Distamycin derivatives, process for preparing them, and...

Details Distamycin derivatives, process for preparing them, and... Distamycin derivatives, process for preparing them, and...

1998-11-13

2001-01-23

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S018700, C514S019300, C514S422000, C514S423000, C514S426000, C530S331000, C530S333000, C548S400000, C548S518000, C548S530000, C548S557000

Reexamination Certificate

active

06177408

ABSTRACT:

The present invention refers to new alkylating antitumor and antiviral agents related to the known antibiotic distamycin A:
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
1
-C
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 an optionally alkyl and/or alkoxy substituted cinnamoyl moiety bearing as alkylating group a N-(halo)alkyl-N-haloethyl-amino 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 compounds of formula:
wherein:
n is 2, 3 or 4;
R
0
is C
1
-C
4
alkyl or C
1
-C
3
haloalkyl;
R
1
and R
2
are selected, each independently, from: hydrogen, C
1
-C
4
alkyl optionally substituted by one or more fluorine atoms, and C
1
-C
4
alkoxy;
X is a halogen atom;
B is selected from:
wherein R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, and R
9
are, each independently, hydrogen or C
1
-C
4
alkyl, and m is 0, 1 or 2; 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 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
1
-C
4
alkyl group is preferably methyl or ethyl, a C
1
-C
4
alkoxy group is preferably methoxy or ethoxy, while a C
1
-C
3
haloalkyl group is preferably 2-chloroethyl. When substituted by one or more fluorine atoms, a C
1
-C
4
alkyl group is preferably a C
1
-C
4
perfluoroalkyl group, e.g. —CF
3
.
In the phenyl ring the cinnamoyl moiety and the N(halo)alkyl-N-haloethyl-amino group are preferably in meta or para position with respect to each other.
As to the R
1
and R
2
groups, they can be in any of the free positions of the phenyl ring. In a first preferred embodiment R
1
is hydrogen, and R
2
is hydrogen, C
1
-C
4
alkyl optionally substituted by one or more fluorine atoms, or C
1
-C
4
alkoxy; in a second preferred embodiment both R
1
and R
2
are, each independently, C
1
-C
4
alkyl optionally substituted by one or more fluorine atoms, or C
1
-C
4
alkoxy. A particularly preferred value of n is 3; X is preferably chloro or bromo. Preferably, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, and R
9
are, each independently, hydrogen, methyl, or ethyl, while R
0
is preferably methyl, ethyl, propyl, 2-chloroethyl or 2-bromoethyl.
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 compounds according to the present invention is that of formula (I) wherein:
n is 3;
X is chloro or bromo;
R
0
is ethyl, propyl, 2-chloroethyl when X is chloro, or 2-bromoethyl when X is bromo;
R
1
and R
2
are, each independently, hydrogen, —CH
3
, —OCH
3
, or —CF
3
;
B is selected from:
wherein R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, and R
9
are, each independently, hydrogen or methyl, and m is 0 or 1; or the pharmaceutically acceptable salts thereof.
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[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
2) 3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methyl-amidine;
3) 3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-bromoethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
4) 3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethyl-amidine;
5) 3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminocynnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoxime;
6) 3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propioncyanamidine;
7) 3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionitrile;
8) 3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamide;
9) 3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]N,N-dimethylpropylamine;
10) 2-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidine;
11) 3-[1-methyl-4[1-methyl-4[1-methyl-4[3-methyl-4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
12) 3-[1-methyl-4[1-methyl-4[1-methyl-4[3,5-dimethyl-4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
13) 3-[1-methyl-4[1-methyl-4[1-methyl-4[3-methoxy-4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine;
14) 3-[1-methyl-4[1-methyl-4[1-methyl-4[3-methyl-4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methyl-amidine;
15) 2-[1-methyl-4[1-methyl-4[1-methyl-4[3-methyl-4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidine;
16) 2-[1-methyl-4[1-methyl-4[1-methyl-4[3,5-dimethyl-4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidine;
17) 2-[1-methyl-4[1-methyl-4[1-methyl-4[3-methoxy-4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidine;
18) 3-[1-methyl-4[1-methyl-4[1-methyl-4[3,5-dimethyl-4-N,N-bis(2-chloroethyl)am

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