Methods for making intermediates and oxytocin analogues
AssigneeFerring B.V.
InventorsKazimierz Wisniewski, Jacek Stalewski, Guangcheng Jiang
Life of this patent
Estimating the term…
Abstract
More efficient and/or economical methods for synthesizing heptapeptide alcohol analogs of oxytocin are provided along with novel intermediates which are useful in synthesizing such oxytocin analogs. Efficient and economical methods for synthesizing intermediates useful in synthesizing these oxytocin analogs are also provided.
Claims7
A method for preparing an equivalent heptapeptide analogue, or a pharmaceutically acceptable salt thereof, having oxytocin antagonist activity and consisting of a moiety A and a residue B having a C-terminal β-aminoalcohol which is bound to the moiety A by an amide bond,
- wherein (1) said residue B is:
- with Q being (CH2)n—NH2, with n being 2, 3 or 4 and R being CH3 or C2H5;
- and
- (2) said moiety A is:
- with Mpa, Ile, Asn and Abu having the following meanings:
- Mpa 3-mercaptopropionic acid residue
- Ile isoleucine residue
- Asn asparagine residue
- Abu α-aminobutyric acid residue;
- with X being a D-aromatic α-amino acid, which may optionally have its side chain protected, and
- with Y being an aliphatic α-amino acid;
- which method includes the following steps:
- (a) reacting an α-amino acid having a protected amino side chain and an acylated α-amino group with a reducing agent to change the acyl group to an alkyl group and to simultaneously change the α-carboxy group to CH2OH to provide a diamino alcohol having the formula:
- wherein P1 is H or an amino-protecting group;
- and Q′ is (CH2)n—NP2P3, with n being 2, 3 or 4, P2 being an amino-protecting group that is different from P1 and not labile under conditions that would remove P1, and P3 being H or an amino-protecting group that is the same or different than P2, provided however that P2 and P3 may be a divalent amino-protecting group;
- (b) reacting said product of step (a) with the pentapeptide:
- wherein P4, P5 and P6 are individually protecting groups to form the linear hexapeptide:
- c) selectively deprotecting and cyclizing the linear compound of step(b) to create the heptapeptide:
A method for preparing a heptapeptide analogue, or a pharmaceutically acceptable salt thereof, having oxytocin antagonist activity and consisting of a hexapeptide moiety A and a residue B having a C-terminal β-aminoalcohol which is bound to the moiety A by an amide bond,
- wherein (1) said residue B is:
- with Q being (CH2)n—NH2, with n being 2, 3 or 4 and R being CH3 or C2H5;
- and
- (2) said moiety A is:
- with Mpa, Ile, Asn and Abu having the following meanings:
- Mpa 3-mercaptopropionic acid residue
- Ile isoleucine residue
- Asn asparagine residue
- Abu α-aminobutyric acid residue;
- with X being a D-aromatic α-amino acid, which may optionally have its side chain protected, and
- with Y being an aliphatic α-amino acid;
- which method includes the following steps:
- (a) providing a resin-linked amino acid having the formula:
- wherein P5 is a protecting group and P7 is H or a protecting group;
- (b) adding residues either singularly or in a group or groups to create the following pentapeptide-resin:
- wherein P4 is H or a protecting group and P6 is a protecting group;
- (c) cleaving the pentapeptide-resin to form the linear free acid pentapeptide:
- (d) coupling
- to the product of step (c) to form the linear hexapeptide:
- wherein Q′ is (CH2)n—NP2P3, with n being 2, 3 or 4, P2 being an amino-protecting group, and P3 being H or an amino-protecting group that is the same or different than P2, provided however that P2 and P3 may be a divalent amino-protecting group;
- (e) selectively deprotecting and cyclizing the linear compound resulting from step (d) to create the equivalent heptapeptide:
- (f) further deprotecting the moiety Q′ to create the cyclic equivalent heptapeptide:
Dependencies are inferred from the claim text.