Acryloyl derivatives analogous to distamycin, process for...

Details Acryloyl derivatives analogous to distamycin, process for... Acryloyl derivatives analogous to distamycin, process for...

2000-09-19

2004-06-22

Russel, Jeffrey E. (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S019300, C514S020800, C514S397000, C514S407000, C530S330000, C530S331000, C530S332000, C548S312400, C548S312700, C548S313100, C548S314700, C548S364100, C548S365100

Reexamination Certificate

active

06753316

ABSTRACT:

The present 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)).
Several compunds analogous to Distamycin A and derivatives thereof are known in the art.
The international patent application WO 97/43258, in the name of the applicant, discloses acryloyl distamycin derivatives wherein the amidino moiety is replaced by different nitrogen-containing ending groups such as, for instance, cyanamidino, N-methylamidino, ethylguanidino, amido, amidoximo, nitrile and the like.
Distamycin derivatives wherein at least one pyrrole ring of the aforementioned polypyrrole framework is substituted by an imidazole or pyrazole ring are also reported in the literature.
See, for a general reference, Anti-Cancer Drug Design 8, 173-192 (1993); J. Am. Chem. Soc. Vol. 114, 5911-5919 (1992); Anti-Cancer Drug Design 6, 501-517 (1991); patent applications EP-A-0246868 and WO 96/05196, both in the name of the applicant.
It has now been found that a new class of distamycin derivatives as defined hereinunder, wherein at least one ring of the polypyrrole framework is other than pyrrole, the formyl group is substituted by an acryloyl moiety and the amidino group is substituted by different nitrogen-containing ending groups, shows valuable biological properties.
Therefore, the present invention provides compounds which are acryloyl substituted distamycin derivatives of formula
wherein:
n is 2, 3 or 4;
m is 1 or 2;
X and Y are the same or different and are selected, independently for each heterocyclic ring of the polyhetherocyclic chain, from N and CH;
R
1
and R
2
, which are the same or different, are selected from hydrogen, halogen, and C
1
-C
4
alkyl;
R
3
is hydrogen or halogen;
B is selected from
wherein R
4
, R
5
, R
6
, R
7
, R
8
, R
10
, R
11
and R
12
are, independently from each other, hydrogen or C
1
-C
4
alkyl; and R
9
is hydrogen or hydroxy;
or a pharmaceutically acceptable salt thereof;
provided that
a) at least one of R
4
, R
5
and R
6
is alkyl;
b) at least one of the heterocyclic rings within the polyheterocyclic chain is other than pyrrole; and
c) X and Y are not both N for the same heterocyclic ring.
The present invention includes within its scope also all the possible isomers covered by the compounds of 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).
In the present description, unless otherwise specified, the term alkyl includes straight or branched alkyl, for instance C
1
-C
4
alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl; the term halogen includes fluorine, chlorine, bromine and iodine.
Preferably, the alkyl groups are selected from methyl and ethyl and the halogen atoms are selected from fluorine, chlorine or bromine.
Pharmaceutically acceptable salts of the compounds of formula (I) are the salts with pharmaceutically acceptable, inorganic or organic, acids. Examples of inorganic acids are hydrochloric, hydrobromic, sulphuric and nitric acid; examples of organic acids are acetic, propionic, succinic, malonic, citric, tartaric, methanesulfonic and p-toluenesulfonic acid.
As above reported, X and Y are selected, independently for each heterocyclic ring of the polyheterocyclic chain, between N and CH. This means that within the compounds of formula (I) and for different heterocyclic rings, X can be either N as well as CH; the same applies for Y provided that X and Y are not contemporaneously N for a single heterocycle.
Examples for the said heterocycles are pyrrole, pyrazole and imidazole.
A preferred class of compounds according to the present invention is represented by the compounds of formula (I) wherein R
4
, R
5
, R
6
, R
7
, R
8
, R
10
, R
11
and R
12
are, independently from each other, hydrogen, methyl, or ethyl.
Even more preferred are the compounds of formula (I) wherein
n is 3 or 4;
m is 1;
R
1
and R
2
are hydrogen;
R
3
is chlorine or bromine;
B is selected from
wherein R
4
, R
5
, R
6
, R
7
, R
8
, R
10
, R
11
and R
12
are, independently from each other, hydrogen or methyl; R
9
is hydrogen.
Another class of preferred compounds of formula (I) are those wherein the acrylamido moiety is directly linked to a pyrazole or imidazole ring.
Examples of specific compounds according to the present invention, especially in the form of salts, preferably with hydrochloric acid, are the following:
(1) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-3-(&agr;-bromoacrylamido)pyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propioncyanamidine;
(2) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-3-(&agr;-bromoacrylamido)pyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N-methylamidine;
(3) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-3-(&agr;-chloroacrylamido)pyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N-methylamidine;
(4) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-3-(&agr;-bromoacrylamido)pyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N′-dimethylamidine;
(5) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-3-(&agr;-chloroacrylamido)pyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N′-dimethylamidine;
(6) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-3-(&agr;-bromoacrylamido)pyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N,N′-trimethylamidine;
(7) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-3-(&agr;-bromoacrylamido)pyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamide;
(8) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-3-(&agr;-bromoacrylamido)pyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N-methylamide;
(9) 2-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-3-(&agr;-bromoacrylamido)pyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)ethylguanidine;
(10) 2-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-3-(&agr;-chloroacrylamido)pyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)ethylguanidine;
(11) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-3-(&agr;-bromoacrylamido)pyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propyl-N,N-dimethylamine;
(12) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-3-(&agr;-bromoacrylamido)pyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamidoxime;
(13) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-3-(&agr;-chloroacrylamido)pyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamidoxime;
(14) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-3-(&agr;-bromoacrylamido)pyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-O-methylamidoxime;
(15) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-3-(&agr;-chloroacrylamido)pyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-O-methylamidoxime;
(16) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-3-(&agr;-bromoacrylamido)pyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionitrile;
(17) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-3-(&agr;-chloroacrylamido)pyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionitrile;
(18) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-bromoacrylamido)imidazole-2-carboxamido)pyrrole-2-carboxa

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