Benzoheterocyclic distamycin derivatives, process for preparing

Details Benzoheterocyclic distamycin derivatives, process for preparing Benzoheterocyclic distamycin derivatives, process for preparing

1999-05-04

2000-11-28

Stockton, Laura L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

548178, 5483061, 548523, 548467, 514367, 514394, 514422, A61K 3141, A61K 314184, C07D40314, C07D40714, C07D40914

Patent

active

061536423

DESCRIPTION:

BRIEF SUMMARY
The present invention refers to new alkylating antitumor and antiviral agents related to the known antibiotic distamycin A: ##STR2## 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.
It has now been found that a new class of distamycin derivatives as defined hereinunder, wherein the distamycin formyl group is substituted by a benzoheterocyclic ring bearing an alkylating group, 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.
Therefore, object of the present invention are distamycin derivatives of formula: ##STR3## wherein: n is 2, 3 or 4; ##STR4## wherein: p is zero or 1; R.sub.2 and R.sub.3 are selected, each independently, from: hydrogen, C.sub.1 -C.sub.4 alkyl optionally substituted by one or more fluorine atoms, and C.sub.1 -C.sub.4 alkoxy; R.sub.4 is C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.3 haloalkyl; X.sub.1 is a halogen atom; and ##STR5## wherein X.sub.2 is a halogen atom; or pharmaceutically acceptable salts thereof.
The present invention includes within its scope also all the possible isomers covered by formula (I) both separately and in admixture, 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, ethyl or propyl, a C.sub.1 -C.sub.4 alkoxy group is preferably methoxy or ethoxy, while a C.sub.1 -C.sub.3 haloalkyl group is preferably 2-chloroethyl or 2-bromoethyl. 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. The halogen atoms X.sub.1 and X.sub.2 are preferably chlorine or bromine. Particularly preferred values of n are 2 and 3.
When T is an alkylating moiety of formula (II) according to item (i) above with p equal to 1, the carboxamido group and the amino group on the phenyl ring are preferably in meta or para position with respect to each other, while R.sub.2 and R.sub.3 can be in any of the free positions.
Pharmaceutically acceptable salts of the compounds of formula (I) are their salts with pharmaceutically acceptable, either inorganic or organic, acids. Examples of inorganic acids are hydrochloric, hydrobromic, sulfuric and nitric acid; examples of organic acids are acetic, propionic, succinic, malonic, citric, tartaric, methanesulfonic and p-toluenesulfonic acid.
A preferred class of distamycin derivatives according to the present invention is the one of formula (I) wherein: 2-bromoethyl; R.sub.2 and R.sub.3 are, each independently, hydrogen or methyl; p is zero or 1; or bromine or chlorine.
Examples of specific compounds according to the present invention, especially in the form of salts, preferably with hydrochloric acid, are the following: 3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminoindole-2- carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxami do]propionamidine; 3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-N,N-bis(2-chloroethyl)amino indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2- carboxamido]propionamidine; 3-[1-met

REFERENCES:
Arcamone F.M. et al.: "Synthesis, DNA-Binding Properties, and Antitumor Activity of Novel Distamycin Derivatives", Journal of Medicinal Chemistry, vol. 32, No. 4, (1989), pp. 774-778.
D'Alessio R., et al.: "Structure-activity relationship of novel distamycin A derivatives: Synthesis and antitumor activity", Bioorganic & Medicinal Chemistry Letters, vol. 4, No. 12, (Dec. 1994), pp. 1467-1472.

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