GB2215332A

GB2215332A - 4-Demethyl-4-0-(p-fluorobenzensulfonyl) anthracycline glycosides

Info

Publication number: GB2215332A
Application number: GB8828830A
Authority: GB
Inventors: Michele Caruso; Stefania Stefanelli; Antonino Suarato
Original assignee: Farmitalia Carlo Erba SRL; Carlo Erba SpA
Current assignee: Pfizer Italia SRL
Priority date: 1988-02-25
Filing date: 1988-12-09
Publication date: 1989-09-20
Anticipated expiration: 2008-12-09
Also published as: IT8919523A0; JPH01254695A; GB2215332B; GB8828830D0; DE3905431A1; IT1228453B; GB8804429D0

Abstract

4-Demethyl-4-0-(p-fluorobenzensulfonyl) anthracycline glycosides of the general formula I or II: <IMAGE> wherein R1 is hydrogen or hydroxy, and their pharmaceutically acceptable salts, are antitumor agents. 4-Demethy-4-0- (p-benzensulfonyl)-daunomycinone of formula (IV): <IMAGE> is a precursor of the above compounds.

Description

e NEW 4-DEMETHYL-4-0-(P-FLUOROBENZENSULFONYL)ANTHRACYCLINE GLYCOSIDES The

present invention refers to anthracycline glycosides, to methods for their preparation, to pharmaceutical compositions containing them and the use of glycosides as antitumor agents.

The present invention provides, in one aspect thereof, a new class of anthracycline glycosides of formula I and II having the C-4-OH group protected as p-fluorobenzensulfonate.

RI OM 9 6 M 4 %(Dz WI F H R, H OH 4 K 9- 6 X", r 0 Sol H CW3 /iAd W1411 11 wherein R, is hydrogen or hydroxy, and pharmaceutically acceptable salt thereof especially acid addition salts such as the hydrochloride. More particularly the new anthracycline glycosides are:

la: 4-demethyl-4-0-(p-fluorobenzensulfonyl)-daunorubicin 1b: -4-demethyl-4-0-(p-fluorobenzensulfonyl)-doxorubicin IIa: 4-demethyl-4-0-(p-fluorobenzensulfonyl)-41-epi- daunorubicin 11b: 4-demethyl-4-0-(p-fluorobenzensulfonyl)-41- epidoxorubicin The anthracycline glycosides I and II and their salts are prepared by a process which comprises: (i) reacting 4-demethyl-4-0-(pfluorobenzensulfonyl)daunomycinone with a reactive derivative of daunosamine or acosamine wherein the 3-amino and 4-hydroxy groups are protected, and removing the protecting groups from the product thusobtained such as to obtain an anthracycline glycoside of formula (1) or of formula (11) wherein R, is hydrogen; (ii) if desired, converting the said glycoside of formula (I) or of formula (II) into a pharmaceutically acceptable salt thereof; (iii) if desired, brominating the said glycoside of formula (1) or of formula (II) or pharmaceutically acceptable salt thereof and hydrolysing the 14-bromo derivative thus obtained so as to form the corresponding glycoside of formula (I) or of formula (II) wherein R, is hydroxy; and P c 1 1 1 m (iv) if desired,-converting the said glycoside of formula (1) or of formula (II) wherein R, is hydroxy with a pharmaceutically acceptable salt theieof. The process is based on the synthesis of the C-4-0-(p- fluorobenzen)sulfonyl derivative IV of the well known 4-demethyl- daunomycinone III, its coupling with a-chloroN,Otrifluoroacetyldaunosamine (V) or with a-chloroN,Otrifluoroacetylacosamine (VI), typically in the presence of silver trifluoromethane sulfonate, and removal of the N,O-protecting groups to afford compound la or lIa.

WH V OH 0 V H 6H 4 4 H 6H NRCC)CF3 SOt Co"3 0 F V1 1V C 0 C F.4 NWCOCF3 The resultant glycoside is converted to compound lb or 1Ib via bromination and hydrolysis, for example by sodium formate treatment in accordance with the method described in US-A-3803124. The process is illustrated in the following Reaction Scheme, in which pTSA signifies p- toluenesulfonic - 4 acid. This example of the present process comprises:

a) protection of the benzylic hydroxyl or 4-demethyl- daunomycinone group (III) by means of dihydropyran in methylene dichloride, followed by reaction at C-4-OH with p-fluorobenzensulfonyl chloride in the presence of N,N-diisopropylethylazine and a catalytic amount of 4-dimethylaminopyridine to give the C-4-0-sulfonyl derivative Ill(b) which is hydrolysed by means of p-toluenesulfonic acid to afford the key intermediate IV; b) coupling of the 4-demethyl-4-0-(p-fluorobenzensulfonyl) daunomycinone (IV) with a protected halo sugars of formula V or VI in methylene dichloride and in presence of silver trifluoromethanesulfonate, to give the new Ntrifluoroacetyl glycosides of formula VII or VIII; C) mild aqueous alkaline treatment of compounds VII or VIII to afford the 4-demethyl-4-0-(p-fluorobenzensulfonyl)-daunorubicin (Ia) or 4-demethyl-4-0-(pfluorobenzensulfonyl)-41-epi-daunorubicin (IIa); and -d) bromination at C-14 of the daunorubicin derivatives Ia or I Ia followed by treatment with aqueous sodium formate to give the corresponding doxorubicin derivatives Ib or IIb. Typically in step (i) of the present process the -4-demethyl-4-0-(p-fluorobenzensulfonyl)- daunomycinone is r reacted with the said protected reactive derivative of daunosamine or acosamine in anhydrous methylene chloride and in the presence of a silver triflate solution in diethyl ether. Step (i) can be effected by reacting 4-demethyl-4-0(p-benzensulfonyl)-daunowycinone with a compound of formula (V) or (V1) as mentioned above. The product of this reaction can then be treated with an aqueous solution of 0.1 N sodium hydroxide at CC for 1 hour to obtain a compound Ia or IIa.

Step (ii) can be effected by treating the said glycoside of formula (1) or of formula (I1) with a methanolic solution of hydrogen chloride and isolating the said glycoside of formula (I) or of f ormula (I1) as its hydrochloride. Preferably step (iii) is effected by treating the said glycoside of formula (I) or of formula (I1) or pharmaceutically acceptable salt thereof with bromine in methylene chloride and hydrolysing the 14-bromo derivative thus obtained with an aqueous solution of sodium formate. Step (iv) can be effected by treating the said glycos ide of formula (I) or of formula (II) wherein R, is hydroxy with a methanolic solution of hydrogen chloride and 1 isolating the said glycoside of formula (I) or of formula (II) wherein R, is hydroxy as its hydrochloride.

The starting 4-demethyl-4-0-(p-fluorobenzensulfonyl) daunomycinone may be prepared by condensing 4-demethyl- dauno mycinone with dihydropyran to form a kb.

tetrahydropyranosyl glycoside of formula (IIIa):

1CODS Qwti. ', 4 d) -) TI-S 10') 4j ' reacting the said tetrahydropyranosyl glycoside with p- fluorobenzensulfonyl chloride to form the 4-0-p-benzensulfonyl derivative of formula (IIIb):

f-O.5c:

C's 11 (1) _and hydrolysing the said 4-0-p-benzensulfonyl derivative. In one embodiment of this process, the 4-demethyldaunomycinone, dissolved in methylene chloride, is condensed in the presence of a catalytic amount of p-toluensulfonic acid with dihydropyran to form the said tetrahydropyranosyl glycoside of formula (IIIa) from which, after reaction with p-fluorobenzensulfonyl chloride at room temperature in the i S - 7 presence of N,N-diisopropylethylamine and a catalytic amount of 4dimethylaminopyridine, the said 4-0-p-toluensulfonyl derivative is obtained which is subsequently hydrolysed by means of p-toluensulfonic acid to form 4-demethyl-4-0(p-fluorobenzensulfonyl)-daunomycinone.

The present invention also provides a pharmaceutical composition comprising as active ingredient an anthracycline glycoside of formula I or II or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent. A therapeutically effective amount of a compound of the invention is combined with an inert carrier. Conventional carriers may be used and the compositions may be formulated in conventional manner.

The compounds of the invention are useful in methods of treatment of the human or animal body by therapy. In particular the compounds of the invention are useful as antitumor agents by administering a therapeutically effective amount of the compound to a patient.

The compounds have been tested in comparison with daunorubicin (DNR) against LoVo and LoVo/doxorubicin resist4ant cells in vitro. The compounds were tested by dissolving them, as hydrochlorides, in water and 10% of Tween 80. The in vitro effect is reported in Table 1. activity of Compound Ia and IIa was tested against disseminated Gross leukemia. The results are reported in Table 2.

- 8 TABLE 1

Cytotoxic effect of Compounds Ia, lIa and DNR a) IDSO (u/ml) Compound LoVo& LOVO/DX b DNR so 1805 Ia 113 849 IIa 46 525 a) dose which gives 50% reduction of cell number in comparison with untreated controls.

TABLE 2

Effect against murine Gross leukemia a dose" Toxic d Compound mg/Kg T/CC death DNR is 220 0/10 Ia 22.5 160 0/10 IIa 10 120 0/10 a Experiments were performed in C3H mice, inoculated with 2 x 10 6 leukemia cells i.v. b Treatment i.v. on day 1 after tumor inoculum.' C Median survival time of treated mice/median survival time of control x 100. d Evaluated on-the basis of autoptic findings.

The following Examples illustrate the invention.

1 Reaction Scheme S X> m S Om X' 14w 4 m 6H 111 2) p-flucrobenzensulfonylchloride N, 1;-diisopropyla=ine 4 -d4=ethyla=inepyr-ldine y /ACSO2CF3 0 0-CS m 4 9 6 scl c F viz 1 01M la lb 1) Dihydropyrane/pTSA IV 1) Br 2 1 2) ECOONa ho f 4(:

ll, H 0 ' UH A 0 ms 1 ' (D III (a) H ZH 4 p WHI z 1 I': (b) 3L1 /A950:cr., HH H c V1-1 -:t 11a 1) Br 2 1 2) NCOONa CHI 11b 1 - Example 1 Preparation of 4-demethyl-4-0-(p-fluorobenzensulfonyl) daunomycinone (IV) To a stirred solution of 1g (2.6 mmol) of 4-demethyldaunomycinone (III) in 500 ml of methylene dichloride 1 ml of dihydropyrane and a catalytic amount of p-toluensulfonic acid are added. After 30 minutes a chromatographic control show the formation of the tetrahydropyranyl glycoside (TLC on silica gel plates Merck F2,4, eluting system: toluene acetone 9: 1 by volume, Rf=0.49). 0.55 ml of N,N-diisopropylethylamine, a catalytic amount of 4-dimethylaminopyridine and 0.6g of p-fluoro- benzensolfochloride are added and the mixture stirrecl.foZ,30.Tpinutes at containingthe intermediate Illb room temperature. Then the mixture/is washed with water.

11 0.1N aqueous hydrochloric acid and water. The organic layer is separated off, poured over anhydrous sodium sulphate, filtered off and evaporated to a small volume in the presence of a catalytic amount of ptoluensulfonic acid. The residue is piked up with little methylene dichloride and chromatographed on a column of silica gel eluting with a mixture toluene acetone (9: 1 by volume) to give, after crystallization from methylene dichloride 0.650g (yield 46%) of 4-demethyl-4-0-(pflucrobenzensulfonyl)-dauno mycinone (1v). FDMS [Mt] 546 TLC on silica gel plates (Merck F254) eluting solvent: toluene acetone (9: 1 by volume) Rf=0.46 1BNM (200 MHz, WC13)fS:

13.55, 13.17 (t, 2H, OH phenolic); 8.38 (dd, j=1.4, 7.8Hz, 1H, H3); 8.04 (dd, J=5.0, 8.9Hz, 2H, H-111 and H-Y1); 7.82 (dd, J=7.8, 8.1Hz, 1H, H2); 7.60 (dd, J=1.4, 8.1HZ, 1H, H1); 7.24 (dd, J=8.4, 8.9Hz, 2H, M-V' and HC); 5.30 (ddd, j=1.9, 4.8, MHz, 1H, M7); 4.50 (s, 1H, OH-9); 330 (d, j=5. 7Hz, 1H, OH-7); 3.16 (dd, J=2.0,.19.0Hz, 1H, H-10eq); -2.95 (d, J=19.0Hz, 1H, H-10ax); 2.42 (s, 3H, COCH 3); 9 Z 2.35 (ddd, j=1.9, 2.0, 14.6Hz, 1H, H-Seq); 2.17 (dd, j=4.8, 14.6Hz, 1H, H- Sax).

Example 2 4-demethyl-4-0-(p-fluorobenzensulfonyl)daunorubicin (Ia) 0.54g (1 mmol) of 4-demethyl-4-0-(p-fluorobenzensulfonyl)- daunomycinone (LV), prepared as described above, are dissolved in 50 ml of anhydrous methylene dichloride and the solution is cooled to O-le C. A solution of 0.357 mg (1 mmol) of tL-chloro-N,O-trif luoroacetyldaunosamine (y), prepared following the procedure described in Cancer Chemotherapy Reports, Part 3, Vol. 6, No 2, p.123, in diethyl ether and a solution of 0.266 mg of silver trifluoromethanesulfonate in methylene dichloride are added simultaneously and rapidly under vigorous stirring.

After 5 minutes a further 0.07g of si.lver trifluoromethane sulfonate is added and after 5 minutes the reaction mixture is quenched with collidine.

The mixture is filtered, washed with saturated aqueous solution of sodium hydrogen carbonate and with water, dried and concentrated under vacuum. The residue is chromatographed on a column of silica gel eluting with a mixture of methylen dichloride acetone (9: 1 by volume), to give 0.46 (Yield 70%) of 4-demethyl-4-0-(p-fluorobenzensulfonyl)-N-triflucro-acetyl-daunorubicin (VII). TLC on silica gel plates (Merck F 254), eluting system methylene dichloridelacetone (8/2 by volume) Rf=0.44 1 (200 MHz', CDC1 3) (r: 13.54, 13.15 (s, 2H, OH phenolic); 8.35 (dd, j=1.4,7.8Hz, 1H, 113); 7.99 (dd, j=7.8, 8.1Hz, 2H, H-111 and H-511); 7.78 (dd, j=7.8, 8.1Hz, 1H, 112); 7.45 (dd, j=1.4, 8.1Hz, 1H, H1); 7.23 (dd, j=8.4, 8.9Hz, 2H, 11-21' and H-C); 6.82 (d, j=8.4Hz, 1H, NHCOW 3); 5.46 (m,1H, H711); 5. 19 8dd, j=1.9, 4.6Hz, 1H, H7); 4.33 (s, 1H, OH-9); 4.3-4.2 (m, 2H, H-31 and 11-5'); 3.67 (d,j=3.0Hz, 1H, H-41); 3.21 (dd, j=2.0, 19.0Hz, 1H, H10eq); 2.93 (d, j=19.0Hz, 1H, 10ax); 2.40 (s, 3H, COCH3); 2.30 (ddd, j=1.9, 2.0, 15.0Hz, 1H, H8eq); 2.09 (dd, J=4.6, 15.0Hz, 1H, H8ax); 2.0-1. 8 (m, 2H, CH 2- 2); 1.30 (dp j=6.5Hz, 3H, CH 3 -51).

Compound VII is dissolved In 10 ml of acetone and treated with 30 ml of OAN aqueous sodium hydroxide at OC for 1 hour. Then to the solution Is added O.IN aqueous hydrochloric acid to adjust the pE to 4.5 and the aglycone is eliminated by extraction with methylene dichloride.. Then the aqueous solution is adjusted to pg '84 and extracted with methylene dichloride, dried over anhydrous sodium sulphate, concentrated to a small volume and acidified to pH 4.5 with OAN methanolic hydrogen chloride to give the title compound as its hydrochloride.

FDMS [Mt] 671 TLC on silica gel plates (Merck F 254 eluting system: methylene dichloride/methanol/acetic acid/water (30/4/110.5 by volume) Rf=0.51 Example 3 4-demethyl-4-0-(p-fluorobenzensulfonyl)-doxorubicin (Ib) 0.29 of 4-demethyl-4-0-(p-fluorobenzensulfonyl)daunorubicin (1a) are effected to chemical transformation into the title compound according to the procedure described in U.S.Patent 4,122,076. 1 Example 4 4-demethyl-4-0-(p-fluorobenzensulfonyl)-41-epidaunorubicin (IIa) The coupling of 4-demethyl-4-0-(p-fluorobenzensulfonyl)daunomycinone (IV) with 4t-chloro-N,O-trifluoroacetyl- acosamine (VI), [see: F.Arcamone et al. J.Med.Chem., 18, p703, 19751 is performed following that described to the example 2.

0.5 g of compound IV - are N-trifluoroacetyl derivative VIII.

transformed into the 1 t t TLC on silica gel plates (Merck F 254), eluting system: methylene dichloride/acetone (8/2 by volume) RF=0.38 EMMS [Mt] 767 IRM, 200 MHz, CDC1 J: 3 13.61, 13.23 (s, 2M, 2H, phenols); 8.40 (dd, J=1.4, MHz, 18, 11-3); 8.01 (dd, J=5.0, 8.9Hz, 2H, M-10 and E-S"); 7.80 (dd, J=7.8, 8.1Hz, 1H, H-2); 7.49 (dd, J=1.4, 8.1HZ, 1H, H-1); 7.25 (dd, J=8.4, 8.9Hz, 2H, M-211 and H- 411); 6.27 (d, j=7.5Hz, 1H, NHCOCF 3); 5.48 (d,j=3.5Hz, 1H, 11-11); 5.27 (m, 1E, M-7); 4.37 (s, 1H, OH-9); 4.0-3.9 (M, 2H, H-31 and M-51); 33-3.2 (m, 1H, M-41); 3.25 (dd, j=1.4, 18.3Hz, 1H, 11-10eq); 2.89 (d, j=18.3Hz, 1H, H-10ax); 2.53 (d, j=7.0Hz, 1H, OH-C); 2.43 (s, 3H, COCH 3); 2.3-1.8 (m, 4H, CH 2- 8 and 2H-2-2'); 1.38 (d,j=6.2Hz, 3H, CH 3 CH).

The alkaline treatment of product VIII afford the title compound IleLwhich is isolated as hydrochloride.

TLC on silica gel plates (Merck F 254), eluting system methylene dichloride/methanol/acetic acid/water (30/4/1/0.5 by volume) Rf=0.56 Example 5 4-demethyl-4-0-(p-fluorobenzensulfonyl)-4'-epidoxorubicin QAb) The title compound is prepared following the procedure described in U.S. Patent 4,122,076.

1 14 -

Claims

1. Anthracycline glycosides having the general formula I or II:

R, 0 F H R, 1 I- I. -L wherein R, is hydrogen or hydroxy, and their pharmaceutically acceptable acid addition salts.

2. A compound according to claim 1, which is 4-demethyl-4-0-(p-fluorobenzensulfonyl)-daunorubicin or th hydrochloride,thereof.

3. A compound according to claim 1, which is 4-demethyl-4-0-(p-fluorobenzensulfonyl)-doxorubicin or th hydrochloride thereof.

4. A compound according to claim 1, which is 4-demethyl-4-0-(p-fluorobenzensulfonyl)-41-epi-daunorubicin r - 0 or the hydrochloride thereof.

5. A compound according to claim 1, which is 4-demethyl-4-0-(pfluorobenzensulfonyl)-41-epi-doxorubicin or the hydrochloride thereof.

6. A process for the preparation of an anthracycline glycoside of formula (1) or of formula (II) as defined in claim 1 or a pharmaceutically acceptable salt thereof, which process comprises (i) reacting 4-demethyl4-0-(p-fluorobenzensulfonyl)daunomycinone with a reactive derivative of daunosamine or acosamine wherein the 3-amino and 4-hydroxy groups are protected, and removing the protecting groups,from the product thusobtained such as to obtain an anthracycline glycoside of formula (I) or of formula (II) wherein R, is hydrogen; (ii) if desired, converting the said glycoside of formula (I) or of formula (II) into a pharmaceutically acceptable salt thereof; (iii) if desired, brominating the said glycoside of formula (I) or of formula (II) or pharmaceutically acceptable salt thereof and hyjdrolysing the 14-bromo derivative thus obtained so as to form the corresponding glycoside of formula (I) or of formula (11) wherein R, is hydroxy; and (iv) if desired, converting the said glyc- oside of formula (1) or of formula (II) wherein R, is hydroxy into a pharmaceutically acceptable salt thereof.

- 16

7. A process according to claim 6, wherein in step (i) the 4-demethyl-4-0- (p-fluorobenzensulfonyl)daunomycinone is reacted with the said protected reactive derivative of daunosamine or acosamine in anhydrous methylene chloride and in the presence of a silver triflate solution in diethyl ether.

8. A process according to claim 6 or 7, wherein step (i) is effected by reacting 4-demethyl-4-0-(pbenzensulfonyl)-daunomycinone with a compound of formula: (V) or (VI):

CAP. C.,0 4 V FN NC 0 C F3 COCF3 NWC0r.F3 CC)C;:3

9. A process according to claim 8 wherein the product of the reaction between the 4-demethyl-4-0-(pbenzensulfonyl)-daunomycinone and the compound of formula (V) or (VI) is treated with an aqueous solution of OAN sodium hydroxide at CC for 1 hour.

10. A process according to any one of claims 6 to 9, wherein step ii) is effected by treating the said glycoside of formula (I) or of formula (II) with a methanolic solution of hydrogen chloride and isolating the said glycoside of formula (I) or of formula (II) as its hydrochloride.

11. A process according to any one of claims 6 to 9 7 11 1 10, wherein step (iii) is effected by treating the said glycoside of formula (I) or of formula (II) or pharmaccutically acceptable salt thereof with bromine in methylene chloride and hydrolysing the 14-bromo derivative thus obtained with an aqueous solution of sodium formate.

12. A process according to any one of claims 6 to 11, wherein step (iv) is effected by treating the said glycoside of formula (I) or of formula (I1) wherein R, is hydroxy with a methanolic solution of hydrogen chloride and isolating the said glycoside of formula (1) or of formula (II) wherein R, is hydroxy as its hydrochloride.

13. A process according to any one of claims 6 to 12, wherein the 4demethyl-4-0-(p-fluorobenzensulfonyl)daunomycinone has been prepared by condensing 4-demethyldaunomycinone with dihydropyran to form a tetrahydropyranosyl glycoside of formula (IIIa):

OH c ">H (S 4 K -) TI-S t,) _ reacting the said tetrahydropyranosyl glycoside with p- fluorobenzensulfonyl chloride to form the 4-0-p-benzensulfonyl deivative of formula (IIIb):

0 H $0, - X (b) and hydrolysing the said 4-0-p-benzensulfonyl derivative.

14. A process according to claim 13, wherein the 4-demethyl-daunomycinone, dissolved in methylene chloride, is condensed in the presence of a catalytic amount of p-toluensulfonic acid with dihydropyran to form the said tetrahydropyranosyl glycoside of formula (II1a) from which, after reaction with p-fluorobenzensulfonyl chloride at room temperature in the presence of N,N-diisopropylethylamine and a catalytic amount of 4dimethylaminopyridine, the said 4-0-p-toluensulfonyl derivative is obtained which is subsequently hydrolysed by means of p-toluensulfonic acid to form 4-demethyl-4-0-(p-fluorobenzensulfonyl)-daunomycinone.

15. A pharmaceutical composition comprising an anthracycline glycoside of formula (I) or of formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims I to 5 in admixture with a phrmaceutically acceptable diluent or carrier.

16. An anthracycline glycoside of formula (I) or of formula (II) asdefined in clalm 1, or a pharmaceutically i 4R 1 - 19 acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.

17. An anthracycline glycoside or salt thereof according to claim 16 for use as an antitumor agent.

18. A process for the preparation of an anthracycline glycoside of formula (I) or of formula (II) as defined in claim 1, or a pharmaceutically acceptable salt thereof, said process being substantially as hereinbefore described in any one of Examples 2 to 5.

19. 4-Demethyl-4-0-(p-fluorobenzensulfonyl)daunomycinone.

20. A process for the preparation of 4-demethyl0-(p-benzensulfonyl)-daunomycinone of formula (IV):

H T0 "CH H 6W SOt 0 F IV which process comprises condensing 4-demethyl-daunomycinone of formula (III):

1 1 - 20 S -0k 4 W146m Ok ill with dihydropyran to form a tetrahydropyranosyl glycoside of formula ill (a):

OK 4 K A 6 :) TY1,) reacting the said tetrahydropyranosyl glycoside with p- fluorobenzensulfonyl chloride, at room temperature, in the presence of N, N-diisopropylethylamine and a catalytic amount of 4-dimethylaminopyridine, the C to form the 4-0-pbenzensulfonyl derivative of formula III (b):

4e Ir (1) and hydrolysing the said 4-0-p-benzensulfonyl derivative.

21. A process according to claim 20, wherein the 1 1 i - 21 4-demethyl-daunomycinone, dissolved in methylene chloride, is condensed in the presence of a catalytic amount of p-toluensulfonic acid with dihydropyran to form the said tetrahydropyranosyl glycoside of formula (IIIa) from which, after reaction with p-fluorobenzensulfonyl chloride at room temperature in the presence of N,N-diisopropylethylamine and a catalytic amount of 4-dimethylaminopyridine, the said 4-0-ptoluensulfonyl derivative is obtained which is subsequently hydrolysed by means of p-toluensulfonic acid to form 4-demethyl-4-0-(pfluorobenzensulfonyl)-daunomycinone.

22. A process for the preparation of 4-demethyl-4-0(pfluorobenzensulfonyl)-daunomycinone, said process being substantially as hereinbefore described in Example 1.

Published 1989 at The Patent O.Moe, State House, 66.71 High Holborn, London.WCIR 4TP. Further copies maybe obtained from The Patent Offize. Sales Branch, St Mary Cray, Orpington, Kent BR5 3BD. Printed by MultaPlex techniques Itd, St. Mary Cray, Kent, Con. 1/87