Organic compounds -- part of the class 532-570 series – Organic compounds – Heavy metal containing
Reexamination Certificate
1999-07-21
2002-10-01
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heavy metal containing
C556S137000, C556S143000, C556S148000, C536S025300
Reexamination Certificate
active
06458983
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a method for synthesizing complexes of platinum with iminoethers and to their use as antitumoral drugs and nucleotide-base modifiers.
Specifically, the present invention relates to a method for synthesizing complexes of platinum(II) with iminoethers and to their use both as broad-spectrum antitumoral drugs and as nucleotide-base modifiers in antisense and/or antigene oligonucleotides.
The inorganic compound cis-diaminodichloroplatinum(II) (cis-[PtCl
2
(NH
3
)
2
], cis DDP, also commonly known as cisplatinum, is a molecule having an antitumoral action which has been widely used clinically, particularly for treating solid tumors.
The chemotherapeutic effect of cisplatinum arises from a biochemical mechanism which is still not entirely known and which, since the drug interacts with cell DNA, forming intra- and interstrand bifunctional adducts, is probably due to structural and functional changes associated with the formation of adducts, particularly intrastrand adducts between adjacent purines. On the basis of current knowledge, however, a significant contribution to the action of cisplatinum by adducts of the interstrand type cannot be ruled out.
It is known that initial structure-activity correlation studies concerning with platinum complexes having the general formula [Pt
n
X
2
A
2
], where X is a leaving anionic group and A
2
are two monodentate amine ligands or a bidentate amine ligand, demonstrated that the compounds having an antitumoral activity had their X groups in a cis configuration and vice versa that the geometric isomer of cisplatinum, trans-[PtCl
2
(NH
3
)
2
], trans-DDP, like other platinum complexes having X-group in trans geometry, had no antitumoral activity. Accordingly, in the past the search for cisplatinum derivatives characterized by lower systemic toxicity and by a different spectrum of activity was orientated almost exclusively toward cis-geometry compounds.
However, platinum complexes with a trans geometry of the leaving ligands have been recently identified which are characterized by antitumoral properties which have been verified in experimental systems in vitro and/or in vivo. In particular, the following are known among these complexes:
complexes having the general formula trans-[PtCl
2
(L)(L′)], where L, L′ is pyridine, thiazole, quinoline. These compounds, particularly with reference to trans-[PtCl
2
(pyridine)
2
], have been shown to have a higher cytotoxic effect in vitro against tumor cells than trans-DDP;
complexes of platinum with iminoethers, with particular reference to the complex trans-[PtCl
2
{E-HN═C(OMe)Me}
2
], where E is the configuration of the iminoether group, indicating that the platinum and the methoxyl are in the trans position with respect to the C═N double bond. This complex has a cytotoxic in vitro effectiveness similar to that of cisplatinum and an antitumoral activity in vivo with respect to solid and lymphoproliferative murine tumors.
complexes of platinum(IV), with particular reference to an octahedral compound of platinum(IV) with trans geometry and having the formula trans-[PtCl
2
(OH)
2
(NH
3
){NH
2
(C
6
H
11
)}] and analogs thereof, have shown antitumoral activity in vitro and in vivo.
Recently it has been found that known antitumoral platinum complexes having a trans geometry have an activity against cisplatinum-resistant tumor cells, thus providing new guidelines for research into platinum complexes having a different mechanism of action with respect to cisplatinum.
Biomedical technology currently uses synthetic oligonucleotides in order to achieve selective inhibition of gene expression for the analysis of specific genetic functions and for the possible pharmacological treatment of diseases caused by alterations of cell gene expression.
These synthetic oligonucleotides are known to be an elective class of drugs for regulating mRNA translation and DNA transcription, in antisense and antigene therapeutic strategies, respectively.
In order to improve the biological effectiveness of synthetic oligonucleotides, providing a stable and irreversible interaction with the target sequences, some chemical functional groups and/or photonically activated agents have been conjugated with synthetic oligonucleotides.
However, this model has been found to have drawbacks, mainly due, in the case of the presence of chemical functional groups, to the onset of non-sequence-specific association reactions, and due, in the case of the presence of photonically activated agents, to difficulty in application in in vivo systems.
SUMMARY OF THE INVENTION
A general aim of the present invention is to avoid or significantly reduce the disadvantages noted in the known art.
A primary object of the present invention is to provide new broad-spectrum antitumoral drugs whose administration entails reduced side effects.
Another object of the present invention is to provide platinum(II) complexes which can be used as agents for modifying nucleotide bases in antisense and/or antigene oligonucleotides which are highly specific and do not entail high production costs.
Another object is to provide a method for synthesizing complexes of platinum with iminoethers which is simple to perform.
In view of this aim, these objects and others which will become apparent hereinafter, according to the present invention, complexes of platinum(II) with iminoethers are provided, said complexes having the formula (I):
[Pt
11
X
2
(L)(L′)] (I),
wherein
X is a monoanionic ligand, preferably a halide, more preferably selected from Cl
−
and I
−
;
L is an iminoether group or ligand, preferably having the formula HN═C(OR′)R, or the formula N═C(OR′)—(CH
2
)
n
—CH
2
, or the formula N═C(R)—O—(CH
2
)
n
—CH
2
, wherein
R and R′ are a linear or branched alkyl, preferably a lower alkyl, more preferably an alkyl containing 1 to 6 atoms of C or an aryl, said aryl preferably being a substituted or unsubstituted phenyl-group and
n═1, 2, 3;
L′ is an amine group or ligand or, exclusively for the case of cyclic iminoethers, a second iminoether group.
Advantageously, said amine group is selected from ammonia, a primary or secondary aliphatic amine or an aromatic amine, such as piridine or quinoline, optionally substituted.
Platinum(II) complexes having the formula (I) according to the present invention can have a cis or trans geometry of the monoanionic ligands and of the aminic and iminoether ligands, with respect to the metallic center; moreover, the iminoether ligand HN═C(OR′)R can have a different configuration (E or Z) according to the relative position (trans or cis) of the OR′ group and of the metallic center with respect to the C═N double bond.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
According to one embodiment of the present invention, said platinum(II) complexes have the following structure forms:
According to another aspect of the present invention, a process is provided for synthesizing compounds of platinum(II) with iminoethers having the formula [Pt
11
X
2
(L)(L′)], wherein
X is a monoanionic ligand, preferably a halide, more preferably selected from Cl
−
and I
−
;
L is an iminoether group or ligand having the formula HN═C(OR′)R or the formula
or the formula
where R and R′ are an alkyl or an aryl and n=1, 2, 3;
L′ is an amine group or ligand or, exclusively for the case of cyclic iminoethers, a second iminoether group; said process comprising the steps of:
1) treatment of cis-[PtX
2
(L′)
2
] in a mixture of water and nitrile (NCR) in order to obtain trans-[PtX
2
(L′)(NCR)];
2) treatment of trans-[PtX
2
(L′)(NCR)] with an alcohol and a base (a hydroxide of an alkaline/alkaline-earth metal) to produce trans-[PtX
2
(L′) (Z-L)];
3) transformation of the trans-[PtX
2
(L′)(Z-
Boccarelli Angelina
Coluccia Mauro
Intini Francesco Paolo
Natile Giovanni
Josif Albert
Modiano Guido
O'Byrne Daniel J.
Universita' Degli Studi di Bari
Wilson James O.
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