IE80627B1 - 4-Demethoxy-4-Amino-Anthracyclines - Google Patents

Description

4-DEMETHOXY-4-AM1NO-ANTHRACYCLINES The invention relates to a process for preparing intermediates for use in the preparation of anthracycline glycosides.

The intermediates may be used to prepare e.g. anthracycline glycosides having the general formula (I): wherein Rx represents a hydrogen atom or a hydroxyl group, one of Ra and Rj represents a hydrogen atom and the other of Ra and r3 represents a hydrogen atom or a hydroxyl group, and their pharmaceutically acceptable addition salts. 0 ο 2 7 - 2 The glycosides of formula (I) and their pharmaceutically acceptable addition salts are prepared by a process in which the starting material is a daunomycinone derivative of formula (II): wherein the 4-amino group is protected. This process is described in Irish application no: 1171/88 from which the present application is divided. - 3 The daunomycinone derivative of formula (II) and protected derivatives thereof wherein the 4-amino group is protected . may be prepared by a process which comprises: (a) removing by hydrogenolysis the 7e-hydroxyl group of carminomycinone of formula (V): (b) reacting the resultant 4-demethyl-7-deoxydaunomycinone of formula (VI): - 4 10 VI with 4-fluorobenzensulfonyl chloride in the presence of Ν,Ν-diisopropylethylamine and a catalytic amount of 4-dimethylaminopyridine; (c) reacting the resultant 4-demethoxy-4-Ol4-fluorobenzensulfonyl]-7-deoxy-daunomycinone of formula (VII): VII with benzylamine; (d) removing the benzyl group from the resultant - 5 4-demethoxy-4-benzylamino-7-deoxy-daunomycinone of formula (VIII): by catalytic hydrogenation; (e) protecting the 4-amino group of the resultant 4-demethoxy-4-amino-7-deoxy-daunomycinone of formula (IX): (f) reintroducing the 7a-hydroxy group into the resultant compound of formula (X): wherein X' represents the amino protecting group, thereby obtaining a protected derivative of formula (XI) of a daunomycinone derivative of formula (II): wherein X’ is defined above; and (g) if desired, removing the 4*».amino protecting group from the protected derivative of formula (XI), thereby obtaining the daunomycinone derivative of formula (II): - Ί - II This process is illustrated in Scheme I below.

The starting compound for the process is the natural carminomycinone (V). The sulfonylation reaction, step (b), leads only the substituted C-4-O-sulfonyl derivative (VII), leaving the C-6-OH and C-ll-OH unaffected. It should be stressed that this unexpected selectivity has been achieved only under the conditions described herein.

Reaction (c) is a new one in anthracycline chemistry, probably due to the withdrawing effect both of the quinone moiety and of the 4-fluoro-benzensulfonyl group at the position C-4. Preferably, the reaction is effected in tetrahydrofuran at room temperature. Step (e) is preferably effected with trifluoroacetic anhydride. Preferably, therefore X' represents a trifluoroacetyl group in formulae (X) and (XI). Step (f) may be performed according to the method described by C.H. Hong et al..

Can.J.Chem., 51, 446 (1973). Preferably, it is effected by protecting the 13-keto group of a 4-demethoxy-4-(protected - 8 Scheme I e>' XIII - 9 amino)-7-deoxy-daunomycinone compound of formula (XII): XII by treatment with ethylene glycol; brominating the resultant compound at the 7-position; and hydrolysing the 7-bromo and 13-ketal groups to give 4-demethoxy-4-N-trifluoroacetamido-daunomycinone of formula (XIII): Bromination is generally achieved by treatment with bromine or N-bromosuccinimide in the presence of 2,2'-azo-bis(isobutyronitrile) .

The intermediates of formula (II) and (IX) are - 10 also useful for the preparation of 4-demethoxy-7-deoxydaunomycinone or 4-demethoxy-daunomycinone. 4-Demethoxy-7-deoxy-daunomycinone can be converted into 4-demethoxy-daunomycinone. Further antitumor anthracycline glycosides can be prepared from 4-demethoxy-daunomycinone.

According to the present invention, there therefore is provided a suitable process for preparing 4-demethoxy-7-deoxy-daunomycinone or 4-demethoxy-daunomycinone of formula (XIV): in which represents hydrogen or hydroxy, which process comprises diazotising the 4-amino group of 4-demethoxy-4-amino-7-deoxy-daunomycinone or 4-demethoxy4-amino-daunomycinone of formula (XV): in which R« is as defined above, and reducing under mild conditions the diazonium compound thus-formed.

Anthracyclinones bearing an amino group at position C-4 are therefore transformed into their corresponding desamino derivatives. The starting compounds are 4-demethoxy-4-amino-7-deoxy-daunomycinone (IX(XVa, R - H)) and 4-demethoxy-4-amino-daunomycinone (IX (XVb, R-OH)). The removal of the 4-amino group, via diazotisation and mild reduction, leads to the well known 4-demethoxy-7-deoxy-daunomycinone (XlVa, R-H) or 4-demethoxy-daunomycinone (XlVb, R-OB). As shown in Scheme II, diazotisation is preferably effected using aqueous sodium nitrite. The mild reduction is preferably effected using hypophosphorous acid. - 12 Scheme II Compound XVa in which R4-H can be easily transformed into compound XVb in which R4«OH by standard methods. Preferably, the 4-demethoxy-4-amino-7-deoxydaunomycinone (XVa) or 4-demethoxy-4-amino-daunomycinone (XVb), dissolved in aqueous 37% hydrochloric acid, is reacted at a temperature of from 0° to 5°C and for 1 hour with an aqueous solution of sodium nitrite and, subsequently, for 5 hours at room temperature under vigorous stirring with an aqueous solution of 50% hypophosphorous acid, the reaction mixture is extracted with methylene dichloride and the solvent is removed under reduced pressure. 4-Demethoxy-7-deoxy-daunomycinone (XlVa) may be converted into 4-demethoxy-daunomycinone (XlVb) by introducing a hydroxy group at the 7-position. This can be achieved according to the invention by bromination of the 7-position, for example by bromine or N-bromo-succinimide (MBS), followed by treatment with - 13 alkali or with silver acetate or methanolysis of the acetate thus formed. 4-Demethoxy-daunomycinone (XlVb) is the aglycone moiety of the useful antitumor drug 4-demethoxydaunorubicin (XVI). Accordingly, the present invention further provides a process for preparing 4-demethoxy-daunorubicin of formula (XVI): I5 . . or a pharmaceutically acceptable salt thereof; which process comprises reacting 4-demethoxy-daunomycinone, which is represented by formula (XIV) in which R4 is hydroxy and which has been prepared from 4-demethoxy-4-amino20 daunomycinone by a process according to the invention, with an appropriate sugar derivative and, if desired, converting the 4-demethoxy-daunorubicin thus-obtained into a pharmaceutically acceptable salt thereof.

The sugar derivative may have the formula (XVII): wherein Bal represents a halogen atom, Rc represents a protected hydroxy group and R? represents a protected amino group. The protecting groups are removed after reaction with 4-demethoxy-daunomycinone. Preferably Bal is a chlorine atom. The hydroxy group may be protected by a trifluoroacetyl group. The amino group may be protected by a trifluoroacetyl group also. - 15 -χ Example 1 Preparation of 4-demethoxy-7-deoxy-daunomycinone (XlVa) 1.78 g (5 mmol) of 4-demethoxy-4-amino-7-deoxy5 daunomycinone (IX) dissolved with 75 ml of aqueous 37% hydrochloric acid, are cooled at 0-5°C and 75 ml of an aqueous solution containing 0.6 g of sodium nitrite is added. The mixture is stirred for one hour at 0-5°C. Then 75 ml of an aqueous solution of 50% hypophosphorous acid is added and the mixture is kept at room temperature for five hours under vigorous stirring.

The solution is diluted with 200 ml of water and extracted with methylene dichloride. The organic layer is separated off, dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure to give a quantitative yield (1.7 g) of 4-demethoxy-7-deoxyI daunomycinone (XlVa), analytically compared with a standard ( sample. - 16 Example 2 Preparation of 4-demethoxy-daunomycinone (XlVb) 1.86 g (5 mmol) of 4-demethoxy-4-amino-daunomycinone (II) are transformed into the corresponding 4-demethoxydaunomycinone (XlVb) following the method above described. Yield: 1.8 g of compound XlVb analytically compared with a standard sample.

Claims (4)

1. A process for preparing 4-demethoxy-7- deoxy daunomycinone or 4-demethoxy-daunomycinone of formula XIV in which R 4 is hydrogen or hydroxy which process comprises diazotising the 4-amino group of 4-demethoxy-4-amino-7daunomycinone or 4-demethoxy-4-amino-daunomycinone of formula XV 0 OH 0 K 10 [OJ OH xv NH 2 0 OH *4 in which R 4 is defined above, and reducing under mild conditions the diazonium compound thus-formed.

2. A process according to claim 1 in which the diazotisation comprises treating the compound of formula XV 15 with an aqueous solution of sodium nitrite.

3. A process according to claim 1 or 2 in which the reduction is carried out by reaction using hypophosphorus acid. - 18

4. A process according to any one of claims 1 to 3 substantially as described herein with reference to the Examples.