CH676985A5 - - Google Patents

Description

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CH 676 985 A5

Description

The invention relates to new glucosidic anthracycline derivatives, to their preparation and to pharmaceutical compositions containing them.

The present invention provides anthracycline glucosides having the general formula (I) and (II);

"OH

OCH, Rt

I a, .b

II a, b a: = H

b: = OH

wherein Rt represents a hydrogen atom or a hydroxyl group; and their pharmaceutically acceptable acid addition salts.

The invention also provides a process for the preparation of a glucoside of formula (I) in which Ri represents a hydrogen atom, i.e. the compound (la), a process which comprises (a reaction of 3'-epi-daunorubicin with salicylic aldehyde so as to obtain the corresponding 3'-epi-N-salicyliden-derivative; the conversion of the hydroxyl group in position 4 'of the said 3'-epi-N-salicyl-denderivate into a "tri-fluoromethanesulfonate group; and the removal from the 3'- epi-N-salicylidene-4'-0-trifluoromethanesum Phosphonate thus obtained from the salicylidene group by acid hydrolysis so as to cause the formation of the required glucoside of formula (I) by displacement of the 4'-0-trifluoromethanesulfonate group.

The compound (la) can then be prepared by reaction of the amnic group in the 3 'position of 3-epi-daunorubicìna (III) [F. Arcamone, A. Bargiotti, G. Cassinelli German patent 2 752 115 (1 June 1978)] with salicylic aldehyde in a mixture of water and acetone at room temperature, to obtain the corresponding 3'-epi-N-saiiciliden-derivative (IVc ) which by treatment with trifluoromethanesulfonic anhydride in anhydrous methylene chloride and in the presence of pyridine gives the corresponding 3'-epi-N-salicyliden-4'-0-trifluoro-methanesulfonate (IVd). This compound, dissolved in methanol, can then be subjected to acid hydrolysis of the protective salicylidene group by means of p-toluenesulfonic acid at room temperature to give, with the displacement of the outgoing trifluoromethanesulfonate group, the required compound of formula (la).

The invention also provides a process for the preparation of a jucoside compound of formula (!) In which Ri represents a hydroxyl group, i.e. compound (Ib), a process which comprises the reaction of 3'-epi-dossorubicin with salicylic aldehyde thus to obtain the corresponding 3'-epi-N-salicylidene-derivative; protecting the hydroxyl group in position 14 of said 3'-epI-N-salicyliden-derivative with a t-buiyl-diphenyl-siliie group, converting the hydroxyl group to position 4 'of the 3'-epi-N-salicyliden- 14-Ö- [t-butyl-diphenyl-silyI-dossorubicin thus obtained in a trifluoromethanesulfonate group; and the removal from the 14-0- [t-butyl-diphenyl-silyl] -3'-epi-N-salicyliden-4'-0-trifiuoromethanesulphonate thus obtained of the salicylidene group by acid hydrolysis of the group 14-0- [t- butyl-diphenyl-silyl] so as to obtain the required glucoside of formula I by displacement of the 4'-0-trifluoromethanesulfonate group.

The compound (Ib) can then be prepared by converting the amino group to the 3 'position of 3'-epi-dossorubicin (V) [see F. Arcamone et al., German patent 2 752 155] in 3'-epi-N -saliciliden-dossorubtcina (Vie) by reaction with salicylic aldehyde, protection of the hydroxyl group in protection 14 with a t-butyl-diphenylsilyl group, obtaining 3'-epi-N-saliciliden-14-0- [t-butìl-diphenyl- silyl] -doxorubicin (Vlf); the conversion of the hydroxyl group in position 4 'into a trifluoromethanesulfonate (Vlg), hydrolysis with p-toluenesulfonic acid with compound formation (Ih), and the reaction with tetra-n-butylamonium fluoride to remove the protective group 14-0- [t-butyl-diphenyl-silylJ and obtain the compound of formula (Ib).

Typically, 3-epi-dossorubicin, dissolved in a mixture of water and acetone, is reacted at room temperature with salicylic aldehyde obtaining the corresponding 3'-epi-N-saIiciIiden-derivative which is subsequently treated, in anhydrous dimethylformamide, at room temperature, with t-butyl-diphenylchloro-silane in the presence of imidazoium to give its 3'-epi-N-salicyliden-14-0- [t-butyl-diphenyl-silyl] ether, which, dissolved in chloride of methylene anhydrous, and converted, by treatment with trifluoromethanesulfonic anhydride in

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CH 676 985 A5

presence of anhydrous pyridine, in its 3'-epi-N-salicyliden-4'-0-trifluoromethanesulphonate-14-0- [t-butyl-dife-nyl-silyl] ether whose protective salicylidene group is subjected to acid hydrolysis at room temperature and in a methanol solution by means of a catalytic quantity of p-toiene sulfonic acid and from which the protective group 14-0- [t-butyl-diphenyl-silyl] is subsequently removed by treatment with tetra-fluoride n-butylammonium in tetrahydrofuran, at room temperature, obtaining the required glucoside of formula

(L).

The invention also provides a process for the preparation of a glucoside of formula (II) in which Ri represents a hydrogen atom, i.e. the compound (Ila), or a hydroxyl group, i.e. the compound (IIb), or a salt thereof of pharmaceutically acceptable acid addition, process comprising the conversion of 3'-deamino-4'-deoxy-3'-epi-4'-epi-3 ', 4'-epimino-daunorubicin in the corresponding N-tri-fluoroacetyl- derivative; the conversion of said N-trifluoroacetyl-derivative into 4'-deoxy-4-epi-N-trifluo-roacetii-3'-deamino-3'-hydroxideunorubicin; and the removal of the N-trifluoroacetyl group from 4'-deoxy-4'-epi-N-trifluoroacetyl-3-deamino-3-hydroxideunorubicin so as to obtain the glucoside of formula (II) wherein Ri is a hydrogen atom.

It is desired, the bromination of said glucoside of formula (II) or of a pharmacologically acceptable salt thereof and the hydrolysis of the 14-bromo-derivative thus obtained so as to form the glucoside of formula (II) in which Ri is a hydroxyl group, and, if so desired, the conversion of the said glucoside of formula (II) wherein R 1 is a hydroxyl group in a pharmaceutically acceptable acid addition salt thereof.

The treatment of the 3 ', 4'-epimino-daunorubicin derivative (la) with trifluoroacetic anhydride gives the corresponding N-trifluoroacetyl derivative (VIII). The reaction of this compound with a catalytic amount of sulfuric acid in acetone of 4'-deoxy-4'-epi-N-trifluoroacetyl-3'-deamino-3'-hydroxy-daunorubicin (VIII) that by treatment with sodium hydrate in an aqueous solution, it gives the compound (Ila). Typically, the N-trifiuoroacetyl group can be removed by mild alkaline hydrolysis, at a temperature of 0 ° C by means of a 0.1 N aqueous solution of sodium hydroxide. Glucoside (ila) can be isolated as hydrochloride by treatment with hydrochloric acid in methanol.

The compound (IIb) can be prepared by bromination of (Ila) with subsequent treatment of the resulting 14-bromo-derivative with sodium formate in an aqueous solution at room temperature, according to the procedure described in the description of U.S. Pat. 3 803 124. It can be isolated as a hydrate in the same way as glucoside (Ila).

The process of the invention can be summarized in the reaction scheme below.

The present invention also provides a pharmaceutical composition comprising as an active ingredient an anthracycline glucoside of the invention or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable carrier or diluent. A therapeutically effective amount of a compound of formula (I) is combined with an inert carrier. Conventional vehicles can be used and the composition can be formulated in a conventional way.

The compounds of the invention are useful for the therapeutic treatment of the human or animal organism. In particular, the compounds of the invention are useful as anticancer agents.

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CH 676 985 A5

REACTION SCHEME

- - the

* »XV c — d

'VI and - g

I b.h la

VII i

viii

_ II a -,

there b c R2: oOHC6H4CH =

d R2: oOHC6H4CH =

and R, = R3 = OH

f R,; -0-Si (C6H5) 2 -t-Bu g R,: -0-Si (C5H5) 2-t-Bu h R,: -0-Si (C6Hs) 2-t-Bu i R4: COCF3

R3: OH R3: 0S02CF3 R2: oOHC6H4CH = R2: O0HC6H4CH = R2: OOHCöH4CH =

Ra t OH R3: OSO2CF3

The following examples illustrate the invention.

EXAMPLE 1 3'-epi-N-saIiciliden-daunorubicin (IVc)

A 2 g solution of 3'-epi-daunorubicin (III) in a mixture of 80 ml of water and 20 ml of acetone was treated at room temperature with 0.5 ml of salicidal aldehyde at a pH of 8. After 10 minutes ethyl acetate was added and the organic phase was separated, washed twice with water, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under vacuum. The residue was first triturated with hexane to eliminate traces of salicidic aldehyde, then collected and dried under vacuum at 30 ° C to give (IVc) with almost quantitative yield. Rf - 0.21 for thin layer chromatography using Kiesetgel F 254 (Merck) and as eluent the mixture of CHaCIs-acetone solvents (8/2 v / v).

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CH 676 985 A5

EXAMPLE 2

3'-deamino-4'-desoxy-3'-epi-4'-epi-3 ', 4'-epimino-daunorubicin (la)

To a solution of 2 g of 3'-epi-N-salicyliden-daunorubicin (IVc) in 20 ml of anhydrous dichloromethane and 2 ml of anhydrous pyridine, kept at -10 ° C, a solution of 0.8 ml of trifluoromethanesulfonic anhydride in 10 ml of dichloromethane. After one hour at -10 ° C, the mixture was diluted with dichloromethane and washed with water, cold 0.1 M hydrochloric acid, 5% cold aqueous solution of baking soda and water. The organic phase, dried over anhydrous sodium sulphate, was filtered and the solvent removed in vacuo to obtain (IVb).

Rf = 0.50 for thin layer chromatography using Kieselgel F 254 (Merck) and as an eluent the mixture of solvents CH2Cl2-acetone (95/5 v / v).

The crude product was dissolved in 50 ml of methanol and added with 0.2 g of p-toluenesulfonic acid monohydrate. The solution was kept at room temperature for one hour, subsequently added with 100 ml of water and extracted with a small amount of dichloromethane. The aqueous phase was adjusted to pH 8 with 0.1 M sodium hydroxide and dichloromethane was added. The organic phase was separated, washed with water, dried over anhydrous sodium sulphate and the small volume solvent evaporated.

The mixture was purified by chromatography on a gel column buffered with pH 7 using di-chloromethane-ethanol as eluent. The euate containing the product (la) was washed with water, evaporated under vacuum, collected with a small amount of dichloro-methane and crystallized.

FD. MS 509 [M +] m.p. 135-137 ° C Rf = 0.38 for thin layer chromatography, Kieselgel F 254 (Merck), using the eluent mixture CH2CI2-CH3OH -CH3COOH-H2O (30/4/1 / 0.5 v / v).

1H - NMR (200 MHz, CDCI3):

8.02 (dd, J = 1.1, 7.7Hz, 1 H, H-1)

7.76 (dd, J = 7.7.7.7Hz, 1 H, H-2)

7.37 (dd, J = 1.1.7.7Hz, 1 H, H-3)

5.31 (dd, J = 3,0,4,8Hz, 1H, H-1 ')

5.17 (dd, J = 2,0,3,6Hz, 1H, H-7)

4.32 (qd, J = <1, 6.7Hz, 1H, H-5 ')

4.07 (s, 3H, OCH.3-4)

3.17 (dd, J = 19.2Hz, 1H, H-1 Oe)

2.95 (d, J = 19.2Hz, 1H, H-10ax)

2.46 (ddd, J = 2,0,2,0,15.0HZ, 1H, H-8e)

2.43 (s, 3H, COCHs)

2.30 (ddd, J = 1,5,4,3,6,4Hz, 1 H, H-5 ')

1,9-2.0 (m, 2H, H-8ax, H-2'ax)

1.87 (ddd, J = 1,5,3,0,14,6HZ, 1H, H2'e)

1.44 (d, J = 6.7Hz, 3H, CH3-5 ')

EXAMPLE 3

3'-epi-N-saliciliden-doxorubicin (Vle)

The title compound was prepared from the corresponding 3'-epi-dossorubicin (V) as described in Example 1.

Rf = 0.15 for thin layer chromatography, Kieselgel F 254 (Merck), using the mixture of solvents CHaCh-acetone (4/1 v / v) as eluent.

EXAMPLE 4

3'-epi-N-salîciliden-14-0- [t-butiI diphenyl-silyl] dossorubìcin (Vf)

A solution of 1 g of 3'-epi-N-salicyliden-dossorubicin (Vie) in 20 ml of anhydrous dimethylformamide was treated with 0.5 ml of t-butii-diphenyl-chlorosilane and 0.3 g of imidazole. The reaction mixture was left to stand overnight at room temperature, after which 200 ml of water was added and the solution was extracted with methylene chloride.

The organic layer was separated, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under vacuum. The residue was triturated with hexane and collected on a sintered glass, washed with a hexane-diethyl ether mixture and dried under vacuum to give the compound (Vlf). Rf = 0.25 for thin layer chromatography, Kieselgel F 254 (Merck), using the mixture of solvents CH2Cl2-acetone (4/1 v / v) as eluent.

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CH 676 985 A5

EXAMPLE 5

3'-epi-3'-deamino-4'-deoxy-4'-epi-3 ', 4'-epimino doxorubicin (Ib)

The title compound was prepared starting from (Vif) through its 3'-epi-4'-0 ~ trifluoromethane sulfate (VIg) prepared as described in Example 2.

The acid hydrolysis of (VIg) in methanol in the presence of a catalytic amount of p-toluenesulfonic acid monohydrate and subsequent handling called Ih.

The crude product was triturated with hexane and collected on a sintered glass, washed with diethyl hexane-ether and dissolved in 100 ml of tetrahydrofuran. The solution was treated with 0.5 g of tetra-n-butylammonium fluoride. After 2 hours the hydrolysis of the t-butyl-diphenyl-silyl group was complete. The residue obtained by evaporating the vacuum solvent was purified by chromatography on a column of silica gel buffered at pH 7 using dichloromethane-ethanol as eluant to obtain pure Ib. The precipitate was collected on a sintered glass, washed with diethyl hexane-ether and dried under vacuum.

Rf = 0.20 for thin layer chromatography, Kieselgel F 254 (Merck), using the solvent mixture CH2CI2-CH3OH-CH3COOH-H2O (30/4/1 / 0.5 v / v) as eluent.

EXAMPLE 6

3'-deamino-4'-deoxy-3'-hydroxy-4'-epi-4'-amino-daunorubicin (Ila).

The title compound was prepared starting from ethylene eliminates. 1 g of la was transformed into N-trifluoroacetyl derivative VIII by treatment with 1.2 ml of trifiuoroacetic anhydride in anhydrous methylene chloride. After handling, the crude compound [Rf = 0.7 for thin layer chromatography, Kieselgel F 254 (Merck), using the mixture of solvents CH2Cl2-acetone (4/1 v / v) as diluent] was dissolved in 20 ml of acetone and treated with a catalytic quantity of sulfuric acid at 10 ° C. The mixture was diluted with 200 ml of methylene chloride, washed with water, sodium bicarbonate in 5% aqueous solution and water. The solvent was removed under vacuum and the residue purified on a silica gel column using methylene chloride as the eluent system to obtain 0.7 g of pure Ila.

Rf = 0.21 for thin layer chromatography, kieselgel F 254 (Merck), using the mixture of solvents CHg-Cfe-acetone (4/1 v / v) as eluent.

The product Ha was slowly dissolved in a 0.1 N aqueous solution of sodium hydroxide at 0 ° C so as to carry out the hydrolysis of the protective N-trifluoroacetyl group.

After one hour at 0 ° C, the solution was adjusted to pH 8.6 with 0.1 N hydrochloric acid and extracted with methylene chloride. The solvent was evaporated, obtaining 0.5 g of a residue which was converted, by treatment with hydrochloric acid into methanol, into the 4'-deoxy-4'-amino-4-epf-3'-deamino-3'- hydrochloride hydroxy-daunorubicin.

MS FD 527 [M +], p, f. 153 ° C (dee). RF = 0.18 for thin layer chromatography, Kieselgel F 254 (Merck), using the solvent system CH2CI2-CH3OH-CH3COOH-H2O (30/4/1 / 0.5 v / v)

1H - NMR (200 MHz, CDCI3)

8.02 (dd, J = 0.9, 8.5Hz, 1H, H-1)

7.77 (dd, J = 8.5.8.5Hz, 1H, H-2)

7.38 (dd, J = 0.9, 8.5Hz, IH, H-3)

5.52 (dd, J = <1.4.0Hz, 1H, H-1 ')

5.28 (dd, J = 1,8,4,0HZ, 1H, H-7)

4.07 (s, 3H, OCH3-4)

3 ^ 69 (dq, J = 6,3,9,5Hz, 1H, H-5 ')

3.51 (ddd, J = 4,8,9,5,11,6Hz, 1H, H-3 ')

3.22 (dd, J = 1,9,18,9Hz, 1H, H-10e)

2.94 (d, J = 18.9Hz, IH, H-10ax)

2.40 (S, 3H, COQH3)

2.2-2.4 (m, 1H, H-8ax)

2.30 (dd, J = 9.5, 9.5Hz, 1 H, H-4 ')

2.0-2.2 (m, 2H, H-8e, H-2'e)

1.70 (ddd, J = 4,0,4,6,13,2Hz, 1H, H-2'ax)

1.31 (d, J = 6.3Hz, 3H, CH3-5 ')

EXAMPLE 7

3'-deamìno-3'-ìdrossi-4'-deoxy-4'-epi-4'-amino-dossorubicin (IIb).

0.5 g of Ila were dissolved in a mixture of methanol and dioxane. The solution was treated, as described in the description of U.S. Pat. No. 3 803 124, first with bromine to give the 14-bromine derivative and then with sodium formate in aqueous solution to give the title compound.

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CH 676 985 A5

This was converted into its hydrochloride by treatment with hydrochloric acid in methanol solution. FD-MS 543 [M +], thin layer chromatography on Kieselgel F 254 (Merck) using the solvent system CH2CI2 CH3OH-CH3COOH-H2O (30/4/1 / 0.5 v / v) Rf = 0.10 .

Biological activity

The cytotoxic activity of the new anthracic glucoside of the invention (FCE 24 782 / X00 - 0333) was examined "in vitro" against HeLa, P388, P388 / DX, L0V0 / DX cells.

Exposure time to the compound: 24 hours in comparison with daunorubicin.

The results are shown in Table 1.

The compound, when examined in vivo for P-388 ascitic leukemia and Gross leukemia, exhibited good anti-tumor activity compared to daunorubicin, especially when administered orally. The results are given in Tables 2 and 3.

Table 1

In vitro activity of 3'-deam \ no-4'-deoxy-3'-hydroxy-4'-epi-4'-amino-daunorubicin (FCE

24 782 / X00-0333) in comparison with DNR (daunorubicin)

ID5o compound (ng / mI) a)

HeLab) P388c) P388 / DXd) LoVoe) LoVo / Dxfl

DNR 19 10.5 730 43 820 FGE 11 24.5 235 37 230

a) Dose that produced a 50% reduction in cell numbers compared to untreated control tests.

b) Human cervical epithelioid carcinoma cells c) Doxorubicin-sensitive P388 leukemia cells d) Dossorubicin-resistant P388 leukemia cells e) Doxorubicin-sensitive human colon adenocarcinoma cells *

f) Human colon adenocarcinoma cells resistant to dossorubicin

Table 2

True leukemia effect 3

ascitic P388

Composed

Dose b

T / C% c

Dead pertotoxicity cl

DNR

2.9

155

0/10

4.4

170

8/10

FCE 24 782 / X00-0333

1.96

155

0/10

2.9

150

0/10

4.4

140

9/10

6.6

100

10/10

a The experiments were carried out with CDF1 mice, inoculated with 106 patent leukemic cells i.p.

b Treatment by i.p. on day 1 after tumor inoculation. c Average survival time of treated mice / average survival time of control animals x 100.

d Evaluate on the basis of what was found in the autopsy.

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Table 3

Gross Compound Leukemia Effect

Doseb mg / kg

T / C% °

Toxic deaths' 1

DNR

10

165

0/20

15

192

2/20

FCE 24 782 / X0Q-0333

8.2

175

0/20

11.5

230

0/10

16.1

240

0/10

22.5

130

0/10

a The experiments were carried out with C3H mice, inoculated with 2 x 10® leukemic cells by i.v.

b Treatment by i.v. on day 1 after tumor inoculation c Average survival time of treated mice / average survival time of control animals x 100.

d Evaluate on the basis of what was found in the autopsy.

Claims (13)

claims 1. GIUGOside of anthracycline having the general formula (I) or (II): CH OH OCH, R, XX wherein Rt represents a hydrogen atom or a hydroxyl group and their pharmaceutically acceptable acid addition salts. 2. Compound according to claim 1, which is 3'-deamino-4'-deoxy-3'-epi-4'-epi-3 ', 4'-epimino-daunorubicin. 3. Compound according to claim 1, which is 3'-deamino-4'-deoxy-3'-epi-4'-epÌ-3 ', 4'-epimino-doxorubicin. A compound according to claim 1, which is 3'-deamino-4'-deoxy-3'-hydroxy-4-epi-4'-amino-daunorubicin or its hydrochloride, 5. A compound according to claim 1, which is 3'-deamino-4'-deoxy-3'-hydroxy-4'-epì-4'-amino-dossorubicin or its hydrochloride. 6. Process for the preparation of a glucoside of formula (!) As defined in claim 1, wherein Ri represents a hydrogen atom, a process which comprises the reaction of 3-epi-daunorubicin with salicylic aldehyde so as to obtain the corresponding 3 ' -epi-N-saliciliden-derivative; converting the hydroxyl group to the 4 'position of said 3'-epi-N-salicyliden-derivative into a trifluoromethanesulphonate group, and removing from the 3'-epi-N-salicyliden-4'-0-trifluoromethanesulfonate thus obtained of the salicylidene group by acid hydrolysis so as to obtain the required glucoside of formula (I) by displacement of the group 4'-0-trifluoromethanesulfonate. Process according to claim 6, wherein 3'-epi-daunorubicin dissolved in a mixture of water and acetone is reacted, at room temperature, with salicylic aldehyde to obtain the corresponding 3-epi-N-salicyliden-derivative which it is subsequently treated, in anhydrous methylene chloride and in the presence of anhydrous pyridine, with trifluoromethanesulfonic anhydride to give the corresponding N-salicyliden-3'-epi-4'-0-trifiuoromethanesulphonate whose protective salicylidene group is subjected to acid hydrolysis with acid 8 5 10 15 20 25 30 35 40 45 50 55 60 65 CH 676 985 A5 p-toluenesulfonic, at room temperature and with said trifluoromethanesulphonate dissolved in methanol, to obtain, by displacement of the leaving trifluoromethanesulfonate group, the required glucoside of formula (I). 8. Process for the preparation of a glucoside of formula (I) defined in claim 1, wherein Ri represents a hydroxyl group, a process which includes the reaction of 3-epi-dossorubicin with aldehyde salicilia so as to obtain the corresponding 3'-epi -N-saliciliden-derived; protecting the hydroxyl group in position 14 of said 3-epi-N-salicyliden-derìvafo with a t-butyl-diphenyl-siliie group, converting the hydroxyl group to position 4 'of the 3'-epi-N-salicyliden-14 -0- [t-butyl-diphenyl-silyl] -doxoru-bicine thus obtained in a trifluoromethanesulfonate group; and the removal of the salicylidene group by acid hydrolysis and the group 14-0- [t from the 14-0- [t-butyl-diphenyl-silyl] -3'-epi-N-salicidylidene-4'-0-trifluoromethanesulphonate thus obtained -butyl-diphenyl-silyl] so as to obtain the required glucoside of formula (I) by displacement of the 4'-0-trifluoromethanesulfonate group. Process according to claim 8, wherein 3'-epi-dossorubicin, dissolved in a mixture of water and acetone, is reacted at room temperature with salicylic aldehyde to obtain the corresponding 3'-epi-N-salicyliden-derivative which it is subsequently treated, in anhydrous dimethylformamide, at room temperature, with p-butyl-diphenylchlorosilane in the presence of imidazole to give its 3'-epi-N-salicyliden-14-0- [t-butyl-diphenll-siiil] ether, which, dissolved in anhydrous methylene chloride, is converted, by treatment with trifluoromethanesulfonic anhydride in the presence of anhydrous pyridine, to its 3'-epi-N-salicyliden-4'-0-trifiuoro-methanesulfonate-14-0- [t- butyldiphenyl-silyl] ether whose protective salicylidene group is subjected to acid hydrolysis at room temperature and in methanol solution by means of a catalytic quantity of p-to-luene sulfonic acid and hence the protective group 14-0- [t- butyl-diphenyl-silyl] is removed by treatment with fluoride of tetra-n-butylammonium in tetrahydrofuran, at room temperature, to obtain the required glucoside of formula (I). 10. Process for the preparation of a glucoside of formula (II) as defined in claim 1 or a pharmaceutically acceptable salt thereof, a process which includes the conversion of 3'-deamino-4'-deoxy-3'-epi-4 '-epi-3', 4'-epimino-daunorubicin in the corresponding N-trifluoroacetyl derivative; the conversion of said N-trifluoroacetyl-derivative into 4-deoxy-4'-epi-N-trifluoroacetyl-3'-deamino-3'-hydroxy-daunorubicin; and the removal of the N-trifluoroacetyl group from 4'-deoxy-4'-epi-N-trifluo-roacetyl-3'-deamino-3'-hydroxideunorubicin so as to obtain the glucoside of formula (II) in which Ri is an atom of hydrogen. 11. Process according to claim 10, which comprises bromination of said glucoside of formula (II) or of a pharmaceutically acceptable salt thereof and hydrolysis of the 14-bromo-derivative thus obtained so as to form the glucoside of formula (II) in wherein Ri is a hydroxyl group; and, if desired, the conversion of said glucoside of formula (II) wherein R 1 is a hydroxy group, into a pharmaceutically acceptable acid addition medium thereof. 12. Process according to claim 10, wherein the 3'-deamino-4'-deoxy-3'-epi-4'-epi-3 ', 4'-epimi-nodaunorubicin is reacted with trifluoroacetic anhydride to give the corresponding N-trifluoroace-tyl-derivative, which for treatment with a catalytic amount of sulfuric acid in acetone, gives 4'-deoxy-4 / -epi-N-trifluoroacetiI-3-deamino-3'-hydroxy-daunorubicin; the removal from it of the N-trifluoroacetyl protective group by mild alkaline hydrolysis at a temperature of 0 ° C by means of a 0.1 N aqueous solution of sodium hydroxide; optionally, the isolation of the glucoside of formula (II) wherein Ri is a hydrogen atom as its hydrochloride by treatment with hydrochloric acid in methanol, optionally, the conversion of said glucoside of formula (II) or its hydrochloride to the glucoside of formula (II) wherein Ri is a hydroxyl group by bromination with subsequent treatment of the resulting 14-bromo-derivative with sodium formate in aqueous solution at room temperature; and optionally, the isolation of said glucoside of formula (II) wherein R 1 is a hydroxy group as its hydrochloride by treatment with a solution of hydrochloric acid in methanol. A pharmaceutical composition comprising an anthracycline glucoside of formula (I) and (II) as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier or diluent. g