Distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents

FIELD OF THE INVENTION 
The present invention refers to new alkylating antitumor and antiviral 
agents related to the known antibiotic distamycin A: 
##STR3## 
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.sub.1 -C.sub.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. 
As alkylating groups, N,N-dihaloethylamino moieties, derived from 
bifunctional nitrogen mustards, have resulted to be particularly 
effective. Conversely, it is well known in the literature that 
mono-functional nitrogen mustards per se (the so-called half mustards) do 
not show antitumor activity (see e.g. T. J. Bardos, J.Med.Chem. 8, 167 
(1965) and references cited therein). 
BRIEF SUMMARY OF THE INVENTION 
It has now been found that a new class of distamycin derivatives as defined 
hereinunder, wherein the distamycin formyl group is substituted by a 
benzoyl moiety bearing as alkylating group a bis-halo-ethylamino moiety 
(mustard moiety) or a N-alkyl-N-haloethyl-amino group (half mustard 
moiety), while the amidine group is substituted by various 
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. 
The present invention provides a distamycin derivative of formula (I): 
##STR4## 
wherein: n is 2, 3 or 4; 
R.sub.0 is C.sub.1 -C.sub.4 alkyl or --CH.sub.2 CH.sub.2 --X.sub.2, wherein 
X.sub.2 is a halogen atom; 
R.sub.1 and R.sub.2 are selected, each independently, from: hydrogen, 
C.sub.1 -C.sub.4 alkyl optionally substituted by one or more fluorine 
atoms, C.sub.1 -C.sub.4 alkoxy, and halogen; 
X.sub.1 is a halogen atom; 
B is selected from: 
##STR5## 
wherein R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, and R.sub.9 
are, each independently, hydrogen or C.sub.1 -C.sub.4 alkyl, and m is 0, 1 
or 2; with the proviso that, when R.sub.0 is --CH.sub.2 CH.sub.2 
--X.sub.2, B is different from --(CH.sub.2).sub.m --NR.sub.6 R.sub.7 and 
at least one of R.sub.3, R.sub.4, and R.sub.5 is C.sub.1 -C.sub.4 alkyl; 
or a pharmaceutically acceptable salt thereof. 
DETAILED DESCRIPTION OF THE INVENTION 
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.sub.1 
-C.sub.4 alkyl group is preferably methyl or ethyl, a C.sub.1 -C.sub.4 
alkoxy group is preferably methoxy or ethoxy. When substituted by one or 
more fluorine atoms, a C.sub.1 -C.sub.4 alkyl group is preferably a 
C.sub.1 -C.sub.4 perfluoroalkyl group, e.g. --CF.sub.3. Halogen is 
preferably fluorine, chlorine or bromine. 
In the phenyl ring, the carboxamide moiety and the half-mustard or the 
mustard moiety are preferably in meta or para position with respect to 
each other. 
As to the R.sub.1 and R.sub.2 groups, they can be in any of the free 
positions of the phenyl ring. In a first preferred embodiment R.sub.1 is 
hydrogen, and R.sub.2 is hydrogen, C.sub.1 -C.sub.4 alkyl optionally 
substituted by one or more fluorine atoms, C.sub.1 -C.sub.4 alkoxy, or 
halogen, preferably fluorine; in a second preferred embodiment both 
R.sub.1 and R.sub.2 are, each independently, C.sub.1 -C.sub.4 alkyl 
optionally substituted by one or more fluorine atoms, C.sub.1 -C.sub.4 
alkoxy, or halogen, preferably fluorine. A particularly preferred value of 
n is 3; X.sub.1 and X.sub.2 are preferably the same halogen atom, 
particularly chloro or bromo. 
Preferably, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, and 
R.sub.9 are, each independently, hydrogen, methyl, or ethyl, while R.sub.0 
is preferably methyl, ethyl, n-propyl, i-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.sub.1 is chloro or bromo; 
R.sub.0 is methyl, ethyl, n-propyl or i-propyl; 
R.sub.1 and R.sub.2 are, each independently, hydrogen, --CH.sub.3, 
--OCH.sub.3, or --CF.sub.3 ; 
B is selected from: 
##STR6## 
wherein R.sub.3, R.sub.4, R.sub.5, R.sub.8 and R.sub.9 are, each 
independently, hydrogen or methyl; or the pharmaceutically acceptable 
salts thereof. 
Another preferred class of compounds according to the present invention is 
that of formula (I) wherein: 
n is 3; 
R.sub.0 is --CH.sub.2 CH.sub.2 --X.sub.2 ; 
X.sub.1 and X.sub.2 are chloro or bromo; 
R.sub.1 and R.sub.2 are, each independently, hydrogen, --CH.sub.3, or 
--OCH.sub.3 ; 
B is selected from: 
##STR7## 
wherein R.sub.3, R.sub.4, R.sub.5, R.sub.8 and R.sub.9 are, each 
independently, hydrogen or methyl, with the proviso that at least one of 
R.sub.3, R.sub.4, and R.sub.5 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 or 
hydrobromic acid, are the following: 
1) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-methyl-N-(2-chloroethyl)aminobe 
nzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-c 
arboxamido]propionamidine; 
2) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-ethyl-N-(2-chloroethyl)aminoben 
zene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-ca 
rboxamido]propionamidine; 
3) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-propyl-N-(2-chloroethyl)aminobe 
nzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-c 
arboxamido]propionamidine; 
4) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N-ethyl-N-(2-chloroethyl 
)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyr 
role-2-carboxamido]propionamidine; 
5) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimethyl-4-N-ethyl-N-(2-chloroe 
thyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido 
]pyrrole-2-carboxamido]propionamidine; 
6) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methoxy-4-N-ethyl-N-(2-chloroethy 
l)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]py 
rrole-2-carboxamido]propionamidine; 
7) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N-ethyl-N-(2-chloroethyl 
)amino-5-methoxybenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carbo 
xamido]pyrrole-2-carboxamido]propionamidine; 
8) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-4-N-ethyl-N-(2-ch 
loroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carbox 
amido]pyrrole-2-carboxamido]propionamidine; 
9) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N-ethyl-N-(2-chloroethyl 
)amino-5-trifluoromethylbenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole 
-2-carboxamido]pyrrole-2-carboxamido]propionamidine; 
10) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-ethyl-N-(2-bromoethyl)aminobenz 
ene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-car 
boxamido]propionamidine; 
11) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N-ethyl-N-(2-bromoethyl) 
aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrr 
ole-2-carboxamido]propionamidine; 
12) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-ethyl-N-(2-chloroethyl)aminoben 
zene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-ca 
rboxamido]propion-N-methyl-amidine; 
13) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-propyl-N-(2-chloroethyl)aminobe 
nzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-c 
arboxamido]propion-N-methyl-amidine; 
14) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N-ethyl-N-(2-chloroethyl 
)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyr 
role-2-carboxamido]propion-N-methyl-amidine; 
15) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimetyl-4-N-ethyl-N-(2-chloroet 
hyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido] 
pyrrole-2-carboxamido]propion-N-methyl-amidine; 
16) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methoxy-4-N-ethyl-N-(2-chloroethy 
l)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]py 
rrole-2-carboxamido]propion-N-methyl-amidine; 
17) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-4-N-ethyl-N-(2-ch 
loroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carbox 
amido]pyrrole-2-carboxamido]propyl-N-methyl-amidine; 
18) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-ethyl-N-(2-bromoethyl)aminobenz 
ene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-car 
boxamido]propion-N-methyl-amidine; 
19) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N-ethyl-N-(2-bromoethyl) 
aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrr 
ole-2-carboxamido]propion-N-methyl-amidine; 
20) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-ethyl-N-(2-chloroethyl)aminoben 
zene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-ca 
rboxamido]propion-N,N'-dimethyl-amidine; 
21) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-propyl-N-(2-chloroethyl)aminobe 
nzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-c 
arboxamido]propion-N,N'-dimethyl-amidine; 
22) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N-ethyl-N-(2-chloroethyl 
)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyr 
role-2-carboxamido]propion-N,N'-dimethyl-amidine; 
23) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimetyl-4-N-ethyl-N-(2-chloroet 
hyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido] 
pyrrole-2-carboxamido]propion-N,N'-dimethyl-amidine; 
24) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methoxy-4-N-ethyl-N-(2-chloroethy 
l)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]py 
rrole-2-carboxamido]propion-N,N'-dimethyl-amidine; 
25) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-4-N-ethyl-N-(2-ch 
loroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carbox 
amido]pyrrole-2-carboxamido]propion-N,N'-dimethyl-amidine; 
26) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-ethyl-N-(2-bromoethyl)aminobenz 
ene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-car 
boxamido]propion-N,N'-dimethyl-amidine; 
27) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N-ethyl-N-(2-bromoethyl) 
aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrr 
ole-2-carboxamido]propion-N,N'-dimethyl-amidine; 
28) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-ethyl-N-(2-chloroethyl)aminoben 
zene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-ca 
rboxamido]propionamidoxime; 
29) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-propyl-N-(2-chloroethyl)aminobe 
nzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-c 
arboxamido]propionamidoxime; 
30) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N-ethyl-N-(2-chloroethyl 
)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyr 
role-2-carboxamido]propionamidoxime; 
31) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimetyl-4-N-ethyl-N-(2-chloroet 
hyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido] 
pyrrole-2-carboxamido]propionamidoxime; 
32) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methoxy-4-N-ethyl-N-(2-chloroethy 
l)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]py 
rrole-2-carboxamido]propionamidoxime; 
33) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-4-N-ethyl-N-(2-ch 
loroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carbox 
amido]pyrrole-2-carboxamido]propionamidoxime; 
34) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-ethyl-N-(2-bromoethyl)aminobenz 
ene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-car 
boxamido]propionamidoxime; 
35) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N-ethyl-N-(2-bromoethyl) 
aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrr 
ole-2-carboxamido]propionamidoxime; 
36) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-ethyl-N-(2-chloroethyl)aminoben 
zene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-ca 
rboxamido]propioncyanamidine; 
37) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-propyl-N-(2-chloroethyl)aminobe 
nzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-c 
arboxamido]propioncyanamidine; 
38) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N-ethyl-N-(2-chloroethyl 
)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyr 
role-2-carboxamido]propioncyanamidine; 
39) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimetyl-4-N-ethyl-N-(2-chloroet 
hyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido] 
pyrrole-2-carboxamido]propioncyanamidine; 
40) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methoxy-4-N-ethyl-N-(2-chloroethy 
l)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]py 
rrole-2-carboxamido]propioncyanamidine; 
41) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-4-N-ethyl-N-(2-ch 
loroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carbox 
amido]pyrrole-2-carboxamido]propioncyanamidine; 
42) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-ethyl-N-(2-bromoethyl)aminobenz 
ene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-car 
boxamido]propioncyanamidine; 
43) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N-ethyl-N-(2-bromoethyl) 
aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrr 
ole-2-carboxamido]propioncyanamidine; 
44) 
2-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-ethyl-N-(2-chloroethyl)aminoben 
zene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-ca 
rboxamido]ethylguanidine; 
45) 
2-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-propyl-N-(2-chloroethyl)aminobe 
nzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-c 
arboxamido]ethylguanidine; 
46) 
2-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N-ethyl-N-(2-chloroethyl 
)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyr 
role-2-carboxamido]ethylguanidine; 
47) 
2-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimetyl-4-N-ethyl-N-(2-chloroet 
hyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido] 
pyrrole-2-carboxamido]ethylguanidine; 
48) 
2-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methoxy-4-N-ethyl-N-(2-chloroethy 
l)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]py 
rrole-2-carboxamido]ethylguanidine; 
49) 
2-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-4-N-ethyl-N-(2-ch 
loroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carbox 
amido]pyrrole-2-carboxamido]ethylguanidine; 
50) 
2-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-ethyl-N-(2-bromoethyl)aminobenz 
ene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-car 
boxamido]ethylguanidine; 
51) 
2-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N-ethyl-N-(2-bromoethyl) 
aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrr 
ole-2-carboxamido]ethylguanidine; 
52) 
2-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N,N-bis(2-chloroethyl)aminobenzen 
e-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carbo 
xamido]ethyl-1-(2-imidazoline); 
53) 
2-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N,N-bis(2-chloroethyl)am 
inobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrol 
e-2-carboxamido]ethyl-1-(2-imidazoline); 
54) 
2-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N,N-bis(2-chloroethyl)aminobenzen 
e-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carbo 
xamido]ethyl-1-[2-(3,4,5,6-tetrahydropirimidine)]; 
55) 
2-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N,N-bis(2-chloroethyl)am 
inobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrol 
e-2-carboxamido]ethyl-1-[2-(3,4,5,6-tetrahydropirimidine)]; 
56) 
2-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminobenzene-1 
-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxam 
ido]ethyl-1-(2-imidazole); 
57) 
2-[1-methyl-4[1-methyl-4[1-methyl-4[3-methyl-4-N,N-bis(2-chloroethyl)amino 
benzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2 
-carboxamido]ethyl-1-(2-imidazole); 
58) 
2-[1-methyl-4[1-methyl-4[1-methyl-4[3,5-dimethyl-4-N,N-bis(2-chloroethyl)a 
minobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrro 
le-2-carboxamido]ethyl-1-(2-imidazole); 
59) 
2-[1-methyl-4[1-methyl-4[1-methyl-4[3-methoxy-4-N,N-bis(2-chloroethyl)amin 
obenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole- 
2-carboxamido]ethyl-1-(2-imidazole); 
60) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminobenzene-1 
-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxam 
ido]propion-N-methyl-amidine; 
61) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[3-methyl-4-N,N-bis(2-chloroethyl)amino 
benzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2 
-carboxamido]propion-N-methyl-amidine; 
62) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminobenzene-1 
-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxam 
ido]propion-N,N'-dimethyl-amidine; 
63) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[3-methyl-4-N,N-bis(2-chloroethyl)amino 
benzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2 
-carboxamido]propion-N,N'-dimethyl-amidine; 
64) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminobenzene-1 
-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxam 
ido]propionamidoxime; 
65) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[3-methyl-4-N,N-bis(2-chloroethyl)amino 
benzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2 
-carboxamido]propionamidoxime; 
66) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminobenzene-1 
-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxam 
ido]propioncyanamidine; 
67) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[3-methyl-4-N,N-bis(2-chloroethyl)amino 
benzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2 
-carboxamido]propioncyanamidine; 
68) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[3,5-dimethyl-4-N,N-bis(2-chloroethyl)a 
minobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrro 
le-2-carboxamido]propioncyanamidine; 
69) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[3-methoxy-4-N,N-bis(2-chloroethyl)amin 
obenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole- 
2-carboxamido]propioncyanamidine; 
70) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminobenzene-1 
-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxam 
ido]propionamidrazone; 
71) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[3-methyl-4-N,N-bis(2-chloroethyl)amino 
benzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2 
-carboxamido]propionamidrazone; 
72) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminobenzene-1 
-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxam 
ido]propionitrile; 
73) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[3-methyl-4-N,N-bis(2-chloroethyl)amino 
benzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2 
-carboxamido]propionitrile; 
74) 
2-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminobenzene-1 
-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxam 
ido]ethylguanidine; 
75) 
2-[1-methyl-4[1-methyl-4[1-methyl-4[3-methyl-4-N,N-bis(2-chloroethyl)amino 
benzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2 
-carboxamido]ethylguanidine; 
76) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-ethyl-N-(2-chloroethyl)aminoben 
zene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-ca 
rboxamido]propionamide; 
77) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-propyl-N-(2-chloroethyl)aminobe 
nzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-c 
arboxamido]propionamide; 
78) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N-ethyl-N-(2-chloroethyl 
)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyr 
role-2-carboxamido]propionamide; 
79) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimetyl-4-N-ethyl-N-(2-chloroet 
hyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido] 
pyrrole-2-carboxamido]propionamide; 
80) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methoxy-4-N-ethyl-N-(2-chloroethy 
l)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]py 
rrole-2-carboxamido]propionamide; 
81) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-4-N-ethyl-N-(2-ch 
loroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carbox 
amido]pyrrole-2-carboxamido]propionamide; 
82) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-ethyl-N-(2-bromoethyl)aminobenz 
ene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-car 
boxamido]propionamide; 
83) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N-ethyl-N-(2-bromoethyl) 
aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrr 
ole-2-carboxamido]propionamide; 
84) 
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N-ethyl-N-(2-chloroethyl)aminoben 
zene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-ca 
rboxamido]propion-N-methyl-amide; 
85) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminobenzene-1 
-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxam 
ido]propionamide; 
86) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[3-methyl-4-N,N-bis(2-chloroethyl)amino 
benzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2 
-carboxamido]propionamide; 
87) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminobenzene-1 
-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxam 
ido]propion-N-methyl-amide; 
88) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-bromoethyl)aminobenzene-1- 
carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxami 
do]propionamidoxime; 
89) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-bromoethyl)aminobenzene-1- 
carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxami 
do]propion-N,N'-dimethyl-amidine; 
90) 
3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-bromoethyl)aminobenzene-1- 
carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxami 
do]propionitrile. 
The present invention also provides a process for the preparation of 
compounds of formula (I), and the salts thereof, which comprises: 
(A) (a) reacting a compound of formula (II): 
##STR8## 
wherein n is 2, 3 or 4, with a compound of formula (III): 
##STR9## 
wherein: R.sub.0 is C.sub.1 -C.sub.4 alkyl or --CH.sub.2 CH.sub.2 
--X.sub.2, wherein X.sub.2 is a halogen atom; 
R.sub.1 and R.sub.2 are selected, each independently, from: hydrogen, 
C.sub.1 -C.sub.4 alkyl optionally substituted by one or more fluorine 
atoms, C.sub.1 -C.sub.4 alkoxy, and halogen; 
X.sub.1 is a halogen atom; and 
Y is hydroxy or a leaving group; 
to obtain a compound of formula (IV): 
##STR10## 
and reacting the compound of formula (IV) with: (i) H.sub.2 
N--(CH.sub.2).sub.p --NH.sub.2, where p is 2 or 3, to obtain a compound of 
formula (I) wherein B is: 
##STR11## 
(ii) H.sub.2 N--CH.sub.2 --CHO to obtain a compound of formula (I) wherein 
B is: 
##STR12## 
(iii) H.sub.2 N--CN to obtain a compound of formula (I) wherein B is: 
##STR13## 
(iv) H.sub.2 N--OH to obtain a compound of formula (I) wherein B is: 
##STR14## 
(v) H.sub.2 N--NH.sub.2 to obtain a compound of formula (I) wherein B is: 
##STR15## 
(vi) HNR.sub.4 R.sub.5 to obtain a compound of formula (I) wherein B is: 
##STR16## 
and if necessary reacting the compound of formula (I) thus obtained with 
H.sub.2 NR.sub.3, to obtain a compound of formula (I) wherein B is: 
##STR17## 
wherein R.sub.3, R.sub.4, and R.sub.5 are, each independently, hydrogen 
or C.sub.1 -C.sub.4 alkyl, with the proviso that at least one of R.sub.3, 
R.sub.4, and R.sub.5 is C.sub.1 -C.sub.4 alkyl; 
(vii) succinic anhydride to obtain a compound of formula (I) wherein B is 
--C.tbd.N; 
(viii) water in an alkaline medium, to obtain a compound of formula (I) 
wherein B is --CO--NR.sub.8 R.sub.9 with R.sub.8 and R.sub.9 equal to 
hydrogen; or 
(ix) HNR.sub.8 R.sub.9 to obtain a compound of formula (I) wherein B is: 
##STR18## 
and reacting the compound of formula (I) thus obtained with water in an 
alkaline medium, to obtain a compound of formula (I) wherein B is 
--CO--NR.sub.8 R.sub.9, with R.sub.8 and R.sub.9, each independently, 
equal to hydrogen or C.sub.1 -C.sub.4 alkyl, with the proviso that at 
least one of R.sub.8 and R.sub.9 is C.sub.1 -C.sub.4 alkyl; 
or: 
(b) reacting a compound of formula (V): 
##STR19## 
wherein n is 2, 3 or 4; B' is selected from: 
##STR20## 
wherein R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 
are each independently hydrogen or C.sub.1 -C.sub.4 alkyl, and m is 0, 1 
or 2; 
with a compound of formula (III): 
##STR21## 
wherein: R.sub.0 is C.sub.1 -C.sub.4 alkyl or --CH.sub.2 CH.sub.2 
--X.sub.2, wherein X.sub.2 is a halogen atom; 
R.sub.1 and R.sub.2 are selected, each independently, from: hydrogen, 
C.sub.1 -C.sub.4 alkyl optionally substituted by one or more fluorine 
atoms, C.sub.1 -C.sub.4 alkoxy, and halogen; 
X.sub.1 is a halogen atom; and 
Y is hydroxy or a leaving group; 
to obtain a compound of formula (I) wherein B is B' as defined above, with 
the proviso that when R.sub.0 is --CH.sub.2 CH.sub.2 --X.sub.2, B and B' 
are different from --(CH.sub.2).sub.m --NR.sub.6 R.sub.7, and at least one 
of R.sub.3, R.sub.4, and R.sub.5 is C.sub.1 -C.sub.4 alkyl; and 
(B) if necessary converting the thus obtained compound of formula (I) into 
a pharmaceutically acceptable salt thereof. 
In formula (III), Y is hydroxy or a leaving group selected, for instance, 
from chloro, 2,4,5-trichlorophenoxy, 2,4-dinitro-phenoxy, 
succinimido-N-oxy, imidazolyl group, and the like. 
The reaction of a compound of formula (II) (process (a)) or of formula (V) 
(process (b)) with a compound of formula (III) can be carried out 
according to known methods, for instance those described in EP-B-246,868. 
The reaction between a compound of formula (II) or of formula (V) and a 
compound of formula (III) wherein Y is hydroxy, is preferably carried out 
with a molar ratio (II):(III) or (V):(III) of from 1:1 to 1:2, in an 
organic solvent, such as, e.g., dimethylsulphoxide, 
hexamethylphosphotriamide, dimethylacetamide, dimethylformamide, ethanol, 
benzene, or pyridine, in the presence of an organic or inorganic base such 
as, e.g., triethylamine, diisopropyl ethylamine, or sodium or potassium 
carbonate or bicarbonate, and of a condensing agent such as, e.g., 
N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide, 
N,N'-dicyclohexyl-carbodiimide, and/or 1-hydroxy-benzotriazole hydrate. 
The reaction temperature may vary from about -10.degree. C. to about 
100.degree. C., and the reaction time from about 1 to about 24 hours. 
The reaction between a compound of formula (II) or of formula (V) and a 
compound of formula (III), wherein Y is a leaving group as defined above, 
may be carried out with a molar ratio (II):(III) or (V):(III) of from 
about 1:1 to about 1:2, in an organic solvent, such as, e.g., 
dimethylformamide, dioxane, pyridine, tetrahydrofurane, or mixtures 
thereof with water, optionally in the presence of an organic base, e.g. 
N,N'-diisopropylethylamine, triethylamine, or an inorganic base, e.g. 
sodium or potassium bicarbonate, at a temperature of from about 0.degree. 
C. to about 100.degree. C., and for a time varying from about 2 hours to 
about 48 hours. 
The reaction between a compound of formula (IV) and one of the reactants as 
described at points (i), (ii), (iii), (iv), (v), (vi), or (ix) can be 
carried out according to known methods, for instance those reported in: 
U.S. Pat. No. 4,766,142, Chem. Revs. 1961, 155; J. Med. Chem. 1984, 27, 
849-857; Chem. Revs. 1970, 151; and "The Chemistry of Amidines and 
Imidates", edited by S. Patai, John Wiley & Sons, N.Y. (1975). 
The reaction of a compound of formula (IV) with succinic anhydride (see 
point (vii) above) is preferably carried out with a molar ratio 
(IV):succinic anhydride of from 1:1 to 1:3 in an organic solvent such as, 
e.g., dimethyl sulphoxide, dimethylformamide, in the presence of an 
organic or inorganic base such as, e.g., triethylamine, 
diisopropylethylamine, sodium or potassium carbonate, and the like. The 
reaction temperature may vary from about 25.degree. C. to about 
100.degree. C., and the reaction time from about 1 hour to about 12 hours. 
The reaction with water in an alkaline medium (see points (viii) and (ix) 
above) may be carried out according to known methods usually employed for 
an alkaline hydrolysis, e.g. by treating the substrate with an excess of 
sodium or potassium hydroxide dissolved in water or in a mixture of water 
with an organic solvent, e.g. dioxane, tetrahydrofurane, or acetonitrile, 
at a temperature of from about 50.degree. to about 100.degree. C., for a 
time varying from about 2 hours to about 48 hours. 
The compounds of formula (II) are known compounds or may be prepared by 
known methods from known compounds: see, for instance, Arcamone et al. 
Gazzetta Chim. Ital. 97, 1097 (1967). The compounds of formula (III) are 
known compounds too or may be prepared starting from known compounds 
through reactions well known in organic chemistry: see, for instance, J. 
Med. Chem. 9, 882 (1966), J. Med. Chem. 25, 178 (1982), J. Org. Chem. 26, 
4996 (1961), J. Heterocyclic Chem. 32, 1063 (1995), Synth. Commun. 24, 
3129-3134 (1994). 
The compounds of formula (V) are known compounds, or can be obtained by 
known methods (see e.g. Tetrahedron Letters 31, 1299 (1990), Anticancer 
Drug Design 9, 511 (1994)), such as: 
(i) by hydrolytic deformylation, in a basic or acid medium, of compounds of 
formula (VI): 
##STR22## 
(ii) by nitro-group reduction, according to known methods, of compounds of 
formula (VII): 
##STR23## 
wherein B' is selected from: 
##STR24## 
The compounds of formula (VI), except when B' is equal to 
##STR25## 
can in turn be prepared starting from distamycin compounds of formula 
(VIII): 
##STR26## 
using the same reactants as reported in the second step of process (a). 
The compounds of formula (VII) can be obtained: 
(i) from a compound of formula (IX): 
##STR27## 
wherein n and Y are as defined above, by reaction with a compound of 
formula: 
##STR28## 
wherein B' is selected from: 
##STR29## 
(ii) except when B' is equal to 
##STR30## 
by Pinner reaction of a compound of formula: 
##STR31## 
with a suitable amine compound as defined at point (i), (ii), (iii), or 
(vi) above. 
In the above reaction (i), when at least one of R.sub.6 and R.sub.7 is 
hydrogen, the amine group may be protected by a suitable protecting group 
(e.g. benzyl, carbobenzyloxy, and the like). 
The compounds of formulas (VIII), (IX), (X) and (XI) are known compounds, 
or may be obtained by known methods (see e.g. Tetrahedron, 34, 2389-2391, 
1978; J. Org. Chem., 46, 3492-3497, 1981). 
Salification of a compound of formula (I), as well as preparation of a free 
compound starting from a salt, may be carried out by known standard 
methods. 
Well known procedures such as, e.g., fractional crystallization or 
chromatography, may also be followed for separating a mixture of isomers 
of formula (I) into the single isomers. 
The compounds of formula (I) may be purified by conventional techniques 
such as, e.g., silica gel or alumina column chromatography, and/or by 
recrystallization from an organic solvent such as, e.g., a lower aliphatic 
alcohol, e.g. methyl, ethyl or isopropyl alcohol, or dimethylformamide. 
PHARMACOLOGY 
The compounds of formula (I) or pharmaceutically acceptable salts are 
useful as antineoplastic and/or antiviral agents. Particularly, they show 
cytostatic properties towards tumor cells, so that they can be useful to 
inhibit growth of various tumors in mammals, including humans, such as, 
for instance, carcinomas, e.g. mammary carcinoma, lung carcinoma, bladder 
carcinoma, colon carcinoma, ovary and endometrial tumors. Other neoplasias 
in which the compounds of the present invention can find application are, 
for instance, sarcomas, e.g. soft tissue and bone sarcomas, and the 
hematological malignancies such as, e.g. leukemias. 
The in vitro antitumor activity was evaluated by cytotoxicity studies 
carried out on murine L.sub.1210 leukemia cells. Cells were derived from 
in vivo tumors and established in cell culture. Cells were used until the 
tenth passage. Cytotoxicity was determined by counting surviving cells 
after 48 hours treatment. 
The percentage of cell growth in the treated cultures was compared with 
that of controls. IC.sub.50 values (concentration inhibiting 50% of the 
cellular growth in respect to controls) were calculated on dose-response. 
The compounds of the invention were tested also in vivo on L.sub.1210 
murine leukemia and on murine reticulosarcoma M 5076 with the following 
procedure. 
L.sub.1210 murine leukemia was maintained in vivo by i.v. serial 
transplantation. For experiments, 10.sup.5 cells were injected i.p. in 
CD2F1 female mice, obtained from Charles River Italy. Animals were 8 to 10 
weeks old at the beginning of the experiments. Compounds were administered 
i.v. at day +1 after tumor cells injections. 
M5076 reticulosarcoma was maintained in vivo by i.m. serial 
transplantation. For experiments, 5.times.10.sup.5 cells were injected 
i.m. in C57B16 female mice, obtained from Charles River Italy. Animals 
were 8 to 10 weeks old at the beginning of the experiments. Compounds were 
administered i.v. at day 3, 7 and 11 after tumor injection. 
Survival time of mice and tumor growth were calculated and activity was 
expressed in term of T/C % and T.I. %. 
##EQU1## 
T.I.=% inhibition of tumor growth respect to control 
Tox: number of mice which died for toxicity. 
Tox determination was made when mice died before the control and/or tested 
significant body weight loss and/or spleen and/or liver size reduction 
were observed. 
The compounds of the invention show also a remarkable effectiveness in 
interfering with the reproductive activity of pathogenic viruses and 
protect tissue cells from viral infections. For example, they show 
activity against DNA viruses such as, for instance, herpes, e.g. herpes 
simplex and herpes zoster viruses, virus vaccinia, RNA viruses such as, 
e.g., Rhinovirus and Adenovirus, and against retroviruses such as, for 
instance, sarcoma viruses, e.g., murine sarcoma virus, and leukemia 
viruses, e.g. Friend leukemia virus. 
For example, effectiveness against herpes, coxsackie and respiratory 
syncytial viruses was tested in a fluid medium as follows. Serial two-fold 
dilutions of the compounds from 200 to 1.5 mcg/ml were distributed in 
duplicate 0.1 ml/well in 96 well microplates for tissue culture. Cell 
suspensions (2.times.10.sup.5 cells/ml) infected with about 
5.times.10.sup.-3 TClD.sub.50 of virus/cell were immediately added 0.1 
ml/well. 
After 3-5 day incubation at 37.degree. C. in CO.sub.2 5%, the cell cultures 
were evaluated by microscope observation and Minimum Inhibiting 
Concentration (MIC) was determined, MIC being the minimum concentration 
which determines a reduction of cytopathic effect in comparison with the 
infected controls. 
The compounds of the invention can be administered to mammals, including 
humans, through the usual routes, for example, parenterally, e.g. by 
intravenous injection or infusion, intramuscularly, subcutaneously, 
topically or orally. The dosage depends on the age, weight and conditions 
of the patient and on the administration route. For example, a suitable 
dosage for administration to adult humans may range from about 0.1 to 
about 150-200 mg pro dose 1-4 times a day. 
The present invention further provides a pharmaceutical composition, which 
comprises a compound of formula (I) or a pharmaceutically acceptable salt 
thereof as an active principle, in association with one or more 
pharmaceutically acceptable carriers and/or diluents. 
The pharmaceutical compositions of the present invention are usually 
prepared following conventional methods and are administered in a 
pharmaceutically suitable form. For instance, solutions for intravenous 
injection or infusion may contain as a carrier, for example, sterile water 
or preferably, they may be in the form of sterile aqueous isotonic saline 
solutions. 
Suspensions or solutions for intramuscular injections may contain, together 
with the active compound a pharmaceutically acceptable carrier, e.g. 
sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, 
and if desired, a suitable amount of lidocaine hydrochloride. 
In the forms for topical application, e.g. creams, lotions or pastes for 
use in dermatological treatment, the active ingredient may be mixed with 
conventional oleaginous or emulsifying excipients. 
The solid oral forms, e.g. tablets and capsules, may contain, together with 
the active compound, diluents, e.g., lactose, dextrose, saccharose, 
cellulose, corn starch and potato starch; lubricants, e.g. silica, talc, 
stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; 
binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, 
carboxymethyl cellulose, polyvinylpyrrolidone; disaggregating agents, e.g. 
starch, alginic acid, alginates, sodium starch glycolate; effervescing 
mixtures; dyestuffs; sweeteners; wetting agents, for instance, lecithin, 
polysorbates, laurylsulphates; and, in general, non-toxic and 
pharmacologically inactive substances used in pharmaceutical formulation. 
Said pharmaceutical preparation may be manufactered by known techniques, 
for example by means of mixing, granulating, tabletting, sugar-coating or 
film-coating processes. 
The present invention also provides a compound of formula (I) or a 
pharmaceutically acceptable salt thereof for use in a method of treating 
the human or animal body by therapy. Furthermore, the present invention 
provides a method for treating tumors and viral infections in a patient in 
need of it, which comprises administering to said patient a composition of 
the invention. 
A further object of the present invention is a combined method for treating 
cancer or for ameliorating the conditions of mammals, including humans, 
suffering from cancer, said method comprising administering a compound of 
formula (I), or a pharmaceutically acceptable salt thereof, and an 
additional antitumor agent, close enough in time and in amounts sufficient 
to produce a therapeutically useful effect. 
The present invention also provides products containing a compound of 
formula (I), or a pharmaceutically acceptable salt thereof, and an 
additional antitumour agent as a combined preparation for simultaneous, 
separate or sequential use in anti-cancer therapy. 
The term "antitumor agent" is meant to comprise both a single antitumor 
drug and "cocktails" i.e. a mixture of such drugs, according to the 
clinical practice. Examples of antitumor agents that can be formulated 
with a compound of formula (I), or alternatively, can be administered in a 
combined method of treatment, include doxorubicin, daunomycin, epirubicin, 
idarubicin, etoposide, fluoro-uracil, melphalan, cyclophosphamide, 
4-demethoxy daunorubicin, bleomycin, vinblastin, and mitomycin, or 
mixtures thereof.