Benzoheterocyclic distamycin derivatives, process for...

Details Benzoheterocyclic distamycin derivatives, process for... Benzoheterocyclic distamycin derivatives, process for...

2000-09-19

2002-10-01

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S014800, C514S019300, C514S408000, C514S422000

Reexamination Certificate

active

06458768

ABSTRACT:

The present invention relates to new alkylating antitumor agents analogous to Distamycin A, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents. Distamycin A, whose formula is reported below,
belongs to the family of the pyrroleamidine antibiotics and it is reported to interact reversibly and selectively with DNA-AT sequences, thus interfering with both replication and transcription. See, for a reference, Nature, 203, 1064 (1964); FEBS Letters, 7 (1970) 90; Prog. Nucleic Acids Res. Mol. Biol., 15, 285 (1975).
Several analogous to distamycin are known in the art. The international patent application WO 97/28123, in the name of the applicant, describes distamycin derivatives in which the distamycin formyl group is substituted by aromatic moieties bearing alkylating groups and the amidino moiety is replaced with other basic and non-basic nitrogen containing ending groups.
It has now been found that a new class of distamycin derivatives as defined hereinunder, wherein the distamycin formyl group is substituted by benzoheterocyclic rings bearing alkylating groups and the amidino moiety is substituted by different nitrogen-containing ending-groups, shows valuable biological properties.
Therefore, the present invention provides compounds which are distamycin derivatives of formula:
wherein:
n is 2, 3 or 4;
A is a heteroatom selected from O and S or is a group NR, wherein R is hydrogen or C
1
-C
4
alkyl;
B is CH or N;
R
1
is hydrogen or C
1
-C
4
alkyl;
G is selected from the group consisting of:
and —C≡N
wherein R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
and R
12
are, independently from each other, hydrogen or C
1
-C
4
alkyl; T is a group of formula (II) or (III) as defined below
wherein p is 0 or 1; R and R
3
are, independently from each other, hydrogen, C
1
-C
4
alkyl optionally substituted by one or more fluorine atoms, or C
1
-C
4
alkoxy; R
4
is C
1
-C
4
alkyl or C
1
-C
3
haloalkyl; X
1
and X
2
are halogen atoms;
or a pharmaceutically acceptable salt thereof;
provided that at least one of R
5
, R
6
and R
7
is alkyl.
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 C
1
-C
4
alkoxy includes straight or branched C
1
-C
4
alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.
Preferred C
1
-C
4
alkyl or alkoxy groups are methyl, ethyl, propyl, methoxy and ethoxy groups.
The term C
1
-C
3
haloalkyl embraces straight or branched C
1
-C
3
alkyl substituted by one or more halogen atoms; the term halogen atom includes fluorine, chlorine, bromine and iodine.
Preferred halogen atoms are chlorine or bromine whilst preferred C
1
-C
3
haloalkyl groups are 2-chloroethyl or 2-bromoethyl. When substituted by fluorine atoms, the C
1
-C
4
alkyl groups are preferably C
1
-C
4
perfluoroalkyl groups, i.e. trifluoromethyl.
Within the compounds of formula (I) wherein T is a group of formula (II) as defined above and p is 1, the carboxamido and amino groups onto phenyl ring are in ortho, meta or para position with respect to each other; preferably the carboxamido and the amino groups are in meta or para position.
Pharmaceutically acceptable salts of the compounds of formula (I) are their salts with pharmaceutically acceptable either inorganic or organic acids such as, for instance, hydrochloric, hydrobromic, sulfuric, nitric, acetic, propionic, succinic, malonic, citric, tartaric, methanesulfonic and p-toluenesulfonic acid.
A preferred class of compounds of the present invention is that wherein, in formula (I):
n is 2 or 3;
A is O, S, NH or NCH
3
;
R
1
is hydrogen;
G is selected from:
 wherein R
5
, R
6
, and R
7
are, independently from each other, hydrogen or methyl; R
8
, R
9
and R
12
are hydrogen; T is a group of formula (II) as above wherein p is 0, X
1
is a chlorine atom and R
4
is 2-chloroethyl or T is a group of formula (III) as above wherein X
2
is chlorine or bromine. 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[5(&agr;-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propioncyanamidine;
2) 3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(&agr;-bromoacrylamido)indazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propioncyanamidine;
3) 3-[1-methyl-4[1-methyl-4[1-methyl-4[5(&agr;-bromoacrylamido)indole-2-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-5(&agr;-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine;
5) 3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(&agr;-chloroacrylamido)indole-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[5(&agr;-bromoacrylamido)benzofurane-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[5(&agr;-bromoacrylamido)benzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine;
8) 3-[1-methyl-4[1-methyl-4[1-methyl-4[5(&agr;-bromoacrylamido)indole-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[5(&agr;-chloroacrylamido)indole-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[1-methyl-5(&agr;-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine;
11) 3-[1-methyl-4[1-methyl-4[1-methyl-4[5(&agr;-bromoacrylamido)benzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine;
12) 3-[1-methyl-4[1-methyl-4[1-methyl-4[5(&agr;-bromoacrylamido)benzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine;
13) 3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(&agr;-bromoacrylamido)indazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine;
14) 3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(&agr;-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoxime;
15) 3-[1-methyl-4[1-methyl-4[1-methyl-4[5(&agr;-bromoacrylamido)indazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoxime;
16) 3-[1-methyl-4[1-methyl-4[1-methyl-4[5(&agr;-chloroacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-ca

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