PT85056B - METHOD FOR PREPARING NEW GLYCOSIDIC DERIVATIVES OF ANTRACYCIN AND OF PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Abstract

Anthracycline glycosides represented by the general formulae (I) and (II): <IMAGE> in which R1 represents a hydrogen atom or a hydroxyl group, and their pharmaceutically acceptable addition salts with an acid. Use of these compounds as antitumour agents.

Description

«PROCESS FOR THE PREPARATION OF NEW GLYCOSIDIC DERIVATIVES FROM ANT3ACIC1IM AND GO * PHARMACEUTICAL POSITIONS THAT CONTAIN THEM1

The present invention concerns new anthracycline glycoside derivatives, their preparation and the pharmaceutical compositions containing them, as well as intermediate compounds useful in the preparation of glycosides.

The present invention relates to anthracycline glycosides of the general formula

I a, b

C0CH ₂ R ₁

OH

II a, b = H b? = OH

en que

Η _χ rehydrates a hydrogen atom or a hydroxy group;

and its pharmaceutically acceptable acid addition salts.

The present invention also relates to a process for the preparation of a glycoside of the general formula I in which representa _χ represents a hydrogen atom, that is, a compound of the formula Ia, which consists of reacting the 3 »-epi -daunorubicin. with salicylaldehyde to obtain the corresponding 3'-epi-smlicylidene derivative; to convert the 4'-hydroxy group of the S4 opi-N-salicylidene derivative, mentioned above, into a trifluoromethane-sulfonate group and to eliminate the 3'-epi-N-selicylidene-4 * -O-trifluoromethane-sulfonate thus obtained the selicilidene group by acid hydrolysis to obtain, via displacement of the 4'-O-trifluoromethane-sulfonate group, the desired glycoside of general formula I.

Another process for preparing compounds of formula Ia is to react the 3'-aaino group of the 3'-oi-d 'unorubicin of formula III / * F. Arcamone, A, Bargiotti G ·. Cassinellií German patent 2752115 (June 1, 1973) J with salicylaldehyde, in a mixture of water and acetone at room temperature, to obtain the corresponding 3'-oi-II-salicylidene derivative of general formula IV C ; to treat a compound of general formula IV G with trifluoromethane-sulfonic anhydride in anhydrous methylene dichloride and in the presence of pyridine to obtain 3'-epi-N-salicylidene-4'-O-trifluoromethane-sulfonate of general formula IV d; en subject, to an acid hydrolysis, the group

protector of the salicylidene radical of a compound of general formula IV d, dissolved in methanol, at room temperature and using p-toluene-sulfonic acid, to obtain, via displacement of the eliminable trifluoromethane sulfonate group a compound of formula Ia.

The present invention also relates to a process for the preparation of a glycosidic compound of

is, a compound of formula Ib which consists of reacting to

3'-epi-doxorubicin with salicylaldehyde to obtain the corresponding 3'-epi-N-salicylidene derivative; to protect the 14-hydroxy group of derivative 3 ^, -epi-N-salicylidene, mentioned above, with a tert-butyl-diphenyl-silicon group; to convert the 4'-hydroxy group of 3'-epi-H-salicylidene-14-0- / ^r butyl tert-diphenyl-silyl Jil-doxorubicin, thus obtained to a trifluoromethane-sulfonate group; and to eliminate from the 14-0- / butyl tert-diphenyl-silyl7-3'-epi-IT-s allylidene-4'-O-trifluoromethane-sulfonate thus obtained the salicylidene group by acid hydrolysis and the group 14-0- / tert-butyl-diphenyl-silyl-7, the desired glycoside of formula I.

A compound of formula Ib can also be prepared by converting the 3'-alpha group of 3 '-epi-doxorubicin of formula V / see P. Arcamone et al., German patent 275211 ^ 7 at 3'-epi -H-salicylidene-doxorubicin of the general formula VI and by co-salicylaldehyde reaction, protection of the 14-hydroxy group with a tertiary butyl-diphenyl-silyl group to obtain 3'-e _; pi-If-galicylidene-14-0- / butyl tert-diphenyl-silyl / -doxorubicin of general formula VI f; according

version of the 4'-hydroxy group in a trifluoromets.no-sulfonate of the general formula VI g, hydrolysis by the action of o-toluenesulfonic acid with formation of the compound of formula Ih and reaction with n-ammonium tetra-butyl fluoride for removing the protecting group from the radical 14-O- / butyl tert-diphenylsilyl7 and obtaining a compound of formula I b.

The reaction of 3'-epi-doxorubicin, dissolved in a mixture of water and acetone, with salicylaldehyde, at room temperature, to obtain the corresponding 3'-epi-H-salicylidene derivative is a characteristic reaction; then the 3'-epi-N-salicylidene derivative, in anhydrous dimethylformamide, at room temperature, with butyl tert-diphenylchlorosilane in the presence of imidazole to obtain the 3'-epi-N-salicylidene-ether 14-0- / butyl tert-diphenylsilyl / corresponding, which, dissolved in anhydrous methylene dichloride is converted, by treatment with trifluoromethane-sulfonic anhydride, in the presence of anhydrous pyridine, in the 3 '-and hi-Ns of the ilidene -4 '-O-trifluoromethanesulfonate-14-0- / butyl tert-diphenylsilyl / corresponding whose salicylidene protecting group undergoes acid hydrolysis, at room temperature and in a metaaolic solution using of a catalytic amount of p-toluenesulfonic acid, after which the protecting group 14-0- / butyl tert-diphenylsilyl is removed by treatment with tetra-butyl n-ammonium fluoride in tetrahydrofuran , at room temperature, to obtain the desired powder glycosylation general formula I.

The present invention also relates to a process for the preparation of a glycoside of formula ge

ral II na. uai represents a hydrogen atom, that is, a compound of formula Ila, or a hydroxy group, that is, a compound of formula Ilb, or a pharmaceutically acceptable acid addition salt thereof, which it consists in converting the 3'-dermino-4'-deoxy-3'-eoi-4 '~ epi-3', 4'-epiminodaunorubicin into the corresponding N-trifluoroacetyl derivative; in converting the H-trifluoroacetyl derivative, cited above, to 4'-deoxy-4'-epi-N-trifluoroacetyl-3'-deamino-3'-hydroxy-daunorubicin; to eliminate the N-trifluoroacetyl group of 4'-deoxy-4'-epi-N-trifluoroacetyl-3'-deamino-3'-hydroxy-daunorubicin, mentioned above, to obtain the glycoside of general formula II in which 3% represents a hydrogen atom; converting, eventually, the glycoside of formula II, mentioned above, into a pharmaceutically acceptable acid addition salt; optionally, to react with bromine the glycoside of general formula II, mentioned above, or its pharmaceutically acceptable salt and to hydrolyze the resulting 14-bromine derivative to obtain the glycoside of general formula II in which 3% represents a hydroxy group; and, eventually, converting the glycoside of general formula II, mentioned above, in which R does _{not show} a hydroxy group in a pharmaceutically acceptable acid addition salt.

treatment of the 3 ', 4'-eimino-daunorubicin derivative of formula I with trifluoroacetic anhydride provides the corresponding .W-trifluoroacetyl derivative of general formula VII X The reaction of this compound with a catalytic amount of sulfuric acid in acetone provides the 4'-deoxy -4 '-e ni-II-trifluoro acetyl-3' -deamino-3 '-hydroxy-daunorubici-

in the formula ¥ 111 which, by treatment with an aqueous solution of sodium hydroxide, provides the compound of formula IIa. The N-trifluoroacetyl group can be removed by means of conventional mild alkaline hydrolysis, at 0 ° C, using an aqueous 0.1 N sodium hydroxide solution. Under treatment with a methanolic solution of hydrogen chloride, the glycoside of formula IIa can be isolated in the form of hydrochloride.

By reacting with bromine the compound of formula IIa, the compound of formula Ilb can be prepared. The resulting 14-bromine derivative is then treated with aqueous sodium formate solution at room temperature, according to the technique described in the specification of the US patent> T2 3803124. The compound of formula Ilb can be isolated resulting in the form of hydrochloride as the glycoside of formula 11a was isolated.

The summary of the processes according to the present invention can be seen in the reaction scheme below.

The present invention also relates to a pharmaceutical composition that includes, as a nective ingredient, an anthracycline glycoside according to the present invention or a pharmaceutically acceptable acid addition salt thereof together with an acceptable diluent or carrier under the pharmaceutical point of view. 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 in a conventional galenic form.

The compounds according to the present invention are used in human or animal therapy. These compounds are especially used as anti-tumor agents.

Reaction Scheme

Rg t oOHCgH ^ CHs d R ₂ oOHCgH ^ CH 'and R. ^ Ry = OH f Rp -O-Si (CgH ^) gt-Bu g RJ -0-Si (C ₆ H ₅ ) gt-Bu h R -jj -O-Si (C ₆ H ₅ ) gt-Bu i R ₄ : COCF ₃

R ^: OH R ^ s OSOgCF ₃ R ₂ : oOHCgH ^ CH- Rg: oOHC ^ H ^ CHs R ₃ : OH Rgí oOHCgH ^ CH ^ r ₃ ^j OSOgCF ₃

The following Examples illustrate the present invention:

Example 1

3'-eDÍ-N-s- ~ licylidene-daunorubicin, compound of general formula IV c

At room temperature, a solution of 2 g of 3'-epi-daunorubicin of formula III in a mixture of 80 µl of water and 20 µl of acetone was treated with 0.5 Λ of salicylaldehyde at pH 8. Ten minutes then ethyl acetate was added and the organic phase was separated, washed twice with water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to dryness. The resulting residue was first triturated with hexane to remove traces of salicylaldehyde and then isolated and dried in vacuo at 30 ° C to obtain the title compound in quasi-quantitative yield. The compound was subjected to thin layer chromatography (T1C) using silica gel F 254 (: ’erck) and the eluent was the mixture of netylene dichloride-ceton- (8: 2) by volume. Rf 0.21.

Example 2

3'-de amino-4'-de oxy-3'-e oi-4'-epi-3 ', 4'-epinino-daunorubicin, compound of formula Ia.

To a solution of 2 g of 3'-eui-IT-salicylidene-daunorubicin of general formula IV and in 2C M of anhydrous dieloromethane and 2 ml of anhydrous pyridine, maintained at a temperature of -10 ° C, was added a solution of 0.8 ml of trifluoromethanesulfonic anhydride in 10 nl of dichloroethane. One hour

- 10 / then, at -10 ° C, the reaction mixture was diluted with dichloromethane and washed with water, with a cold solution of hydrochloric acid 0.1.71, with a cold aqueous solution of carbonate of hydrogen and sodium at 5% and with water. The organic phase was dried over anhydrous sodium sulfate, filtered off and the solvent was removed in vacuo. A compound of formula IV d was obtained, which was subjected to thin layer chromatography using silica gel P 254 (merck) and, as an eluent, the mixture of dichloromethane and acetone 95-5 by volume. lif 0.50.

The crude product obtained was dissolved in 50 ml of methanol and 0.2 g of p-toluenesulfonic acid monohydrate was added. The resulting solution was kept at room temperature for 1 hour, after which 100 ml of water was added and extracted with a little dichloromethane. The pH of the aqueous phase was adjusted to 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 evaporated the solvent until a small volume was obtained.

The reaction mixture was purified by chromatography using a pH 7 buffered silica gel column and a mixture of dichloromethane-ethanol with the eluent.

The eluted product containing the compound of formula 1 was washed with water, evaporated in vacuo, separated with a small amount of dichloromethane and crystallized.

FD EJI 509 £ J P.F. 135-137 ° D.

By thin layer chromatography (TL0) using silica gel? 254 (ilerclc) and, as an eluent, the

methylene dichloride / methyl alcohol / acetic acid

glac i? l / water (30: 4: 1 : 0, 5) in volume, a value was obtained lor from Rf equal to 0.3θ » fíall ¹ H (; 200 17Hz, CUCl ₃ ) r 8.02 (dd, J = 1.1, 7.71-Iz, 1H, H — 1) 7.76 (dd, J = 7.7, 7.7 Hz, 1H, H-2) 7.37 (dd, J = 1.1, 7.7 Hz, 1H, H-3) 5.31 (dd, J = 3.0, 4.8Hz, 1H, H-l ') 5.17 (dd, J = 2.0, 3.6Hz, 1H, Ξ-7)

) 4.32 (qd, J = <1, β, 7Ηζ, 1H, H-5 ’)

4.07 (s, 3H, 0CH ₃ -4)

3.17 (dd, J = 19.2Hz, 1H, H-10e)

2.95 (d, J «19.2Hz, 1H, H-lOax)

2.46 (ddd, J = 2.0, 2.0, 15.0Hz, 1H, H-8e)

2.43 (s, 3H, COOH ₃ )

2.30 (ddd, J = 1.5, 4.3, 6.4Hz, 1H, H-3 ')

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, CH ₃ -5 ')

Example 3

3'-epi-N-salicylidene-dexorubicin., Compound of general formula VIe

The title compound was freed from the corresponding 3'-epi-doxorubicin compound of formula V according to ·? technique described in Example 1. ε thin layer chromatography was used using silica gel F 254 (? 'erck) and, as an eluent, the • methylene dichloride-acetone (4: 1), by volume . RF. 0.15.

Example 4

3'-eoi-N-s ^ lycylidene-14-0- / butyl tert-diphenyl-silyl / -doxorubicin, compound of general formula VI f

A solution of 1 g of 3'-epi-N-salicylidene-doxorubicin, of the general formula VIe, was treated in 20> η1 of diffletilfor.mamide anhydrous with 0.5 ΰΐ of butyl tert-diphenyl-chlorosilane and 0.3 g of imidazole. The reaction mixture was kept overnight at room temperature after which 200 ml of water was added and the resulting solution was extracted with methylene dichloride.

The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to dryness. The resulting residue was triturated with hexane and separated by filtration through a porcelain funnel. normal, washed with the mixture hexane-ethyl ether and dried in the vessel. The title compound was obtained, which was subjected to. thin layer chromatography using silica gel F 254 (Merck) and as an eluent the methylene dichloride-acetone mixture (4: 1) by volume. Itf 0.25.

Example 5 ’-epi-3 '-deamino-4’ -deoxy-4 ’-epi-3', 4 * -eoinino-doxorubicin, compound of formula Ib

The title compound was made up from a compound of the general formula VI f ^H via ^tt a compound of the general formula VI g such as, for example, the corresponding 3'-epi-4'-0-trifluoromethane-sulfonome, prepared according to

- 13 technique, described in Example 2.

k hydrolysis by an acid of a compound of the general formula VI g, mentioned above, in methanolic solution using a catalytic amount of p-toluenesulfonic acid monohydrate provided, during the reaction, a compound of formula I h.

The crude product thus obtained was triturated with hexane and separated using a porous filter, washed with the hexane-ethyl ether mixture and dissolved in 100 ml of tetrahydrofuran. The solution was treated with 0.5 g of tetra-butyl n-ammonium fluoride. Two hours later the hydrolysis of butyl-tert-diphenyl-silyl was completed. The solvent was removed in vacuo and the resulting residue was purified by chromatography using a silica gel column buffered to pH 7 and the methylene dichloride-ethanol mixture as eluent. The fula compound Ib was obtained. The precipitate was filtered off through a porous porcelain filter, washed with the hexane-ethyl ether θ mixture and dried in vacuo. The above precipitate was subjected to thin-layer chromatography (TIC) using silica gel F 254 (? Ierck) and as the eluent the mixture of netylene dichloride / methyl alcohol / glacial acetic acid / water (30: 4: 1: 0.5) by volume. 3f? 0.20.

Example 6

3 '- from to mino-4' '-deoxy-3' -hydroxy-4 '-eni-4' -ainino-daunorubicins, as a formula IIa.

The title compound was prepared from aziridine of formula Ia. 1 g of the compound of formula Ia, cited above, was transformed into the N-trifluoroacetyl derivative of general formula VIIi by treatment with 1.2 ml of trifluoroacetic anhydride in anhydrous methylene dichloride. Completed a. The resulting crude material was first subjected to thin layer chromatography (TLC) using silica gel F 254 (ilerck) Rf 0.7 and, as an eluent, the methylene dichloride-ketone mixture (4: 1 ) by volume and then dissolved in 20 ml of acetone · Treated with a catalytic amount of sulfuric acid at a temperature of 10 ° C.

The reaction mixture was diluted with 200 ml of methylene dichloride, washed with water, with a 5% aqueous solution of sodium hydrogen carbonate and with water. The solvent was removed in vacuo and the resulting residue was purified using a column of silica gel and, as an eluting agent, methylene dichloride. 0.7 g of the pure formula IIa compound were obtained, the compound of formula IIn was subjected to thin layer chromatography (TIC) using silica gel F 254 (lerck) and, as an eluting agent, the dichloride mixture methylene / acetone (4: 1) by volume. Rf: 0.21.

The product of formula IIa, mentioned above, was slowly dissolved in an aqueous solution of sodium hydroxide

Λ sodium O, 1N, at a temperature of 0 C, for the hydrolysis of the protecting group H-trifluoroacetyl to be carried out.

One hour later, at 0 ° C, the pH of the solution was adjusted to 8.6 with 0.1N hydrochloric acid and extracted with methylene dichloride. The solvent was removed by evaporation. 0.5 g of a residue were obtained

- 15 poured, by treatment with hydrogen chloride in methanolic solution, into the 4'-deoxy-4'-amino-4'-epi-3'-deamino-3 * -hydroxy-daunorubicin hydrochloride.

IN FD £ 527. F.F. 153 ° O (with decomposition)

The hydrochloride mentioned above was subjected to thin layer chromatography (TLO) using silica gel F 254 (Herck) and, as a solvent, the mixture of letylene dichloride / methyl alcohol / glacial acetic acid / water (30: 4:: 1: 0.5) by volume. Rf: 0.18.

RHN ¹ H (200 HHz, CDO1: 8.02 (dd, J = 0.9, .8.5 Hz, 1H, Hl) 7.77 (dd, J = 8.5, 8.5Hz, 1H, H-2) 7.38 (dd, J = 0.9, 8.5Hz, 1H, H-3) 5.52 (dd, J = <1, 4.0I-Iz, 1H, H-l ') 5.28 (dd, J = 1.8, 4.0Iz, 1H, H-7) 4.07 (s, OCH ^ -4) 3.69 (dq, J = 6.3, 9.5Hz, 1H, H-5 ') 3.51 (ddd , J = 4.8, 9.5, 11.6Hz, 1H

3.22 (dd, J = 1.9, 18.9Hz, 1H, H-10e)

2.94 (d, J = 18.9Hz, 1H, H-lOax)

2.40 (s, 3H, COCIÍ ₃ )

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

2.30 (dd, J = 9.5, 9.5Hz, 1H, H-4 ·)

2.0-2.2 (m, 2H, H-8e, Η-2'e)

1.70 (ddd, J - 4.0, 4.6, 13.2Hz, 1H, Η-2'ax)

1.31 (d, J = 6.3Hz, 3H, CH ₃ -5 ')

Example 7

3 '-deai.iino-3' '-hydroxy-4' '-deoxy-4' '-epi-4' '-amino-doxorubicin, compound of formula Ilb.

0.5 g of the compound of formula IIe was dissolved. in a mixture. methanol and dioxane. The solution was treated according to the technique described in the specification of US patent NS 3803124, first with bromine to obtain the 14-bromine derivative and then with a sodium formate solution to obtain the compound of the title. The title compound was converted into the corresponding hydrochloride by treatment with a methanolic solution of hydrogen chloride. Elã - í'D 543/3 + /. The resulting hydrochloride was subjected to a thin layer chromatography (TLC) using silica gel F 254 (/ Terck) and, as an eluent, the mixture methylene dichloride / methyl alcohol / glacial acetic acid / water ( 30: 4: 1: 0.5) by volume. Rft 0.10.

‘Biological activity

The cytotoxic activity of the new anthracycline glycosides according to the present invention, such as 3'-deamino-4'-deoxy-3'-hydroxy-4'-eoi-4'-, was evaluated in vitro * amino-daunorubicin (PCE 24782 / ΣΌΟ-Ο333) in relation to Hela, 1388, F388 / DX, L0V0 and LoVo / DX cells.

Contact time with the compound: 24 hours using daunorubicin as a comparison term.

Table 1 shows the results.

This taste, when tested “in vivo '· in situations of ascitic leukemia P-388 and leukemia Gross exhibited,

- 17 esecularly when administered orally, excellent anti-tumor activity, using daunorubicin as a comparison term.

In Tables 2 and 3 you can see the results.

Table 1

In vitro activity of 3'-deaminO “4'-deoxy-3 '“ b.hydroxy-4 ^, ~ epi-4'-anino-daunorubicin (FCE 24732 / AOO-O333) with the term of how? daunorubicin (Dí®)

Compound

Dl® 19 10.5 730 43 820 FCE 24782 / X00-0333 11 24.5 235 37 230

a) Dose that allows a 50% reduction in the number of cells using untreated controls as a comparison term.

b) Carcinoma cells, from human cervix epithelial tissue

c) Ρ3θθ leukemia cells sensitive to daunorubicin

d) P338 leukemia cells resistant to daunorubicin

e) Adenocarcinom cells? colon cancer sensitive to doxorubicin.

f) Doxorubicinn resistant human colon adenocarcinoma cells

- 18 Table 2

Action against ascitic leukemia · ?. 1338 '

Compound ι b dose T / C / ^e llorts caused by toxicity DN ·! 2.9 155 0/10 4.4 170 o / lQ FC1 24782 / 1.96 155 0/10 / io-0333 2.9 150 0/10 4.4 140 9/10 6.6 100 10/10 o The experiences ·; : .t> forara performed with innocuous mice

with 10 ° of leukemia cells intraperitoneally t Trento administered intraperitoneally on the first day after inoculation of the tu.:ior c Ratio between the mean survival time of the treated mice and the mean survival time of the controls xx 100 .

Baseline assessment and observations made during the autopsy.

/

/ '. · «

Table 3 Action against leukemia Gross ^a

Compound dose mg / kg T / C% ° Deaths caused by toxicity DNR 10 165 0/20 15 192 2/20 FCE 24782 / 8.2 175 0/20 XOO-O333 11.5 230 0/10 16.1 240 0/10 22.5 130 0/10

a Experiments performed on C3H mice, inoculated with x104 leukemia cells intravenously.

b Treatment administered intravenously one day after tumor inoculation.

c Ratio between the average survival time of the treated mice and the average survival time of the controls x x 100.

d Assessment based on observations made during the autopsy.

Claims (9)

Claims 1.- Process for the preparation of clinical antraci glycosides of general formula I II wherein R4 represents a hydrogen atom or a hydroxy group; and its pharmaceutically acceptable acid addition salts, characterized by the fact that (a) for the preparation of glycosides of general formula I, in which R4 represents a hydrogen atom, it is reacted 3'- epi-daunorubicin with salicylaldehyde to obtain the corresponding 3'-epi-N-salicylidene derivative; to convert the 4'-hydroxy group of the 3'-epi-N-salicylidene derivative, mentioned above, into a trifluoromethane-sulfonate group and to eliminate the 3'-epi-N-salicylidene-4'-O-trifluoromethane- sulfonate thus obtained the salicylidene group by acid hydrolysis to obtain, via displacement of the group 4'-O-trifluoromethane-sulfonate, the glycoside of - desired of general formula I; or (b) for the preparation of glycosides of general formula I, in which R ₁ represents a hydroxy group, of reacting 3'-epi-doxorubicin with salicylaldehyde to obtain the corresponding 3'-epi-N-salicylidene derivative ; protecting the 14-hydroxy group of the 3 ¹ -epi-N-salicylidene derivative, mentioned above, with a tert-butyl-diphenylsilyl group; converting the 4'-hydroxy group of 3'-epi-N-salicylidene-14-0-7 butyl tert-diphenyl-silyl J-doxorubicin thus obtained into a trifluoromethane-sulfonate group; and to remove from the 14-0- / butyl tert-diphenyl-silyl / -3'-epi-Nsalicylidene-4'-O-trifluoromethane-sulfonate thus obtained the salicylidene group by acid hydrolysis and the 14-0- / * tert-butyl-diphenyl-silyl J to obtain via group displacement 4'-O-trifluoromethane-sulfonate, the desired glycoside of general formula I; or (c) for the preparation of glycosides of general formula II, converting 3'-deamino-4'-deoxy-3'-epi-4'-epi-3 ', 4'-epimino-daunorubicin to derivative N - corresponding trifluoroacetyl; to convert the N-trifluoroacetyl derivative, mentioned above, to 4'-deoxy-4'-epi-N-trifluoroacetyl-3 ¹ -deamino-3'-hydroxy-daunorubicin; and to remove the N-trifluoroacetyl group from 4'-deoxy-4 ¹ -epi-N-trifluoroacetyl-3'-deamino-3'-hydroxy-daunorubicin to obtain a glycoside of formula II in which it represents an atom of hydrogen; of eventually converting the glycoside of general formula II, mentioned above, into its addition salt (3.θ acid acceptable from the pharmaceutical point of view; of reacting, eventually, with bromine, the glycoside of general formula II mentioned above or their pharmaceutically acceptable salts and to hydrolyze the resulting 14-bromo derivative to obtain the glycoside of formula II in which R4 represents a hydroxy group and, eventually, to convert the glycoside mentioned above, of general formula II, in which R R represents a hydroxy group in a pharmaceutically acceptable acid addition salt. 2. A process according to claim 1 for the preparation of compounds of the general formula I, in which R4 represents a hydrogen atom, characterized by the fact that 3 ¹ -epi-daunorubicin is reacted at room temperature dissolved in a mixture of water and acetone, with salicylaldehyde to obtain the corresponding 3'-epi-N-salicylidene derivative, then to treat the 3'-epi-N-salicylidene derivative, mentioned above, with trifluoromethane-sulfonic anhydride, in anhydrous methylene dichloride and in the presence of anhydrous pyridine, to obtain the corresponding N-salicylidene-3'-epi-4'-O-trifluoromethane-sulfonate, to undergo acid hydrolysis, at room temperature, protecting groups of N-salicylidene-3'-epi-4 ¹ -O-trifluoromethane-sulfonate, mentioned above, dissolved in methanol, using p-toluenesulfonic acid, to obtain, via displacement of the eliminable groups of trifluoromethane -sulfonate, a glycoside of the general formula I. 3. A process according to claim 1 for the preparation of compounds of the general formula I in which R 4 represents a hydroxy group, characterized in that the 3'-epi-doxorubicin is dissolved at room temperature in a mixture of water and acetone, with salicylaldehyde, to obtain the corresponding 3'-epi-N-salicylidene derivative, to be treated, at room temperature, the 3 ¹ -epi-N-salicylidene, mentioned above, within of anhydrous dimethylformamide, with butyl tert-diphenylchlorosilane in the presence of imidazole to obtain the 3'-epi-N-salicylidene-14-0- / butyl tert-diphenylsilyl / ether, to convert the resulting compound, mentioned above, dissolved in anhydrous methylene dichloride in the 3'-epi-N-salicylidene-4'-0-trifluoromethane-sulfonate-14-0- / butyl tert-diphenylsilyl J ether, by treatment with trifluoromethane-anhydride sulfonic acid, in the presence of anhydrous pyridine, to undergo acid hydrolysis in u in a methanolic solution and at room temperature the salicylidene ether protecting groups 3 ¹ -epi-N-salicylidene-4'-0-trifluoromethanesulfonate-14-0- / butyl tert-diphenyl-silylicq / mentioned above, using a catalytic amount of p-toluenesulfonic acid and then to remove the 14-0- / butyl tert-diphenyl-silyl J protecting groups by treatment with tetra-butyl-n-ammonium fluoride in tetrahydro furan at room temperature to obtain the desired glycoside of formula I. 4. A process according to claim 1 for the preparation of compounds of general formula II, characterized in that 3'-deamino-4'-deoxy-3'-epi-4'-epi-3 is reacted ', 4'-epiminodaunorubicin with trifluoroacetic anhydride to obtain the corresponding N-trifluoroacetyl derivative, to treat the N-trifluoroacetyl derivative, mentioned above, with a catalytic amount of sulfuric acid, in acetone, to obtain the 4'-deoxy-4'-epi-N-trifluoroacetyl-3'-deamino-3'-hydroxy-daunorubicin; eliminating the N-trifluoroacetyl protecting groups of 4'-deoxy-4'-epi-N-trifluoroacetyl-3'-deamino-3'-hydroxy-dauno rubicina, mentioned above, by gentle alkaline hydrolysis at a temperature of 0 ° C, using an aqueous 0.1N sodium hydroxide solution; to optionally isolate the glycoside hydrochloride of general formula II, in which R4 represents a hydrogen atom, by treatment with a solution of hydrogen chloride in methanol; to eventually convert a glycoside of formula II mentioned above or a hydrochloride thereof to a glycoside of formula II, in which it represents a hydroxy group, by reacting with bromine and treating the resulting 14-brominated derivative with an aqueous solution of sodium formate at room temperature; and, if necessary, isolating the glycoside hydrochloride, mentioned above, of general formula II, in which R1 represents a hydroxy group, by treatment with a methanolic solution of hydrogen chloride. 5. Process according to claim 1 for the preparation of 3 ¹ -deamino-4'-deoxy-3'-epi-4'-epi-3 ', 4'-epiminodaunorubicin, characterized in that compounds are used correspondingly replaced initials. 6. A process according to claim 1 for the preparation of 3'-deamino-4 ¹ -deoxy-3'-epi-4'-epi-3 ¹ , 4'-epiminodox rubicina, characterized in that it is used correspondingly substituted starting compounds. 7. Process according to claim 1 for the preparation of 3'-deamino-4'-deoxy-3'-hydroxy-4'-epi-4'-amino-daunorubicin or its hydrochloride, characterized in that if Ο / 5S use correspondingly substituted starting compounds. 8. Process according to claim 1 for the preparation of 3'-deamino-4 ¹ -deoxy-3'-hydroxy-4'-epi-4'-amino-doxorubicin or its hydrochloride, characterized in that if correspondingly substituted starting compounds are used. 9, - Process for the preparation of pharmaceutical compositions used as anti-tumor agents, characterized by the fact that an effective amount of an anthracycline glycoside of general formula I or II or an acid addition salt acceptable from the point of view is mixed pharmaceutical, as an active ingredient, prepared by the process according to claim 1, with pharmaceutically acceptable carriers or diluents.