Hemi-phorboxazole A derivatives and methods of their use
The present invention is directed to hemi phorboxazole A: and its stereoisomers, as well as derivatives of hemi phorboxazole A of formula I: wherein ring A is aryl or a 5- or 6-membered heteroaryl optionally substituted with one or more of halogen, —OH, or —C 1-6 alkyl; and R is —CN, a 5- or 6-membered heteroaryl, or halogen; and the pharmaceutically acceptable salt forms thereof, in addition to methods of using these compounds.
1. A compound of formula I:
wherein ring A is aryl or a 5- or 6-membered heteroaryl optionally substituted with one or more of halogen, —OH, or —C 1-6 alkyl; and
R is —CN, a 5- or 6-membered heteroaryl, or halogen;
or a pharmaceutically acceptable salt form thereof;
with the proviso that if A is oxazolyl, then R is —CN or a 5- or 6-membered heteroaryl.
2. The compound of claim 1 , wherein ring A is aryl.
3. The compound of claim 1 , wherein ring A is phenyl.
4. The compound of claim 1 , wherein ring A is a 5-membered heteroaryl.
5. The compound of claim 1 , wherein ring A is oxazolyl.
6. The compound of claim 1 , wherein ring A is thiazolyl.
7. The compound of claim 1 , wherein R is —CN.
8. The compound of claim 1 , wherein R is oxazolyl.
9. The compound of claim 1 , wherein R is thiazolyl.
10. The compound of claim 1 , wherein R is iodo.
11. The compound of claim 1 , wherein the geometry of the C(2-3) double bond is Z.
12. The compound of claim 1 , wherein the geometry of the C(2-3) double bond is E.
13. The compound of claim 1 , wherein the geometry of the C(19-20) double bond is Z.
14. The compound of claim 1 , wherein the geometry of the C(19-20) double bond is E.
15. The compound of claim 1 , wherein the geometry of the C(2-3) double bond is Z and the geometry of the C(19-20) double bond is E.
16. The compound of claim 1 , wherein the geometry of the C(2-3) double bond is E and the geometry of the C(19-20) double bond is E.
17. The compound of claim 1 , wherein the geometry of the C(2-3) double bond is E and the geometry of the C(19-20) double bond is Z.
18. The compound of claim 1 that is:
R
C(2-3), C(19-20)
—CN
(Z, E)
—I
(Z, E)
—I
(E, E)
—I
(E, Z)
—CN
(E, E)
—CN
(E, Z)
(Z, E)
(Z, E).
19. The compound of claim 1 that is:
R
C(2-3), C(19-20)
—CN
(Z, E)
—I
(Z, E)
—I
(E, E)
—I
(E, Z)
—CN
(E, E)
—CN
(E, Z)
(Z, E)
(Z, E).
20. The compound of claim 1 that is:
R
C(2-3), C(19-20)
—CN
(Z, E)
—CN
(E, E).
21. The compound of claim 1 that is:
R
C(2-3), C(19-20)
—CN
(Z, E)
—CN
(E, E).
22. A method of treating a Candida albicans infection in a patient comprising administering to the patient a therapeutically effective amount of a compound that is
R
C(2-3), C(19-20)
(Z, E)
(Z, E)
or
R
C(2-3), C(19-20)
—CN
(Z, E)
—CN
(E, E).
23. A method of treating breast cancer in a patient comprising administering to the patient a therapeutically effective amount of the following compound:
R
C(2-3), C(19-20)
—CN
(Z, E).
24. A method of treating colon cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound that is:
R
C(2-3), C(19-20)
—CN
(E, E)
or
R
C(2-3), C(19-20)
—CN
(Z, E)
(Z, E)
(Z, E).