Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1996-03-18
1998-05-19
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 19, 514422, 530330, 530331, 548518, A61K 3800, C07K 500
Patent
active
057536295
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EPA/02814 filed Jul. 18, 1995.
BACKGROUND OF THE INVENTION
The invention relates to new peptidic compounds analogous to Distamycin A, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents.
Distamycin A is an antibiotic substance with antiviral and oncolytic properties, having a polypyrrole framework (Nature 203, 1064 (1964); J. Med. Chem. 32, 774-778 (1989)).
The peptidic compounds of the invention are analogous to Distamycin A wherein the pyrrole rings are substituted partially or completely by other heteromonocyclic rings.
Analogous of Distamycin A, Netropsin or Lexitropsin wherein one or more pyrrole rings are substituted by a 1,2,4-triazole ring are reported, for example, in Chem. Res. Toxicol. 4, 241-252 (1991) and Heterocycles Vol. 31, 1629 (1990).
Distamycin derivatives wherein a pyrrole ring is substituted by a thiazole ring are reported in Anti-Cancer Drug Design 5, 3-20 (1990) and J. Org. Chem. 55, 728-737 (1990).
Distamycin derivatives wherein a pyrrole ring is substituted by an imidazole ring are reported in Anti-Cancer Drug Design 8, 173-192 (1993) and J. Am. Chem. Soc. Vol. 114, 5911-5919 (1992).
Distamycin derivatives wherein a pyrrole ring is substituted by a pyrazole ring are reported in Anti-Cancer Drug Design 6, 501-517 (1991).
SUMMARY OF THE INVENTION
The present invention relates to compounds of the following formula (I) ##STR2## wherein n is 0 or 1; C.sub.1 -C.sub.3 alkyl group; ##STR3## and either R.sub.1 and R.sub.2 are the same and they are both a C.sub.1 -C.sub.6 alkyl group unsubstituted or substituted by halogen or hydroxy; or one of R.sub.1 and R.sub.2 is hydrogen and the other is a group ##STR4## in which m is zero or an integer of 1 to 4 and R.sub.4 is aziridinyl; cyclopropyl; a vinyl group unsubstituted or substituted in position 1 or 2 by halogen or C.sub.1 -C.sub.3 alkyl; an oxyranyl group unsubstituted or substituted in position 2 by a C.sub.1 -C.sub.3 alkyl or halogen; or ##STR5## in which R.sub.5 and R.sub.6 are both a C.sub.1 -C.sub.6 alkyl group unsubstituted or substituted by a halogen or hydroxy group, each of R.sub.a and R.sub.b independently is hydrogen, C.sub.1 -C.sub.3 alkyl or C.sub.1 -C.sub.3 alkoxy, provided that: unsubstituted or substituted by a C.sub.1 -C.sub.3 alkyl group; and and they are 2-chloroethyl, then A is not 1-methylimidazole or thiazole; and the pharmaceutically acceptable salt thereof.
The invention includes also all the possible isomers covered by formula (I), both separately and in mixture.
The alkyl groups may be branched or straight chain.
A pentatomic heteromonocyclic ring is preferably a pentatomic saturated or unsaturated, most preferably unsaturated, heteromonocyclic ring containing one or two or three heteroatoms chosen from S or N.
An unsubstituted pentatomic heteromonocyclic ring is, for example, thiophene, thiazole, imidazole, pyrrole, pyrazole, 1,2,4-triazole.
A pentatomic heteromonocyclic ring substituted by C.sub.1 -C.sub.3 alkyl is, for example, 1-methylpyrazole, 1-methyl-1,2,4- triazole, 1-methylpyrrole and 1-methylimidazole.
The imidazole and pyrrole rings are preferably linked in position 2 to the ##STR6## group and in position 4 to the --NH-- group.
The thiazole rings are preferably linked in position 2 to the --N-- and in position 4 to the --CO-- group.
The pyrazole and the 1,2,4-triazole rings are preferably linked in position 3 to the --N-- group and in position 5 to the --CO-- group.
A C.sub.1 -C.sub.6 alkyl group is preferably a C.sub.1 -C.sub.3 alkyl group, for example methyl, ethyl.
A halogen atom is preferably chlorine, bromine or fluorine.
When R.sub.1 and R.sub.2 are both a C.sub.1 -C.sub.6 alkyl group they are preferably a C.sub.1 -C.sub.3 alkyl group, for example methyl and ethyl.
When R.sub.1 and R.sub.2 are both a C.sub.1 -C.sub.6 alkyl group substituted by halogen they are preferably 2-chloroethyl, 2-bromoethyl, 2-fluoroethyl.
When R.sub.1 and R.sub.2 are both a C.sub.1 -C.sub.6 alkyl group substituted b
REFERENCES:
Abstract 1971:74952 De Ratuld et al, Progr. Antimicrob. Anticancer Chemo. Proc. Int. Cong. Chemoth. 6th Mtg Date 1969 vol. 2 14-19.
WO, A, 94 25436, Nov. 10, 1994.
WO, A, 94 20463, Sep. 15, 1994.
J. Med. Chem., vol. 32, No. 4, 1989, pp. 774-778, Arcamone et al, "Synthesis, DNA-binding properties, and antitumor activity of . . . ".
Bioorg. Med. Chem., vol. 4, No. 12, 1994, pp. 1467-1472, D'Alessio et al., "Structure-activity relationship of novel distamycin A derivatives: . . . ".
Baraldi Pier Giovanni
Beria Italo
Capolongo Laura
Mongelli Nicola
Pesenti Enrico
Celsa Bennett
Pharmacia S.p.A.
Tsang Cecilia J.
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