Glycoconjugates from modified camptothecin derivatives...

Details Glycoconjugates from modified camptothecin derivatives... Glycoconjugates from modified camptothecin derivatives...

1999-03-24

2002-12-10

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S027000, C514S032000, C514S034000, C514S081000, C514S283000, C546S023000, C546S048000

Reexamination Certificate

active

06492335

ABSTRACT:

The present invention relates to glycoconjugates of camptothecin derivatives in which at least one carbohydrate component is linked via suitable spacers with the 20-hydroxyl group of a camptothecin derivative. The invention furthermore relates to processes for preparing the compounds according to the invention and to their use as medicaments, in particular in connection with cancer.
20(S)-Camptothecin is a pentacyclic alkaloid which was isolated in 1966 by Wall et al. (J.Am.Chem.Soc. 88, 3888 (1966)). It has a high antitumour activity potential in numerous in vitro and in vivo tests. Unfortunately, however, the promising potential failed to be realized in the clinic because of toxicity and solubility problems.
By opening the E ring lactone and formation of the sodium salt, a water-soluble compound was obtained which is in a pH-dependent equilibrium with the ring-closed form. Here too, clinical studies have been unsuccessful until now.
Approximately 20 years later, it was found that the biological activity is to be attributed to an enzyme inhibition of the topoisomerase I. Since then, the research activities have been increased again in order to find camptothecin derivatives which are more compatible and active in vivo.
To improve the water-solubility, salts of A ring- and B ring-modified camptothecin derivatives and of 20-O-acyl derivatives having ionizable groups have been described (Vishnuvajjala et al. U.S. Pat. No. 4,943,579). The latter prodrug concept was later also applied to modified camptothecin derivatives (Wani et al. WO 9602546). In vivo, however, the 2-O-acyl prodrugs described have a very short half-life and are very rapidly cleaved to give the parent structure.
Surprisingly, we have now found that the linkage of carbohydrate derivatives for example via peptide spacers on the 20-hydroxyl group of A- and/or B-ring-modified camptothecin derivatives leads to a class of compounds having highly interesting properties:
By means of the ester-like linkage of the carrier radicals to the 20-hydroxyl group, the lactone ring in the camptothecin derivatives, which is important for the action, is stabilized.
The conjugates obtained in this manner have high in vitro activity against tumour cell lines and tumour xenografts.
Compared with the underlying toxophores, they have markedly higher tolerability and tumour selectivity and improved solubility, in particular in aqueous media.
In vivo, they exhibit excellent therapeutic activity over several dose stages.
In extracellular medium and in blood, they are considerably more stable than the above-described 20-O-acyl prodrugs of camptothecin.
The invention relates to compounds of the general formula (I)
A—Cp—B  (I)
in which
Cp represents a group of the formulae
in which
R
1
, R
2
, R
3
and R
4
independently of one another may represent hydrogen, alkyl having up to 3 carbon atoms, halogen, amino, hydroxyl or nitro or
R
2
and R
3
together represent a group of the formula
m may have the values 1 or 2 and
R
5
represents —CH
2
—O—*, —CH
2
—NH*,
or represents
in which R
6
represents arylmethyl or hetarylmethyl,
in which
R
7
and R
8
are as defined for R
2
and R
3
and may be identical or different to these,
in which
R
9
represents hydrogen or —CH
2
—N(CH
3
)
2
and
R
10
represents hydrogen or ethyl,
or
in which
R
11
and R
12
are as defined for R
2
and R
3
and may be identical or different to these,
or
in which
R
13
and R
14
are as defined for R
2
and R
3
and may be identical or different to these,
where Cp is attached to A on the positions labelled # and attached to B on the positions labelled *,
A represents a radical of the formula
where 1≦(n+o+p)≦3,
B represents hydrogen or a radical of the formula
where 0≦(q+r+s)≦3, in which
M
1
and M
2
independently of one another each represent a bridge grouping whose main chain includes up to 21 atoms in linear order,
L
1
, L
2
, L
3
, L
4
, L
5
and L
6
independently of one another each represent linker groupings customaily used in glycoconjugate chemistry, (see review article Lee Y. C. and Lee R. in Lectins and Cancer 1991, 53-69, ed. by Gabius H. J. and Gabius S., Springer-Verlag),
Sp
1
, Sp
2
, Sp
3
, Sp
4
, Sp
5
and Sp
6
independently of one another each represent arylene having up to 10 carbon atoms or represent alkylene having up to 8 carbon atoms which are in each case optionally substituted, and K
1
, K
2
, K
3
, K
4
, K
5
and K
6
independently of one another each represent a radical of the formula (II)
in which
C represents methyl, hydroxymethyl, alkoxymethyl having up to 6 carbon atoms, acyloxymethyl having up to 6 carbon atoms or a radical of the formula —CH
2
—D in which
D represents a radical of the formula (II),
R
15
, R
16
and R
17
independently of one another each represent hydrogen, hydroxyl, optionally hydroxyl-substituted alkoxy having up to 6 carbon atoms, amino which is optionally substituted by alkyl or acyl having up to 6 carbon atoms, halogen, sulphate or a group of the formula
in which
R
18
and R
19
independently of one another each represent hydroxyl or alkoxy having up to 6 carbon atoms or represent amino which is optionally substituted by alkyl having up to 6 carbon atoms, and
u and v independently of one another may each have the values 0, 1, 2, 3 or 4;
or
R
15
, R
16
and R
17
independently of one another each represent a radical of the formula (II)
or
two of the radicals R
15
, R
16
, R
17
together represent an epoxy group,
or compounds of the formula:
in which
R
1
, R
2
, R
3
, R
4
, and A are as defined above;
R
5
represents H, —CH
2
CH
3
,
or represents —CH
2
—N(CH
2
CH
3
)R
6
,
in which R
6
represents arylmethyl or heterylmethyl,
and their isomers, isomer mixtures and salts.
Unless stated otherwise in the context of the invention, the term “alkyl groups” includes straight-chain, branched, cyclic and cycloalkyl-radical-containing alkyl radicals. Correspondingly, this definition also applies to all the other radicals containing alkyl groups, such as, for example, alkoxy, acyl, etc.
The terms arylmethyl and hetarylmethyl given in the definition of R
6
may represent, for example, phenylmethyl or pyridylmethyl.
Preference is given to compounds of the general formula (I) in which K
1
, K
2
, K
3
, K
4
, K
5
and K
6
independently of one another may each represent a radical of the formula (II) where
C represents methyl, hydroxymethyl, methoxymethyl or acetoxymethyl,
R
15
represents hydrogen, hydroxyl, methoxy or a group of the formula
in which
u and v independently of one another may each have the values 1 or 2 and
R
18
and R
19
independently of one another each represent hydroxyl or alkoxy having up to 4 carbon atoms,
or
R
15
represents a radical of the formula (II),
R
16
represents hydrogen, hydroxyl, halogen, alkoxy having up to 4 carbon atoms, sulphate or a group of the formula
in which
u and v independently of one another may each have the values 1 or 2 and
R
18
and R
19
independently of one another each represent hydroxyl or alkoxy having up to 4 carbon atoms or represent amino which is optionally substituted by alkyl having up to 4 carbon atoms,
R
17
represents hydroxyl, alkoxy having up to 4 carbon atoms which is optionally substituted by hydroxyl, amino which is optionally substituted by alkyl or acyl having up to 4 carbon atoms, or a group of the formula
in which
u and v independently of one another may each have the values 1 or 2 and
R
18
and R
19
independently of one another each represent hydroxyl or alkoxy having up to 4 carbon atoms,
or in which
R
15
and R
16
together represent an epoxy group,
and their isomers, isomer mixtures and salts.
Very particularly preferably, K
1
, K
2
, K
3
, K
4
, K
5
and/or K
6
represent a radical of the formula (II), where
C represents methyl, hydroxymethyl, methoxymethyl or acetoxymethyl,
R
15
and R
17
each represent a hydroxyl group and
R
16
represents hydrogen, hydroxyl, halogen, alkoxy having up to 4 carbon atoms, sulphate or a group of the formula
in which
u and v independently of one another may each hav

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