US 2004/0171797 A1Published application

Method for synthesizing KPV tripeptide diamide derivates

AssigneeL'oreal

InventorSylvie Genard

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Abstract

The object of the invention is to provide an improved method for synthesizing a KPV tripeptide diamide derivate having the formula (I) such as defined in the specification. The synthesis method according can be implemented with any of the stereoisomers of each of the Lysine (K), Proline (P) or Valine (V) amino acid residues.

Claims31

Dependent claims

A solution synthesis method for a KPV tripeptide diamide derivate represented by the following formula (I)

39
or for a salt thereof, independently from the stereochemistry of the implemented amino acids wherein:
a) R1, R′1 and R″1 represent, independently from each other, a hydrogen atom or
a linear or branched C1-C22 alkyl moiety, optionally interrupted by a heteroatom such as O or N or S or Si,
C4-C10 cycloalkyl moiety,
a linear or branched C1-C22 polyfluoroalkyl or perfluoroalkyl moiety,
an aryl moiety optionally substituted by one or more halogen atoms such as Cl, F, Br or I or one or more linear or branched C1-C4 alkyl moieties,
an aralkyl moiety,
or R1 and R′1 could form with C(R″1) a saturated ring with from 3 to 7 atoms, optionally substituted by one or more linear or branched C1-C4 alkyl moieties and/or optionally containing a heteroatom such as O, S or N,
with the proviso that the R1(R′1)(R″1)CO group does not represent an amino acid residue or a peptide residue;
b) R2 and R3 represent, independently from each other, a hydrogen atom or represent
a linear or branched C1-C24 alkyl moiety, optionally interrupted by a heteroatom such as O or N or S or Si,
a C4-C10 cycloalkyl moiety,
a linear or branched C1-C22 polyfluoroalkyl or perfluoroalkyl moiety,
an aryl moiety optionally substituted by one or more halogen atoms such as Cl, F, Br or I, or one or more linear or branched C1-C4 alkyl moieties,
an aralkyl moiety,
or R2 and R3 could form with the nitrogen atom a saturated ring with from 5 or 6 atoms optionally substituted by one or more linear or branched C1-C4 alkyl moieties, said saturated ring optionally containing a heteroatom such as O, S or also an additional nitrogen atom,
with the proviso that the N(R2) (R3) group does not represent an amino acid or a peptide residue;
said method comprising:
a) reacting a lysine diprotected residue having the following formula (II):
40
optionally salified by a mineral or organic base,
wherein P1 and P2, may be the same or diffient and each represent independently from one another a protective group,
with a Proline residue having the following formula (III):
41
optionally salified by a mineral or organic acid,
wherein P3 represents a protective group differing from any of the P1 and P2 protective groups, or wherein P3 represents a hydroxyl group,
in the presence of an activation reagent or a coupling reagent in a solvent, so as to obtain the following compound having the formula (IV):
42
wherein P1, P2 and P3 have the above-mentioned meanings,
b) and, in any order,
1) coupling a valine compound having the following formula (V) on the C-terminal function of the Proline residue of the compound with formula (IV) wherein P3 represents OH,:
43
wherein R2 and R3 have the same meanings as hereinabove, and removing the P1 protective group,
2) amidating the NH2(α) group in a N-terminal position of the lysine residue by a compound having the following formula (VI-A) or (VI-B):
44
so as to obtain the following compound having the formula (XII):
45
wherein P2, R1, R′1, R″1, R2 and R3 have the same meaning as hereinabove;
c) removing the P2 protective group from the compound having the formula (XII) so as to obtain the compound having the formula (I), optionally under the form of a mineral or organic salt.

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A KPV tripeptide diamide derivate or salt thereof represented by the following formula (IA):

63
wherein:
a) R1, R′1 and R″1 represent, independently from each other, a hydrogen atom or
a linear or branched C1-C22 alkyl moiety, optionally interrupted by a heteroatom such as O or N or S or Si,
C4-C10 cycloalkyl moiety,
a linear or branched C1-C22 polyfluoroalkyl or perfluoroalkyl moiety,
an aryl moiety optionally substituted by one or more halogen atoms such as Cl, F, Br or I or one or more linear or branched C1-C4 alkyl moieties,
an aralkyl moiety,
or R1 and R′1 could form with C(R″1) a saturated ring with from 3 to 7 atoms, optionally substituted by one or more linear or branched C1-C4 alkyl moieties and/or optionally containing a heteroatom such as O, S or N,
hydrogen,
with the proviso that the R1(R′1)(R″1)CO group does not represent an amino acid residue or a peptide residue with at least one of R1, R′1, R″1 being different from hydrogen.
b) R2 and R3 represent, independently from each other, a hydrogen atom or represent
a linear or branched C1-C24 alkyl moiety, optionally interrupted by a heteroatom such as O or N or S or Si,
a C4-C10 cycloalkyl moiety,
a linear or branched C1-C22 polyfluoroalkyl or perfluoroalkyl moiety,
an aryl moiety optionally substituted by one or more halogen atoms such as Cl, F, Br or I, or one or more linear or branched C1-C4 alkyl moieties,
an aralkyl moiety,
or R2 and R3 could form with the nitrogen atom a saturated ring with from 5 or 6 atoms optionally substituted by one or more linear or branched C1-C4 alkyl moieties, said saturated ring optionally containing a heteroatom such as O, S or also an additional nitrogen atom, with at least one of the residues R2 or R3 being different from hydrogen,
with the proviso that the N(R2) (R3) group does not represent an amino acid or a peptide residue.

16 more elements

Dependencies are inferred from the claim text.

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Abstract

A solution synthesis method for a KPV tripeptide diamide derivate represented by the following formula (I)

39
or for a salt thereof, independently from the stereochemistry of the implemented amino acids wherein:
a) R1, R′1 and R″1 represent, independently from each other, a hydrogen atom or
a linear or branched C1-C22 alkyl moiety, optionally interrupted by a heteroatom such as O or N or S or Si,
C4-C10 cycloalkyl moiety,
a linear or branched C1-C22 polyfluoroalkyl or perfluoroalkyl moiety,
an aryl moiety optionally substituted by one or more halogen atoms such as Cl, F, Br or I or one or more linear or branched C1-C4 alkyl moieties,
an aralkyl moiety,
or R1 and R′1 could form with C(R″1) a saturated ring with from 3 to 7 atoms, optionally substituted by one or more linear or branched C1-C4 alkyl moieties and/or optionally containing a heteroatom such as O, S or N,
with the proviso that the R1(R′1)(R″1)CO group does not represent an amino acid residue or a peptide residue;
b) R2 and R3 represent, independently from each other, a hydrogen atom or represent
a linear or branched C1-C24 alkyl moiety, optionally interrupted by a heteroatom such as O or N or S or Si,
a C4-C10 cycloalkyl moiety,
a linear or branched C1-C22 polyfluoroalkyl or perfluoroalkyl moiety,
an aryl moiety optionally substituted by one or more halogen atoms such as Cl, F, Br or I, or one or more linear or branched C1-C4 alkyl moieties,
an aralkyl moiety,
or R2 and R3 could form with the nitrogen atom a saturated ring with from 5 or 6 atoms optionally substituted by one or more linear or branched C1-C4 alkyl moieties, said saturated ring optionally containing a heteroatom such as O, S or also an additional nitrogen atom,
with the proviso that the N(R2) (R3) group does not represent an amino acid or a peptide residue;
said method comprising:
a) reacting a lysine diprotected residue having the following formula (II):
40
optionally salified by a mineral or organic base,
wherein P1 and P2, may be the same or diffient and each represent independently from one another a protective group,
with a Proline residue having the following formula (III):
41
optionally salified by a mineral or organic acid,
wherein P3 represents a protective group differing from any of the P1 and P2 protective groups, or wherein P3 represents a hydroxyl group,
in the presence of an activation reagent or a coupling reagent in a solvent, so as to obtain the following compound having the formula (IV):
42
wherein P1, P2 and P3 have the above-mentioned meanings,
b) and, in any order,
1) coupling a valine compound having the following formula (V) on the C-terminal function of the Proline residue of the compound with formula (IV) wherein P3 represents OH,:
43
wherein R2 and R3 have the same meanings as hereinabove, and removing the P1 protective group,
2) amidating the NH2(α) group in a N-terminal position of the lysine residue by a compound having the following formula (VI-A) or (VI-B):
44
so as to obtain the following compound having the formula (XII):
45
wherein P2, R1, R′1, R″1, R2 and R3 have the same meaning as hereinabove;
c) removing the P2 protective group from the compound having the formula (XII) so as to obtain the compound having the formula (I), optionally under the form of a mineral or organic salt.

37 more elements