Compounds for use in synthesis of peptidomimetics
View Patent ↗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 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) 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, —CHO, 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, —CHO, methoxy, ethoxy, propoxy, a C 1 -C 6 haloalkyl, and a protecting group.
2. The compound according to claim 1 , which is a compound of Formula (II):
wherein
M is selected from the group consisting of H, halo, C 1 -C 6 alkyl, hydroxy, —COOH, —CHO, methoxy, ethoxy, propoxy, and C 1 -C 6 haloalkyl.
3. The compound according to claim 2 , wherein R is the residue of a β-amino acid or an aliphatic 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, —CHO, methoxy, ethoxy, propoxy, a C 1 -C 6 haloalkyl, and a protecting group.
4. The compound according to claim 3 , wherein the β-amino acid is selected from the group consisting of L-β-homotyrosine, β-alanine, L-β-homoasparagine, L-β-homoalanine, L-β-homophenylalanine, L-β-homoproline, L-beta-homolysine, L-beta-homoarginine, and L-β-proline.
5. The compound according to claim 3 , wherein the aliphatic amino acid is selected from the group consisting of 6-aminohexanoic acid, 2-amino-3-methoxybutanoic acid, 1-aminocyclopentane-1-carboxylic acid, 2-(aminooxy) acetic acid, and 2-(2-(aminoethoxy)ethoxy)acetic acid.
6. The compound according to claim 1 , which is a compound of Formula (IV):
wherein
M is selected from the group consisting of H, halo, C 1 -C 6 alkyl, hydroxy, —COOH, —CHO, methoxy, ethoxy, propoxy, and C 1 -C 6 haloalkyl.
7. The compound according to claim 6 , wherein R is the residue of a β-amino acid or an aliphatic 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, —CHO, methoxy, ethoxy, propoxy, a C 1 -C 6 haloalkyl, and a protecting group.
8. The compound according to claim 7 , wherein the β-amino acid is selected from the group consisting of L-β-homotyrosine, β-alanine, L-β-homoasparagine, L-β-homoalanine, L-β-homophenylalanine, L-β-homoproline, L-beta-homolysine, L-beta-homoarginine, and L-β-proline.
9. The compound according to claim 7 , wherein the aliphatic amino acid is selected from the group consisting of 6-aminohexanoic acid, 2-amino-3-methoxybutanoic acid, 1-aminocyclopentane-1-carboxylic acid, 2-(aminooxy)acetic acid, and 2-(2-(aminoethoxy)ethoxy)acetic acid.
10. The compound according to claim 1 , wherein the protecting group is selected from the group consisting of Phth, Boc, Fmoc, and Ddz.
11. The compound according to claim 1 , which is a compound of Formula (IB), which is
12. The compound according to claim 1 , wherein the unnatural amino acid is selected from the group consisting of a β-amino acid, an aliphatic amino acid, β-cyclohexyl-L-alanine, 6-aminohexanoic acid, L-α,β-diaminopropionic acid, L-propargylglycine, α-aminoisobutyric acid, β-(2-pyridyl)-L-alanine, β-(3-pyridyl)-L-alanine, β-cyclopropyl-L-alanine, β-t-butyl-L-alanine, (2,4-dinitrophenyl)-L-α,β-diaminopropionic acid, (allyloxycarbonyl)-L-α,β-diaminopropionic acid, D-α,β-diaminopropionic acid, (N-γ-1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl)-L-α,γ-diaminobutyric acid, (N-γ-4-methyltrityl)-L-α,γ-diaminobutyric acid, L-α,γ-diaminobutyric acid, 4-fluoro-L-phenylglycine, 5,5,5-trifluoro-DL-leucine, L-α-t-butylglycine, L-2-amino-3-(dimethylamino)-propionic acid, L-2-aminocaproic acid, L-allylglycine, lysine azide, (N-δ-4-methyltrityl)-L-ornithine, Arg(Me)(Pbf)-OH, symmetrical dimethyl-L-arginine, unsymmetrical dimethyl-L-arginine, L-2-amino-3-guanidinopropionic acid, L-citrulline, ε-acetyl-L-lysine, Lys(ivDde)-OH, Lys(Me)2-OH·HCl, Lys(Me3)-OH chloride, α-methyl-DL-glutamic acid, γ-carboxy-L-glutamic acid, γ,γ-di-t-butyl ester, (N-γ-ethyl)-L-glutamine, 2,6-diaminopimelic acid, Glu(OAll)-OH, L-cysteic acid, α-methyl-DL-methionine, DL-buthionine, L-selenomethionine, S-[2-(4-pyridyl)ethyl]-L-cysteine, S-[2-(4-pyridyl)ethyl]-L-cysteine, S-diphenylmethyl-L-cysteine, S-trityl-L-homocysteine, S-trityl-L-penicillamine, (Se-p-methoxybenzyl)-L-selenocysteine, O-hydroxyphenylalanine, 2-cyano-L-phenylalanine, L-thyroxine, O-methyl-L-tyrosine, β-methyl-DL-phenylalanine, 3,4-dichloro-L-phenylalanine, 3,4-difluoro-L-phenylalanine, 3,4-dihydroxy-L-phenylalanine, 3-amino-L-tyrosine, 3-chloro-L-tyrosine, 3-fluoro-DL-tyrosine, 3-nitro-L-tyrosine, 4-amino-L-phenylalanine, 4-aminomethyl-L-phenylalanine, 4-(phosphonomethyl)-phenylalanine, 4-benzoyl-D-phenylalanine, 4-(bis(2-chloroethyl)amino)-L-phenylalanine, 4-cyano-L-phenylalanine, 4-fluoro-L-phenylalanine, 4-iodo-L-phenylalanine, DL-m-tyrosine, 2,6-dimethyl-tyrosine, L-homophenylalanine, Phe(4-guanidino)-OH, O-benzyl-L-phosphotyrosine, (2S,3R)-3-phenylpyrrolidine-2-carboxylic acid, (2S,4S)-4-phenyl-pyrrolidine-2-carboxylic acid, (2S,3aS,7aS)-Octahydro-1H-indole-2-carboxylic acid, (2S,4R)-(−)-4-t-butoxypyrrolidine-2-carboxylic acid, trans-4-fluoro-L-proline, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, 4-amino-3-hydroxybutanoic acid, L-α-methylserine, (2S,3S)-2-amino-3-methoxybutanoic acid, O-benzyl-L-phosphoserine, O-benzyl-D-phosphothreonine, O-benzyl-L-phosphothreonine, 4-methyl-DL-tryptophan, 6-fluoro-DL-tryptophan, 6-methyl-DL-tryptophan, DL-7-azatryptophan, (R)-7-Azatryptophan, 5-benzyloxy-DL-tryptophan, 5-bromo-DL-tryptophan, 5-chloro-DL-tryptophan, 5-fluoro-DL-tryptophan, 5-hydroxy-L-tryptophan, 5-methoxy-L-tryptophan, 6-chloro-L-tryptophan, 7-methyl-DL-tryptophan, 5-azido-pentanoic acid, 2-amino-N-(3-azidopropyl)-3-mercaptopropionamide, Azidohomoalanine, L-propargylglycine·DCHA, azidolysine, p-azidophenylalanine, D-propargylglycine, tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine, 2-(7′-octenyl) alanine, 2-(4′-pentenyl) alanine, 2-(4′-pentenyl) glycine, [5-((2-aminoethyl)amino)naphthalene-1-sulfonic acid], L-glutamic acid-γ-[2-(1-sulfonyl-5-naphthyl)-aminoethylamide], N-ε-(5-carboxyfluorescein)-L-lysine, N-ε-(4,4-dimethylazobenzene-4′carbonyl)-L-lysine, N-ε-2,4-dinitrophenyl-L-lysine, N-ε-[(7-methoxycoumarin-4-yl)-acetyl-L-lysine, glycosylated amino acids, Ser(β-D-GlcNAc(Ac) 3 )-OH, Thr(β-D-GlcNAc(Ac) 3 )-OH), 3-azabicyclo[3.1.0]hexane-2-carboxylic acid, 4-amino-(1-carboxymethyl) piperidine, 4-phenylpiperidine-4-carboxylic acid, Na-methyl-N-im-trityl-L-histidine, Nα-methyl-O-benzyl-L-serine dicyclohexylammonium salt, Nα-methyl-Nω-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-L-arginine, Nα-methyl-L-leucine, Nα-methyl-L-norvaline, Nα-methyl-L-phenylalanineNα-methyl-O-t-butyl-L-serine, Nα-methylglycine, 2-(2-(aminoethoxy)ethoxy)acetic acid, 6-amino-4-oxahexanoic acid, 5-amino-3-oxapentanoic acid, NH-(PEG) 10 -CH 2 CH 2 COOH, NH-(PEG) 12 -CH 2 CH 2 COOH, 9-amino-4,7-dioxanonanoic acid, 12-amino-4,7,10-trioxadodecanoic acid, 15-amino-4,7,10,13-tetraoxapentadecacanoic acid, 18-amino-4,7,10,13,16-pentaoxaoctadecanoic acid, 21-amino-4,7,10,13,16,19-hexaoxaheneicosanoic acid, NH-(PEG) 8 -CH 2 CH 2 COOH, 11-amino-3,6,9-trioxaundecanoic acid, N-(Fmoc-8-amino-3,6-dioxa-octyl)succinamic acid.
13. A method of preparing an azapeptide comprising
a step of activating a compound according to claim 1 ; 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 B is selected from the group consisting of hydrogen, —NH 2 , —NNH 2 , —CONH 2 , —COOR 3 , —COOH, —CHO, —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, —CHO, —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 are 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 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, —CHO, methoxy, ethoxy, propoxy, a C 1 -C 6 haloalkyl, and a protecting group.
14. The method according to claim 13 , wherein the compound according to claim 1 is activated by iodomethane.
15. The method of claim 13 , wherein said coupling is in acetonitrile.
16. The method of claim 15 , wherein DIPEA is added to the acetonitrile.
17. The method of claim 13 , wherein said coupling is during solid phase azapeptide synthesis.
18. The method of claim 13 , wherein said coupling is during liquid phase azapeptide synthesis.
19. A compound of Formula (IA):
wherein
A is N-phthalimidyl (NPhth) or NR 1 R 2 ;
R 1 is H; or
R 2 is tert-butoxycarbonyl (Boc) or 2-(3,5-dimethoxyphenyl)propan-2-yloxycarbonyl (Ddz);
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, —CHO, 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, —CHO, methoxy, ethoxy, propoxy, a C 1 -C 6 haloalkyl, and a protecting group.
20. The compound according to claim 19 , which is a compound of Formula (II):
wherein
M is selected from the group consisting of halo, C 1 -C 6 alkyl, hydroxy, —COOH, —CHO, methoxy, ethoxy, propoxy, and C 1 -C 6 haloalkyl.
21. The compound according to claim 20 , wherein R is the residue of a β-amino acid or an aliphatic 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, —CHO, methoxy, ethoxy, propoxy, a C 1 -C 6 haloalkyl, and a protecting group.
22. The compound according to claim 21 , wherein the β-amino acid is selected from the group consisting of L-β-homotyrosine, β-alanine, L-β-homoasparagine, L-β-homoalanine, L-β-homophenylalanine, L-β-homoproline, L-beta-homolysine, L-beta-homoarginine, and L-β-proline.
23. The compound according to claim 19 , wherein 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, —CHO, methoxy, ethoxy, propoxy, a C 1 -C 6 haloalkyl, —NH 2 .
24. A method of preparing an azapeptide comprising
a step of activating a compound according to claim 19 ; 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 B is selected from the group consisting of hydrogen, —NH 2 , —NNH 2 , —CONH 2 , —COOR 3 , —COOH, —CHO, —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, —CHO, —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 are 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 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, —CHO, methoxy, ethoxy, propoxy, a C 1 -C 6 haloalkyl, and a protecting group.
25. The method according to claim 24 , wherein the compound according to claim 1 is activated by iodomethane.
26. The method of claim 24 , wherein said coupling is in acetonitrile.
27. The method of claim 26 , wherein DIPEA is added to the acetonitrile.
28. The method of claim 24 , wherein said coupling is during solid phase azapeptide synthesis.
29. The method of claim 24 , wherein said coupling is during liquid phase azapeptide synthesis.