Biologically active compounds

Details Biologically active compounds Biologically active compounds

1994-12-20

1996-11-05

Peselev, Elli

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 34, 530322, 536 64, A61K 3816, A61K 3170, C07K 900, C07H 1524

Patent

active

055717853

DESCRIPTION:

BRIEF SUMMARY
This is a national phase application of International application No. PCT/EP94/01100, filed Apr. 8, 1994.
The present invention relates to soluble synthetic polymer-bound anthracyclines, to their preparation and to pharmaceutical compositions containing them.
Doxorubicin, 4'-epidoxorubicin and 4-demethoxydaunorubicin are examples of anthracyclines which are known from the prior art and which are currently used in the clinical treatment of neoplastic malignancies; see for example, F. Arcamone: "Doxorubicin" Medicinal Chemistry monograph, vol 17, Academic Press 1981.
Many polymeric derivatives of doxorubicin, endowed with antitumour activity, have been prepared. Amongst these, a particularly promising candidate for clinical development is soluble polymer-bound doxorubicin, which consists of hydrophilic moieties and peptide chains to which doxorubicin and 2-hydroxypropylamine are linked. This polymer-bound-doxorubicin derivative is prepared by condensing doxorubicin hydrochloride with a methacrylic polymeric precursor containing peptidyl chains, activated as the p-nitrophenyl ester, in dimethylsulfoxide in the presence of triethylamine followed by aminolysis of the remaining ester groups with 1-amino-2-hydroxypropane. Incubation of this material with rat lysosomal enzymes (tritosomes) cleaves the amidic bond between the terminal amino acid and doxorubicin [J.Kopecek et al., Biomaterials 10, 335 (1989); R.Duncan et al., Biochem. Pharmacol., 39 1125 (1990); R.Duncan et al., J.Controlled Release 10, 51 (1989); 18 123 (1992) and 19 331 (1992)].
A problem with conventional processes, for example as described above, is that it can be difficult to remove the doxorubicin from the doxorubicin polymer conjugate. This is due to the formation of .pi.-complexes between bound and free doxorubicin; the material has been shown to behave as one entity in dialysis, molecular filtration and gel chromatography [J. Feijen et al., J. Controlled Release 1, 301 (1985)].
The polymer-bound-anthracycline systems of the present invention are based on methacrylic polymers bearing hydrophilic moieties, peptidyl pendant chains linked only to the amino group of anthracycline and residues of glycine, either in the form of free acid or in the form of amide derivative. These systems have the advantage over the prior art that the anthracycline may be easily released from the polymer to which it is bound. In addition, the polymer-bound anthracyclines of the invention have broader antitumour activity and lower general toxicity than the corresponding free anthracyclines.
Accordingly, the present invention provides a polymer-bound anthracycline of formula A which consists essentially of three units represented by formulae 1, 2 and 3: ##STR2## wherein: Gly represents glycine; hydroxy groups; and
The aminoglycoside anthracycline of which [NH--D] is a residue is represented herein as [NH.sub.2 --D] wherein D denotes the structure of an anthracycline aminoglycoside minus the amino group of the sugar moiety.
The polymer-bound anthracycline preferably contains the units 1 in a range of from 90 to 98 mol %, the units of formula 2 from 1 to 10 mol % and the units of formula 3 from 1 to 10 mol %.
The enzymatic in vivo hydrolysis of the peptidyl chains gives rise to the release of only the active drug D--NH.sub.2, whilst unit 3 remains intact.
Suitable alkyl groups which R.sub.1 may represent are C.sub.1 -C.sub.4 alkyl groups substituted by one or more hydroxy groups; examples include hydroxyethyl, 2-hydroxypropyl and 3-hydroxypropyl groups.
The peptide spacer Y should be susceptible to intracellular hydrolysis. The spacer may be resistant to extracelluar hydrolysis. The peptide spacer may be from 1 to 10, for example 2 to 4, amino acid residues long. Typically the peptide spacer is a tripeptide or a tetrapeptide.
Each of the constituent amino acid residues of the peptide spacer Y which is chiral may be present as either the D or the L optical isomer, or as a D/L mixture. The conventional three letter system of denoting amino acids is employed herein, wherei

REFERENCES:
patent: 4642335 (1987-02-01), Miyashiro et al.
patent: 5162512 (1992-10-01), King et al.
patent: 5169937 (1992-12-01), Clark et al.
patent: 5387578 (1995-02-01), Angelucci et al.

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