Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-12-07
1998-05-26
Higel, Floyd D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
5483381, 5483415, C07D23354, C07K 106
Patent
active
057567581
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to intermediate compounds useful in peptide synthesis.
2. Brief Description of Related Art
The regioselective chemical reaction of a compound with several reactive chemical functions which are also different requires the protection of all these functions except for that (those) with which a chemical reaction is to be entered into. To protect these functions, molecule groups (protective groups) are introduced. These can subsequently be removed mildly and selectively with reformation of the original function. For complex and multi-stage syntheses, in particular of natural substances, such as oligopeptides and oligonucleotides, various types of protective groups are necessary. They are distinguished by highly different cleavage conditions. A system of protective groups in which the individual types are selectively cleavable in such a way that in each case all other protective groups remain untouched is called orthogonal. The person skilled in the art is familiar with the principle of protective group chemistry. Reference may be made to the literature mentioned in the following text. If the protective group type additionally contains a further reactive function such that it can be linked covalently and stably with a support material for solid-phase synthesis, the person skilled in the art speaks of an "anchor group" or "linker group". A special type of protective group is present if the protective group first has to be brought into a labile form by a chemical reaction inserted before the removal, which can then be removed in a second step under mild conditions. In this case a protected protective group or "safety-catch group" is spoken of. Although two reaction steps are necessary for removal here, a group of this type can offer great advantages: but can be removed by the sequence of two specific, very mild reaction steps; it offers good or better possibilities for the isolation and purification of the final product.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a compound with which a carboxyl function (COOH) can be reacted with formation of an ester bond, by means of which a protective group and, in particular, an anchor group for the carboxyl function can be provided which has the following features: able to be converted into a labile intermediate; conditions, for example those of a solid-phase synthesis of peptides, and allow purification of the intermediates; solution, preferably at neutral pH (approximately pH 7) or almost neutral pH (5 to 9), and be able to reform the original carboxyl function so that the synthesis product having a free carboxyl function is employable directly (without further purification) in a cytobiological or biochemical test experiment.
In particular, this protective group type should be employable as an anchor group for the solid-phase synthesis of peptides, in particular according to the Fmoc/tBu method; compare, for example, Fields & Noble in Int. J. Peptide Protein Res., 35 (1990) 161-214.
According to the invention, for this a compound of the formula substituting the Y group with formation of an ester bond, by means of which a protective group and, in particular, an anchor group for the carboxyl function is provided, where hydrolysis-sensitive acyl compounds and in deprotected form can catalyze the hydrolysis of the ester bond intramolecularly, catalysis, formation of the ester bond and its hydrolysis.
BRIEF DESCRIPTION OF THE DRAWINGS
The FIGURE shows graphically the kinetics of peptide removal from some anchor groups in solutions. In graph A (o) represents Compound (9a) in 0.01M KH.sub.2 PO.sub.4 /Na.sub.2 HPO.sub.4 (pH 7.5), (.DELTA.) Compound (9a) in 0.01M KH.sub.2 PO.sub.4 /Na.sub.2 HPO.sub.4 (pH 7.5), (.smallcircle.) Compound (9a) in 0.01M TEAAc (pH 7.3), (.box-solid.) Compound (11a) in 0.01M KH.sub.2 PO.sub.4 /Na.sub.2 HPO.sub.4 (pH 7.5) at 50.degree. C. In graph B (.circle-solid.) represents Compound (9a), (.smallcircle.) Compound (8a) and (.box-solid.) Comp
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Frank Ronald
Hoffmann Stefan
Gesellschaft fur Biotechnologische Forschung mbH IGBF)
Higel Floyd D.
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