COMPOUNDS FOR USE IN SYNTHESIS OF PEPTIDOMIMETICS
Synthesis of O-benzotriazole and O-imidazole synthons are described. Uses of synthons in synthesis of azapeptides and other peptidomimetics, azapeptides and other peptidomimetics synthesized from the synthons and uses of azapeptides and other peptidomimetics are also described.
1 . A method of preparing an azapeptide comprising:
a step of activating a compound of Formula (IA):
wherein
A is N-phthalimidyl (NPhth) or NR 1 R 2 ;
R 1 is H;
R 2 is tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), or 2-(3,5-dimethoxyphenyl)propan-2-yloxycarbonyl (Ddz), or
R and R 1 are joined together by -(CH 2 —CH 2 —CH 2 )—;
X is selected from the group consisting of unsubstituted or substituted imidazolyl and unsubstituted or substituted benzotriazolyl, wherein the substituents on said substituted imidazolyl and benzotriazolyl are selected from the group consisting of halo, C 1 -C 6 alkyl, hydroxy, —COOH, —COH, methoxy, ethoxy, propoxy, a C 1 -C 6 haloalkyl, —NH 2 , and —NH 3 ; and
R is a side chain radical of an unnatural amino acid, which is unsubstituted or substituted by one or more substituents selected from the group consisting of halo, a C 1 -C 6 alkyl, hydroxy, —COOH, —COH, methoxy, ethoxy, propoxy, a C 1 -C 6 haloalkyl, and a protecting group; and
a step of coupling the activated compound with N-terminal of an amino acid or N-terminal of an aza-amino acid;
wherein the azapeptide is a compound of Formula (V):
wherein
is at the N-terminus and/or the C-terminus of the compound of Formula (V), is adjacent to the N-terminus and/or the C-terminus of the compound of Formula (V) or hydrolysis site of the compound of Formula (V);
B is selected from the group consisting of hydrogen, —NH 2 , —NNH 2 , —CONH 2 , —COOR 3 , —COOH, —COH, —COC 1 -C 4 alkyl, —COC 1 -C 4 haloalkyl, —OH, an amino acid, an aza amino acid, a 2 to 60-mer peptide, a 2 to 60-mer aza peptide, and a 2 to 60-mer azatide,
D is selected from the group consisting of —OR 4 , —OH, —NH 2 , —NNH 2 , —NHCOCH 3 , —NHCH 3 , —N(CH 3 ) 2 , —CONH 2 , —COOH, —COH, —COC 1 -C 4 alkyl, —COC 1 -C 4 haloalkyl, an amino acid, an aza amino acid, a 2 to 60-mer peptide, a 2 to 60-mer aza peptide, and a 2 to 60-mer azatide,
R 3 and R 4 is each independently selected from the group consisting of C 1 -C 6 alkyl, methoxy, ethoxy, propoxy, C 1 -C 6 haloalkyl and a protecting group, and
R is side chain radical of an unnatural amino acid, which is unsubstituted or substituted by one or more substituents selected from the group consisting of halo, a C 1 -C 6 alkyl, hydroxy, —COOH, —COH, methoxy, ethoxy, propoxy, a C 1 -C 6 haloalkyl, and a protecting group.
2 . The method according to claim 1 , wherein the compound is activated by iodomethane.
3 . The method of claim 1 , wherein said coupling is in acetonitrile.
4 . The method of claim 3 , wherein DIPEA is added to the acetonitrile.
5 . The method of claim 1 , wherein said coupling is during solid phase azapeptide synthesis.
6 . The method of claim 1 , wherein said coupling is during liquid phase azapeptide synthesis.