CH657622A5 - ANALOGUE COMPOUNDS OF DAUNORUBICINA AND DOXORUBICINA, THEIR PREPARATION AND USE. - Google Patents

Description

The present invention describes anthracyclinonic glucosides of formula I:

Ch_x

OH

OH

X

CH

R

NH,

R

wherein X is hydrogen or a hydroxyl group; R] is hydrogen or a methyl group; one of R2 and R? is it a methoxy group and the other of R2 and R? it is hydrogen; and the addition salts of said compounds with pharmaceutically acceptable acids.

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Said compounds are indicated as follows:

4-demethoxy-4 '-O-methyl-daunorubicin

(la: Ri = R3 = X = H, R2 = OCH3),

4-demethoxy-4 '-epi-4' -O-methyl-daunorubicin

(Ib: Ri = R2 = X = H, R3 = OCH3), 4-demethoxy-2,3-dimethyl-4'-O-methyl-daunorubicin

(le: R, = CH3, R2 = OCH3, R3 = X = H),

4-dimethoxy- 2,3-dimethyl-4 '-epi-4' -O-methyl-daunorubicin

(Id: R, = CH3, R2 = X = H, R3 = OCH3), 4-demethoxy-4'-O-methyl-doxorubicin

(le: R, = R3 = H, R2 = OCH3, X = OH),

4-demethoxy-4 '-epi-4' -O-methyl-doxorubicin

(If: R, = R2 = H, R3 = OCH3) X = OH), 4-demethoxy-2,3-dimethyl-4 '-O-methyl-doxorubicin

(Ig: Ri = CH3, R2 = OCH3, R3 = H, X = OH), and 4-demethoxy-2,3-dimethyl-4 '-epi-4' -O-methyl-doxorubicin (Ih: Ri = CH3 , R2 = H, R3 = OCH3, X = OH). The invention further describes processes for the preparation of the anthracyclinonic glucosides of formula I. Said processes include the condensation of 4-demethoxy-dauno-myconone or 2,3-dimethyl-4-demethoxy-daunomycinone (USP No. 4.046.878) with 2,3,6-tridesoxy-3-trifluoroacetamido-4-0-methyl-L-lixo-hexopyranosyl chloride or with 2,3,6-tridesoxy-3-tri-fluoroacetamido-4-O-methyl-L -arabino-hexopyranosyl chloride (USP No. 4.183.919) to give one of the protected glucosides of formula Ila - Ild:

1

0

Ila: Ri = R3 = H; R2 = OCH3 IIb: R, = R2 = H; R3 = OCH3 Ile: R, = CH3; R2 = OCH3; R3 = H lld: R, = CHj; R2 = H; R3 = OCHj elimination of the N-trifluoroacetyl protective group by mild alkaline hydrolysis to give the corresponding derivatives of daunomycin Ia-Id and optionally converting said daunorubicin derivatives into the corresponding derivatives of doxo-rubicin Ie-Ih by bromination and treatment of the resulting 14-bromine derivatives with aqueous sodium formate.

The transformation of the derivatives of daunorubicin Ia-Id into the corresponding derivatives of doxorubicin Ie-Ih, follows the procedure described in the PU.S.P. No. 3,803,124. In another aspect, the invention provides pharmaceutical compositions which comprise an anthracyclinonic glucoside of formula 1 or a pharmaceutically acceptable salt thereof in mixture with a pharmaceutically acceptable diluent or support.

The invention is illustrated by the following Examples and by biological data.

Example 1

5 4-demethoxy-4 '-O-methyl-daunorubicin (la)

A solution of 3.68 g of 4-demethoxy-daunomycinone in 400 ml of anhydrous methylene chloride containing 1.4 g of l-chloro-4-O-methyl-N-trifluoroacetyl-daunosamine was stirred vigorously in the presence of 30 g of molecular sieve (4A Merck) ® and 1.3 g of silver trifluoromethanesulfonate. After 10 minutes at room temperature, the reaction mixture was neutralized with 0.55 ml of sym-collidine.

The suspension was filtered after 40 minutes and the organic phase was washed with 0.01 N aqueous solution of hydrochloric acid, with water, with saturated sodium bicarbonate solution and again with water to neutral.

The residue obtained by evaporation of the solvent in vacuo was dissolved in 150 ml of acetone treated with 600 ml of 0.2 N aqueous solution of sodium hydrate and then diluted with 450 ml of water. After 5 hours at 0 ° C, the pH was brought to 8.5 and extracted with chloroform until the chloroform extracts were no longer colored. The combined organic extracts were acidified to pH 5 with 0.1 N methanolic hydrochloric acid. By evaporation under vacuum in small volume (150 ml), crystallized pure 4-demethoxy-4 '-O-methyl-daunorubicin (0.6 g) . The mother liquors were purified on a column of silica gel buffered with phosphate buffer M / 15 at pH 7, using the chloroform system: methanol: water (10: 2: 0.2 by volume) as eluent. The eluate containing 30 the pure compound was diluted with water, the organic phase was separated which was washed with water, evaporated to a small volume and subsequently acidified to pH 5 with 0.1 N methanolic hydrochloric acid.

A further jet (0.4 g) of 4-demethoxy-4 '-O-35 methyl-daunorubicin hydrochloride was obtained.

mp 189 ° -190 ° C (with decomposition).

TLC on Kieselgel plates (Merck F 254) using the chloroform: methanol: water system (10: 2: 0.2 by volume).

HPLC: experimental analysis: Cis microbondapack column; 40 mobile phase: water: acetonitrile (69:31 by volume) at pH 2 with 10% orthophosphoric acid: flow rate 1.5 ml / min, retention time 22 minutes.

FD-MS: m / z 511 (M +).

45 Example 2

4-demethoxy-4 '-O-methyl-doxorubicin (le)

A solution of 0.5 g of 4-demethoxy-4 '-O-methyl-dauno-rubicin, prepared as described in Example 1, in a 50 ml mixture of methanol (8 ml) and dioxane (20 ml) was treated with bromine to obtain the 14-bromine derivative. The treatment of said 14-bromine derivative with an aqueous sodium formate solution, at room temperature for 18 hours, called 0.310 g of 4-demethoxy-4 '-O-methyl-doxorubicin which was isolated as 55 hydrochloride. mp 164-165 ° C (with decomposition).

TLC on Kieselgel plates (Merck F 254) using the chloroform: methanol: water (10: 2: 0.2 by volume) as eluent; Rf = 0.18.

HPLC: experimental conditions: microbondapack column 6o Ci "; mobile water phase: acetonitrile (69:31 by volume) at pH 2 with 10% orthophosphoric acid; flow rate 1.5 ml / min; retention time: 10 minutes.

Example 3

65 4-demethoxy-2,3-dimethyl-4 '-O-methyl-daunorubicin (le)

The condensation reaction between 4-demethoxy-2,3-dimethyl-daunomycinone and l-chloro-4-O-methyl-N-trifluoroacetyl-dau-

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4

nosamine, under the conditions described for Example 1, provided the title compound.

Example 4

4-demethoxy-2,3-dimethyl-4 '-O-methyl-doxorubicin (Ig)

The conversion of the compound 1 to the title compound was carried out using the procedure described in Example 2.

Example 5

4-demethoxy-4 '-epi-4' -O-methyl-daunorubicin (Ib) and 4-demethoxy-2,3-dimethyl-4 '-epi-4' -O-methyl-daunorubicin (Id)

The condensation reactions, as described in Example 1, of 4-demethoxy-daunomycinone and 4-demethoxy-2,3-dimethyl-daunomycinone with 2,3,6-tridesoxy-3-trifluoroacetamido-4-0-methyl- L-arabino-esopiranosil chloride, after hydrolysis of the N-protective group, provided the title compounds.

Example 6

4-demethoxy-4 '-epi-4' -O-methyl-doxorubicin (If) and 4-demethoxy-2,3-dimethyl-4 '-epi-4' -O-methyl-doxorubicin (Ih)

The compounds Ib and Id were transformed, via their 14-bromine derivatives and under the conditions described in Example 2, into the compounds If and Ih respectively.

Biological activity of the and the

Compounds la and le were tested, in comparison with the compounds from which they derive, respectively daunorubicin (DNR) and doxorubicin (DX) on several experimental systems, to ascertain their cytotoxicity, antitumor activity and cardiac toxicity in experimental animals.

The data reported in Table 1 show that the is about 5 times more cytotoxic than the DNR and the is about 9 times more cytotoxic than the DX.

A first in vivo screening was carried out on CDF-1 mice carrying ascitic leukemia P 388 (10® cells / mouse). The results are shown in Table 2. Both were shown to be more toxic and more potent than the compounds from which they derive. A comparison with the Maximum Tolerated Dose shows that it is comparable in efficacy to DNR (providing an equal increase in the life of mice) and has good anti-tumor activity which is of the same order of magnitude as that of DX.

Several studies were carried out on C3H mice carrying Gross leukemia injected i.v. (2x IO6 cells / mouse). The la data are shown in Table 3. Administered i.v. on day 1 after tumor inoculation, it was markedly more toxic and more potent than DNR. At the Maximum Tolerated Dose of 1.25-1.3 mg / kg, it proved to be more effective than DX at the Maximum Tolerated Dose of 10 mg / kg. It is well known that DNR is not active when administered orally, unless very high doses (> 50 mg / kg) are administered. I. Data reported in Table 3 show that it has good anti-tumor activity against Gross leukemia even when administered orally. Administered orally on day 1 only, it is shown to be active at the dose of 1.25-1.3 mg / kg, which is also the optimal dose in the case of i.v.

This result suggests that the uptake of la through the gastrointestinal tract is very efficient. Administered on days 1, 2 and 3 orally, it is more active than when administered only on day I; at the optimal dose of 0.66 mg / kg / day, the product has an anti-tumor activity of the same order of magnitude as 4-demethoxy-dauno-rubicin which was tested in parallel with the optimal dose of 1.9 mg / kg / day. The observation that the optimal dose of la is lower than that of 4-demethoxy-daunorubicin suggests a more efficient absorption through the gastrointestinal tract in comparison with this compound.

Data on le's anticancer activity in comparison with DX against Gross leukemia are shown in Table 4.

The compounds were administered on day 1 after tumor cell inoculation; DX was administered i.v .; she was given i.v. and orally.

When administered i.V., at the Maximum Tolerated Dose of 1 mg / kg, it showed a good anticancer activity, similar to that observed after treatment with DX. In addition, it was also shown to be active when it was administered orally at doses of 1.3 mg / kg and more.

was tested against L1210 leukemia which was inoculated i.p. in CDF-1 mice (ascitic form) or i.v. (IO5 cells / mouse).

The treatment was carried out on day 1 after inoculation respectively i.p. or i.v. cancer cells. The data reported in Table 5 show that, in the i.p.-i.p. experiment, the at the Maximum Tolerated Dose of 0.83 mg / kg was more active than the DX at the Maximum Tolerated Dose of 4.4 mg / kg. In the i.v.-i.V. experiment, the at the tolerated doses of 1 and 1.3 mg / kg demonstrated an anticancer activity higher than that of the DX.

In order to ascertain the antitumor activity against a solid tumor, it was tested in comparison with the DX against breast cancer of C3H females. A third generation with transplanted tumor was used. The treatment began 15 days after the tumor transplant and was carried out via the i.v. once a week for 4 weeks.

The tumor was measured weekly using a caliper.

Non-tumor bearing mice were treated in parallel in order to evaluate the general toxicity and cardiac toxicity which was investigated in 5 mice, treated with the higher dose of the two compounds and which were sacrificed 5 weeks after the last treatment. The results of this experiment are shown in Table 6.

DX proved to be very effective, inhibiting tumor growth by 93-94% (in comparison with untreated controls) and both proven doses (6 and 7.5 mg / kg). In non-tumor bearing mice treated with DX at 7.5 mg / kg, toxic deaths (2/3) were observed and all mice examined showed histologically proven cardiac lesions. le at a dose of 0.4 mg / kg was shown to be not very active; at doses of 0.6 and 0.75 mg / kg it produced a marked inhibition of tumor growth. No lesions of the atrium were observed in non-tumor-bearing mice treated with le at a dose of 0.75 mg / kg and only 2 of 5 mice showed verifiable lesions of the ventricle, which however were less severe than those observed after treatment with DX.

The data reported here show that ed are new analogues of anthracyclines with very interesting biological properties. In comparison with DNR, the is about 3 times more potent when given i.p. and about 8 times more potent when i.v. At the Maximum Tolerated Dose it has an anticancer activity against ascitic P388 and against Gross systemic leukemia equal to that of DNR. In addition, it is also active when it is administered orally, particularly when the treatment is carried out for 3 consecutive days, at lower doses than 4-demethoxy-daunorubicin.

it is about 10 times more powerful than DX in vivo.

The comparison with the Maximum Tolerated Dose compared to DX shows an equal activity against ascitic P388, LI210 leukemia, Gross systemic leukemia and breast cancer and which is more effective than DX, against leukemia systems5

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mica L1210 (injected i.V.). In addition, it is also active against Gross leukemia when it is administered orally and in a preliminary cardiac toxicity test in C3H treated mice. chronically, it produced only minimal cardiac injury.

The compound la was studied on P388 leukemic cells resistant to doxorubicin (P388 / DX), in vivo and in vitro. P388 leukemic cells resistant to doxorubicin (received by Dr. Schabel) are maintained by transfer in mice treated with DX i.p.

For experimental purposes, BDF-1 mice were injected i.p. with IO4 leukemic cells and treated i.p. on day 1 after tumor inoculation. The results, reported in Table 7, show that daunorubicin (DNR) was less active against this tumor, while the compound la, at the optimal dose of 0.8 mg / kg increased the life span of the treated mice.

P 388 and P388 / DX leukemic cells were collected from the ascitic fluid of the mice and accustomed to growing in suspension in vitro.

Cytotoxicity assays were performed by exposing the cells to different drug concentrations for 48 hours; at the end of the exposure period, the cells were counted with a Coulter Celi Counter and the ID5o was calculated (dose that gives 50% reduction in the number of cells in comparison with the untreated controls). The results, reported in Table 8, show that the was approximately 2 times more cytotoxic than DNR on P388 leukemia cells and that it was also very active against P388 / DX leukemic cells, while the DNR was 163-152 times less active on the type resistant than sensitive.

The compound was further tested against the breast cancer of C3H mice. Mice carrying a measurable tumor (3rd generation transplanted) were treated once a week for 4 weeks i.v. with or with DX.

Normal mice were treated in parallel to evaluate toxicity.

The results reported in Table 9 confirm that it was about 10 times more potent than DX and showed remarkable antitumor activity in this experimental system at non-toxic doses, while DX was toxic.

Due to its good activity against breast cancer, the compound was further tested against two solid tumors: colon adenocarcinoma 26 and colon 38, transplanted s.c. in BALB / c and BDF1 mice, respectively.

Treatment began on day 1 after tumor inoculation (early) or when the tumor was already palpable (advanced), and i.v. once a week or every 6 days, 3 or 4 times.

Tumor growth was estimated by measuring with a caliper. Non-tumor-bearing mice were treated in parallel for an estimate of toxicity and were kept under observation for 90 days. The results of the three experiments are shown in Table 10. Against early colon 26, at the maximum tolerated dose of 0.9 mg / kg / day it was more active than DX at the maximum tolerated dose of 7.5 mg / kg / day. Against advanced colon 26, le at the maximum tested dose of 0.7 mg / kg / day was non-toxic and provided a higher inhibition of tumor growth compared to DX at the maximum tolerated dose of 6 mg / kg / day. Against advanced colon 38, at the maximum tested dose of 0.9 mg / kg / day, it was as active as DX at the dose of 9 mg / kg / day in inhibiting tumor growth, but produced a higher increase in the duration of the life.

In conclusion, all the data reported here confirm that the compounds la and le are extremely interesting new anthracyclines, endowed with high potency, oral activity, activity against anthracycline resistant tumors (la), activity against solid tumors higher than that of DX and free of cardiotoxicity (le).

Table 1 - In vitro Hela cell inhibition assay (24 hour treatment)

Composed

Dose (ng / ml)

%to

ID5o (ng / ml)

DNR

12.5

42

6.2

66

~ 12

3.1

121

there

25

0

6.2

0

~ 2.5

1.5

73

DX

12.5

20

6.2

79

~ 9

3.1

177

the

10

0

2.5

9.9

~ 1

0.62

82

00:15

84

to No. of colonies; % of untreated controls.

Table 2 - Antitumor activity against leukemia P 388. Treatment i.p. on day 1

Composed

Dose (mg / kg)

T / Ca%

LTSB

Toxic deaths

DNRD

2.9

154

0/10

0/10

4.4

140.154

0/20

4/20

6.6

109.163

0/20

13/20

there

0.5 •

127

0/10

0/10

0.64

127

0/10

0/10

0.8

172.127

0/20

1/20

1.0

145

0/10

0/10

1.3

95

0/10

10/10

DX

4.4

180

0/10

0/10

6.6

200

2/10

0/10

10.0e

315

4/10

0/10

the

00:44

180

0/10

0/10

0.66

215

0/10

0/10

1.0

250

0/7

1/7

1.5

245

2/10

4/10

a Average survival time; % on untreated controls. b Long-term survivors (> 60 days).

c Evaluated on the basis of autopsy findings on dead mice.

d Data from two experiments.

c This is the Maximum Tolerated Dose of DX in this experimental system.

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Table 3 - Activities against Gross leukemia

Treatment

T / Cb

Deaths

Street

Schedula3

Compound mg / kg / day

%

toxic i.v.

1

DNR

10

133.150

0/20

15

175,175,166

3/30

22.5

208,191,216

6/30

fully paid

1

there

00:58

116

0/10

0.76

133

0/10

1.0

158.166

0/20

1.25-1.3

183.208

0/20

1:56

100

9/10

1.95

116

6/10

oral

1

1.1

133

0/10

1.25-1.3

133.166

1/20

1.56-1.6

166.166

3/20

1.95-2.0

175.183

2/20

oral

1,2,3

4-demethoxy

1:31

125

0/10

DNR

1:58 to 1:46

133.150

1/20

1.9

133.190

1/20

2.5

210

2/10

3.3

140

6/10

oral

1,2,3

there

00:44

133

0/9

0.66

183

0/10

1.0

200.220

9/20

1:25

140

8/10

a Days after tumor inoculation. b, c See Table 2.

Table 4 - Le activity against Gross leukemia

Treatment

T / Cb

Deaths

Street

Compound mg / kg

<%

toxic i.v.

D.X.

10

200

2/8

13

200.216

2/18

16.9

250.266

3/18

the

1.0

183.233

0/18

1.3

192.208

4/18

1.7

217.200

7/18

2.2

142

7/10

oral le

1.0

125

0/8

1.3

150

0/8

1.7

166

0/8

2.5

166

0/8

a On day 1 after tumor inoculation. b, c See Table 2.

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Table 5 - Le activities against leukemia L1210

L1210 Compound Treatment mg / kg

T / Ca

LTSB

Dead inoculum

%

toxic i.p. intraperitoneal DX

4.4

150

0/9

0/9

6.6

150

0/10

1/10

10.0

162

0/10

1/10

the

0.83

162

2/10

0/10

1.0

187

1/10

1/10

1.2

393

4/10

3/10

fully paid fully paid DX

10.0

120

0/10

0/10

13.0

120

0/10

0/10

16.9

133

0/10

0/10

the

1.0

200

0/10

0/10

1.3

173

0/10

0/10

1.7

> 580

5/10

0/10

a, b, c See Table 2.

Table 6 -

Activity against C3H breast cancer, le toxicity and cardiac toxicity in comparison with DX

Cancer-carrying mice

Non-tumor carrying mice

Inhibition

heart injury

Compound mg / kg / day growth of growth

MSTC

T / C%

dead

TO

V

tumor% a tumor% b

n. G

n.

G

4845

53

DX

6

318

93

77

145

n.d.

7.5

277

94

74

140

2/3

4/4 1.3

5/5

1.5

the

0.4

1740

64

65

123

n.d.

0.6

748

85

76

143

n.d.

0.75

344

93

81

153

1/4

0/5 0

2/5

0.2

a Tumor weight on day 43 / tumor weight at the start of treatment X 100.

b 100- [tumor growth in treated mice / tumor growth in X 100 controls].

c Average survival time (days).

d Observed for 90 days.

c A = others; V = ventricles; n = number of hearts showing lesions / total; G = degree of injury.

Table 7 - Effect on P 388 leukemia resistant to doxorubicin in vivo

Compound Dose T / Ca

(mg / kg)%

DNR 2.9 93

4.4 87

6.6 84

there

00:53

133

0/10

0/10

0.8

142

1/10

0/10

1.2

106

0/10

4/10

65

a Average survival time; % on untreated controls. b Long-term survivors (> 60 days).

"■ Estimated on the basis of autopsy findings on dead mice.

Table 8 - Effect on P388 sensitive leukemia and resistant doxorubicin in vitro

ID5o (ng / ml) b P388c P388 / DXd Re

5.8.2.3 950.350 163.152

0.35.1.3 1.4.5 4.3.8

a Data from two experiments.

b Dose which gives 50% reduction in cell number in comparison with untreated controls.

c P388 leukemia cells sensitive to DX.

d DX-resistant P388 leukemia cells.

and Ratio between ID50 on P388 / DX and ID50 on P388.

LTSb Dead 55

toxic0 Compound

0/10 0/10 Dt

0/10 1/10

0/10 3/10 "o r la

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Table 9 - Le activity against breast cancer of C3H mice

Composed

Mg / kg / day

Tumor weight (mg)

Mice with tumor

T / Cb MSTC%

T / Cd%

Dead tumorless mice 5

-

-

651

115.5

0/10

DX

6.0

238

37

149

129

1/10

7.5

209

32

100

87

7/10

the

0.6

422

65

118

103

0/10

0.75

263

40

126.5

110

0/10

a Evaluated 1 week after the last treatment, by means of a gauge measurement.

b Tumor weight of treated mice / tumor weight of controls X 100.

c Average survival time (days).

d Average survival time of treated mice / Average survival time in controls (X 100). and Mice were observed for 90 days.

Table 10 - Effect of le and DX against two colon adenocarcinoma transplanted in mice

Cancer

Stadioa

Schedulab

Composed

Dose (mg / kg)

<% C

Inhibit.

T / Cd%

Toxic deaths

Colon 26

early q7dx4

DX

6

56

217

0/10

7.5

82

224

0/10

9.3

81

161

9/10

the

0.6

81

258

0/10

0.75

85

227

0/10

0.9

93

246

1/10

advanced q6dx3

DX

6

34

237

0/9

9

62

237

4/9

the

0.6

48

232

0/9

0.7

52

195

0/9

Colon 38

advanced q7dx4

DX

6

65

ninety two

0/10

9

83

144

1/10

the

0.6

55

133

0/10

0.75

60

129

0/10

0.9

81

184

0/10

a Starting time of treatment with respect to tumor development.

b Days of administration i.v.

c% of tumor growth inhibition compared to untreated controls.

d Average survival time of treated mice / average survival time of controls, X 100.

and Evaluation in non-tumor-bearing mice treated in parallel and observed for 90 days.

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Claims (16)

657 622 2 CLAIMS 1. An anthracyclinonic glucosidic compound having formula I: CH "X "OH OH CH R NH. R wherein X is hydrogen or a hydroxyl group; Ri is hydrogen or a methyl group; one of R2 and R3 is a methoxy group and the other of R2 and R3 is hydrogen, and their addition salts with pharmaceutically acceptable acids. 2. A compound according to claim 1, which is 4-demethoxy-4'-0-methyl-daunorubicin. 3. A compound according to claim 1, which is 4-demethoxy-4'-0-methyl-doxorubicin. A compound according to claim 1, which is 4-demethoxy-4 '-epi-4' -O-methyl-daunorubicin. 5. A compound according to claim 1, which is 4-demethoxy-4 '-epi-4' -O-methyl-doxorubicin. 6. A compound according to claim 1, which is 4-demethoxy-2,3-dimethyl-4 '-O-methyl-daunorubicin. 7. A compound according to claim 1, which is 4-demethoxy-2,3-dimethyl-4'-O-methyl-doxorubicin. 8. A compound according to claim 1, which is 4-demethoxy-2,3-dimethyl-4 '-epi-4' -O-methyl-daunorubicin. 9. A compound according to claim 1, which is 4-demethoxy-2,3-dimethyl-4 '-epi-4' -O-methyl-doxorubicin. 10. A process for the preparation of anthra-cyclinonic glucosides, according to claim 1 of formula I where Ri = X = H, which comprises the reaction of 4-demethoxy-daunomycin dissolved in anhydrous methylene chloride, with 2, 3,6-tri-deoxy-3-trifluoroacetamido-4-0-methyl-L-lixo-hexopyranosyl chloride or with 2,3,6-tridesoxy-3-trifluoroacetamido-4-0-methyl-L-arabino hexopyranosyl chloride , in the presence of silver trifluoromethanesulphonate and molecular sieves, to obtain the corresponding N-trifluoroacetyl protected by a-glucoside, removing the protective group N-trifluoroacetyl by means of mild alkaline hydrolysis with 0.2 N aqueous sodium hydrate solution, to obtain the corresponding derivative of daunorubicin. 11. A process for the preparation of anthra-cyclinonic glucosides according to claim 1 of formula I where X = H and Ri = CH3, which comprises the reaction of 2,3-dimethyl-4-dime-toxo-daunomycinone, dissolved in chloride of anhydrous methylene, with 2,3,6-tridesoxy-3-trifluoroacetamido-4-0-methyl-L-lixo-hexo-pyranosyl chloride or with 2,3,6-tridesoxy-3-trifluoroacetamido-4-O -metiI-L-arabino hexopyranosyl chloride, in the presence of silver trifluoromethanesulfonate and molecular sieves, to obtain the corresponding N-trifluoroacetyl protected a-glucoside, removing the protective group N-trifluoroacetyl by means of mild alkaline hydrolysis with aqueous solution 0.2 N of sodium hydrate, to obtain the corresponding daunorubicin derivative. 12. A process for the preparation of anthra-cyclinonic glucosides according to claim 1 of formula I where X = OH, which comprises the bromination of the derivatives of daunorubicin of formula I where X = H and subsequent treatment of the formed 14-bromine derivatives with a aqueous sodium formate solution. A pharmaceutical composition comprising a therapeutically effective amount of an anthracyclinonic glucoside according to claim 1, in combination with an inert support. 14. As a means of carrying out the process according to claim 10, a protected glucoside of formula OH OH OH 0 NHCOCF R. wherein Ri is hydrogen or a methyl group; R; it is hydrogen or a methoxyl group and R3 is hydrogen or a methoxyl group with the proviso that R2 and R3 are not simultaneously the same.