Chelating agents

Details Chelating agents Chelating agents

1999-08-26

2001-08-28

Hartley, Michael G. (Department: 1619)

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

Diagnostic or test agent produces in vivo fluorescence

C424S009100

Reexamination Certificate

active

06280706

ABSTRACT:

This invention relates to complexants and metallated complexes thereof and to their use in diagnostic, therapeutic and prophylactic compositions, in particular to the use of such complexants metallated with radionuclides as diagnostic imaging and therapeutic agents.
Radiopharmaceuticals, the class of drug compounds containing radionuclides, are useful for the diagnosis and treatment of various disease states, in particular certain cancers.
The radionuclide in such radiopharmaceuticals may be a metal (eg. a transition metal or lanthanide) or a nonmetal (eg. an iodine or hydrogen radionuclide). Where the radionuclide is a metal, it is conventionally administered as a complex (usually a chelate complex) of a mono- or polyatomic ion of or containing the metal, with a complexing agent. The present invention is particularly concerned with complexed metal radionuclides and complexants which can be metallated with metal ion radionuclides.
In the use of complexed metal radiopharmaceuticals, the diagnostic or therapeutic properties are selected by appropriate selection of the metal radionuclide (eg. by virtue of its decay pattern or half life) while the biodistribution and bioelimination properties are selected by appropriate selection of the complexant and, if desired of a vector moiety coupled directly or indirectly to the complexant so as to cause the complexed radionuclide to be targeted to a particular body site or tissue type, eg. cancerous tissue.
Examples of complexants that have been proposed for use with metal radionuclides in therapeutic or diagnostic compositions include the terpyridine chelants disclosed in WO (TMT cases) and the BAT chelants discussed by Ohmomo et al. in J. Med. Chem. 35: 157-162 (1992) and by Kung et al. in J. Nucl. Med. 25: 326-332 (1984).
Nevertheless there is a continuing need for complexants which are capable of adequately complexing diagnostic and therapeutic metal radionuclides and which preferably also may be coupled to effective vector moieties so as to target the complexed radionuclide to a desired target site within the patient's body.
In particular there is a continuing need for complexants that may be used to complex both diagnostically effective metal radionuclides and therapeutically effective metal radionuclides. In this way a disease site may be imaged and treated using diagnostic and therapeutic agents which have substantially identical biodistributions since the carrier portion of the metal: carrier complex, which determines the biodistribution pattern of the complex, may be the same in both the diagnostic agent and the therapeutic agent.
We have now found that a new class of complexants possesses appropriate properties in this regard.
The novel complexants are referred to as N
2
S
2
X complexants since they contain a carbon chain interrupted, in order by S, N, X, N and S heteroatoms (where X is an O, S, N or P heteroatom). Between these heteroatoms there are carbon chains 2, 3 or 4 atoms long. Such complexants, and the salts and complexes thereof, including the targeted complexes thereof, form one aspect of the invention.
Viewed from a further aspect the invention provides a complexant compound of formula I
R
3
S(CR
1
2
)
n
N(R
2
)
i
(CR
1
2
)
n
X(CR
1
2
)
n
N(R
2
)
i
(CR
1
2
)
n
SR
3
  (I)
(wherein
each n, which may be the same or different, is an integer 2, 3 or 4 (preferably 2);
each i, which may be the same or different, represents 0 or 1;
each R
3
, which may be the same or different, is H or a thiol protecting group, preferably a protecting group;
X is 0, S, N, NR
4
or a substituted phosphorus (eg. oxo substituted phosphorus), preferably S or N;
each R
4
, which may be the same or different, is hydrogen or an optionally substituted organic group;
each R
1
, which may be the same or different, is hydrogen or an optionally substituted organic group, or a moiety CR
1
2
may represents a carbonyl group or two, three or four R
1
s on two different carbons together with those carbons and any intervening atoms may represent an optionally substituted saturated or unsaturated homocyclic or heterocyclic ring; and preferably, at least one CR
1
2
moiety is other than CH
2
or CH(CH
3
)) or a salt or complex thereof, wherein optionally at least one of the R
1
, R
2
, R
3
and R
4
moieties is coupled directly or indirectly to a vector moiety.
Viewed from a further aspect the invention provides a pharmaceutical composition comprising an effective amount (eg. an amount effective to enhance image contrast in in vivo imaging or an amount sufficient to achieve a desired therapeutic effect) of a complex of an optionally vector coupled complexant of formula I together with at least one pharmaceutically effective carrier or excipient.
Viewed from a still further aspect the invention provides the use of a complex of an optionally vector coupled complexant of formula I for the manufacture of a contrast medium for use in a method of diagnosis involving administration of said contrast medium to an animate subject and generation of an image of at least part of said subject.
Viewed from a still further aspect the invention provides the use of a complex of an optionally vector coupled complexant of formula I for the manufacture of a therapeutic agent, eg. a radiopharmaceutical, for example for use in tumor therapy.
Viewed from a still further aspect the invention provides a method of generating an image of an animate human or non-human (preferably mammalian or avian) animal subject involving administering a contrast agent to said subject, eg. into the vascular system or the gi tract, and generating an image of at least a part of said subject to which said contrast agent has distributed, eg. by X-ray, MR, ultrasound, scintigraphic, PET, SPECT, electrical impedance, light or magnetometric imaging modalities, characterised in that as said contrast agent is used a complex of an optionally vector coupled complexant of formula I.
Viewed from a still further aspect the invention provides a method of treatment of an animate human or non-human (preferably mammalian or avian) animal subject involving administering a therapeutic agent to said subject, eg. into the vascular system or the gi tract, characterised in that as said therapeutic agent is used a complex of an optionally vector coupled complexant of formula I.
Viewed from a yet further aspect the invention provides a process for the preparation of a complex of an optionally vector coupled complexant of formula I, said process comprising metallating an optionally vector coupled complexant of formula I with a diagnostically or therapeutically effective metal ion or metal-containing complex ion.
Metallation may be effected using conventional techniques, eg. reacting the complexant or a salt thereof in solution with a soluble salt of the desired metal.
Where, in the compounds of formula I, R
1
groups together with intervening atoms form a cyclic group it is particularly preferred that this be a 5 to 8 membered ring containing 0, 1, 2 or 3 heteroatoms selected from N, S and O. More especially it is preferred that one such heteroatom is provided by a N(R
2
)
i
or X group and it is even more especially preferred that the R
1
groups are on two carbons adjacent but on different sides of an N(R
2
)
i
or X group. Preferably the compound of formula I will contain zero, one or three such heterocycles, preferably unsaturated and especially preferably aromatic heterocycles, incorporating ring nitrogens oxygens or sulphurs from N(R
2
)
i
and X moieties. Particularly preferably the resultant heterocycle is an unsaturated N
1
, N
2
, O
1
, N
1
O
1
or S
1
heterocycle, preferably a thiophene, pyrrolidine, piperidine, piperazine, morpholine, pyran, pyrrole, imidazole, pyrazine, pyrimidine, imidazolidine, imidazolidinone, furan or pyridine ring. Pyridine, thiophen and furan rings, especially pyridine rings are especially preferred.
It is also preferred that the two (CR
1
2
)
n
groups between the N(R
2
)
i
and X moieties should be (CH
2
)
n
or (CR
1
2
) (CH
2
)
n-1
groups where X is S and where the CR
1
2

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