Distamycin a derivatives as anti-malarial agents

Details Distamycin a derivatives as anti-malarial agents Distamycin a derivatives as anti-malarial agents

1996-02-16

1997-09-23

McKane, Joseph

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

548518, A61K 3140, C07D40314

Patent

active

056705344

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP94/01235 filed Apr. 21, 1994.


FIELD OF THE INVENTION

The present invention refers to pyrrol-amidinic compounds of general formula (I) ##STR1## and their pharmaceutically acceptable salts wherein: n is 0 or an integer comprised between 1 and 4; cycloalkyl, arylalkyl, aromatic residue; of: eterocycle-residue possibly substituted with a formamido- or carbamoyle-group group --(CH.sub.2).sub.2 --O--(CH.sub.2).sub.2 or a group --(CH.sub.2).sub.2 --NH--(CH.sub.2).sub.2 --; --CO--NH--Z wherein Z is chosen in the group consisting of an alkylene residue, aromatic residue; R.sub.7, ##STR2## an heterocyclic residue containing nitrogen wherein: ring, arylalkyl, steroid-residue; of: joined together form an alkylene-group, a group --(CH.sub.2).sub.2 --O--(CH.sub.2).sub.2 -- or a group --(CH.sub.2).sub.2 --NH--(CH.sub.2).sub.2 -- with the proviso that: not a simple chemical bond; is NH.sub.2, A is the group CO--NH--Z, wherein Z is --CH.sub.2 --CH.sub.2 and R.sub.1 is ##STR3## then n is different from 1; when R is the group NH.sub.2, R.sub.1 is --COOH and A is a simple chemical bond, then n is different from 0; ##STR4## and A is the group --CO--NH--Z, than Z is different from --CH.sub.2 --CH.sub.2.


STATE OF THE ART

Malaria is one of the most important diseases transmitted by arthropods largely diffused in tropical and also temperate zones either endemically or epidemically.
The world population living in malaric areas is more then 40%. The Health World Organisation calculates that there are 210-220 millions cases of infection per year, 85% of which caused by the parasite Plasmodium falciparum, with more than one million of casualties.
These records, joined with the drawback of Plasmodi falciparum strains resistent to the most common pharmaceticals in use, for example chloroquine, makes it necessary the development of new anti-malaric agents .


DETAILED DESCRIPTION OF THE INVENTION

The present invention provides new antiparasitic compounds, particularly structurally related to the antibiotic Dystamicine A (II), characterized by the presence of a carboxylic group, suitably derivatized, replacing the N-terminal chain in the naturally occurring product, and, possibly, further characterized by the introduction of chemical modifications in the C-terminal chain and by a different number of pyrrole-rings. ##STR5## These compounds present an high antiparasitic activity, particularly with respect to protozoa as for example plasmodia which are responsible of the desease, trypanosomes, which are responsible of various trypanosomiasis, and protozoa belonging to the genus Leishmania which are responsible of leishmaniasis and also with respect to Toxoplasma gondii, Pneumocystis carinii and Criptosporidum parvum, this latter being the agents of serious infections especially in immunodepressed patients as for example patients affected by AIDS.
Furthermore the compounds according to the invection present an antiviral action.
The compounds according to the invention are compounds of formula (I) as previously defined.
Among the compounds of formula (I) as above defined preferred are those wherein: alkyl, C.sub.3-7 cycloalkyl, arylC.sub.1-4 alkyl; other, are chosen in the group consisting of H, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, phenyl, arylC.sub.1-4 alkyl, heterocycle-residue containing one or more O, N, S atoms possibly substituted with a formamido or carbamoyl-group or, taken together, R.sub.3 and R.sub.4 form an C.sub.3-4 alkylene-residue, --(CH.sub.2).sub.2 --O--(CH.sub.2).sub.2 --, --(CH.sub.2).sub.2 --NH--(CH.sub.2).sub.2 --; alkylene-residue, o-phenylene, p-phenylene, m-phenylene; arylC.sub.1-4 alkyl, phenyl, steroid-residue; and R.sub.7, independently from each other, are H, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, arylC.sub.1-4 alkyl; or taken together form a C.sub.3-4 alkyl residue, --(CH.sub.2).sub.2 --O--(CH.sub.2).sub.2 --, --(CH.sub.2).sub.2 --NH--(CH.sub.2).sub.2 ; ##STR6## an heterocyclic residue containing one or more N atoms.
Among the compounds as above defined particularly prefe

REFERENCES:
Gendler et al. J. of Medicinal Chem., 24, 33-38 (1980).

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