Organic compounds -- part of the class 532-570 series – Organic compounds – Heavy metal containing
Reexamination Certificate
2000-04-27
2001-11-06
Nazario-Gonzalez, Porfirio (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heavy metal containing
C514S592000, C544S225000, C546S002000, C548S101000, C548S402000, C549S003000
Reexamination Certificate
active
06313333
ABSTRACT:
The present invention relates to tetra- and penta-nuclear platinum complexes with antitumor activity, to a method for preparing them and to pharmaceutical compositions containing them.
STATE OF THE ART
The use of platinum complexes in the antitumor chemotherapy is well known. A number of platinum complexes, such as cis-platin, are used in the treatment of testicular, ovarian, head and neck and small cell lung carcinomas. However, the treatment with cis-platin may result in severe nephrotoxicity. A further clinical disadvantage is the problem of acquired drug resistance resulting in the tumor becoming refractory to treatment by the agent.
It is generally believed that platinum complexes such as cis-platin manifest their biological activity through covalent interaction with DNA. In partcular, cis-platin induces the formation of a range of adducts on DNA including monodentate adducts, bidentate adducts, such as GG or AG, and GNG intrastrand crosslinks [Reedijk et al., Structure and Bonding, 67, 53-89 (1987)]. To a lesser extent, cis-platin also results in interstrand GG crosslinks and DNA-protein crosslinks [Rahmouni et al., Biochemistry, 26, 7229-7234 (1987)]. These DNA lesions result in conformational changes which are reflected in bending and local unwinding of the DNA. These DNA lesions have been reported to inhibit the activity of various DNA polymerases [Vallan et al., Nucl. Acids Res., 16, 4407-4418 (1988); Pinto et al., Proc. Natl. Acad. Sci., 82, 4616-4619 (1985); Gralla et al., Cancer Res., 47, 5092-5096 (1987)]. The interstrand crosslink between two neighboring guanine bases has also been shown to inhibit RNA polymerase function [Lemaire et al., Proc. Natl. Acad. Sci., 88, 1982-1985 (1991)]. Accordingly, the cytotoxic effects of cis-platin are most likely attributable to the combined effects of these DNA lesions, rather than the result of any one specific lesion event.
Mono(platinum) and bis(platinum) complexes, containing respectively one or two platinum atoms, are compounds known in the art (U.S. Pat. Nos. 4,225,529, 4,250,189, 4,533,502, 4,565,884, 4,571,335 e 4,797,393).
Examples of tri-nuclear platinum complexes (also named tri-platinum complexes) were recently reported in the letterature [Yun Qu et al., Inorg. Chem., 32, 2591-2593 (1993)]. Said compounds, in which the ligands have a cis configuration, are complexes neutral or bearing an overall charge of +2 and they can be represented by the following general formulae:
in which X means a labile ligand (such as a chlorine atom) and R means an alkylene chain. It can be seen that, in the case of the complexes with an overall charge of +2, said charge is located on the central platinum atom, bearing four neutral ligands, whereas the two peripheral platinum atoms are formally neutral and. as defined above, bifunctional.
WO95/26968 describes tri-platinum complexes in which the three platinum atoms are linked by diamine chains and in which the central platinum atom coordinates four neutral ligands, whereas the two peripheral platinum atoms coordinates each three neutral ligands and one ligand having −1 charge.
Such compounds have an overall charge of +4 and in particular the central platinum atom bears a formal charge of +2 and the two periferal platinum atoms bear a formal charge of +1 each. Moreover, the two periferal platinum atoms are monofunctional.
We have now found that by increasing the number of platinum cores linked by diamine ligands, new platinum complexes endowed with high antitumor activity are obtained.
In particular, the invention relates to tetra- and penta-platinum complexes of formula (I):
[PtXL
2
NH
2
—(CH
2
)
n
—NH
2
—(PtL
2
NH
2
—(CH
2
)
n
—NH
2
)
m
PtXL
2
]
+q
.q/z A
−z
(I)
wherein
n is an integer from 2 to 7;
m is the integer 2 or 3;
X is selected in the group consisting of chlorine, bromine, iodine, (C
1
-C
4
)alkyl-carboxylate, di-(C
1
-C
4
)alkylsulfoxide;
L is independently selected in the group consisting of ammonia, (C
1
-C
8
)alkyl-amine, di(C
1
-C
8
)alkyl-amine or is an heterocylcle selected in the group consisting in pyridine, quinoline, isoquinoline, imidazole, thiazole, pyrimidine, purine, acridine, pyrazole, benzimidazole, benzothiazole.
A
−z
is a pharmaceutically accetable anion.
The complex's charge +q depends both on the number of the platinum cores present and on the nature of the X ligand. In particular, when the X ligand is a group bearing a negative charge, then the charge +q is given by the formula
q=2m+2
in which m is as above defined.
However, when the X ligand is a neutral molecule, then the charge +q is determined by the following formula
q=2m+4
The expert of the art will appreciate the fact that the ligands may be in cis or trans position with respect to the platinum atom:
In the present invention are included all the possible isomers, enantiomers and diastereoisomers of the compounds of formula (I). More particularly, compounds of formula (I) in which m is the integer 2 and 3 respectively, are represented by the general formulae (Ia) and (Ib):
wherein X, L and A
−z
have the meanings above defined, n is an integer which independently ranges from 2 to 7 and q′ is 0 if X is a ligand with −1 charge or the integer 2 if X is a neutral ligand.
The stereochemistry of the ligands in the formulae (Ia) and (Ib) is just indicative, being encompassed in the invention, as said above, all the possible stereoisomers.
The X ligands are preferably selected in the group consisting of chlorine, bromine and iodine.
The ligands L are preferably ammonia.
A
−z
is preferably selected in the group consisting of chloride, bromide, iodide, nitrate. sulfate, hydrogensulfate, perchlorate.
Tetra- and penta-platinum complexes having the same n value inside the molecule, that is in which the various platinum cores are linked by the same diamine, are preferred.
Preferred compounds of formula (I) are those in which the ligands are in position trans with respect to the platinum atom.
Particularly preferred compounds of formula (I) are those in which X is selected in the group consisting of chlorine, bromine and iodine, L is ammonia and A
−z
is selected in the group consisting of chloride, bromide, iodide, nitrate, sulfate, hydrogensulfate, perchlorate and in which the stereochemistry of platinum core's ligands is trans.
Even more particularly preferred compounds of formula (I) are those in which, in addition to the above limitations, n is the integer 6.
The present invention encompasses also methods for obtaining the compounds of formula (I).
The compounds of formula (Ia) are prepared according to scheme 1.
In particular, such a synthesis scheme comprises the following steps:
(a) activation of the bis-platinum complex of formula (II) through substitution of the two chlorine atoms with two molecules of dimethylformamide and subsequent reaction of the so obtained intermediate with two equivalents of mono-protected diamine of formula (III), to give the intermediate of formula (IV);
(b) removal of the two protecting groups of the amines from intermediate of formula (IV) and subsequent optional exchange of the counterion so obtained with nitrate ion to give the intermediate of formula (V);
(c) reaction of the intermediate of formula (V) with two equivalents of platinum complex of formula (Va) to give compounds of formula (Ia);
(d) optional transformation of one compound of formula (Ia) into another compound of formula (Ia) having a different counterion, by means of exchange reaction of said counterion with the wanted anion.
The compounds of formula (II) are known and can be prepared according to the method described in WO 91/03482, which encompasses the reaction of two equivalents of trans- or cis-platinum with a &agr;,&ohgr;-alkanediamine in water overnight.
The compounds of formula (Va) can be prepared from the known platinum complexes of formula [PtClXL2] according to the method described in W
Da Re Giovanni
Di Domenico Roberto
Farrell Nicholas
Spinelli Silvano
McGuireWoods LLP
Nazario-Gonzalez Porfirio
Setanta Therapeutics, Inc.
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