NL8701349A - NEW ANTHRACYCLINES. - Google Patents

Description

* s VO 9119

New anthracyclines.

The present invention relates to new anthracycline glycoside derivatives / to their preparation and to pharmaceutical compositions / containing them, as well as to intermediates useful in the preparation of the glycosides.

The present invention provides anthracycline glycoside of the general formulas 1 and 2 of the formula sheet, wherein: R 1 represents a hydrogen atom or a hydroxy group, as well as their pharmaceutically acceptable acid addition salts.

The invention further provides a process for the preparation of a glycoside of the formula 1, wherein: represents a hydrogen atom, ie compound la, which process comprises reacting 31-epi-daunorubicin with salicyl-15 aldehyde to give the corresponding Obtain 31-epi-N-salicylidene derivative; converting the 4'-hydroxy group of said 3'-epi-N-salicylidene derivative to a trifluoromethanesulfonate group; and removing the salicylidene group from the 31-spi-N-20 salicylidene-41-O-trifluoromethanesulfonate thus obtained by acid hydrolysis, to obtain the desired glycoside of formula 1 by removing the 4, O-trifluoromethanesulfonate group .

The compound 1a can therefore be prepared by reacting the 3'-amino group of 31-epidaunorubicin (3) (F. Acamony A. Bargiotti, 25 G. cassinelli: German Patent Publication 2,752,115 (June 1, 1978)) with salicylaldehyde, in a mixture of water in acetone at room temperature to obtain the corresponding 3'-epi-N-salicylidene derivative (4c) which, by treatment with trifluoromethanesulfonic anhydride in anhydrous methylene dichloride, in the presence of pyridine, the corresponding 3'-epi-N-salicylidene -4'-O-trifluoromethanesulfonate (4d). This compound, dissolved in methanol, can then be subjected to acid hydrolysis of the salicylidene protecting group by means of paratoluene sulfonic acid at room temperature to yield the desired compound of formula la via removal of the trifluoromethanesulfonate leaving group.

- - r ** Λ * -2-

The invention also provides a process for the preparation of a glycoside compound of the formula 1, wherein: represents a hydroxyl group, i.e. compound 1b, 5 which process comprises reacting 3'-epidoxorubicin with salicyl aldehyde to give the corresponding Obtain 3 * -epi-N-salicylidene derivative; protecting the 14-hydroxy group of said 3'-epi-N-salicylidene derivative with a tertiary butyldiphenylsilyl group; 10 ·. converting the 41-hydroxy group of the 3'-epi-N-salicylidene-14-0- (tert-butyl-diphenyl-silyl) -doxorubicin, thus obtained, to a trifluoromethanesulfonate group; and removing the 14-0- (tert-butyl-diphenyl-silyl) -31-epi-N-salicylidene-4'-0-trifluoromethanesulfonate of the salicylidene group thus obtained by acid hydrolysis and the 14-0- ( tert-butyl-diphenyl-silyl) group, in order to obtain the desired glycoside of the formula 1 by removing the 4'-O-trifluoromethanesulfonate group.

Compound 1b can therefore be prepared by converting the 31-amino group of 3r-epi-doxorubicin (5) (see F. Arcamone et al., German Patent 2,752,155) into 3'-epi-N-salicylidene-doxorubicin ( 6e) by reaction with salicylaldehyde, protecting the 14-hydroxy group with a tert-butyl-diphenyl-silyl group, to form 31-epi-N-salicylidene-14-0- (tert.bptyl-diphenyl-silyl) -doxorubicin ( 6f); conversion of the 4'-hydroxy group into a trifluoromethanesulfonate (6g); hydrolysis by paratoluene sulfonic acid to form compound 1h and reaction with tetra-n-butylammonium fluoride to remove the 14-0- (tert-butyl-diphenyl-silyl) protecting group to form compound of formula Ib.

3'-Epi-doxorubicin, dissolved in a mixture of water and acetone, is reacted at room temperature with salicylaldehyde to obtain the corresponding 3'-epi-N-salicylidene derivative, which is then treated in anhydrous dimethylformamide, at room temperature with tert .-butyl-diphenylchlorosilane in the presence of imida-35 sole to form the 3'-epi-N-salicylidene-14-0- (tert-butyl-diphenyl-silyl) ether, which is dissolved in anhydrous methylene dichloride *, By treatment with trifluoromethanesulfonic anhydride, in the presence of dry pyridine, converts 3'-epi-N-salicylidene-4'-O-trifluoro-. its methanesulfonate-14-0- (tert-butyl-diphenyl-silyl) ether, the salicylidene protecting group of which is subjected to acid hydrolysis at room temperature and in a methanolic solution using a catalytic amount of paratoluenesulfonic acid and then 14 -O- {tert-butyl-diphenylsilyl) protecting group is removed by treatment with tetra-n-butylammonium fluoride in tetrahydrofuran, at room temperature to form the desired glycoside of the formula 1.

The invention also provides a process for the preparation of a glycoside of formula 2, wherein represents a hydrogen atom, i.e. compound 2a, 15 or a hydroxy group, i.e. compound 2b, or a pharmaceutically acceptable acid addition salt thereof, the process comprising converting 3f-deamino-4'-deoxy-3'-epi-4'-epi-31,4'-epiminoda unorubizine to the corresponding N-trifluoroacetyl derivative? converting said N-trifluoroacetyl derivative to 4, -deoxy-4'-20 epi-N-trifluoroacetyl-3'-deamino-31-hydroxydaunorubicin? removing the N-trifluoroacetyl group from the 4'-deoxy-4'-epi-N-trifluoroacetyl-31-deamino-3 * -hydroxydaunorubicin to form the glycoside of formula 2, wherein: 25 is a hydrogen atom,

If desired, can one convert said glycoside of formula 2 into a pharmaceutically acceptable acid addition salt thereof? if desired, one can bromine said glycoside of the formula 2 or a pharmaceutically acceptable salt thereof and hydrolyze the thus obtained 14-bromo derivative to form the glycoside of the formula 2, wherein: R 1 is a hydroxy group? and if desired, the glycoside of formula 2 can be converted, wherein: R 1 is a hydroxy group in a pharmaceutically acceptable acid addition salt thereof.

* * -4-

Treatment of the 3 ', 4' epiminoda unorubicin derivative 1a with trifluoroacetic anhydride gives the corresponding N-trifluoroacetyl derivative 7i. Reaction of this compound with a catalytic amount of sulfuric acid in acetone gives 41-deoxy-41-epi-N-trifluoroacetyl-3'-5 hydroxy-daunorubicin (8), which gives treatment by aqueous sodium hydroxide compound 2a. The N-trifluoroacetyl group can typically be removed by mild alkaline hydrolysis at a temperature of 0 ° C using 0.1N sodium hydroxide. Glycoside 2a can be isolated as the hydrochloride salt by treatment with hydrogen chloride in methanol.

Compound 2b can be prepared by bromination of 2a, followed by treatment of the resulting 14-bromo derivative with aqueous sodium formate at room temperature according to the method described in U.S. Patent 3,803,124. It can be isolated as a hydrochloride salt in the same manner as glycoside 2a.

The methods of the invention are summarized in the attached reaction scheme.

The present invention also provides a pharmaceutical composition comprising as an active ingredient an anthracycline glycoside of the invention or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier or diluent. A therapeutically effective amount of the compound of formula 1 is combined with an inert carrier. Conventional carriers can be used and the composition can be known in a known manner; be formulated.

The compounds of the invention are. suitable for methods of treatment of the human or animal body by therapy. In particular, the compounds of the invention are useful as anti-tumor agents.

The following examples illustrate the invention.

EXAMPLE I

3'-Epi-N-salicylidene-daunorubicin (6c) ......

A solution of 2 g of 3'-epi-daunorubicin (3) and a mixture of 80 ml of water and 20 ml of acetone was treated at room temperature with 0.5 ml of salicylaldehyde at a pH of 8. After 10 minutes, ethyl acetate was added and the organic phase separated, washed twice with water, “r r '·: 7 1} · 1

W 0 0 V

-5- dried over anhydrous sodium sulfate, filtered and evaporated to dryness under vacuum. The residue was first triturated with hexane to remove the traces of salicylaldehyde, then collected and dried under vacuum at 30 ° C, yielding 4c in near quantitative. R ^ 0.21 on TLC silica gel F-254 (Merck) using as eluent a mixture of CK ^ Cl ^ acetone (8/2 v / v).

EXAMPLE II

31-Deamino-4'-deoxy-3'-epi-4'-epi-3 ', 4'-epimino-daunorubicin (1a)

To a solution of 2 g of 3'-epi-N-salicylidene-daunorubicin 10 (4c) in 20 ml of anhydrous dichloromethane and 2 ml of dry pyridine at a temperature of -10 ° C, a solution of 0.8 ml of trifluoromethane-sulfonic anhydride was added in 10 ml of dichloromethane. After 1 hour at -10 ° C, the mixture was diluted with dichloromethane and washed with water, cold 0.1N hydrochloric acid, cold aqueous 5% sodium hydrogen carbonate and water. The organic phase, dried over anhydrous sodium sulfate, was filtered off and the solvent was removed in vacuo to yield product 4d.

0.50 on TLC silica gel · F-254 (Merck), eluting with the solvent mixture CHCl acetone (95/5 v / v).

A A

The crude product was dissolved in 50 ml of methanol and 0.2 g of paratoluene sulfonic acid monohydrate was added thereto. The solution was kept at room temperature for 1 hour, then 100 ml of water was added and extracted with little dichloromethane. The water phase was adjusted to pH 8 with 0.1N sodium hydroxide and dichloromethane was added. The organic phase was separated, washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated to a small volume. The mixture was purified by chromatography on a column of silica gel buffered at pH 7 using dichloromethane-ethanol as an eluent. The eluate containing product 1a was washed with water, evaporated in vacuo, taken up with little dichloromethane and crystallized.

FD MS 509 (M +) melting point 135-137 ° C.

R ^ 0.38 on TLC silica gel F-254 (Merck) using a mixture of CH2C12-CH30H-CH3C00H-H2O (30/4/1 / 0.5 v / v) as eluent. 1 35

J

1 <-6-1H - NMR (200 MHz, CDCl3): 8.02 (dd; J = 1.1; 7.7Hz; 1H; Hl) 7.76 (dd; J = 7.7; 7.7Hz ; 1H; H-2) 7.37 (dd; J-1.1; 7.7Hz; 1H; H-3) 5 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; 00 ^ -4) 3.17 (dd; J = 19.2Hz; 1H; H-10E) 10 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; COCB ^) 2.30 (ddd; J = 1.5; 4.3; 6.4Hz; 1H; H-3 ') 1.9-2.0 (m; 2H; H-8ax; H-2'ax) 15 1.87 (ddd; J = 1.5; 3.0; 14.6Hz; 1H; H2'e) 1.44 (d; J = 6.7Hz; 3H; CH -5 ')

EXAMPLE III

'31 -Epi-N-salicylydendoxorubicin (6th)

The title compound was prepared from the corresponding 3'-epi-20 doxorubicin (5) as described in Example I.

0.15 on TLC, silica gel F-254 (Merck) using as the eluent the solvent mixture CH2Cl2-acetone (4/1 v / v).

EXAMPLE IV

3'-Epi-N-salicylidene-14-O- (tert-butyl-diphenyl-silyl) -doxorubicin (5f). A solution of 1 g of 3'-epi-N-salicylidene-doxorubicin (6e) in 20 ml of anhydrous dimethyl fontland was added treated with 0.5 ml of tert-butyl-diphenyl-chlorosilane and 0.3 g of imidazole. The reaction mixture was allowed to stand at room temperature overnight, then 200 ml of water was added and the solution was extracted with methylene dichloride.

The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under vacuum. The residue was triturated with hexane and collected on a sintered glass, washed with hexane diethyl ether and dried in vacuo to afford compound 6f.

Rf 0.25 on TLC, silica gel F-254 (Merck) using the solvent CH 2 Cl 2 acetone (4/1 v / v) as eluent.

* '- · f -cj Λ r —7 «

EXAMPLE V

3'-Epi-3 * -deaminc-41-deoxy-41-epi-31,4'-epiminodoxorubicin (lb)

The title compound was prepared starting from compound 6f via its 3'-epi-41-O-trifluoromethanesulfonate (6g) prepared as described in Example II.

Acid hydrolysis of 6a in methanol with a catalytic amount of paratoluene sulfonic acid monohydrate after working up gave compound 1h.

The crude product was triturated with hexane and collected on sintered glass, washed with hexane diethyl ether and dissolved in 100 ml of tetrahydro-10 furan. The solution was treated with 0.5 g of tetra-n-butyl monofluoride.

After 2 hours, the hydrolysis of the tert-butyl-diphenyl-silyl group was complete.

The residue, obtained by evaporation of the solvent under vacuum, was purified by chromatography on a column of silica gel buffered to pH 7 using dichloromethane-ethanol as the eluent-15 system to give pure lb. The precipitate was collected on sintered glass, washed with hexane diethyl ether and dried in vacuo.

0.20 on TLC, silica gel F-254 (Merck) using as the eluent of the solvent mixture C ^ Cl ^ -CH ^ OH-CH ^ COOH-H ^ O 20 (30/4/1 / 0.5 v / v ).

EXAMPLE VI

3 "-deamino-41-deoxy-3r-hydroxy-4'-epi-4'-amino-daunorubicin (2a)

The title compound was prepared starting from the aziridine 1a.

1 g of 2a was converted into the N-trifluoroacetyl derivative (6i) by treatment with 1.2 ml of trifluoroacetic acid in anhydrous methylene chloride.

After reprocessing. the crude material (Rf 0.7 on TLC, silica gel F-254 (Merck) eluent: CH 2 Cl 2 acetone (4/1 v / v) was dissolved in 20 ml acetone and treated with a catalytic amount of sulfuric acid at 10 ° C.

The mixture was diluted with 200 ml of methylene dichloride, washed with water, 5% aqueous sodium hydrogen carbonate and water. The solvent was removed in vacuo and the residue was purified on a column of silica gel using methylene dichloride as the elution system to obtain 0.7 g of the pure compound 2a.

R_ 0.21 on TLC, silica gel F-254 (Merck) using 35 eluent of the solvent mixture CH 2 Cl 4 acetone (4/1 v / v).

♦ k · -8-

The product (2a) was slowly dissolved in aqueous 1.1N sodium hydroxide at 0 ° C to obtain the hydrolysis of the N-trifluoroacetyl protecting group. After 1 hour at 0 ° C, the solution was adjusted to pH 8.6 with 0.1N hydrochloric acid and extracted with methylene dichloride. The solvent was evaporated to give 0.5 g of a residue, which was reacted by treatment with methanolic hydrochloric acid in the hydroxide of 4, -deoxy-4, -amino-4, -epi-3'-deamino-S ' -hydroxy-daunorubicin.

MS FD 527 (M +) melting point 153 ° C (dec.).

10. Rf 0.18 on TLC, silica gel F-254 (Merck): CH 2 Cl 2 -CH 3 • OH-CH 3 COOH-H 2 O (30/4/1 / 0.5 v / v).

1 H - NMR (200 MHz, CDCl 3: 8.02 (dd; J = 0.9, 8.5 Hz; 1 H, H 1) 7.77 (dd? J = 8.5; 8.5 Hz; 1 H, H - 2) 15 7.38 (dd; J = 0.9; 8.5Hz; 1H, H-3) 5.52 (dd, J = <1? 4 / OHz; 1H, H-1 ') 5.28 (dd, J = 1.8; 4.0Hz; 1H, H-7) 4.07 (s; 3H, 00 ^ -4) 3.69 (dq; J = 6.3; 9.5Hz; 1H, H- 51) 20 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; 1H; H-10ax) 2.40 (s, 3H, COCH 3) 2.2-2.4 (m; 1H? H-8ax) 25-2, 30 (dd; J = 9.5; 9.5Hz; 1H; 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-20ax) 1.31 (d; J = 6.3Hz; 3H; CH3-5 ')

EXAMPLE VII

31-deamino-3'-hydroxy-41-deoxy-41-epi-4'-amino-doxorubucine (2b) 0.5 g 2a was dissolved in a mixture of methanol and dioxane.

The solution was treated as described in U.S. Patent 3,803,124 with initial bromine to obtain the 14-bromo derivative and then with aqueous sodium formate to form the title compound. It was converted into its hydrochloride by treatment with methanolic hydrochloric acid.

0 / V i g · ') $' r -r -9- FD-MS (M +), TLC on silica gel F-254 (Merck); CH2CX2-CH30H-CH3C00H-H20 (30/4/1 / 0.5 v / v) Rf 0.10.

ORGANIC ACTIVITY

The cytotoxic activity of the new anthracycline glycosides according to the invention (FCE 24782 / XOQ - 0333) was tested in vitro against HeLa cells, P3S8, P388 / DX, LoVo and LoVo / DX.

Time of exposure to the compound; 24 hours / compared to daunorubicin.

The results are shown in Table A.

The compound, when tested "in vivo" against P-388 ascetic leukemia and Gross leukemia, showed good anti-tumor activity, compared to daunorubicin, especially when administered orally.

The results are shown in Tables B and C.

«I ·: J> -10- TABLE A -

In vitro activity of 31-deamino-41-deoxy-31-hydroxy-41-amino-daunorubicin (FCE 24782 / XOO-Q333) compared to DNR

Id5 {Y (ng / ml) a)

Link -

Helab) P388C) P388 / DXd) LoVoe) LoVo / DXf) DNR 19 10.5 730 43 820 FCE 24782 / XOO-0333 11 24.5 235 37 230 a) Dose giving 50% reduction in cell number compared to untreated check.

b) Human cervical epithelioid careinoma cells, c) P 388 leukemia cells, sensitive to doxorubicin.

d) P 388 leukemia cells, resistant to doxorubicin.

e) Human colon adenocarcinoma cells sensitive to doxorubicin.

f) Human colon adenocarcinoma cells resistant to doxorubicin.

- ~.-r .Λ b / v -) i v? £ · Λ; . -11 "TABLE Β

Effect against P 388 ascetic leukemia3-

Compound doseb T / C% c Toxic ^ _____ deaths DNR 2.9 155 0/10 4.4 170 8/10 FCE 24782 / X00-0333 1/96 155 0/10 2.9 150 0/10 4.4 140 9/10 6, 6 100 10/10 a,

Experiments were performed on CDF mice inoculated with 6 10 leukemia cells i.p. fc

Treatment i.p. on day 1 after tumor inoculation, c

Median consultation time of treated mice divided by median survival time of control group x 100.

Evaluated based on autopsic findings.

-12-

TABLE C

. a.

Effect against Gross leukemia 3d c cd

Compound dose T / C% Toxic mg / kg kill DNR 10 165 0/20 15 192 2/20 FCE 24782 / XOO-0333 8.2 175 0/20 11.5 230 0/10 16.1 240 0/10 22.5 130 0 / 10

Experiments were performed on C3H mice inoculated β 'with 2 x 10 leukemia cells i.v. b

Treatment i.v. on day 1 after tumor inoculation. c

Median survival time from treated mice / median survival time from control group x 100; d

Evaluated based on autopsic findings.

···, λ ·? % i \ A 5 y y, v “ί ί ·;

Claims (3)

An anthracycline glycoside of the general formula 1 or 2 of the formula sheet, wherein: represents a hydrogen atom or a hydroxyl group and pharmaceutically acceptable acid addition salts thereof. A compound according to claim 1, which is 3, -deamino-4, -deoxy-3I-epi-4'-epi-3 ', 4'-epiminoda unorubicin. The compound of claim 1 which is 31-deamino-4'-deoxy-3'-epi-4'-epi-31,4'-epiminodoxorubicin. The compound of claim 1 which is 31-deamino-41-deoxy-3'-hydroxy-4'-epi-4'-aminodaunorubicin, or its hydrochloride. A compound according to claim 1, which is 3'-deamino-4'-deoxy-31-hydroxy-4'-epi-4'-amino-doxorubicin, or its hydrochloride. A process for the preparation of a glycoside of the formula 1, 15 as defined in claim 1, wherein R 1 represents a hydrogen atom comprising reacting 3'-epi-daunorubicin with salicyl aldehyde to form the corresponding 3 ' epi-N-salicylidene derivative; converting the 41-hydroxy group of said 3'-epi-N-salicyli-20 derivative to a trifluoromethanesulfonate group; removing the 31-epi-N-salicylidene-41-O-trifluoromethane sulfonate thus obtained from the salicylidene group by acid hydrolysis to obtain the desired glycoside of the formula 1. by removing the 4'-O- trifluoromethane sulfonate group. The method of claim 6, wherein 3 * -epi-daunorubicin, which is dissolved in a mixture of water and acetone, is reacted at room temperature with salicylaldehyde to form the corresponding 3'-epi-N-salicylidene derivative, which is then anhydrous methylene dichloride and in the presence of dry pyridine, is treated with trifluoromethanesulfonic anhydride to form the corresponding N-salicylidene-3'-epi-4'-0-trifluoromethanesulfonate, the protective salicylidene group of which is subjected to acid hydrolysis using p-toluenesulfonic acid at room temperature, wherein said trifluoromethane sulfonate. is dissolved in methanol, 1 -14- to obtain the desired glycoside of formula 1 by removing the leaving trifluoromethanesulfonate group. 8. A process for the preparation of a glycoside of formula 1, as defined in claim 1, wherein represents a hydroxy group, the process comprising reacting 31-epidoxorubicin with salicylic aldehyde to form the corresponding 3'-epi -N-salicylidene derivative; protecting the 14-hydroxy group of the 3'-epi-N-salicylidene derivative with a tertiary butyldiphenylsilyl group; Converting the 4'-hydroxy group of the thus obtained 3'-epi-N-salicylidene-14-0- (tert-butyl-diphenyl-silyl) -doxorubicin into a trifluoromethanesulfonate group; and removing the 14-0- (tert-butyl-diphenyl-silyl) -3'-epi-N-salicylidene-4'-O-trifluoromethanesulfonate, thus obtained, from the salicylidene group by acid hydrolysis and from the 14 -O- (tert-butyl-diphenyl-silyl) group to give the desired glycoside of formula 1 via the 4'-O-trifluoromethanesulfonate group. 9. The method of claim 8, wherein 3'-epi-doxorubicin, dissolved in a mixture of water and acetone, is reacted at room temperature with salicylaldehyde to form the corresponding 3'-epi-N-salicylidene derivative, which is then treated in anhydrous dimethylformamide at room temperature with tert-butyl-diphenyl-chlorosilane in the presence of imidazole to form the 3'-epi-N-salicylidene-14-0- (tert-butyl-diphenyl-silyl) ether thereof, which is dissolved in anhydrous methylene dichloride by treatment with trifluoromethanesulfonic anhydride, in the presence of dry pyridine, in the 3'-epi-N - salicylidene-4'-0-trifluoromethanesulfonate-14-0- (tert-butyl-diphenyl-) its silyl) ether, the protective salicylidene group of which is subjected to acid hydrolysis at room temperature and in a methanolic solution by means of a catalytic amount of p-toluenesulfonic acid, and of which the 14-0- (tert. butyl-dife nyl-silyl) protecting group is removed by treatment with tetra-n-butylammonium fluoride in tetrahydrofuran at room temperature to form the desired glycoside of formula 1. A process for the preparation of a glycoside of formula 2 as defined in claim 1 or a pharmaceutically acceptable salt ft 7 n '7 rt $ • V * * 3 w V -15- thereof, which process comprises deprotection of 3 '-deamino-4'-deoxy-3'-epi-4 * -epi-3', 4'-epimino-daunorubicin in the corresponding N-trifluoroacetyl derivative; deprotection of this derivative in 41-deoxy-4'-epi-N-trifluoroacetyl-5 31 -deamino-3 '-hydroxydaunorubicin; removing the N-triflucroacetyl group from the 4'-deoxy-41-epi-N-trifluoroacetyl-3'-deamino-3 * -hydroxydaunorubicin to form the glycoside of formula 2, wherein R 1 is a hydrogen atom; if desired converting this glycoside of formula II into a pharmaceutically acceptable acid addition salt thereof; if desired, brominating this glycoside of formula 2 or the pharmaceutically acceptable salt thereof and hydrolyzing the 14-bromo derivative thus obtained to form the glycoside of formula 2, which is a hydroxy group and, if desired, reacting this glycoside with the formula 2, wherein R 1 is a hydroxy group in a pharmaceutically acceptable acid addition salt thereof - The method of claim 2, wherein 3'-deamino-4'-deoxy-31-epi-41-epi-3 *, 4'-epimino-daunorubicin is reacted with trifluoro-acetic anhydride to form the corresponding N-trifluoro-anhydride. Acetyl derivative which, by treatment with a catalytic amount of sulfuric acid and acetone, gives 4'-deoxy-4'-epi-N-trifluoroacetyl-3 * -deamino-3'-hydroxy-daunorubicin; removing the N-trifluoroacetyl protecting group thereof by mild alkaline hydrolysis at a temperature of 0 ° C using 0.1N aqueous sodium hydroxide; optionally isolating the glycoside of formula II, wherein R 1 is a hydrogen atom in the form of the hydrochloride by treatment with hydrochloride in methanol; optionally converting this glycoside of formula 2 or its hydrochloride to the glycoside of formula 2, wherein R 1 is a hydroxy group by bromination followed by treatment of the resulting 14-bromo derivative with aqueous sodium formate at room temperature; and optionally isolating this glycoside of formula 2.35 in which R1 is a hydroxy group as its hydrochloride by treatment with a methanolic solution of hydrogen chloride. f * 9 'K' 7 -16-12 "A pharmaceutical composition comprising an anthracyclone glycoside of the formula 1 or 2, as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier or diluent. An anthracycline glycoside of the formula 1 or 2, as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in a method of therapeutic treatment of the human or animal body. Anthracycline glycoside or salts thereof according to claim 13, 10 'for use as an anti-tumor agent. A process for the preparation of an anthracycline glycoside of formula 1 as defined in claim 1, which process is essentially as described above in Examples I and II together or Examples II-V together. A process for the preparation of an anthracycline glycoside of the formula 2, as defined in claim 1, or a pharmaceutically acceptable salt thereof, which process is essentially as described above in example VI or examples VI and VII together. 20 t: ·. i. 1 i O OH / V / k / COChLR, 9 (οΓμΎ ^ c oh CH '° 0 0H; ^ ΛΎοΓ ¥' ÓH Farmitalia Carlo Erba SpA * »f- Λ ~» RESPONSE SCHEDULE O OH n «u C0CHg? © Η vCvC ^ "© öécy-" 3 CM OO OH, '3 * "O - __ CMO O OH I' * -" 3 R3 k Cd O OH ^ vvC ^ H CHO O OM I 2 o - * C ^ ° ° OH j; py ^ ~ ^ 5 * 2 e be-g ch3o O j O ® 1 bh ^ sli ^ roc ^ O OH focpoo ^ ^ 000 ^ ° ° ^ 3 Ch3® O OH, CH2 OO OH I I o - - 3 o - II-IIb SiÊ / cF.coHs ^ E ^ y ^ 7 1 8 y; ,, · .. ·: '^ Farmitalia Carlo Erba S.p.A.