Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1991-10-22
1993-09-21
Springer, David B.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
540474, 424 9, 424 11, K07D25502, C07D40302, C07D40314, A61K 3155, A61K 31555
Patent
active
052470750
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to functionalised tri-aza macrocycles, to metal complexes thereof, to conjugate compounds containing the functionalised tri-aza macrocycles and metal complexes thereof and to their use in diagnosis and therapy.
BACKGROUND OF THE INVENTION
The attachment of metal ions to proteins, peptides and other, smaller molecules is a fast expanding technology, which has numerous proven and potential applications in research, in industry and, particularly, in medicine.
In recent years, much of the impetus behind the development of this technology has been the ability to link metal ions to antibodies, especially monoclonal antibodies. Such metal labelled antibodies have found a widespread use, especially in medicine, where they have been employed, for example, to target the metal ion to a specific tissue type, both in vitro and in vivo. Thus, metal labelled antibodies have applications in locating specific tissue types (e.g. employing computer-aided tomographic techniques where the metal ion is in some way detectable) and in the treatment of cell disorders (e.g. treating mammalian tumours where the metal ion is a cytotoxic radionuclide).
Conventionally, attachment of the metal ion to a protein such as an antibody has been achieved by complexation by an acylic chelate such as a substituted diethylenetriaminepentaacetic acid [Gansow O. A. et al, Inorg. Chem., (1986), 25, 2772] or ethylenediaminetetraacetic acid [Meares, C. F. et al, Acc. Chem. Res., (1984), 17, 202] covalently linked to the antibody. Such acyclic complexes however tend to be unstable in vivo either as a result of acid-catalysed decomplexation or competitive chelate binding by Ca.sup.2+ or Zn.sup.2+ in serum, or as a result of competition from transferrin [Moerlein, S. M. et al, Int. J. Nuc. Med. Biol., (1981) 8, 277]. The lack of stability can result in uncomplexed metal atoms in the body which have a cytotoxic effect on healthy tissue (e.g. bone marrow) or which markedly reduce the signal-to-noise ratio of an imaging technique.
A possible alternative to the use of acyclic chelates in the labelling of antibodies is the use of macrocyclic ligands, which has been suggested in broad terms [Gansow O. A. et al. Am. Chem. Soc. Symp. Ser., (1984), 241, 215; UK Patent Specification Publication No. 2122641; and Moi M. K. et al, Anal. Biochem., (1985), 148, 249-253].
We have now found a new class of functionalised tri-aza macrocyles, members of which are able to form more kinetically inert complexes with metal ions than are chelating agents conventionally in use for the attachment of metal ions to proteins and other molecules. The macrocycles of the invention are particularly useful for attachment to proteins, especially antibodies, to provide conjugate compounds capable of binding metals to give complexes which are advantageously stable in vivo.
SUMMARY OF THE INVENTION
Thus, according to one aspect of the present invention we provide a compound of general formula (1): ##STR2## wherein m and n, which may be the same or different, is each zero or an integer 1, 2, or 3; hydrogen atom or an alkyl, alkoxyalkyl, --CO.sub.2 H, --SO.sub.3 H, --PO.sub.3 H.sub.2 or aryl group; when L is a covalent bond Z is a reactive functional group;
In the compounds of formula (1), alkyl groups represented by R.sup.1, R.sup.2 and R.sup.3 may be for example C.sub.1-6 alkyl groups such as methyl or ethyl groups. Alkoxyalkyl groups represented by R.sup.1, R.sup.2 or R.sup.3 may be for example C.sub.1-3 alkoxyC.sub.1-3 alkyl groups e.g. methoxymethyl. When R.sup.1, R.sup.2 or R.sup.3 is an aryl group it may be for example a substituted phenyl group, such as a group of formula ##STR3## (where R.sup.4 is a hydrogen atom or a C.sub.1-6 alkyl, e.g. methyl, C.sub.1-3 alkoxy.sub.1-3 alkyl, e.g. methoxymethyl, or C.sub.6-12 aryl, e.g. phenyl group).
In general, compounds of formula (1) in which R.sup.1, R.sup.2 and R.sup.3 are the same are preferred. Compounds of this type in which q is an integer from 1 to 6 inclusive, particularly an integer 1
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Millican Thomas A.
Parker David
Celltech Limited
Springer David B.
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