Chemistry: analytical and immunological testing – Tracers or tags
Reexamination Certificate
2001-01-31
2004-11-23
Warden, Jill (Department: 1743)
Chemistry: analytical and immunological testing
Tracers or tags
C556S011000, C556S020000
Reexamination Certificate
active
06821783
ABSTRACT:
The invention relates to new traceless linkers which use transition metal complexes to link a &pgr;-orbital containing substrate for subsequent synthesis by, for example, combinatorial chemistry or multiple parallel synthesis (MPS) to a support.
Combinatorial chemistry and MPS are techniques that are of great value in the efficient production of large numbers of molecules. Such large collections of molecules are of use in screening for useful properties or effects. The development of combinatorial chemistry and of MPS has been greatly facilitated by the use of solid-phase-synthesis in which substrate molecules are covalently attached to a solid support. The product of the reaction can be isolated by mechanically separating the solid support from the other components of the reactions and the product separated from the solid support by, for example, chemical cleavage. The whole process can be carried out quickly and efficiently and in many cases can be automated.
Members of a set of molecules made by combinatorial chemistry or MPS will have a recognisable common framework inherited from each different substrate and optionally modified during the combinatorial chemical steps. Disposed about the framework are the variable parts that derive from combinatorial modification of the substrate, for instance by combinatorial refunctionalisation of its functional groups. It is the variation in these parts that determines the diversity of the collection of molecules.
In most examples of solid-phase-synthesis the substrate is attached to the solid support through a covalent bond formed by functional groups on the substrate and support, for example by the formation of a carboxamide group between the support and the substrate.
This has three main limitations:
1. The functional group that is used to bind the substrate could have been used to introduce further variable reagents. This lost opportunity is a combinatorial reduction in the potential diversity of the molecules produced.
2. Although the object is to produce sets of compounds of great diversity in order to screen for useful properties or effects, the functional group that is linked to the support is a feature that all members of the combinatorial set of compounds share so that the diversity of the compounds produced is compromised by this common feature.
3. The chemistry required to attach a molecule through a functional group to a support varies as the functional group varies. In general, each different functional group will need to be linked to a support that has been specially prepared to react with it. Each differently linked functional group will need a different chemical treatment to release it from the support. Each different linking functional group will place different restrictions on the type of chemistry which can be carried out on the supported molecules.
A number of attempts have been made to link substrates to supports by linkers which are designed to be traceless, i.e. the linker leaves no feature on the final product. Traceless linkers are those that are not being used as a protecting group for a specific functional group, and that are removed from the product molecules as part of the process of releasing the molecules from the support. The traceless linkers reported so far (e.g Sucho Leiki I. Tetrahedron Lett., (1994), 35, 7307: Chenera B et. al., J. Am. Chem. Soc., (1995), 117, 11999: Plunkett, M. S. et. al., (1995), 60, 6006) have been developed for specific applications and are either of limited generality or require specific chemical synthesis of every variation of the first supported reagent, or leave behind a characteristic functional group that limits the diversity of the molecules produced. For instance, the existing examples of acid labile arylsilane linkers or reductively cleavable alkylthioether linkers are limited in scope and synthetically limited in accessibility. Acid labile arylsilane linkers are obtained by separate functionalisation or refunctionalisation of an aromatic ring of each linked substrate and after acid-induced cleavage of the linker every product contains a hydrogen atom at the position previously occupied by the silane functional group. The alkylthioether linkers similarly require a separate functionalisation or refunctionalisation of each linked substrate and cleavage of the thioether functional group that constitutes the link results in a reduction of the degree of functionality of the product.
Organometallic chemistry is a subset of chemistry dealing with the area of metals containing ligands bonded through a carbon atom. The area is extremely diverse due to the number of different interactions possible with the metal group, thus allowing any number of diverse compounds to be produced. One form of interaction between a metal and an organic group is in the form of a &pgr;-complex between an organic ligand having a &pgr;-bond, such as is present on an olefinic or an aromatic compound, and a transition metal. A characteristic of such complexes is that the bond between the transition metal and the organic group is formed to the &pgr;-orbitals of the organic group and not the &sgr;-orbitals of the framework. Although the reactivity of the &pgr;-orbitals is thereby changed the connectivity of the framework of the organic group remains intact. Such &pgr;-bonded transition metal complexes constitute a well-known class of compounds that is described, for instance, in “Comprehensive Organometallic Chemistry” Wilkinson G., Stone G. A., and Abel E. W. Eds., Pergamon Press, 1982, Oxford, U.K. and in “Transition Metals in the Synthesis of Complex Organic Molecules” Hegedus L. S., University Science Books, 1994, Mill Valley, Calif., USA. Examples of such complexes with common organic compounds include (1) (“Comprehensive Organometallic Chemistry” Vol. 3, Chapter 26.2, Tables 10 and 11 1003-1005) and (2) (“Transition Metals in the Synthesis of Complex Organic Molecules” Chapter 7.3, 221).
Transition metal complexes serve as masking or protective groups for &pgr;-bonded ligands of organic compounds. Soluble &pgr;-bonded complexes of arenes with chromium(0), of alkynes with cobalt(0), dienes and enones with iron(0) and olefines with iron (+1) are well known and have been used as protective groups for organic groups during functional group manipulation.
In addition &pgr;-bonded transition metal complexes have been immobilised on solid polymer supports via a polymer attached phosphine ligand for use as catalysts in organic and polymer chemistry. The polymer support is needed so as to aid isolation of the catalyst from the reaction mixture.
We have now found that transition metal complexes can be used as traceless linkers of remarkable simplicity, generality, and utility. These transition metal complexes may be used to &pgr;-bond unsaturated organic substrate ligands, such as arenes, alkynes, alkenes, and dienes, to a support for use in combinatorial chemistry and MPS.
The invention is illustrated below.
A feature of the traceless linker illustrated is its versatility: not only can the transition metal attach to a wide variety of &pgr;-orbital containing substrates, to allow an enormous diversity of library components to be synthesised, but it can also be attached to a great variety of supports. The transition metal+linker ligand constitutes a “traceless” linker because no trace of the link in the form of a characteristic functional group remains on the chemically modified substrate molecule after it has been released, as the product, from the support. This is true also in cases where the original &pgr;-orbital containing framework (an unsaturated system) of the substrate ligand has itself been modified during the synthesis or cleavage of the product since the modification to the original &pgr;-orbital containing framework is a modification to the core or backbone of the molecule rather than to its functional groups. Therefore all the functional groups of a substrate supported in this way are available for diverse modification.
Presented as a first feature of the invention is the use of a tra
Comely Alex C
Gibson Sue E
Hales Neil J
Peplow Mark A
Astrazeneca AB
Cole Monique T.
Fish & Richardson P.C.
Warden Jill
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