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US 6,569,993 B1Granted
Process for the preparation of resin-bound cyclic peptides
AssigneeAventis Pharma S.A.
InventorsAdam W. Sledeski, James J. Mencel
Life of this patent
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Abstract
This invention is directed to a process for the solid phase, fragment-based synthesis of resin-bound cyclic peptide analogs of parathyroid hormones and analogs of parathyroid hormone-related proteins, which analogs contain at least one bridge between the side chains of two non-adjacent amino acid residues, and to peptide fragments useful therefor.
Claims7
A method for preparing a peptide having the formula:
- wherein
- J, L, and M are linear peptide fragments, and
- K2 is a cyclic peptide fragment;
- this method comprising the steps of:
- (1) preparing
- by sequential attachment of suitably protected amino acid residues to a resin to provide:
- where
- is a suitable peptide synthesis resin and M is a peptide fragment;
- (2) preparing separately by conventional peptide synthesis an N-terminally protected cyclic peptide of formula IV
- wherein P is a suitable amine protecting group,
- (3) coupling peptide III with peptide IV to provide a peptide of formula V
- (4) either (a) preparing peptide fragments J and L as a single peptide of formula VI
- then removing the protecting group from the N-terminus of peptide V and coupling peptide VI to the thus deprotected derivative of peptide V to provide a peptide of formula VII
- or (b) removing the protecting group from the N-terminus of peptide V and adding the protected individual amino acid elements of peptides J and L sequentially to the thus deprotected derivative of peptide V (using appropriate deprotection between individual additions),
- or (c) separately preparing either or both of peptides J and L as peptide fragments and coupling these peptide fragments to the growing peptide starting with the peptide of formula V;
- and
- (5) cleaving the resulting peptide from the resin, deprotecting said peptide and recovering it from the reaction medium.
14 more elements
A method for preparing a peptide having the formula:
- wherein
- J, L, and M are linear peptide fragments
- K1 is a cyclic peptide fragment, and
- K2 is a cyclic peptide fragment;
- this method comprising the steps of:
- (1) preparing
- by sequential attachment of suitably protected amino acid residues to a resin to provide:
- where
- is a suitable peptide synthesis resin and M is a peptide fragment;
- (2) preparing separately by conventional peptide synthesis an N-terminally protected cyclic peptide fragment of formula IV
- wherein P is a suitable amine protecting group,
- (3) Coupling peptide III with peptide IV to provide a peptide of formula V
- (4) (a) preparing separately N-terminal protected cyclic peptide of formula VIII
- wherein
- P is a suitable amine protecting group,
- by conventional peptide synthesis procedures;
- (b) preparing a peptide of formula IX
- (c) removing the protecting group from the N-terminus of peptide V and coupling peptide fragment IX with the thus deprotected derivative of peptide V to provide a peptide of formula X
- and (d) removing the protecting group from the N-terminus of peptide X and coupling cyclic peptide VIII with the thus deprotected derivative of peptide X to provide a peptide of formula XI
- (e) preparing peptide XII
- (f) removing the protecting group from the N-terminus of peptide XI and coupling peptide XII with the thus deprotected derivative of peptide XI;
- and
- (5) cleaving the resulting peptide from the resin, deprotecting said peptide and recovering said deprotected peptide from the reaction medium.
20 more elements
Dependencies are inferred from the claim text.