, 0.35 mmole) is dissolved in anhydrous dichloromethane (mi 60) and cooled to WC under nitrogen. A solution of 1-chloro N,O-di(trifluoroacetyi)-daunosamine (0.45 9 1.26 mmole) in anhydrous dichloromethane (20 mi) 55 and a solution of silver. trif luorometha nesu 1 phonate (g 0.32, 1.26 mmole) in anhydrous diethy lether (mi 20) are simultaneously added to the former solution. After stirring at +WC for 15', sym-collidine (mi 0.18) is added and the reaction mixture left to stand 10'. Sat. aq. sodium bicarbonate is added and the stirring continued for 30'. The organic layer is washed with water and dried over sodium sulphate. The residue is suspended in methanol (mi 50) and kept 60 overnight at 4'C. The solution is concentrated and dropped into an excess petroleum ether. The precipitate is filtered, washed with petroleum ether and purified by flash chromatography (eluant:

dichloromethane-methanol 100: 1) giving the title compound (mg 35) and its 7(13), 9(R) diastereoi somer (mg 20).

6 GB2191479A 6 CD=Ae,,,,,,,=+4.1, A 8261 =+4.0, Ae211,,,,,=0.75, A8117,,,,=+0.70, 5 LIV (MeOH) A z,: 210, 260, 478 rim H-NMR (200 MHz, CDCI,, & 1.36 (d, J=6.5 Hz, 3H, CH,-6), 1.9-2.2 (m, 3H, CH2-Z, H-8ax), 2.34 (m, 1 H, H-Beq), 2.39 (s, 3H, COCH3), 3.21, 3.34 (two cl, J= 17.7 Hz, 2H, CH2-10), 3.70 (ddd, J<1, 2.0, 7.0 Hz, 1H, H-,4), 4.0-4.5 (m, 2H, H-J, H-6), 4.21 (s, 1H, OH-9), 5.07 (dd, J=4.0, 4.0 Hz, 1H, H-7), 5.13 (dd, J=2.2 2.2 Hz, 1H, H-1'), 6.69 (bd, J=8. 0 Hz, 1H, NHCO), 10 7.32 (s, 2H, H-2, H-3), 8.17 (s, 1 H, H- 11), 8.27 (s, H-6), 12.86, 12.89 (two s, 2H, OH- 1, OH4).

Example 8

Preparation of 4-demethyl- 1-hydroxy-6, 1 1-dideoxy daunomycin hydrochloride lb 15 8 mi of 0. 1 N NaOH is added to 35 mg (0.059 mmole) of 4-demethyl 1 - hydroxy-6,1 1 -dideoxy N-trifluoroacetyidaunorubcin la in 5 mi of acetone under nitrogen at WC. After stirring at O'C for 1.5 h the pH is lowered to 4.5 and the neutral products are extracted with dichloromethane.

The acid layer is adjusted to pH 8.5 and extracted with dichloromethane. The organic solution is reduced to small volume and treated with a few drops of methanolic hydrogen chloride. The 20 product is precipitated in diethyl ether. After filtration 15 mg of the tital compound is obtained.

m.p. 162-166C (dec.) MS=498 (MH+) UV (MeOH);1,,ax=222, 262, 334, 480 nm HPLC (two columns Spherisorb (RTM) S3 ODS2 (C18-3 p), 150 mmX4.5 each, wavelenght 254 rim, eluant A: KHIPO4 0.05M+H,PO, 1 M/CH,OH 80:20 (v/v), pH 3.0; eluant B: CH30H, 25 isocratic 66.4% CH30H speed of elution 0.6 m]/minute temperature columns: 4WC) Rt 14.5 minutes Rf (TLC on kieselgel 60 F154 Merck (RTM), eluant: dichloromethane- methanol-acetic acid-water 30 60:8:2A by volume)=0.125 Example 9

Preparation of 4-demethyl- 1-hydroxy-6, 1 1-dideoxy doxorubicin hydrochloride lc Following the process described in United States Patent Specification No. 3803124 and using as 35 starting material 4-demethyl- 1 -hydroxy-6,1 1 -dideoxy daunorubicin hydrochloride prepared accord ing to Example 8, the title compound was isolated as its hydrochloride.

Claims (10)

1. An anthracycline glycoside having the general formula (1): 40 0 0 'bH CH2 R OH 0 0 45 He 0 0) HO 2 50 wherein R represents a hydrogen atom or a hydroxy group, and pharmaceutically acceptable acid addition salts thereof.

2. A compound according to claim 1, which is 4-demethyl- 1 -hydroxy-6,1 1 -dideoxydaunorubi cin or its hydrochloride. 55

3. A compound according to claim 1, which is 4-demethyl- 1 -hydroxy-6,1 1 -dideoxydaunorubi- cin or its hydrochloride.

4. A process for the preparation of an anthracycline glycoside of formula (1) as defined in claim 1, or a pharmaceutically acceptable salt thereof, which process comprises condensing 4-demethyl-l-hydroxy-6,1 1 -dideoxydaunomyci none of formula (11): 60 7 GB2191479A 7 OH 0 0 0 bN CH OH 0 H 5 with 1 -chloro-N,O-di(trifluoroacetyi)-daunosamine so as to form a mixture of 7S: 9S and 7R: 9R 4-demethyi-l-hydroxy-6,1 1-dideoxy-N,Oditrifluoroacetyi) cz-glycosides; removing the 0-trifluoroa- cetyl group; separating the 7S:9S N-trifluoroacetyl a-glycoside thus obtained from the 7R:9R N- 10 trifluoroacetyl a-glycoside thus obtained; removing the N-trifluoroacetyl group from the 7S: 9S Ntrifluoroacetyl) a-glycoside so as to obtain a glycoside of formula (1) as defined in claim 1 wherein R represents a hydrogen atom; if desired, converting the said glycoside of formula (1) into a pharmaceutically acceptable salt thereof; if desired, brominating the said glycoside of formula (1) or pharmaceutically acceptable salt thereof and hydrolysing the 14-bromo derivative 15 thus obtained so as to form a glycoside of formula (1) as defined in claim 1 wherein R is a hydroxy group; and, if desired, converting the said glycoside of formula (1) wherein R is a hydroxy group into a pharmaceutically acceptable salt thereof.

5. A process according to claim 4, wherein the ( )-4-demethyi- 1 -hydroxy6,1 1 -dideoxydau nomycinone, dissolved in anhydrous dichloromethane, is reacted at a temperature of 5% and 20 under nitrogen with 1-chloro-N,O-di(trifluoroacetyi)-daunosamine, in the presence of silver trifluo romethanesulfonate, to give a mixture of 7S: 9S and 7R: 9R 4-demethyl- 1 - hydroxy-6,1 1 -dideoxy N,O-di(trifluoroacetyi) cz-glycosides; removing the 0-trifluoroacetyl protecting groups from the glycosides by overnight treatment with methanol at a temperature of 4T; separating by chro- matography (eluent dichloromethane-methanol 100: 1 v/v) the so obtained 711: 9R N-trifluoroace- 25 tyl a-glycoside from the desired corresponding 7S: 9S diastereoisomer, which after treatment with acetone at OT for 1.5 hours gives the desired 4-demethyl-l-hydroxy-6, 1 1-dideoxydaunoru bicin of formula (1) as defined in claim 1 wherein R represents a hydrogen atom which, by treatment with methanolic hydrogen chloride is isolated as the corresponding hydrochloride and 30 reacted, if desired, with a chloroform solution of bromine to give the corresponding 14-bromo derivative from which, after a treatment with an aqueous solution of sodium formate, the desired 4-demethy]-1-hydroxy-6,1 1-dideoxydoxorubicin of formula (1) as defined in claim 1 wherein R represents a hydroxy group is obtained and isolated, by treatment with methanolic hydrogen chloride, as the corresponding hydrochloride.

6. A pharmaceutical composition comprising an anthracycline glycoside of formula (1) as 35 defined in claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent.

7. An anthracycline glycoside of formula (1) as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy. 40

8. An anthracycline glycoside or salt thereof according to claim 7 for use as an antitumor agent.

9. A process for the preparation of an anthracycline glycoside of formula (1) as defined in claim 1 or a pharmaceutical ly acceptable salt thereof, said process being substantially as herein- before described in Examples 7 and 8 together or Examples 7, 8 and 9 together. 45

10. A compound of formula (V):

0 0 CH2 9 9 & 50 C_ 9 - - -tH OH 0 M4,e 0 Ho H 55 COCF3 Printed for Her Majesty's Stationery Office by Burgess & Son (Abingdon) Ltd, Dd 8991685, 1987.

Published at The Patent Office, 25 Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.