Cortistatin analogues and syntheses thereof
The present invention relates to analogs of cortistatin A, J, K, and L, having the general formula: and salts thereof, wherein R 1 , R 2 , R 3 , R 4 , n, and m are as defined herein; processes for preparing such compounds and intermediates thereto; pharmaceutical compositions comprising such compounds; methods for treating a proliferative disease; methods for treating a disease associated with aberrant angiogenesis; methods for inhibiting angiogenesis; and processes for preparing cortistatin A, J, K, and L, and analogs thereof.
1. A compound selected from:
wherein:
m is 1, 2,3, 4, 5, or 6;
X is halogen;
each PG is independently an oxygen protecting group that temporarily blocks oxygen during reaction at another functional moiety of the molecule;
R 1 is hydrogen or OR A wherein R A is independently a hydrogen, an oxygen protecting group that temporarily blocks oxygen during reaction at another functional moiety of the molecule, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety, a heteroaryl moiety, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio moiety; and
R 2 is hydrogen or C 1 -C 6 aliphatic.
2. The compound of claim 1 , wherein m is 1.
3. The compound of claim 2 , wherein X is Br.
4. The compound of claim 3 , wherein R 2 methyl.
5. The compound of claim 1 , wherein a PG is selected from methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), tert-butyldimethylsilyl (TBS), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), acetyl, benzyl and C 1 -C 6 alkyl.
6. The compound of claim 1 , wherein R 1 is OR A and R A is an oxygen protecting group that temporarily blocks oxygen during reaction at another functional moiety of the molecule.
7. The compound of claim 6 , wherein R A is selected from TBS, TMS, TES, TIPS, acetyl, benzyl, and C 1 -C 6 alkyl.
8. The compound of claim 7 , wherein R A is TBS.
9. A compound selected from:
wherein:
Z is SiMe 3 or Si(O i Pr) 2 Me; and
each PG is independently an oxygen protecting group that temporarily blocks oxygen during reaction at another functional moiety of the molecule.
10. The compound of claim 9 , wherein a PG is selected from methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), tert-butyldimethylsilyl (TBS), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), acetyl, benzyl and C 1 -C 6 alkyl.
11. The compound of claim 9 , wherein Z is SiMe 3 .
12. The compound of claim 9 , wherein Z is Si(O i Pr) 2 Me.
13. The compound of claim 1 selected from:
14. The compound of claim 13 , wherein m is 1.
15. The compound of claim 14 , wherein R 2 is methyl.
16. The compound of claim 13 , wherein a PG is selected from methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), tert-butyldimethylsilyl (TBS), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), acetyl, benzyl and C 1 -C 6 alkyl.
17. The compound of claim 13 , wherein R 1 is OR A and R A is an oxygen protecting group that temporarily blocks oxygen during reaction at another functional moiety of the molecule.
18. The compound of claim 17 , wherein R A is selected from TBS, TMS, TES, TIPS, acetyl, benzyl, and C 1 -C 6 alkyl.
19. The compound of claim 18 , wherein R A is TBS.
20. The compound of claim 1 , selected from:
21. The compound of claim 20 , wherein m is 1.
22. The compound of claim 21 , wherein X is Br.
23. The compound of claim 22 , wherein R 2 is methyl.
24. The compound of claim 20 , wherein a PG is selected from methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), tert-butyldimethylsilyl (TBS), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), acetyl, benzyl and C 1 -C 6 alkyl.
25. The compound of claim 20 , wherein R 1 is OR A and R A is an oxygen protecting group that temporarily blocks oxygen during reaction at another functional moiety of the molecule.
26. The compound of claim 25 , wherein R A is selected from TBS, TMS, TES, TIPS, acetyl, benzyl, and C 1 -C 6 alkyl.
27. The compound of claim 26 , wherein R A is TBS.
28. The compound of claim 1 , selected from:
29. The compound of claim 28 , wherein m is 1.
30. The compound of claim 29 , wherein R 2 is methyl.
31. The compound of claim 28 , wherein a PG is selected from methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), tert-butyldimethylsilyl (TBS), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), acetyl, benzyl and C 1 -C 6 alkyl.
32. The compound of claim 28 , wherein R 1 is OR A and R A is an oxygen protecting group that temporarily blocks oxygen during reaction at another functional moiety of the molecule.
33. The compound of claim 32 , wherein R A is selected from TBS, TMS, TES, TIPS, acetyl, benzyl, and C 1 -C 6 alkyl.
34. The compound of claim 33 , wherein R A is TBS.
35. The compound of claim 1 , wherein each PG is selectively removable by reagents that do not significantly attack the other functional groups.
36. The compound of claim 1 , wherein a PG does not have a stereogenic center.