Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-10-27
2003-01-14
Fonda, Kathleen Kahler (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S027000, C514S032000, C514S034000, C514S081000, C514S283000, C536S017200, C536S017300, C536S017400, C546S023000, C546S048000
Reexamination Certificate
active
06506734
ABSTRACT:
The present invention relates to glycoconjugates of 20(S)-camptothecin, in which a 3-O-methylated &bgr;-L-fucose unit is linked to the 20-hydroxyl group of a camptothecin derivative via thiourea-modified peptide spacers. The invention furthermnore relates to processes for the preparation of the compounds according to the invention and to their use as medicaments, in particular in connection with oncoses.
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 active 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 of 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 20-O-acyl prodrugs described have a very short half-life and are very rapidly cleaved to give the parent structure.
WO 9631532 A1 describes sugar-modified cytostatics in which the linkage of various cytotoxic or cytostatically active compounds to, for example, regioselectively modified carbohydrate units via specific spacers lead to an improvement in the tumour selectivity. From the combinations of carbohydrate, spacer and active compound widely described there, we then surprisingly found that the linkage of &bgr;-L-fucose units modified in the 3-position via a thiourea-modified peptide spacer consisting of a sterically demanding non-polar side chain-containing and a basic side chain-containing amino acid on the 20-hydroxyl group of 20(S)-camptothecin leads to very particularly preferred conjugates having the following properties:
By means of the ester-like linkage of the carrier radical to the 20-hydroxyl group, the lactone ring in the camptothecin moiety, which is important for the action, is stabilized.
By means of the special conformation of the dipeptide spacers, the conjugates in extracellular medium and in blood have a stability which is again markedly improved in comparison with similar conjugates having other spacers previously described in WO 9631532. In particular, the conjugates according to the invention are more stable than the 20-O-acyl prodrugs of camptothecin described in U.S. Pat. No. 4,943,579.
The conjugates according to the invention have better water solubility in comparison with similar conjugates from WO 9631532.
In vitro, the conjugates according to the invention have a high activity against tumour cell lines and tumour xenografts.
In vivo, the conjugates according to the invention have excellent therapeutic activity over several dose stages against various tumours after i.v. administration.
Compared with the underlying toxophore they have a markedly higher tolerability and tumour selectivity, in particular with respect to bone marrow toxicity.
The invention relates to compounds of the formula (I)
in which
R
1
represents a sterically demanding non-polar side chain of an amino acid and
R
2
represents a basic side chain of an amino acid and their salts, stereoisomers and stereoisomer mixtures.
Preferred compounds of the formula (I) are those
in which
R
1
is a branched alkyl radical having up to 4 carbon atoms and
R
2
is a radical of the formula —(CH
2
)
n
—R3, where
and
n is a number 1 to 4.
Particularly preferred compounds of the general formula (I) are those in which
R
1
is a branched alkyl radical of the formula
and
R
2
is a radical of the formula
The camptothecin unit can be present in the 20(R) or in the 20(S) configuration or as a mixture of these two stereoisomeric forms. The 20(S) configuration is preferred.
The amino acids can occur in the L or in the D configuration or alternatively as a mixture of D and L form.
The term “amino acids” in particular designates the &agr;-amino acids occurring in nature, but moreover also comprises their homologues, isomers and derivatives. As an example of isomers; enantiomers may be mentioned. Derivatives can be, for example, amino acids provided with protective groups.
Amino acids having “sterically demanding” side chains are understood as meaning those amino acids whose side chain has a branching in the &bgr;- or &ggr;-position; examples which may be mentioned are valine and isoleucine or leucine.
Typical examples of amino acids having non-polar side chains which may be mentioned are:
alanine, valine, leucine, isoleucine, proline, tryptophan, phenylalanine, methionine.
Typical examples of amino acids having basic side chains which may be mentioned are:
lysine, arginine, histidine, ornithine, diaminobutyric acid.
The compounds according to the invention are preferably present in the form of their salts. In general, salts with organic or inorganic acids may be mentioned here.
The acids which can be adducted preferably include hydrohalic acids, such as, for example, hydrochloric acid and hydrobromic acid, in particular hydrochloric acid, furthermore phosphoric acid, nitric acid, sulphuric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, such as, for example, acetic acid, trifluoroacetic acid, maleic acid, malonic acid, oxalic acid, gluconic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid and lactic acid and also sulphonic acids, such as, for example, p-toluenesulphonic acid, 1,5-naphthalenedisulphonic acid or camphorsulphonic acid.
The glycoconjugates according to the invention can be prepared, for example, by linkage of 20(S)-camptothecin to activated carboxyl components, which for their part can be moieties of protected amino acids, peptides or carbohydrate-modified peptides.
Preferably, the synthesis of the glycoconjugate takes place sequentially, beginning with the acylation of 20(S)-camptothecin with an N-protected carboxyl-activated unit of a non-polar sterically demanding amino acid in a suitable solvent, if appropriate in the presence of a base, according to customary methods. The amino protective group is then removed selectively by means of known methods. A unit of a basic amino acid, which, if necessary, is suitably protected is then linked and subsequently, if appropriate with retention of the side chain protective group, deblocked at the &agr;-amino function. In the key step, the linkage to the carbohydrate radical is carried out by conversion of p-aminophenyl-3-O-methyl-&bgr;-L-fucopyranoside into the corresponding isothiocyanate and subsequent linkage to the deblocked &agr;-amino group of the peptidyl camptothecin. Side chain protective groups which may still be present are detached and the free amino group is optionally converted into a suitable ammonium salt.
The invention thus furthermore relates to a process for the preparation of the glycoconjugates of the formula (I)
in which
R
1
represents a sterically demanding non-polar side chain of an amino acid and
R
2
represents a basic side chain of an amino acid,
or of their salts, characterized in that the isothiocyanate of the formula (II)
is reacted with the peptidyl-camptothecin, optionally bearing a protective group in the side chain, of the formula (III)
in which
R
1
has the abovementioned meaning and
R
2′
has the meaning of the abovementioned basic radical R
2
, which moreover can carry a protective group customary in peptide chemistry on the basic group
Baumgarten Jörg
Lerchen Hans-Georg
Sperzel Michael
von dem Bruch Karsten
Bayer Aktiengesellschaft
Chiu Jerrie L.
Fonda Kathleen Kahler
Maier Leigh C.
LandOfFree
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