GB2120667A - Anthracycline glycosides - Google Patents

Abstract

Condensation of one of daunomycinone, 1 4-(t-butyldiphenyl-siloxy)- adriamycinone or their 4-demethoxy analogues with 3,4-di-O-acetyl-2,6- dideoxy-???-L-arabinohexopyranosyl chloride gives a mixture of two compounds which on removal of the protecting groups can be separated to give the anthracycline glycosides I and II (R1=H or OH, R2=H or OCH3> <IMAGE> The process as claimed and the compounds I (R2=H) and II are also claimed. The compounds have antitumour properties.

Description

SPECIFICATION Anthracycline glycosides The invention relates to a process for the preparation of anthracycline glycosides, to certain of the anthracycline glycosides so prepared and to pharmaceutical compositions containing them.

The invention provides a process for the preparation of anthracycline glycosides having the general formula I or the general formula II

wherein R, represents a hydrogen atom or a hydroxy group and R2 represents a hydrogen atom or a methoxy group. The process comprises condensing an anthracyclinone of the general formula Ill below, wherein R represents a hydrogen atom or a t-butyl-diphenyl-siloxy group and R2 is as above defined, with 3,4-di-O-acetyl-2,6-dideoxy-a-L-arabino-hexopyranosyl chloride, which has the formula IV below, and removing the acetyl protecting group(s) and, if necessary, the t-butyl-diphenyl-silyl protecting group from the resultnt anthracycline glycosides of the general formula V and Vl wherein R and R2 are as above defined.The process is illustrated by the following reaction scheme:

The anthracyclinones Ill used as starting materials are the known compounds daunomycinone (III, R=H, R2=CH3O: hereinafter Illa) and 4-demethoxy-daunomycinone (III, R=R2=H: hereinafter Illb) and the novel compounds 1 4-0-(t-butyl-diphenyl-silyl)-adriamycinone (Ill, R=t-butyl-diphenyl-siloxy, R2=CH3O: hereinafter Illc) and 14-0-(t-butyl-diphenyl-silyl)-4-demethoxy-adriamycinone (III, R=tbutyl-diphenyl-siloxy, R2=H: hereinafter Iliad). The compounds Illc and Iliad may be prepared by condensing the known compounds adriamycinone and 4-demethoxyadriamycinone with t-butyldiphenyl-chlorosilane in a solvent such as anhydrous dimethylformamide in the presence of an organic base such as imidazole. The t-butyl-diphenyl-silyl protecting group offers the advantages of remaining unaffected throughout the condensation and the removal of the acetyl protecting group(s) and of being readily cleaved by treatment with tetra-n-butylammonium fluoride. The other starting material, the protecting chloro-sugar IV, is also a known compound (H. S. El Khadem et al., Carbohydr. Res. 58, 1977, 230).

The condensation may be effected in modified Koenigs-Knorr reaction conditions, dissolving the anthracyclinone Ill in a solvent such as dichloromethane and reacting it with the chloro-sugar IV in a heterogeneous phase catalysed by mercuric bromide and mercuric oxide or in a homogeneous phase catalysed by silver trifluoromethanesulphonate. A mixture of anthracycline glycosides V and Vl is obtained.Specifically, use of the anthracyclinone Illa gives a mixture of the anthracyclíne glycosides V, R=H, R2=CH 30 (hereinafter Va) and VI, R=H, R2=CH3O (hereinafter Vla); use of the anthracyclinone Illb gives a mixture of the anthracycline glycosides V, R=R2=H (hereinafter Vb) and VI, R=R2=H (hereinafter Vlb); use of the anthracyclinone Illc gives a mixture of the anthracyclinone glycosides V, R=t-butyl-diphenyl-siloxy, R2=CH3O (hereinafter Vc) and VI, R=t-butyl-diphenyl-siloxy, R2=H (hereinafter Vlc);; and use of the anthracyclinone Iliad gives a mixture of the anthracycline glycosides V, R=t-butyl-diphenyl-siloxy, R2=H (hereinafter Vd) and VI, R=t-butyl-diphenyl-siloxy, R2=H (hereinafter Vld).

The anthracycline glycoside mixtures Va and Vla, Vb and Vc and Vlc, and Vd and Vld may be separated into their respective components by fractional crystallisation or by chromatographic techniques. Removal of the acetyl protecting group(s), by treatment with catalytic amounts of sodium methoxide in methanol or with aqueous sodium hydroxide solution, from Va, Vb, Vla and Vlb gives, respectively, the anthracycline glycosides 7-0-(2,6-dideoxy-cz-L-arabino-hexopyranosyl)- daunomycinone (I, R1=H, R2=CH3O: hereinafter la), 4-demethoxy-7-0-(2,6-dideoxy--L-arabino- hexopyranosyl)-daunomycinone (I, R,=R2=H: hereinafter Ib), 7-0-(2,3,6-trideoxy-cr-L-erythro-hex-2- enopyranosyl)-daunomycinone (II, R,=H, R2=CH30: hereinafter Ila) and 4-demethoxy-7-0-(2,3,6enopyranosyl)-daunomycinone (11, R1-H R -CH trideoxy-a-L-erythro-hex-2-enopyranosyl)-daunomycinone (II, R,=R2=H: hereinafter llb).

Removal of the acetyl protecting group(s), as above described, followed by removal of the t-butyldiphenylsilyl protecting group by treatment with tetra-n-butylammonium chloride in tetrahydrofuran, from Vc, Vd, VIc and Vld gives, respectively, the anthracycline glycosides 7-0-(2,6-dideoxy-a-L- arabino-hexopyranosyl)-adriamycinone (I, R=OH, R2=CH30: hereinafter Ic), 4-demethoxy-7-0-(2,6 dideoxy-c'-L-arabino-hexopyranosyl)-adriamycinone (I, R,=OH, R2=H: hereinafter Id), 7-0-(2,3,6 trideoxy-a-L-erythrn-hex-2-enopyrnnosyl)-adnamycinone (II, R=OH, R2=CH3O; hereinafter lIc) and 4 demethoxy-7-0-(2,3,6-trideoxy-c-L-erythro-hex-2-enopyranosyl)-adriamycinone (II, R,=OH, R2=H; hereinafter lid).

The compounds la and Ic are known compounds, described in our British Patent Specification No.

8128252. The remaining anthracycline glycosides I and II, that is compounds Ib, Id, Ila, llb, Ile and lid, are new compounds and are included within the scope of the invention. Like compounds la and Ic, they have properties useful in treating certain tumours in animals, and the invention accordingly further provides a pharmaceutical composition comprising an anthracycline glycoside Ib, Id, Ila, llb, llc or lid in admixture with a pharmaceutically acceptable diluent or carrier.

Of the following Examples, Nos 3 to 6 illustrate the invention and Nos 1 and 2 the preparation of certain starting materials.

Example 1 Preparation of I 4-O-(t-butyl-diphenyl-silyl)-adriamycinone (Illc) A solution of 0.414 g of adriamycinone in 20 ml of anhydrous dimethylformamide was treated with 0.28 ml of t-butyl-diphenyl-chloro-silane and 0.15 g of imidazole. The reaction mixture was left standing overnight at room temperature, after which 200 ml of water was added and the solution was extracted with methylene dichloride. The organic layer was separated off, dried over an hydros sodium sulphate, filtered and evaporated to dryness under vacuum. The residue was then purified by chromatography on silica gel using the solvent mixture ethyl acetate:toluene (1 :2 by volume) as eluting system. The pure llic (0.46 g) melts at 208-2090C, FD-MS: m/z 652 (M+ ) PMR (CDCI3): inter alia at 1.14 a (s, (CK3)3-C), 3.98 gs (s, CH3O) and 4.89 ö (s, CH2-Si-).

Example 2 Preparation of 4-demethoxy-1 4-O-( 5-butyl-diphenyl-silyl)-adriamycinine (hid) A solution of 0.385 g of 4-demethoxyadriamycinone in 15 ml of anhydrous dimethylformamide was treated with 0.3 ml of t-butyl-diphenyl-chloro-silane and 0.15 g of imidazole. The reaction mixture was left for 4 hours at room temperature, after which 200 ml water was added and the solution was extracted with methylene dichloride. The organic layer was separated off, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under vacuum. The residue was then purified by chromatography on silica gel using the solvent mixture toluene:acetone (95:5 by volume) us eluting system.The pure Iliad (0.6g) melts at 101-1020C. FD-MS:m/z622 (M+.). PMR (CDCI3): inter alia at 1.13 ot (s, (CH3)3, 3.41 8 (d, OH-C-7), 4.878(s, CH2-Si-), 5.248 (m, C-H-7).

Example 3 Preparation of 7-O-(2,6-dideoxy-a-L-arabinohexopyranosyl)-daunomycinone (la) and 7-0-(2,3,6- trideoxy-a-L-erythro-hex-2-enopyranosyl-daunomyci none (ill) To a solution of 2 g of duanomycinone (Illa) in 200 ml of anhydrous methylene dichloride was added 1.25 g of 3,4-di-0-acetyl-2,6-dideoxy-cg-L-arabino-hexopyranosyl chloride (IV) dissolved in 30 ml of methylene dichloride in the presence of 12 g of molecular sieve (4A Merck (RTM)). The mixture was treated with 1.28 g of silver trifluoromethane sulphonate dissolved in 30 ml of anhydrous diethyl ether. After 5 min, the reaction mixture was neutralized with 0.65 ml of anhydrous collidine.After 30 min. at room temperature the organic solution was washed with a saturated aqueous solution of sodium bicarbonate, water, aqueous 0.1 N hydrochloric acid and finally with water. The organic phase was separated off and evaporated to dryness under vacuum. The resulting residue was purified by chromatography on a silicic acid column using ethyl acetate:cyclohexane (1:1 by volume) as the eluting system. There were obtained, separately, 0.9 g of product Va, m.p. 117-11 18 , PMR (CDCI3): inter alia at 1.23 8 (d, CH3-C-5'), 1.95 8 (s, CH3COOC), 2.07 8 (s, CH3COOC), 2.43 8 (s, CH3CO), 5.20 8 (CH-7) and 5.53 8 (CH-1'), and 0.9 g of product Vla, m.p. 8384 .

The compound Va (0.7 g) was dissolved in acetone (45 ml) and treated with 50 ml of 0.2 N aqueous sodium hydroxide at room temperature. After one hour the solution was adjusted to pH 7 and extracted with chloroform. The evaporation of organic solvent under vacuum afforded pure la in quantitative yield: m.p. 161-1 620C, FD-MS: m/z 528 (M+). Analogously the compound Vla after basic treatment under the above mentioned conditions afforded the pure Ila: m.p. 181-1820C, FD MS: m/z 510 (M+), PMR (CDCI3): inter alia at 1.408 (d, CH3-C-5'), 2.42 8 (s, CH3CO), 5.33 8 (CH-7), 5.58 8 (CH-1') and 5.5-6.0 8 (m, CH-2', CH-3').

Example 4 Preparation of 4demethoxy-7-O-(2,6-dideoxy-a-L-arabinohexopyranosyl)-daunomycinone (Ib) and 4-demethoxyj-O-(2,3,6-trideoxy-a-Lerythrn-hex-2-enopyranosyl)-daunomycinone (lib) To a solution of 0.74 g of 4-demethoxy-daunomycinone (Illb) in anhydrous methylene dichloride (70 ml) were added 0.65 g of the halosugar IV in 10 ml of methylene dichloride in the presence of 5 g of molecular sieve (4 Merck). The mixture was treated with 0.64 g of silver trifluoromethanesulphonate dissolved in 1 5 ml of anhydrous diethyl ether. After 5 min. the reaction mixture was neutralized with 0.4 ml of an hydros collidine.After 1 hour at room temperature the organic solution was washed with a saturated aqueous solution of sodium bicarbonate, water, aqueous 0.1 N hydrochloric acid, and finally with water. The organic phase was separated off and evaporated to dryness under vacuum. The resulting residue was purified by chromatography on a silicic acid column using chloroform:acetone (96:4 by volume) as the eluting system. There were obtained 0.48 g of product Vb, m.p. 65-660C, FD-MS: m/z 582 (M+), and 0.45 g of product Vlb. The compound Vb was dissolved in 20 ml of acetone and treated with 20 ml of 0.2 N aqueous sodium hydroxide at room temperature. After 1 hour the solution was adjusted to pH 7 and extracted with chloroform.

Evaporation off of the organic solvent under vacuum afforded pure Ib in quantitative yield: m.p. 1 65- 1 660C, FD-MS: m/z 498 (M+). Analogously the compound Vlb after basic treatment under the above mentioned conditions afforded pure llb. PMR (CDCI3) inter alia at 1.39 S (CH3-C-5'), 2.42 out (s, CH3-CO), 3.50--4.00 8 (m, C-H-4' and C-H-5'), 4.08 8 (s, CH3O), 5.33 8 (bs, C-H-7), 5.58 8 (bs, C-H-1'), 5.65 8 (d, C-H-3'), 5.93 8 (d, C-H-2').

Example 5 Preparation of 7-0-(2,6-dideoxy--L-arabinohexopyranosyl)-adriamycinone (Ic) and 7-0-(2,3,6- trideoxy--L-erythro-hex-2-enopyranosyl)-adriamycinone (ill) To a solution of 1.25 g of Illc, prepared as described in Example 1, in 100 ml of anhydrous methylene dichloride was added 2.4 g of mercuric oxide, 0.75 g of mercuric bromide, 8 g of molecular sieve (4A Merck) and 0.85 g of the chlorosugar IV. The mixture was stirred at room temperature overnight and then filtered. The filtrate was evaporated to dryness under vacuum to yield a residue, which was purified by chromatography on a silicic acid column using toluene:acetone (9:1 by volume) as the eluting system. There were obtained 1.2 g of product Vc: m.p. 55-560C, FD-MS: m/z 866 (M+), and 0.15 g of product Vlc: m.p. 88-890C. The compound Vc (0.87 g) was dissolved in anhydrous methylene dichloride (10 ml) and treated with 200 ml of a 0.01 N solution of sodium methoxide in anhydrous methanol. After three hours at room temperature the acetyl protecting groups had been removed. The reaction mixture was acidified with acetic acid and evaporated under vacuum.

The obtained oil was dissolved in 200 ml of tetrahydrofuran and treated with 0.7 g of tetra-n butylammonium fluoride. After 1.5 hours the hydrolysis of the t-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 using toluene:acetone (1:1 by volume) as the eluting system to afford pure Ic (0.35 g); m.p. 1 89--1900C, PMR (CDCl3) inter alia: at 1.34 8 (d, CH3-C-5'), 4.08 8 (s, CH3O), 4.77 8 (s, CH2OH), 5.30 8 (dd, CH-7), 5.50 8 (d, CH-1').

Analogously the compound VIc by hydrolysis of the protecting groups gave Ic; m.p. 205 207 OC, PMR (CDCl3) inter alia: at 1.38 8 (d, CH3-C-5'), 3.25-4.008 (m, C-H-4' and C-H-5'), 4.08 8 (s, CH3O), 4.768 (d, CH2OH), 5.368 (broad s, C-H-7), 5.578 (broad s, C-H-1'), 5.63 8 (d, C-H-3'), 5.93 or (d, C-H-2').

Example 6 Preparation of 4-demethoxy-7-0-(2,6-dideoxy-cg-L-arabino-hexopyranosyl)-adriamycinone (Id) and 4-demethoxy-7-0-(2,3,6-trideoxy--L-erythro-hex-2-enopyrano.syl)-adriamycinone (lid) To a solution of 0.63 g of Iliad, prepared as described in Example 2, in 50 ml of anhydrous methylene dichloride were added 1.2 g of mercuric oxide, 0.4 g of mercuric bromide, 8 g of molecular sieve (4A Merck) and 0.75 g of the chlorosugar IV. The mixture was stirred at room temperature overnight and then filtered. The filtrate was evaporated under vacuum to yield a residue, which was purified by chromatography on a silicic acid column using toluene:acetone (96:4 by volume) as the eluting system.There were obtained 0.585 g of product Vd, m.p. 212213 , FD-MS: m/z 236 (M+) and 0.200 g of product Vld. The product Vd (0.5 g) was dissolved in anhydrous methylene dichloride (10 ml) and treated with 150 ml of a 0.01 N solution of sodium methoxide in an hydros methanol.

After three hours at room temperature the removal of the acetyl protecting groups was complete. The reaction mixture was acidified with acetic acid and evaporated to dryness under vacuum. The residue was dissolved in 1 00 ml of tetrahydrofuran and treated with 0.5 g of tetra-n-butyl-ammonium fluoride.

After 2 hours the hydrolysis of the t-butyl-diphenylsilyl group was complete. The residue obtained by evaporating off the solvent under vacuum was purified by chromatography on a column of silica gel using toluene: acetone (1:1 by volume) as the eluting system to afford 0.2 g of pure Id, m.p. 204 2060C, FD-MS m/z 514 (M+), PMR CDCI3): inter alia at 1.3 8 (d, CH3-C-5'), 4.78 8 (s, CH2OH), 5.34 8 (broad s, CH-7), 5.54 8 (bs, C-H-1').Analogously the compound Vld by hydrolysis of the protecting groups gave lid, m.p. 166-1 670C, PMR (CDCI3): inter alia at 1.39 8 (d, CH3-C-5'), 3.96 8 (d, C-H-4'), 4.77 6 (s, CH2OH), 5.35 or (broad s, C-H-7), 5.558 (broad s, C-H-1'), 5.71 8 (m, CH-3'), 5.95 or (d, CH2').

Biological activity of Ila, Ib, llc and Id The compounds Ila and llc have been tested in comparison with daunorubicin (DNR) and doxorubicin (DX) respectively, in in vitro and in vivo systems in order to ascertain their cytotoxicity and antitumour activity.

Table I summarizes the effect on HeLa cells cloning efficiency in vitro. Ila is about 25 times less cytotoxic than DNR and lic is about 5 times less cytotoxic than DX.

The primary screening in vitro was carried out in CDF-1 mice bearing ascitic P388 leukemia (106 cells/mouse). Results are reported in Table 2. Both Ila and llc were suspended in 10% Tween 80 and injected intraperitoneally. The two compounds proved less toxic and potent than the parent drugs DNR and DX. Ila was inactive on the P388 ascitic leukemia at the two doses tested, including the Maximal Tolerated Dose (Mx TD) of 100 mg/kg, while llc was found to have a certain antitumour activity, but lower than thai of DX.

Compounds Ib and Id have been studied in vitro in HeLa and P388 leukemia cells sensitive (P388) and resistant (P388/DX) to DX and in vitro on P388 and Gross leukemia. Data reported in Table 3 shows that Ib tested on HeLa cells cloning efficiency in Table 3 shows that Ib tested on HeLa cells cloning efficiency in vitro in comparison to the parent compounds DNR and 4-demethoxy-DNR (4-dm DNR) is 3 and 6 fold less cytotoxic than DNR and 4-dm-DNR respectively, while Id is as cytotoxic as DX in the same test.

Compound lb has been studied on P388/DX in vitro. P388 and P388/DX leukemia cells were harvested from mice ascitic fluid and adapted to grow in suspension in vitro. Cytotoxicity tests were carried out exposing the cells to various drug concentrations for 48 hours; at the end of the exposure period, cells were counted with a coulter cell counter, and the ID50 (dose which gives 50% reduction of the cell number in comparison with untreated controls) was calculated.

Table 4 shows that Ib about as cytotoxic as DNR on P388 leukemia cells and was very active on P388/DX leukemia cells. DNR was about 500 fold less active on the resistant than on the sensitive line.

Results of the primary screening in vivo carried out in CDF-1 mice bearing P388 ascitic leukemia and treated i.p. the day after tumour transplantation, are reported in Table 5.

Ib was found to be 2 fold more potent than DNR and about 1.5 fold less potent than 4-dm-DNR; comparison at the Mx TD shows that the compound is less active than DNR and 4-dm-DNR. Compound Id was about 5 fold more potent than DX. The antileukemia activity against P388 leukemia was good but lower than that of DX.

Results of studies performed in C3H/Me mice carrying i.v. transplated Gross leukemia and treated i.v. the day after tumour transplantation, are reported in Table 6. Both Ib and Id resulted more toxic and more potent than the parent compounds. Comparison of the Mx TD shows that Ib is more active than DNR and Id has a good antitumour activity, which is of the same order of magnitude as that of DX. The compounds Ib and Id were further investigated for oral activity, on Gross leukemia transplanted i.v., in comparison with DNR, DX given i.v. and 4-dm-DNR given per oral route.

Data reported in Table 7 shows that Ib has a good antitumour activity when given orally at day 1, comparable to that of 4-dm DNR (already demonstrated to be active by oral route) and DNR injected i.v. Data on antitumour activity of Id given orally at day 1 or 1, 2, 3 after tumour transplantation are also reported in Table 7.

When given orally at day 1, Id at the Mx TD was less active than DX i.v. However with a different schedule of treatment (1, 2, 3) the antitumour activity of the compound was higher than that of DX given i.e.

Table 1 Colony inhibition test against HeLa cells "in vitro" (treatment for 24 hrs) Dose Compound (ng/ml) o/oa 1D50(ng/ml) DNR 25 12 12.5 74 16 6.2 106 Compound Ila 400 146 100 136 400 25 143 6.2 127 1.5 120 DX 25 24 10 12.5 40 6.2 69 Compound llc 400 4 100 33 50 25 65 6.2 68 1.5 86 al No of colonies; % of untreated controls.

Table 2 Antitumour activity against ascitic P388 leukemia.

Treatment i.p. on day 1.

Dose Compound Img/kg) TICa % LTSb Toxic deathsc DNR 2.9 160 0/10 0/10 44d 165-170 0/10 0/20 6.6d 150-160 0/10 7/20 Compound lla 75 120 0/5 0/5 100 90 0/10 1/10 DX 44d 220-227 2/18 0/18 6.6e 227-305 2/26 0/26 10e 268- > 610 7/26 3/26 Compound llc 1 7.6 11 8 0/8 0/8 23 127 0/7 0/7 30d 125-136 0/17 0/17 45 130 0/10 0/10 67.5 140 0/10 0/10 100 150 0/7 0/7 a) median survival time; % over untreated controls b} long term survivors ( > 60 days) c} evaluated on the basis of autoptic findings on dead mice d} data of two experiments (range) e' data of three experiments (range) Table 3 Colony inhibition test against HeLa cells "in vitro" (treatment for 24 hrs).

Dose ID50 Compound (ng/mI) %a {ng/ml) DNR 25 9 12.5 51 12 6.2 83 4-dm-DNR 25 0 12.5 18 6.3 6.2 53 3.1 84 Compound 100 0 25 67 35 6.2 87 1.5 107 DX 25 0 12.5 28 7.5 6.2 59 Compound Id 100 0 25 0 7 6.2 59 1.5 106 a} No of colonies; % of untreated controls.

Table 4 Effect on sensitive and doxorubicin-resistant P388 leukemia "in vitro" ID50 (ng/mi)a Compound P388b P388/DXe Rd DNR 1.7 800 470 Compound Ib 1.2 30 25 al Dose giving 50% reduction of cell number in comparison with untreated controls b) P388 leukemia cells sensitive to DX c) P388 leukemia cells resistant to DX d) Ratio between ID50 on P388/DX and ID50 on P388 Table 5 Antitumour activity of Ib and Id against ascitic P388 leukemia Treatment i.p. on day 1 Dose Compound (mg/kg) T/Ca% LTSb Toxic deathsC DNR 289d 159-194 0/18 0/8 4,4d 140-184 0/18 7/18 4-dm DNR 0.75 163 0/8 0/8 Compound Ib 1.25 140 0/8 0/8 2.5 163 0/9 3/9 5 63 0/10 10/10 DX 4.4 220 1/10 0/10 6.6 305 0/10 0/10 10 > 610 5/10 0/10 Compound Id 1.12 170 0/10 0/10 1.68 185 0/10 0/10 2.53 230 1/10 2/10 a, b.c. d see Table 2.

Table 6 Antitumour activity against i.v. Gross leukemia Treatment i.v. on day 1 Dose T/Ca Compound (mg/kg) % Toxic deathsb DNR 15 171 0/8 22.5 171 0/8 Compound lb 2.9 214 0/7 4.4 100 7/8 DX 10 171 0/10 13 200 0/10 16.9 207 3/10 Compound Id 1.2 171 1/10 2.16 200 1/10 3.8 114 5/9 a. b) See Table 2.

Table 7 Oral activity of Ib and Id against Gross leukemia Treatment dose route schedulea compound (mg/kg) T/C %b Toxicdeethsc i.v. +1 DNR 15 200 0/10 22.5 125 6/10 Oral +1 4-dm DNR 3 150 0/6 3.6 150 0/6 4.3 216 0/3 Oral +1 Compound Ib 2.9 167 0/10 4.4 208 0/10 6.6 116 4/9 i.v. +1 DX 10d 171-171 1/20 13d 200-200 1/20 16.9d 200-207 3/13 Oral +1 Compound Id 1.2 171 0/9 2.1 185 0/8 3.8 214 3/8 Oral 1,2,3 Compound Id 0.48 183 0/10 0.62 208 0/10 0.8d 233-258 2/20 a) days after tumour transplantation b-c) see Table 2 d) data of two experiments (range)

Claims (14)

Claims

1. A process for the preparation of an anthracycline glycoside having the general formula I or II as defined herein, the process comprising condensing an anthracyclinone having the general formula III as herein defined with 3,4-di-0-acetyl-2,6-dideoxy-a-L-arabi no-hexopyranosyl chloride, separating the resultant mixture of anthracycline glycosides having the general formulae V and Vl as defined herein, and removing the acetyl protecting group(s) and, if necessary, the t-butyldiphenyl-silyl protecting group.

2. A process according to claim 1 wherein the condensation is carried out in methylene dichloride in the presence of a mixture of mercuric bromide, mercuric oxide and molecular sieve.

3. A process according to claim 1 wherein the condensation is carried out in methylene chloride in the presence of silver trifluoromethanesulphonate.

4. A process according to any of claims 1 to 3 in which the acetyl group(s) is or are removed by treatment with sodium methoxide in methanol.

5. A process according to any of claims 1 to 3 in which the acetyl group(s) is or are removed by treatment with dilute aqueous sodium hydroxide.

6. A process according to any preceding claim in which the compound of the general formula Ill is 1 4-0-(t-butyl-diphenyl-silyl)-adriamycinone or 4-demethoxy-1 4-0-(t-butyl-diphenyl-silyl)- adriamycinone, prepared by condensing adriamycinone or 4-demethoxy-adriamycinone with t-butylchloro-diphenyl-silane in dimethylformamide in the presence of imidazole.

7. A process according to any preceding claim in which the compound of the general formula Ill is 1 4-0-(t-butyl-diphenyl-silyl)-adriamycinone or 4-demethoxy-1 4-0-(t-butyl-diphenyl-silyl)- adriamycinone, and the removal of the t-butyl- diphenyl-silyl protecting group is effected by the action of tetra-n-butyl-ammonium fluoride in tetrahydrofuran.

8. A process according to any preceding claim in which the separation is effected chromatographically.

9. A process according to claim 1 substantially as described herein with reference to any of Examples 3 to 6.

1 0. A process according to claim 1 and claim 6 substantially as described herein with reference to Examples 1 and 5 or Examples 2 and 6.

11. 4-Demethoxy-7-0-(2,6-dideoxy- a-L-arabino-hexapyranosyl)-dau nomycinone.

1 2. 4-Demethoxy-7-0-(2,6-dideoxy-a-L-arabino-hexopyranosyl)-adriamycinone.

13. 4-Demethoxy-7-0-(2,3 ,6-trideoxy-a-L-erythro-hex-2-enopyra nosyl)-daunomycinone.

14. 4-Demethoxy-7-0-(2,3,6-trideoxy-a-L-erythro-hex-2-enopyranosyl)-adriamycinone.

1 5. 7-0-(2,3,6-Trideoxy-a-L-erythro-hex-2-enopyranosyl)-daunomycinone.

1 6. 7-0-(2 ,3,6-Trideoxy-cg-L-erythro-hex-2-enopyra nosyl)-adriamycinone.

1 7. A pharmaceutical composition comprising an anthracycline glycoside according to any of claims 11 to 1 6 in admixture with a pharmaceutically acceptable diluent or carrier.