Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.
Reexamination Certificate
2000-12-04
2003-07-22
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
Reexamination Certificate
active
06596845
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.
DE-A-1795539 discloses distamycin derivatives in which the formyl group is replaced by a hydrogen atom or by the carboxylic acid residue of a C
1
-C
4
aliphatic or cyclopentylpropionic acid.
EP-A-246,868 describes distamycin analogues in which the distamycin formyl group is substituted by aromatic, alicyclic or heterocyclic moieties bearing alkylating groups.
WO 97/28123 describes distamycin analogues in which the distamycin formyl group is substituted by an aromatic moiety bearing alkylating groups and the amidino group is replaced with different nitrogen-containing ending moieties.
WO 97/43258 discloses cinnamoyl distamycin derivatives amidino-modified as above reported.
Distamycin derivatives wherein at least one pyrrole ring of the polypyrrole framework is substituted by an imidazole or pyrazole ring are also reported in the literature; see, for a 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.
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 a cinnamoyl moiety and the amidino group is optionally substituted by different nitrogen-containing ending groups, shows valuable biological properties.
Therefore, the present invention provides compounds which are cinnamoyl distamycin derivatives 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
, which are the same or different, are selected 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;
Y and Z are the same or different and are selected, independently for each heterocyclic ring of the polyheterocyclic chain, from N and CH;
B is selected from:
wherein R
3
, R
4
, R
5
, R
6
, and R
7
are, independently from each other, hydrogen or C
1
-C
4
alkyl;
or pharmaceutically acceptable salts thereof;
provided that at least one of the heterocyclic rings within the polyheterocyclic chain is other than pyrrole.
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, both terms alkyl and alkoxy include straight or branched C
1
-C
4
alkyl and alkoxy groups such as, for instance, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 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, methoxy and ethoxy groups.
When substituted by one or more fluorine atoms, the C
1
-C
4
alkyl groups are preferably C
1
-C
4
perfluoroalkyl groups, e.g. trifluoromethyl.
The term halogen atom includes fluorine, chlorine, bromine and iodine, being chlorine and bromine preferred.
As above reported, Y and Z 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 Y can be either N as well as CH; the same applies for Z provided
that at least for one of the heterocyclic rings, Y and Z are not both CH.
Examples of the said heterocycles are pyrrole, pyrazole and imidazole.
Within the cinnamoyl derivatives of formula (I) the N,N-disubstituted amino group onto phenyl ring is in ortho, meta or para position; preferably, it is in meta or para position.
As to the R
1
and R
2
groups, they can be in any of the free positions of the phenyl ring.
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 3;
R
0
is ethyl or 2-chloroethyl;
R
1
and R
2
which are the same or different, are selected from hydrogen, methyl, methoxy or trifluoromethyl;
X is chloro;
Y and Z are the same or different and are selected, independently for each heterocyclic ring of the polyheterocyclic chain, from N and CH;
B is selected from:
wherein R
3
, R
4
, R
5
, R
6
, and R
7
are, independently from each other, hydrogen or methyl;
or the pharmaceutically acceptable salts thereof;
provided that at least one of the heterocyclic rings within the polyheterocyclic chain is other than pyrrole.
Examples of specific compounds according to the present invention, especially in the form of salts, preferably with hydrochloric acid, are the following:
3-[1-methyl-3[1-methyl-3[1-methyl-4[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrazole-5-carboxamido]pyrazole-5-carboxamido]propionamidine;
3-[1-methyl-3[1-methyl-3[1-methyl-4[4-N-ethyl-N-(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrazole-5-carboxamido]pyrazole-5-carboxamido]propionamidine;
3-[1-methyl-3[1-methyl-3[1-methyl-4[3-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrazole-5-carboxamido]pyrazole-5-carboxamido]propionamidine;
3-[1-methyl-3[1-methyl-3[1-methyl-4[3-methyl-4-N,N-bis(2-chloroethyl)aminocinnamoyl]pyrrole-2-carboxamido]pyrazole-5-carboxamido]pyrazole-5-carboxamido]propionamidine;
3-[1-methyl-3[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrazole-5-carboxamido]propionamidine;
3-[1-methyl-3[1-methyl-4[1-methyl-4[4-N-ethyl-N(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrazole-5-carboxamido]propionamidine;
3-[1-methyl-4[1-methyl-4[1-methyl-4 [4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]imidazole-2-carboxamido]propionamidine;
3-[1-methyl-4[1-methyl-3[1-methyl-4[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrazole-5-carboxamido]imidazole-2-carboxamido]propionamidine;
3-[1-methyl-4[1-methyl-3[1-methyl-4[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrazole-5-carboxamido]pyrrole-2-carboxamido]propionamidine;
3-[1-methyl-3[1-methyl-3[1-methyl-4[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrazole-5-carboxamido]pyrazole-5-carboxamido]propioncyanamidine;
3-[1-methyl-3[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrazole-5-carboxamido]propioncyanamidine;
3-[1-methyl-4[1-methyl-4[1-methyl-4[4-N,N-bis(2-chloroethyl)aminocinnamoylamido]pyrrole-2-carboxamido2pyrrole-2-carboxamido]imidazole-2-carboxamido]propioncyanamid
Baraldi Pier Giovanni
Beria Italo
Caldarelli Marina
Cozzi Paolo
Geroni Maria Cristina
Arent Fox Kintner Plotkin & Kahn
Low Christopher S. F.
Lukton David
Pharmacia Italia S.p.A.
LandOfFree
Cinnamoyl distamycin analogous derivatives, process for... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Cinnamoyl distamycin analogous derivatives, process for..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cinnamoyl distamycin analogous derivatives, process for... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3021914