Spirodiamino acid scaffold for combinatorial synthesis

Details Spirodiamino acid scaffold for combinatorial synthesis Spirodiamino acid scaffold for combinatorial synthesis

1999-04-09

2001-01-16

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C520S001000

Reexamination Certificate

active

06175020

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to azaspirononanes, to their synthesis and to their use as templates for the construction of synthetic receptors and libraries thereof and as intermediates in the synthesis of enzyme inhibitors.
BACKGROUND OF THE INVENTION
Receptors are molecules which selectively interact with other molecules. Antibodies, which represent one class of naturally occurring receptor molecules, bind to other molecules (antigens) with very high selectivity; they are also known to catalyze chemical reactions by selectively binding the transition states. Monoclonal antibodies are used as medicinal and diagnostic agents. Although antibodies are proteins, all receptor molecules need not be proteins. Receptor molecules perform a variety of tasks from selective binding of substrates to catalyzing chemical reactions, and their effectiveness is dependent upon their ability to bind molecular species (substrates or acceptors) with high selectivity. For example, the free energy for an antibody binding its antigen is normally from 6-15 kcal/mol.
There is considerable interest in synthetic receptors and libraries thereof For example, Still et al., WO95/19567 have described synthetic receptors which comprise a polyfunctional organic template covalently linked to two or more oligomers. In Still's case, as well as in the present invention, the oligomers may be oligoamides, oligoesters, oligoureas, oligourethanes, oligoamines, oligoethers, oligosulfonamides, oligonucleotides, oligosaccharides, peptides, etc.
In the construction of a library, a template or scaffold (the two will be used interchangeably herein) may be linked to a solid substrate and to an identifier which uniquely defines the synthetic receptor. The identifier is a stable chemical molecule or a plurality of stable chemical molecules distinguishable and detectable to picomolar levels. Usually the template is covalently linked to a solid support which is in turn covalently linked to the identifier, but in some embodiments the template may be directly attached to the identifier. (See PCT application WO 95/19567.)
Throughout this application, various references are referred to within parentheses or square brackets. The disclosures of these publications in their entireties are hereby incorporated by reference into this application. Variables are defined when introduced and retain that definition throughout. The term “combinatorial library” refers to a collection of molecules based on logical design and involving the selective combination of building blocks by means of simultaneous chemical reactions. Each species of molecule in the library is referred to as a member of the library.
SUMMARY OF THE INVENTION
In one aspect, the invention relates to compounds of formula I
wherein R
1
is hydroxy, lower alkoxy, benzyloxy, —NR
4
R
5
or the residue of a solid substrate; R
2
is hydrogen, a first amino-protecting group, or an oligomer residue; R
3
is hydrogen, a second amino-protecting group or an oligomer residue; R
4
is hydrogen, alkyl, aryl, heterocyclyl, arylalkyl or heterocyclylalkyl; and R
5
is hydrogen, alkyl, aryl, heterocyclyl, arylalkyl or heterocyclylalkyl or the residue of a solid substrate. The compounds are useful as scaffolds or templates for constructing synthetic receptors, enzyme inhibitors and libraries of synthetic receptors and enzyme inhibitors.
In another aspect the invention relates to compounds of formula II
in which R
1a
and R
3a
are subsets of R
1
and R
3
. R
1a
is hydroxy, lower alkoxy or benzyloxy and R
3a
is hydrogen or an amino-protecting group. These compounds are intermediates in the synthesis of the compounds of formula I.
In another aspect the invention relates to method of preparing a synthetic receptor library, optionally having identifiers associated with members of the library. The library comprises a plurality of different synthetic receptor members. Each synthetic receptor library member will commonly be a solid substrate having a single type of synthetic receptor attached. The method comprises the steps of:
(a) coupling a compound of formula I in which R
1
is hydroxy; R
2
is a first amino-protecting group, R
3
is a second amino-protecting group and R
2
and R
3
are orthogonally removable, to a solid substrate to provide a substrate-linked template having two protected active sites;
(b) reacting the substrate-linked template with an activator to remove a protecting group therefrom to expose an active site;
(c) coupling a protected oligomer monomer to the exposed active site to provide a protected, nascent oligomer;
(d) reacting the protected, nascent oligomer with an activator to remove a protecting group therefrom to expose an active site; and
(e) repeating steps (b) through (d) for each oligomer of the synthetic receptor.
The method may include the additional step of coupling an identifier to the solid substrate between steps (c) and (d).
In another aspect, the invention relates to a process for synthesizing an azaspirononane. The process comprises reacting a compound of formula III
wherein R
1b
is lower alkoxy, with a hydrazine of formula H
2
N—NH—R
3b
, wherein R
3b
is an amino-protecting group, followed by heating to provide a diazatricyclododecane of formula IV
The process may comprise the additional steps of cleaving the amine protecting group R
3b
and reductively cleaving the N—N bond to provide an azaspirononane of formula V
The azaspirononane may then be differentially protected as described below.


REFERENCES:
Armstrong et al., “Tandem Intramolecular Michael Addition and 1,3-Dipolar Cycloaddition . . . ”J. Chem. Soc., Chem. Comm.1327-1328 (1987).
Chiacchio et al. “Stereoselective Synthesis of Isoxazole and Pyrazole Annulated . . . ”Tetrahedron 53, 13855-13866 (1997).
Gallos et al. “Highly diastereoselective synthesis of densely functionalized . . . ”J. Chem. Soc.,Perkin Trans. 1, 2-4 (1997).

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