Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Synthesis of peptides
Patent
1997-03-03
1999-11-23
Celsa, Bennett
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Synthesis of peptides
530331, 530334, 530335, 530336, 530345, 564133, 564138, 564188, 564192, A61K 3802, C07K 100
Patent
active
059902787
DESCRIPTION:
BRIEF SUMMARY
TECHNOLOGICAL FIELD
The present invention pertains to protective and anchor groups useful in peptide synthesis, particularly in multistep peptide synthesis.
BACKGROUND OF THE INVENTION
Regioselective chemical conversion of a compound with a plurality of different chemical functions requires the protection of all these functions as far as that/those by means of which the chemical reaction is to be initiated. Molecule groups (protective groups) are introduced in order to protect these functions. In conjunction with this, these can be removed in a non-disruptive manner and selectively, with re-formation of the original function. For complex multi-stage syntheses, particularly of natural substances, such as oligopeptides and oligonucleotides, various types of protective groups are necessary. They are characterised by intensely differing conditions of splitting. A system of protective groups in which the individual types are so selectively splittable that all the other respective groups remain unaffected, it termed orthogonal. The principle is the subject of the chemistry of protective groups (see Protective Groups in Organic Synthesis, Greene, T. W. & Wuts, P. G. M. Eds., 2.sup.nd ed., 1991, John Wiley & Sons Inc., New York).
If the type of protective group has a further reactive function, it can be linked covalently and in a stable way with a carrier material for solid-phase synthesis. Then the terms "active group" or "linker group" are used (see e.g. Breitpohl et al. In Tetrahedron Lett. 28 (1987) 5651-5654 and Guibe et al. in Tetrahedron Lett. 30 (1989) 2641-2644). A special type of protective group or also active group is that which must firstly be brought into a labile form by a preceding chemical reaction, and which then in a second step can be split off under very gently conditions (protected protective group--"Safety-Catch" grouping; cf. E.g. Patek in Int. J. Peptide Protein Res. 42 (1993) 97-1176). Although in such a case two reaction steps are required for splitting, such groupings can have great advantages. conditions, but can be split by the sequence of two specific extremely mild reaction steps. sufficiently stable to offer good, or better, opportunities for isolation and cleaning the end product.
SUMMARY OF THE INVENTION
The object underlying the invention is to propose for a carbamide function (CONH.sub.2 -function) a special type of protective or anchor group having the following features: reaction conditions and permit cleaning of the intermediate products; physiological buffer solution at neutral pH (7) or almost neutral pH (5 to 9), and re-form the original carbamide function, so that the synthesis product can be used directly (without further cleaning) with a free carbamide function in a biocellular or biochemical test experiment.
According to the invention, there is also to be provided, for a carbamide function (CO--NH.sub.2 -function), a special type of protective group as an active group for the solid-phase synthesis of peptides (but also other molecular structures with a carbamide function), particularly according to the Fmoc-tBu-method (Fmoc SPPS) (see Fields & Noble in Int. J. Peptide Protein Res. 35 (1990) 161-214)and Boc/Bzl method (Boc SPPS) (see Barany et al. Int. J. Peptide Protein Res.(1987) 705-739.
The object underlying the invention is now achieved by a carbamide of the general formula: the chain of a peptide, and can have one or a plurality of amino acid residues; function, whereby R2 and R3 can be identical or different, but are different when one of the two residues means a hydrogen atom;
DETAILED DESCRIPTION OF THE INVENTION
The chemical bond between protective group and carbamide function can thus be a N-acyl-N.O-- or N-acyl-N.S acetal structure. This N-acyl-N.O-- or N-acyl-N.S acetal can be introduced by conversion of the carboxyl function with the amino function of a suitable N.O-- or N.S-acetal, the oxygen or sulphur function being protected and the amino function being free (reaction path A, see illustration). It can further be introduced by conversion of t
REFERENCES:
patent: 4454065 (1984-06-01), Gilvarg et al.
patent: 4922015 (1990-05-01), Breipohl et al.
Masao Kawai et al, Preparation of Protected .alpha.-Methoxyglycine and its Incorporation into Peptide Synthesis, Chemistry Letters, pp. 557-580, 1990.
A.R. Brown et al., Solid Phase Synthesis of .alpha.-Hydroxyglycine Extended Peptides-Biological Precursors of Peptede Amides, Tetrahedron Letters, vol. 35, No. 5, pp. 789-792, 1994.
N. Nichifor et al, Synthesis of Peptide Derivatives of 5-Fluorouracil, Tetrahedron, vol. 50, No. 12, pp. 3747-3760, 1994.
Kahns & Bundgaard Pharm Res. vol. 8 No. 12 1991 pp. 1533-1538.
JAPIO AN. 93-097789/CAPLUS AN. 1993: 603855/WPIDS AN 93-164426 of JP 05097789.
Frank Ronald
Hoffmann Stefen
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