Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.
Reexamination Certificate
1999-01-22
2002-11-19
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Tripeptides, e.g., tripeptide thyroliberin , etc.
C530S330000, C514S018700, C514S019300, C548S400000
Reexamination Certificate
active
06482920
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.
International patent application WO 90/11277 discloses a broad class of acryloyl substituted distamycin derivatives wherein the acryloyl moiety is linked to the pyrrole ring through a single bond or an aromatic or heterocyclic dicarboxamide group.
It has now been found that a new class of distamycin derivatives as defined hereinunder, wherein the distamycin formyl group is substituted by an acryloyl moiety while the amidine group is substituted by different nitrogen-containing end-groups, 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 acryloyl substituted distamycin derivatives of formula:
wherein:
n is 2, 3 or 4;
R
1
and R
2
are selected, each independently, from: hydrogen, halogen, and C
4
-C
4
alkyl;
R
3
is hydrogen or halogen;
B is selected from:
wherein R
4
, R
5
, R
6
, R
7
, and R
8
are, each independently, hydrogen or C
1
-C
4
alkyl, with the proviso that at least one of R
4
, R
5
and R
6
is C
1
-C
4
alkyl;
or pharmaceutically acceptable salts thereof.
The present invention includes within its scope also all the possible isomers covered by formula (I) both separately and as a 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 groups may have branched or straight chains. A C
1
-C
4
alkyl group is preferably methyl or ethyl. A halogen atom is preferably chlorine, bromine or fluorine. Preferably, R
4
, R5, R
6
, R
7
, and R
8
are, each independently, hydrogen, methyl, or ethyl, with the proviso that at least one of R
4
, R
5
and R
6
is methyl or ethyl.
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 or 4;
R
1
and R
2
are hydrogen;
R
3
is chlorine or bromine;
B is selected from:
wherein R
4
, R
5
, R6, R
7
, and R
8
are, each independently, hydrogen or methyl, with the proviso that at least one of R
4
, R
5
and R
6
is methyl;
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-(&agr;-bromo-acrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propioncyanamidine;
(2) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propioncyanamidine;
(3) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propioncyanamidine;
(4) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-bromo-acrylamido)pyrrole2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N-methylamidine;
(5) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N-methylamidine;
(6) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N-methylamidine;
(7) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-bromo-acrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N′-dimethylamidine;
(8) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N′-dimethylamidine;
(9) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N′-dimethylamidine;
(10) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-bromo-acrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamidoxime;
(11) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamidoxime;
(12) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamidoxime;
(13) 2-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-bromo-acrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)ethylguanidine;
(14) 2-(1-methyl-4-(1-methyl-4-(-methyl-4-(1-methyl-4-(&agr;-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)ethylguanidine;
(15) 2-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)ethylguanidine;
(16) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-bromo-acrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionitrile;
(17) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-bromoacrylamido)pyrrole-2-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;-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionitrile;
(19) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-bromo-acrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido) pyrrole-2-carboxamido)propionamide;
(20) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamide;
(21) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamide;
(22) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N-methylamide;
(23) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-bromoacrylamido)pyrrole-2carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N-dimethylamidine;
(24) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-bromoacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N-dimethylamidine;
(25) 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(1-methyl-4-(&agr;-chloroacrylamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propion-N,N-dimethylamidine;
(26) 3-(1-methyl-4-(1-methyl-4-(1-met
Beria Italo
Biasoli Giovanni
Caldarelli Marina
Capolongo Laura
Cozzi Paolo
Arent Fox Kintner Plotkin & Kahn
Low Christopher S. F.
Lukton David
Pharmacia Italia S.p.A.
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