AU595328B2

AU595328B2 - New anthracyclines

Info

Publication number: AU595328B2
Application number: AU74108/87A
Authority: AU
Inventors: Michele Caruso; Fernando Giuliani; Sergio Penco; Antonino Suarto
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1986-06-12
Filing date: 1987-06-10
Publication date: 1990-03-29
Anticipated expiration: 2007-06-10
Also published as: SE500732C2; DK169076B1; KR950004897B1; GB8614323D0; DE3719377A1; GB2195998A; NZ220604A; SE8702409D0; BE1000158A4; DK298787A; CH676985A5; PT85056B; IE871538L; JP2516769B2; DE3719377C2; DK298787D0; IT8720834A0; HU196220B; FI84075B; KR880000459A

Description

COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION FOR OFFICE USE Form Short Title: Int. Cl: Application Number: Lodged: Complete Specification-Lodged: Accepted: Lapsed: Published: Priority: 595328 p:.

J41 r r 0 Q4 10 0e vi *o p." Related Art: TO BE COMPLETED BY APPLICANT Name of Applicant: Address of Applicant: Actual Inventor: Address for Service: FARMITALIA CARLO ERBA S.p.A.

Via Imbonati 24, 20159 MILAN, ITALY Antonino SUARATO; Michele CARUSO; Sergio PENCO and Fernando GIULIANI GRIFFITH HASSEL FRAZER 71 YORK STREET SYDNEY NSW 2000

AUSTRALIA

Complete Specification for tho invention entitled: NEW ANTHRACYCLINES The following statement is a full description of this invention, including the best method of performing it known to me/us:- 8321A:rk DE~SC RI PTION NTW ANTHRACYCLJINES The invention relates to no~vel arthracycline glycoside derivatives, to their preparation and to pharmaceutical compositions containing them as well as to intermediates useful in the preparation of the glycosides.

The prasent invention provides anthracyclirve glycosides having the ge~neral formulae and (II): S.H

H

2 OC;R CC CCR I1 aq II ab b:3 OH1 *0

S.

wherein R 2 represents a hyudrogen atom or hydroxyl group; and pharmaceutically acceptable acid addition salts thereof.

The invention further providos a process for the preparation of a glycoside of formula whereinR1 represents a hydrogen atom, i.e. compound which process compiises reacting 3 '-epi-daunorubicin with salicylaldehyde so as to obtain the corresponding 2 3'-epi-N-salicylidene derivative; converting the 4'-hydroxy group of the said 3'-epi-N-salicylidene derivative into a trifluoromethanesulfonate group; and removing from the 3'epi-N-salicylidene-4'-0trifluoromethanesulfonate thus obtained the salicylidene group by acid hydrolysis so as to cause the desired glycoside of formula to be obtained via displacement of

U

the 4 '-0-trifluoromethanesulfonate group.

The compound (Ia) may therefore be prepared by reaction of the 3'-amino group of 3'-epi-daunorubicin (III) Arcamone, A. Bargiotti, G. Cassinelli: Ger.Patent Olea. 2752115 (June 1, 1978] with salicylaldehyde, in a mixtur.

of water and acetone at room temperature, to obtain the corresponding 3'-epi-N-salicylidene derivative (IVc) which

OS

15 oy treatment wYith trifluorometharlesulfonic anhydride in anhydrous methylene dichloride and in the presence of *pyridine gives the corresponding e 3'-epi-N-salicylidene-4'-0- -trifluoromethansulfonate (IVd). This compoud, dissolved in methanol, can then be subjected to acidic hydrolysis of the salicylidene protecting group by means of Ce..

:p-toluensulfonic acid at room temperature to give, via the displacement of trifluoromethanesulfonate leaving group, the desired compound of formula (Ia).

The invention also provides a process for the preparation of a glycoside compound of formula wherein I 1 1 -3- R represents a hydroxyl group, i.e. compound (Ib) which process comprises reacting 31-epidoxorubicin with salicylaldehyde so as to obtain the corresponding 3'-epi-N-salicylidene derivative; protecting the 14-hydroxy group of the said 3 '-epi-N-salicylidene derivative with a tert.butyl-diphenyl-silyl group, converting the 4'-hydroxy group of the 3 '-epi-N-salicylidene-14-O- [ter t.butyl-diphenyl-silyl]doxorubicin thus obtained into a trifluoromethanesulfonate group; and removing from the 14-O-[tert.butyl-diphenylsilyl]-3-epi-N-salicylidene-4 1 -0O-trifluoromethanesulfonate thus obtained the salicylidene group by acid hydrolysis and too* the 14-O-[tert.butyl-diphenyl-silylI group so as to cause the desired glycoside of formula to be obtained via displacement of the 4'-O-trifluoroiethanesulfonate group.

The compound (Tb) may therefore be prepared by e the conversion of the 3'-amino group of 3'-epi-doxorubicin s O (see F. Arcamone et al. Ger.Patent 2752155] into 3'-epi-N-salicylidene-doxorubic,L (VIe) by reaction with saJicylaldehyde, protection of the 14-hydroxy group with a n t-butyl-diphenyl-s ilyl group, obtaining 3 1-epi-N-salicyl idene- 14-0- [ter t- butyl--dighenyl- silyl] -doxorubicin (VIf) conversion of the 4 '-hydroxy group into a trifluoromethanesulfonate (VIg) hydrolysis by means of p-toluensulfonic acid with fe,rmation of compound (Ih), and reaction with tetra-n-butyl- ammonium fluoride to remove

MW

4 the 14-0-[tert-butyl-diphenyl-silyl]-protecting group and obtain compound of formula (Ib).

Typically 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 subsequently treated, in anhydrous dimethylformanide, at room temperature, with t-butyl-diphenylchlorosilane in the presence of imidazole to give its 3'-epi-N-salicylidene-14- -0-[t-butyl-diphenyl-silyll ether, which dissolved in anhydrous methylene dichloride is converted, by treatment ~with trifluoromethanesulfonic anhydride, in the presence of dry pyridine, into its 3'-epi-N-salicylidene-4'-0- *so: 15 trifluoromethanesulfonate-14-0-[t-butyl-diphenyl-sily] 0S ether of which the salicylidene protecting group is subjected to acidic hydrolysis at room temperature and in a s omethanolic solution by means of a catalytic amount of 0S p-toluensulfonic acid and from which subsequently the 14-0-

S.

G 20 -[t-butyl-diphenyl-silyll protecting group is removed by treatment with tetra-n-butyl ammonium fluoride in 0 0. tetrahydrofuran, at room temperature, to obtain the desired G:oose glycoside of formula The invention also provide6 a process for the preparation of a glycoside of formula (II) wherein R1 represents a hydrogen atom, i.e. compound or a hydroxy group, i.e. compound (IIb), or a pharmaceuticaly 5 acceptable acid addition salt thereof, which process comprises converting 3'-deamino-4'-deoxy-3'-epi-4'-epi-3',4'-epimino- -daunorubicin into the corresponding N-trifluoroacetyl derivative; converting the said N-trifluoroacetyl derivative into 4'-deoxy-4'-epi-N-trifluoroacetyl-3'-deamino-3'-hydroxy daunorubicin; removing the N-trifluoroacetyl group from the 4'-deoxy-4'-epi-N-trifluoroacetyl-3'-deamino-3'-hydroxy daunorubicin so as to obtain the glycoside of formula (II) wherein R 1 is a hydrogen atom; if desired, converting the said glycoside of formula (II) into a pharmaceutically Oe acceptable acid addition salt thereof; if desired, brominating the said glycoside of formula (II) or 15 pharmaceutically acceptable salt thereof and hydrolysing the 14-bromo derivative thus obtained so as to form the Sao glycoside of formula (II) wherein R is a hydroxy group; and, if desired, converting the said glycoside of formula (II) wherein R 1 is a hydroxy group into a pharmaceutically acceptable acid addition salt thereof.

Treatment of the 3',4'-epimino daunorubicin derivative (Ia) with trifluoroacetic anhydride gives the corresponding N-trifluoroacetyl derivative (VIIi).

Reaction of this compound with a catalytic amount of sulfuric acid in acetone gives 4'-deoxy-4'-epi-N- -trifluoroacetyl-3'-deamino-3'-hydroxy-daunorubicin (VIII) 18 6. A process for the preparation of a glycoside 6 which, by treatment with aqueous sodium hydroxide, gives the compound (IIa). Typically, the N-trifluoroacetyl group may be removed by mild alkaline hydrolysis, at a temperature of 0 C by means of 0.1N aqueous sodium hydroxide. Glycoside (IIa) can be isolated as its hydrochloride by treatment with hydrogen chloride in methanol.

The compound (IIb) can be prepared by bromination of (IIa) followed by treatment of the resultant 14-bromo derivative with aqueous sodium formate at room temperature, according to the procedure described in United Patent Specification No. 3803124. It may be isolated as its hydrochloride in the same manner as glycoside (IIa).

The processes of the invention are summarized in 15 the reaction scheme below.

The present invention also provides a pharmaceutical composition comprising as active ingredient e* an anthracycline glycoside of the invention or pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable carrier or diluent. A therapeutically effective amount of a compound of formula is combined with an inert carrier.

Conventional carriers may be used and the composition may be formulated in conventional manner.

The compounds of the invention are useful in methods of treatment oit the human or animal body by 1 -7 therapy. In particular, the compounds of the invention are useful as antitumor agents.

:0.

*of.

0 0006

S

HOCHI

00 C bs- 0 OCK

OH

000

NH~

CM

44 8- REACTION SCHEME

OCH,

01 0 C9H

I

OC

H

0 0 ~ON C H1 C9q VIe- *g 9 9 *9 *9~ 9 S. SO g~ 9 S S SS .5 ~0* 000 I b,h 0 0 HO-K C~ 0 O H 0CH, 0 0 'OH Cf PCOHN H HO0

VIII

11a Ii b

S

9, 9 9 9S 9 *5 0 4 See.

vii i

S'S.

S

*9e.

9 *559 9*

S

R2:

R

2 oOHC 6

H

4

CH=

OOHC

6

H

4

CH=

R'

3

OH

-Q-Si(C 6

H

5 2 -t-U -0-Si (C 6

H

5 2 -t-BU

CCF

3 R3:, R3: R2: R 2: R2:

OK-

OSO

2

CF

3 oOHC 6

H

4

CH=

OOHC

6

H

4

CH-

oOHCSH 4

CH=

R

3

OH

R~3: OSO 2

CF

3 P-1 acceptable acid addition salt ther~eof; if desired, 9 The following Examples illustrate the invention, but are not intended to limit the scope of the invention in any way.

EXAMPLE 1 3'-Epi-N-salicylidene-daunorubicin (IVc) A solution of 2 g of 3'-epi-daunorubicin (III) in a mixture of ml of water and 20 ml of acetone, was treated at room temperature with 0.5 ml of salicylaldehyde at pH 8. After 10 min. ethyl acetate was added and the organic phase separated off, washed with wate' twice, dried over anhyrous sodium sulphate, filtered and evaporated to dryness under vacuum.

The residue was first triturated with hexane to eliminate the traces of salicylaldehyde, then collected and dried under vacuum at 30°C to give (IVc) in almost quantitative yield.

Rf 0.21 on TLC Kieselgel F 254 (Merck) using as eluent the S solvent mixture CH 2 Cl2-Acetone (8/2 v/v).

15 EXAMPLE 2 o 3 -deamino-4 -deoxy-3'-epi-4'-epi-3 ,4 '-epimino-daunorubicin (Ia) To a solution of 2 g of 3'-epi-N-salicylidene daunorubicin (IVc) in 20 ml of anhydrous dichloromethane and 2 ml of dry pyridine kept at -10 3 C, was added a solution of 0.8 ml of trifluoromethane sulfonic anhydride in 10 ml of dichloromethane. After 1 hour at 0 C, the mixture was diluted with dichloromethane and washed with water, cold 0.1M hydrocloric acid, cold aqueous 5% sodium hydrogen carbonate and water. The organic phase, dried over anhydrous sodium sulphate, was filtered off and the solvent removed in vacuo to give (IVd) Rf 0.50 on TLC Kieselgel F 254 (Merck) using as eluent the solvent mixture CH 2 C12-Acetone (95/5 v/v).

The crude product was dissolved in 50 ml of methanol and added with 0.2 g of p-toluensulfonic acid monohydrate. The solution was S 30 kept at room temperature for 1 hr, then was added 100 ml of water and extracted with little dichloromethane. The aqueous phase was adjusted to pH 8 with 0.1M sodium hydroxyde and dichloromethane added. The organic phase was separated off, washed with water, dried over anhydrous sodium sulphate and the solvent evaporated to small volume.

T'he mixture was purified by chromatography on a column of silica gel buffered at pH 7 using dichloromethane-ethanol as eluent.

The eluate containing the product (la) was washed with water, evaporated in vacuum, picked up with a little dichloromethane and crystallyzed FD MS 509 mp. 135-137 0

C

4treatment with a methanolic solution of hydrogen chloride.

We tU il w a^ W Ti 1 1 .a c ifl~^ e treatment with a mebhanolic solution o£ drgen choride.

10 Rf 0.38 on TLC Kieselgel F 254 (Merck) using as eluent the mixture

CH

2 Cl 2

-CH

3

OH-CH

3

COOH-H

2 0 (30/4/1/0.5 v/v).

1H NNPR (200 M2-z, CDC1 3 8.02 (dd, J-1.1, 7.7Hz, 1H, H-1) 7.76 (dd, J-7.7, 7.7Hz, 1H, fi-2) 5.31 (dd, J=3.0, 4.8Hz, 1H, R-I 5.17 (dd, J=2.0, 3.6Hz, lH, Hi-7) 4.32 (qd, 6.7Hz, 1H, H-51) 4.07 3H, OCH 3 -4) 3.17 (dd, J=19.2Hz, 1H, LU-1e) 2.95 J-19.2H-z, 1H, H-l0ax) 2.46 (ddd, J-2.0, 2.0, 15.0Hz, 1H, H-Se) 2.43 3Ht COC~ro) 2.30 (ddd, J=1.5, 4.3, 6.4Hz, 1H, Lj-3') 1.9-2.0 (mn, 2H, H-8ax, Li-2'ax) 1,.87 (ddd, J=1.5, 3.0, 14.6Hz, 1H, H21e) 1.44 J.=6.7Hz, 3H1, CH 3 see EXML 3 oe*0 203-p--aiiy.n oouii Ve 3 A. 2 soluins fci1deg o 1eiNscidndoxorubicin (VIe) i The titl cophydousndiehloxd was prprermated with0.5 di of r'ei-oouicin was lef dscrnieg ivenih aap t romte.raue Pafte 0.15 h on 0 ml ofes wter Fw5 Mrc) uigas eddedeat the slto a solracent itrethyle-nee (4/hlo v/v).

glss wapiNsaicywihdee-1-d-(et-buth-drphnydie-s vac)doouumcio giveh)opon Vf 2f0.25 o aThyro, iethyforgwed wa trete withck 0.5n as ofe h e0xtracete ithr mehylenace ich1oride.

I

11 EXAMPLE 3'-epi-3'-deamino-4'-deoxy-4'-epi-3',4'-epimino doxorubicin (Ib) The title compound was prepared starting from (VIf) "via" its 3' -pi-4'-0-trifluoromethanesulfonate (VYg) prepared as described in example 2.

Acidic hydrolysis of VIg in methanol with a catalitic amount of p-toluensulfonic acid monohydrate, gave, after work up Ih.

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

Rf 0.20 on TLC Kieselgel F 254 (Merck) using as aluent the solvent mixture CH 2 Cl 2

-CH

3

OH-CH

3

COOH-H

2 0 (30/4/1/0.5 v/v) 0 000 @00..

@0 *0

U

EXAMPLE 6 -deamino-4'-deoxy-3'-hydroxy-4 '-epi-4'-amino-daunorubicin (IIa) Th title compound was prepared starting from the aziridine Ia, ig of Ia was transformed into the N-trifluoroacetyl derivative VIii by treatement with 1.2 ml of trifluoroacetic anhydride in anhydrous methylene dichloride. After work up the crude material S* [Rf 0.7 on TLC, Kieselgel F 254 (Merck) using as eluent the solvent mixture CH 2 Cl 2 -Acetone (4/1 v/v) was dissolved in 20 ml of acetone and treated with a catalitic amount of sulforic acid at 10 °C.

The mixture was diluted 200 ml of methylene dichloride, washed with water, aqueous 5% sodium hydrogen carbonate and water. The solvent was re-oved in vaccuum and the residue purified on a column of silic gel using methylene dichloride as the eluting system to afford 0.7 g of pure IIa.

Rf 0.21 on TLC, Kieselgel F 254 (Merck) using as eluent the solvent mixture CH 2 C1 2 -Acetone (4/1 v/v).

The product IIa was slowly dissolved in aqueous 0.1N sodium hydroxyde, at 0OC in order to perform the hydrolysis of the N-trifluoroacetyl protecting group.

After 1 hr 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 off, affording 0.5g of a residue that was converted by treatment with methanolic hydrogen chloride into the hydrochloride of 4'-deoxy-4 '-amino-4 -epi-3 -deamino- 3'-hydroxy-daunorubicin.

l*"a 12 MS FD 527 in.p.153 0 C (dec) Rf 0.18 on TLC Kieselgel F 254 (Merck) using the solvent system CH 2 Cl 2

-CH

3 0H-CH 3 C0OH-H 2 O (30/4/l/0.5 V/v) 1H1 NNtR (200 M4Hz, CDC1 3 83.02 (dd, J=0.9, 8.5Hz, 111, Ui-1) 7.77 (dd, J-8.50 8.5Hz, 1H, H-2) 7.38 (dd, J-0.9, 8.5Hz, 1H1, L-3) 5.52 (dd, 4.0Hz, 1H, Hi-1') 5.28 (dcl, J=1.8, 4.0Hz, 1H, H-7) 104.07 3H1, OCH 3 -4) 3.69 (dq, J-6.3, 9.5Hz, 1H, 3.51 (ddd, J-4.8, 9.5, 11.6Hz, 1H, U-31) 2.94 JT18.9HiZI 111, 152.40 3H, COCH3) 2.2-2.4 (mn, 1H, H-Sax) 2.30 (ddl 9.5Hz, 11-, jH-4') 2.0-2.2 (mn, 2H, H-8e, 1i-2'e)-2 1.70 (ddd, J=4.0, 4.6, 13,2Hz, 1HI -2aX) *201-31 J=6.3Hz, 3H1, CH 3

EXAMPLE

3.dai~-1hdoy4-e~-1ei4-iin-~oi in(1S 0.Sjo l asdsovdi amxueo etei eaa bos Teslto a rae, a eoie 2$gcfctinN 10314-frs ih.omn, h 14boodrvt* an.te ihCqetst'Iw th til..moud Thi Sgo a wanverteslned it aydro,'turid bym~ ae inethanolic hydrogen chloride. VD-MS 543 TLC t KjO ,aLget :30 F254 (Merck) using the solvent systemn CjJ.CjC 3 0HC 3 CO0R i 1

Q

C (3Q/4/l/0.5 v/v) 1Rf 0.10 t- -1 11- 111 1- -13- BIOLOGICAL ACTIVITY The Oytotoxic activity of the new anthracycline glycoside of the invention (Ccompo'1d IIa) was tested "in vitro" against HeLa cells, P388, P388/OX, LoVo and LoVo/DX.

Time of voxposure to the compound: 24 hotqrs/in comparison with daunorubicin.

The results are shown, in Table 1.

The compound, when tested "in vivo" against P-388 ascitic leukemia and goes e'ss 0 Gross leukemia, exibited good antitunour activity, in comparison with daunort~bicin, espccially when orally administered.

04 The r'esults are SIven in Tables 2 and 3.

b g 4 a 0 eggs *4000 '*see* ~y 1

Y

4-

I

Table 1 In vitro activity of 31- deamino-4 1 -deoxy-3' -hy~roxy-4' -epi-4-amino-daunorubicin (compound Ila) in comparison with DNR CompoundID a) b) c) d) e) f) HeLa P388 P3588/DY LoVo LoVo/Dx DNR 19 10.5 730 43 820 FCE 24782/XOO-0333 11 24.5 235 37 230 Dose, giving 59/. reduction'of cell number in comparison with untreated controls.

Human cervix epithelioid carcinoma cells P 388 leukemia cells sensitive to Ijoxorubicin L~388 leukemia cells resistant' toDoxorubicin Human colon adenocarcinoma, cells sensitive to Doxorubicin Human colon adenocarcinoma cells resistant to Doxcorubicin Ile

L

S U U S U U ,a U U U U U U a *a U U S U U **U U U U 5 U S U U U U U SC

U

ir Table 2 Effect agains" P 388 ascitic leukemiaa Compound do-q_ Toxicd deaths

DNR

FCE 24782/ XOO-0333 155 170 155 150 '40 100 0/10 8/10 0/10 0/10 9/10 10/10 1.96 2.9 4.4 6.6 p.

p p p

OS

pp Pp*e p P*pp p. Pt p.

p p..

p.

pp pp.

pp p pp

PP

p p pp pp

PP..

ppPPp p p a Experiments were performed in C mice, inoculated with 106 leukemia cells i.p.

b Treatment i. p. on day 1 after tumor inoculum.

CMedia survival time of treated mice/median survival time of controls x 100.

d Evaluated on the basis of autaptic findings.

i I7~ 16 Table 3 Effect against Gros. loukemia a Compound dose bT/C%C mg/Kg

RR

DNR

FCE 24782/ XOO-0333 8.2 11.5 16.1 22.5 0/20 2/20 0/20 0/10 0/10 0/10

U*

S

p p p 0*

S

*5@ S5.

p 9* *5 0

I*

0.05 0**0

S

aExpegiments were performed in Wx1 leukemia cells i.v.

C3H mice, inoculated with bTetet i.V. on day 1 after tumor inoculum.

cMedia survival time of treated mice/median survival time of controls x 100.

dEvaluated on the basis of autoptic findings.

Claims

1. An anthracycline glycoside having the general formula or (II): 0 0 0 O 0 2 0 H0 H 0 *9 1-4 0:000: wherein R 1 represents a hydrogen atom or a hydroxyl group, 5 and pharmaceutically acceptable acid addition salts the reof.

2. h compound according to claim 1, which is 3'-deamino-4'-deoxy-3'-epi-4'-epi-3 4'-epimi-no- daunorubic in. Moog 10

3. A compound according to claim 1, which is 9999 doxorubicin.

4. compound according to claim 1, which is 3 '-deamino-4 '-deoxy-3 '-hydroxy-4 '-epi-4 '-amino-daunorubicin or its hydrochloride.

A compound according to claim 1, which is 3 '-deamino-4 '-deoxy-3 '-hydroxy-4 '-epi-4 '-amino-doxorubicin or its hydrochloride. 18

6. A process for the preparation of a glycoside of formula as defined in claim 1 wherein R 1 represents a hydrogen atom, which process comprises reacting 3'-epi-daunorubicin with salicylaldehyde so as to obtain the corresponding 3'-epi-N-salicylidene derivative; converting the 4'-hydroxy group of the said 3'-epi-N-salicylidene derivative into a trifluoromethanesulfonate group; and removing from the 3'epi-N-salicylidene-4'-0-trifluoromethanesulfonate thus 10 obtained the salicylidene group by acid hydrolysis so as to cause the desired glycoside of formula to be obtained via displacement of the 4'-O-trifluoromethanesulfonate group.

7. A process according to claim 6, wherein 3'-epi-daunorubicin dissolved in a mixture of water and acetone is reacted, at room temperature, with 9* salicylaldehyde to obtain the corresponding 3'-epi-N-salicylidene derivative which is subsequently treated, in anhydrous methylene dichloride and in the 20 presence of dry pyridine, with trifluoromethanesulfonic anhydride to give the corresponding N-salicylidene-3'- of which the salicylidene protecting group is subjected to acidic hydrolysis by means of p-toluensulfonic acid, at room temperature with the said trifluoromethanesulfonate being dissolved in methanol, to obtain, via the displacement of 19 the trifluoromethanesulfonate leaving group, the desired glycoside of formula

8. A process for the preparation of a glycoside of formula as defined in claim 1 wherein R 1 represents a hydroxy group, which process comprises reacting 3'-epi- doxorubicin with salicylaldehyde so as to obtain the corresponding 3'-epi-N-salicylidene derivative; protecting the 14-hydroxy group of the said 3'-epi-N-salicylidene derivative with a tert.butyl-diphenyl-silyl group, S 10 converting the 4'-hydroxy group of the 3'-epi-N-salicylidene-14-0-[tert.butyl-diphenyl-silyl]- ~doxorubicin thus obtained into a trifluoromethanesulfonate ~group; and removing from the 14-0-[tert.butyl-diphenyl- *f silyl] -epi-N-salicylidene-4 '-O-trifluoromethanesulfonate thus obtained the salicylidene group by acid hydrolysis and the 14-0-[tert.butyl-diphenyl-silyl] group so as to cause .the desired glycoside of formula to be obtained via displacement of the 4'-O-trifluoromethanesulfonate group.

9. A process according to claim 8, wherein 3'-epi-doxorubicin, dissolved in a mixture of water and *545 acetone, is reacted at room temperature with .St(e9 salicylaldehyde to obtain the corresponding 3'-epi-N- salicylidene derivative which is subsequently treated, in anhydrous dimethylformamide, at room temperature, with t-butyl-diphenylchlorosilane in the presence of imidazole to give its 3'-epi-N-salicylidene-14- Ir d 20 -0-[t-butyl-diphenyl-silyl]ether, which dissolved in anhydrous methylene dichloride is converted, by treatment with trifluoromethanesulfonic anhydride, in the presence of dry pyridine, into its 3'-epi-N-salicylidene-4'-0- trifluoromethanesulfonate-14-0-[t-butyl-diphenyl-silyl] ether of which the salicylidene protecting group is subjected to acidic hydrolysis at room temperature and in a methanolic solution by means of a catalytic amount of p-toluensulfonic acid and from which subsequently the 14-0- -[t-butyl-diphenyl-silyl] protecting group is removed by 99 treatment with tetra-n-buyl ammonium fluoride in tetrahydrofuran, at room temperature, to obtain the desired glycoside of formula 9 15

10. A process for the preparation of a glycoside of formula (II) as defined in claim 1 or a pharmaceutically acceptable salt thereof, which process comprises converting 99 3'-deamino-4'-deoxy-3'-epi-4'-epi-3',4'-epimino- ,-daunorubicin into the corresponding N-trifluoroacetyl derivative; converting the said N-trifluoroacetyl derivative into 4 '-deoxy-4 '-epi-N-trifluoroacetyl-3 '-deamino-3 '-hydroxy daunorubicin; removing the N-trifluoroacetyl group from the 4'-deoxy-4'-epi-N-trifluoroacetyl-3'-deamino-3'-hydroxy daunorubicin so as to obtain the glycoside of formula (II) wherein R 1 is a hydrogen atom; if desired, converting the said glycoside of formula (II) into a phariaceutically -e S21_ acceptable acid addition salt thereof; if desired, brominating the said glycoside of formula (II) or pharmaceutically acceptable salt thereof and hydrolysing the 14-bromo derivative thus obtained so as to form the glycoside of formula (II) wherein R 1 is a hydroxy group; and, if desired, converting the said glycoside of formula (II) wherein R 1 is a hydroxy group into a pharmaceutically acceptable acid addition salt thereof.

11. A process according to claim 10, wherein the 10 3'-deamino-4'-deoxy-3'-epi-4'-epi-3',4'-epimino- daunorubicin is reacted with trifluoroacetic anhydride to obtain the corresponding N-trifluoroacetyl derivative which, by treatment with a catalytic amount of sulfuric acid in acetone gives 4'-deoxy-4'-epi-N-trifluoroacetyl-3'- deamino -3'-hydroxy-daunorubicin; removing the N-trifluoroacetyl protecting group therefrom by mild .0 alkaline hydrolysis, at a temperature of 0 C, by means of S 0.1N aqeuous sodium hydroxide; optionally, isolating the glycoside of formula (II) wherein R 1 is a hydrogen atom as 20 its hydrochloide by treatment with hydrogen chloride in S methanol; optionally, converting the said glycoside of formula (II) or hydrochloride thereof to the glycoside of formula (II) wherein R 1 is a hydroxy group by bromination followed by treatment of the resultant 14-bromo derivative with aqueous sodium formate at room temperature; and, optionally, isolating the said glycoside of formula (II) -22- wherein R 1 is a hydroxy group as its hydrochloride by treatment with a methanolic solution of hydrogen chloride.

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

13. A pharmaceutical composition for the treatement of the human body or animal body by therapy which composition comprises an anthracycline glycoside of formula or formula (II) as claimed in claim 1, together with a pharmaceutically acceptable carrier.

14. A pharmaceutical composition for the treatement of tumours which composition comprises an anthracycline glycoside of formula or formula (II) as defined in claim 13 together with a pharmaceutically acceptable carrier.

S j A process for the preparation of an anthracycline glycoside of formula as defined in claim 1, said process being substantially as hereinbefore described in Examples 1 and 2 together or Examples 3 to 25 together.

16. A process for the preparation of an anthracycline glycoside of formula (II) as defined in claim 1 or a pharmaceutically acceptable salt thereof, said 30 process being substantially as hereinbefore described in i .Example 6 or Example 6 and 7 together. DATED this 2nd day of January 1990 A* FARMATALIA CARLO ERBA S.p.A. SBy their Patent Attorneys GRIFFITH HACK CO 7600S/sy