Organic compounds -- part of the class 532-570 series – Organic compounds – Radioactive metal containing
Reexamination Certificate
1998-08-25
2001-06-19
Jones, Dameron (Department: 1619)
Organic compounds -- part of the class 532-570 series
Organic compounds
Radioactive metal containing
C534S014000, C534S015000, C534S016000, C424S001650, C424S001690, C424S009340
Reexamination Certificate
active
06248870
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel unsymmetrical oligo-2,6-pyridine complexing agents as well as to novel immunoreagents, preferably targeting radioactive immunoreagents, which comprise the novel unsymmetrical oligo-2,6-pyridine complexing agents, and which find particular utility in therapeutic and diagnostic imaging compositions and methods.
BACKGROUND OF THE INVENTION
The use of oligo-2,6-pyridines as complexing agents that may be incorporated in targeting immunoreagents is disclosed, for example, in WO 92/08494 (PCT/US91/08253).
As discussed in WO 92/08494, these complexing agents solve several problems in the prior art, particularly as regards therapeutic and diagnostic imaging uses of targeting radioactive immunoreagents. The targeting radioactive immunoreagents of that patent application comprise a metal radionuclide ion, a complexing agent, and an immunoreactive group covalently bonded through a protein reactive group to the complexing agent.
The complexing agents of that application have the general structure A-I
wherein
R represents hydrogen, alkyl, alkoxy, alkylthio, alkylamino, alkylformamido, aryl, aryloxy, heterocyclyl or a protein reactive group;
R
1
represents hydrogen, alkyl, alkoxy, alkylthio, alkylamino, alkylformamido, aryl, aryloxy, heterocyclyl or a protein reactive group;
R
2
represents hydroxy, carboxy, hydroxyalkyl, thioalkyl, carbonyliminodiacetic acid, methyleneiminodiacetic acid, methylenethioethyleneiminodiacetic acid, carboxyalkythioalkyl, hydrazinylidenediacetic acid, or a salt of such acids, or two R
2
groups, taken together, represent the atoms necessary to complete a macrocyclic ring structure containing at least one heteroatom coordinating site and at least one, preferably two, alkylene groups forming part of the ring structure;
R
3
represents hydrogen, alkyl, alkoxy, alkylthio, alkylamino, alkylformamido, aryl, aryloxy, heterocyclyl or a protein reactive group;
R
4
represents hydrogen or a protein reactive group;
n is 1, 2, 3 or 4;
o is 0 or 1;
m is 0 or 1;
provided that at least one of n and m is 0 and at least one of R, R
1
, R
3
and R
4
is a protein reactive group.
While a significant advance over the prior art, one limitation regarding those oligo-2,6-pyridine chelators of structure A-I which contain 3, 4, 5, or 6 pyridine rings is their requirement of substitution by R
2
at both the 6-position of the first pyridine ring and the respective 6″-, 6″′, 6″″- and 6″″′-positions of the third, fourth, fifth, and sixth pyridine ring. In the synthesis of these compounds, each R
2
substitutent requires at least one chemical reaction to occur at some point in the synthetic sequence at both the 6-position of the first pyridine ring and at the respective 6″-, 6″′, 6″″- and 6″″′-positions of the third, fourth, fifth, and sixth pyridine ring of the oligo-2,6-pyridines, and the overall yield of the oligo-2,6-pyridine chelator comprises the arithmetical product of the yield of the reaction to generate the appropriate R
2
at each of the two reaction sites. This yield is necessarily reduced to less than 100% when one of the reactions involving introduction and/or modification of the substituent at the 6-position and the substituents at the respective 6″-, 6″′, 6″″- and 6″″′-positions is less than 100%, as is most often the case.
Furthermore, in those non-macrocyclic oligo-2,6-pyridine chelators of structure A-I which contain 3, 4, 5, or 6 pyridine rings, wherein each R
2
represents hydroxy, carboxy, hydroxyalkyl, thioalkyl, carbonyliminodiacetic acid, methyleneiminodiacetic acid, methylenethioethyleneimino-diacetic acid, carboxyalkythioalkyl, hydrazinylidenediacetic acid, or a salt of such acids, the capacity of a given chelator to bind with a high binding constant to a given metal ion of a fixed charge is limited by conformational energies attainable by the oligo-2,6-pyridine molecular geometry. The molecular geometry and conformational strain energies impose a limit to the amount of interpyridine bond angle bending that can occur in the oligo-2,6-pyridine component. In an s-cis configuration, the restrictions in the interpyridine bond angle bending in the oligo-2,6-pyridine component limit the extent to which the two R
2
groups can approach one another and participate with the oligo-2,6-pyridine nitrogens in the chelation of a metal ion. Consequently, the configuration that the chelating moiety can achieve about a metal ion can be limited with respect to attainment of rapid kinetics of metal binding and large binding constant between the chelator and the metal than can be achieved with a chelating oligo-2,6-pyridine that is not constrained by the interpyridine bond energies.
With respect to chelated radioisotopes by the oligo-2,6-pyridines disclosed in WO 92/08494 and incorporated in targeting immunoreagents (radioimmunoconjugates) which comprise an immunoreactive agent, a chelating group and a metal ion, it is advantageous to be able to detect the accumulation of said radioimmunoconjugate at a tumor site so as to be able to better monitor the course of treatment of a patient with said radioimmunoconjugate. Few metal ion radioisotopes have properties which are optimally suited for both diagnostic imaging and for therapeutic applications. As such it is often necessary to use two different metal ions such as, for example,
111
In
+3
for diagnostic imaging purposes and such as, for example,
90
Y
+3
for therapeutic purposes in the above application. Because these metal ions have different sizes and chelate binding requirements, and although the oligo-2,6-pyridines disclosed in WO 92/08494 bind these metal ions rapidly and hold them tenaciously, there is still a limit to the respective binding rates and binding constants that is imposed by the disubstituted nature of the oligo-2,6-pyridines outlined above.
It is, therefore, desireable to have oligo-2,6-pyridine chelating agents that are not limited in their ability to bind a metal ion because of restrictions imposed by the interpyridine binding energetics and which oligo-2,6-pyridine chelating agents are capable of binding both a diagnostic imaging isotope and a therapeutic isotope rapidly and with a high binding constant.
SUMMARY OF THE INVENTION
In accordance with the present invention, there are provided novel 6-substituted-6′
(i-1)
-H-oligo-2,6-pyridine-containing complexing (or chelating) agents containing i pyridine rings which are derivatives of a terpyridine (i=3), or a quaterpyridine (i=4), or a quinquepyridine (i=5) or a sexipyridine (i=6) and in which the substituent in the 6-position is a chelating group capable of chelating to a metal ion. These novel oligo-2,6-pyridine-containing complexing (or chelating) agents (sometimes hereinafter referred to as unsymmetrical oligo-2,6-pyridine complexing agents or unsymmetrical oligo-2,6-pyridine chelating agents) have the advantage over chelating agents of the prior art in that they can form metal ion complexes comprising a metal ion, a chelating substituent in the 6-position of an oligo-2,6-pyridine and pyridine rings of the oligo-2,6-pyridine in which complexes the energies arising from interpyridine bond angle bending in the oligo-2,6-pyridine component do not limit the chelating interaction of the 6-position substituent with the metal ion. As such, the novel unsymmetrical oligo-2,6-pyridine chelating agents of this invention are capable of binding rapidly and of binding tenaciously to a variety of metal ions which metal ions differ from one another in charge, size and coordination geometry.
Novel radioimmunoconjugates containing the novel unsymmetrical oligo-2,6-pyridine chelating agents of this invention have the advantage that they can be employed in both diagnostic imaging as well as therapeutic applications, particularly in the diagnosis and treatment of cancer such that, in diagnostic imaging of a tumor tissue, the nove
Delecki Daniel J.
Saha Ashis Kumar
Snow Robert A.
Fish & Richardson P.C.
Jones Dameron
Nycomed Imaging AS
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