L-arabino-disaccharides of anthracyclines, processes for...

Details L-arabino-disaccharides of anthracyclines, processes for... L-arabino-disaccharides of anthracyclines, processes for...

2001-12-18

2003-11-25

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S006400, C536S018500, C536S018600

Reexamination Certificate

active

06653289

ABSTRACT:

FIELD OF THE INVENTION
The present invention refers to compounds of general formula (I)
and pharmaceutically acceptable salts thereof having anticancer properties, where
R is OH;
R
1
is H or OH;
R
2
is H or OH or NH
2
.
The present invention also refers to the processes for the preparation of said compounds, their pharmaceutically acceptable salts, and the pharmaceutical compositions containing them.
PRIOR ART
Daunorubicin and doxorubicin are established anticancer drugs currently used in the clinical practice for the treatment of a variety of solid tumours and leukaemia (F. Arcamone in “Doxorubicin: Anticancer Antibiotics”, Academic Press, N.Y., 1981).
It is however known that the severe side effects (first of all, chronic cardiotoxicity and secondly acute myelosuppression) caused by said antibiotics and the other anthracyclines used at present impose limits on the use of same in a large number of patients who, otherwise, would benefit from the treatment. Said side effects, in fact, set a limit to the maximum administrable dose and to the number of treatment cycles.
Therefore, there is an urgent need for the coming onto the market of drugs highly selective in their inhibitory action against the proliferation of diseased cells in respect of the normal ones, and characterised by a lower cardiotoxicity, which would allow their use in higher doses as well as the achievement of increased therapeutic indices.
It is an object of the present invention to provide new anticancer drugs, in particular anthracycline analogues, in which the carbohydrate portion consists of a disaccharide residue.
In general, in the known natural or synthetic anthracyclines with anticancer activity, which contain two or more carbohydrate residues, the sugar directly bound to aglycone always contains a free or substituted amino group.
A recent industrial invention (WO 95/09173) refers to anthracyclines with a disaccharide residue, in which the sugar directly bound to aglycone never contains amino groups.
DETAILED DESCRIPTION OF THE INVENTION
The anthracyclines being the object of the present invention always contain an L-arabino group, or an amino derivative thereof, in the disaccharide portion, and said arabino group is always the furthest sugar from the aglycone bond.
Furthermore, unlike most active anthracyclines containing two or more carbohydrate residues, the sugar directly bound to aglycone never contains an amino group.
For facility of understanding, it is worth noting that in the present invention the substituents of the disaccharide group, defined in WO 95/09173 as R
3
, R
4
and R
5
, are all in equatorial position and the group defined therein as R
5
is always a hydroxyl group. The equatorial position of the hydroxyl group in position 4 on the second sugar of the compounds of general formula (I) is of particular importance to the present invention.
It has surprisingly been found that, compared with the anthracycline disaccharides described in WO 95/09173, which contain the hydroxyl group in position 4 on the second sugar in axial position [see general formula (I)], the anthracyclines of the present invention are characterised by a higher anticancer activity and selectivity as well as by a lower cardiotoxicity. The decrease in cardiotoxicity could not be expected to exclusively depend on the presence of said hydroxyl group in the carbohydrate residue.
The compounds of the present invention are the compounds of general formula (I), as reported above, and their pharmaceutically acceptable salts, in which R, R
1
, R
2
are as described above.
The invention also refers to pharmaceutical compositions containing the aforementioned compounds or salts thereof with pharmaceutically acceptable acids, preferably the hydrochloric acid.
Particularly preferred are the following compounds:
a) 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-&agr;-L-arabino-hexopyranosyl)-&agr;-L-lyxo-hexopyranosyl ]-4-demethoxy-doxorubicinone chlorhydrate (R=R
1
=OH, R
2
=NH
2
);
b) 7-O-[2,3,6-trideoxy-4-O-(2,3,6-trideoxy-3-amino-&agr;-L-arabino-hexopyranosyl)-&agr;-L-lyxo-hexopyranosyl ]-4-demethoxy-doxorubicinone chlorhydrate (R=OH, R
1
=H, R
2
=NH
2
);
c) 7-O-[2,6-dideoxy4-O-(2,6-dideoxy-&agr;-L-arabino-hexopyranosyl)-&agr;-L-lyxo-hexopyranosyl ]-4-demethoxy-doxorubicinone chlorhydrate (R=R
1
=R
2
=OH);
d) 7-O-[2,3,6-trideoxy-4-O-(2,6-dideoxy-&agr;-L-arabino-hexopyranosyl)-&agr;-L-lyxo-hexopyranosyl ]4-demethoxy-doxorubicinone chlorhydrate (R=R
2
=OH, R
1
=H).
The compounds of general formula (I) can be prepared on the basis of a process consisting in the following steps:
a) condensation of a compound of formula (II)
where R
3
is the OR
4
group, in which R
4
is a protective group for an alcoholic function, preferably selected among the acetyl-, chloroacetyl-, dimethylterbutylsilyl or p-methoxyphenyidiphenylmethyl- groups, with a compound of formula (111)
where R
5
is H or a protected —OH group, preferably p-nitrobenzoate or allyloxycarbonate; R
6
is a H group or a protected —OH group, preferably p-nitrobenzoate or allyloxycarbonate or a protected NH
2
group, preferably trifluoroacetamide or allylcarboxyamide; R
7
is a protected —OH group, preferably p-nitrobenzoate or allyloxycarbonate, and X is a group capable of generating, under the condensation conditions, a stable carbo-cation that can bind itself to a hydroxyl group in position C-7 of the compound of formula (II), said group X being conveniently selected among the groups used in the glycosidation reaction, e.g. a halogen such as chlorine or bromine, preferably chlorine, or a p-nitrobenzoyloxy group or a thiophenyl or thioethyl group, preferably thiophenyl. Compounds of formula (IV) are thus obtained:
where R
3
, R
5
, R
6
, R
7
are as defined above;
b) one or more removal reaction/s of protective groups of OH and/or NH
2
functions from compounds of formula (IV) to give compounds of formula (I), where R, R
1
, R
2
are as defined above;
c) conversion, if any, of the aforesaid glycosides of formula (I) into a pharmaceutically acceptable salt thereof, preferably chlorhydrate.
The reaction conditions for the glycosidation of a compound of formula (II) with a compound of formula (III) to give a compound of formula (IV) may vary depending on the type of substituents present in the compounds of formula (Ill).
Alternatively, if,so desired, anthracycline glycosides of formula (I), where R
1
, R
2
are as defined above, and R is an OH group, can be prepared from glycosides of formula (I) or from pharmaceutically acceptable salts thereof, where R
1
, R
2
are as defined above, and R is H, by bromination of the carbon in position 14 with bromine in chloroform followed by hydrolysis, at room temperature for 48 hrs, of the resulting 14-bromo derivatives with sodium formate.
The sequence of reactions giving the compounds of general formula (I) is carried out according to methods already described in literature (see e.g. WO 95/09173) and, therefore, are already known in the art.
The present invention also refers to pharmaceutical compositions containing, as active ingredient, a compound of formula (I) or a pharmaceutically acceptable salt thereof combined with a pharmaceutically acceptable diluent or carrier.
According to the present invention, a therapeutically effective dose of a compound of formula (I) is combined with an inert carrier.
The compositions can be formulated by conventional methods using common carriers.
The claimed compounds are useful for the therapeutic treatment on humans and other mammals. In particular, said compounds are efficacious anticancer agents when administered in therapeutically effective doses.
The activity of a compound representative of formula (I) was evaluated by comparing its cytotoxicity in vitro with the cytotoxicity of compound 7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-&agr;-L-lyxo-hexopyranosyl)-&agr;-L-lyxo-hexopyranosyl ]-4-demethoxy-doxorubicinone chlorhydrate of general formula (V)
(

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