Distamycin derivatives, process for preparing them, and their us

Details Distamycin derivatives, process for preparing them, and their us Distamycin derivatives, process for preparing them, and their us

1998-07-17

2000-12-26

Moezie, E. T.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 18, 514422, 514256, 514396, 514397, 548518, 5483147, 544333, A61K 3800

Patent

active

061659800

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention refers to new alkylating antitumor and antiviral agents related to the known antibiotic distamycin A: ##STR3## which belongs to the family of the pyrroleamidine antibiotics and is reported to interact reversibly and selectively with DNA-AT sequences interfering with both replication and transcription [Nature, 203, 1064 (1964); FEBS Letters, 7 (1970) 90; Prog.Nucleic Acids Res.Mol.Biol., 15, 285 (1975)].
DE-A-1795539 describes the preparation of distamycin derivatives in which the formyl group of distamycin is replaced by hydrogen or by the acid residue of an organic C.sub.1 -C.sub.4 aliphatic acid or of cyclopentylpropionic acid. EP-B-246,868 describes distamycin analogues in which the distamycin formyl group is substituted by aromatic, alicyclic or heterocyclic moieties bearing alkylating groups.
As alkylating groups, N,N-dihaloethylamino moieties, derived from bifunctional nitrogen mustards, have resulted to be particularly effective. Conversely, it is well known in the literature that mono-functional nitrogen mustards per se (the so-called half mustards) do not show antitumor activity (see e.g. T. J. Bardos, J.Med.Chem. 8, 167 (1965) and references cited therein).


BRIEF SUMMARY OF THE INVENTION

It has now been found that a new class of distamycin derivatives as defined hereinunder, wherein the distamycin formyl group is substituted by a benzoyl moiety bearing as alkylating group a bis-halo-ethylamino moiety (mustard moiety) or a N-alkyl-N-haloethyl-amino group (half mustard moiety), while the amidine group is substituted by various nitrogen-containing end-groups, shows valuable biological properties.
Accordingly, the present invention relates to new distamycin derivatives of formula (I) as defined hereinunder, to a process for preparing them, to pharmaceutical compositions containing them and to their use in therapy, particularly as antitumor and antiviral agents.
The present invention provides a distamycin derivative of formula (I): ##STR4## wherein: n is 2, 3 or 4; X.sub.2 is a halogen atom; C.sub.1 -C.sub.4 alkyl optionally substituted by one or more fluorine atoms, C.sub.1 -C.sub.4 alkoxy, and halogen; ##STR5## wherein R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are, each independently, hydrogen or C.sub.1 -C.sub.4 alkyl, and m is 0, 1 or 2; with the proviso that, when R.sub.0 is --CH.sub.2 CH.sub.2 --X.sub.2, B is different from --(CH.sub.2).sub.m --NR.sub.6 R.sub.7 and at least one of R.sub.3, R.sub.4, and R.sub.5 is C.sub.1 -C.sub.4 alkyl;


DETAILED DESCRIPTION OF THE INVENTION

The present invention includes within its scope also all the possible isomers covered by formula (I) both separately and in mixture, as well as the metabolites and the pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I).
The alkyl and alkoxy groups may have branched or straight chains. A C.sub.1 -C.sub.4 alkyl group is preferably methyl or ethyl, a C.sub.1 -C.sub.4 alkoxy group is preferably methoxy or ethoxy. When substituted by one or more fluorine atoms, a C.sub.1 -C.sub.4 alkyl group is preferably a C.sub.1 -C.sub.4 perfluoroalkyl group, e.g. --CF.sub.3. Halogen is preferably fluorine, chlorine or bromine.
In the phenyl ring, the carboxamide moiety and the half-mustard or the mustard moiety are preferably in meta or para position with respect to each other.
As to the R.sub.1 and R.sub.2 groups, they can be in any of the free positions of the phenyl ring. In a first preferred embodiment R.sub.1 is hydrogen, and R.sub.2 is hydrogen, C.sub.1 -C.sub.4 alkyl optionally substituted by one or more fluorine atoms, C.sub.1 -C.sub.4 alkoxy, or halogen, preferably fluorine; in a second preferred embodiment both R.sub.1 and R.sub.2 are, each independently, C.sub.1 -C.sub.4 alkyl optionally substituted by one or more fluorine atoms, C.sub.1 -C.sub.4 alkoxy, or halogen, preferably fluorine. A particularly preferred value of n is 3; X.sub.1 and X.sub.2 are preferably the same halogen atom, particularly chloro

REFERENCES:
D'Alessio et al., "Structure-Activity Relationship of Novel Distamycin a Derivatives: Synthesis and Antitumor Activity" Bioorg. Med. Chem. Lett., vol. 4, No. 12, 1994, 1467-1472.
Wyatt et al., "Structure-activity Relationship of a Series of Nitrogen Mustard- and Pyrrole-Containing Minor Groove-Binding Agents Related to Distamycin" Anti-Cancer Drug Design 9:511-525, 1994.

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