Inhibition of macrophage migration inhibitory factor in melanoma and colon cancer
View Patent ↗Compounds and compositions are provided which inhibit MIF. Methods of treatment of melanoma and colon cancers are also provided.
1. A compound having the following structure:
wherein bond α is either present or absent, and when bond α is absent R 1 is a monohalo substitution or a dihalo substitution and R2 is a C2-C10 alkenyl, a C2-C10 alkynyl, or —CH 2 C(O)(OH), and when bond α is present R 1 is H, a monohalo substitution or a dihalo substitution,
R 2 is a C1-C10 alkyl, a C2-C10 alkenyl, a C2-C10 alkynyl, an aryl, a heterocyclic, or —CH2C(O)(OH)—,
or a stereoisomer of the compound thereof or a pharmaceutically acceptable salt of the compound.
2. The compound, stereoisomer or pharmaceutically acceptable salt of claim 1 , wherein the halogen of the monohalo or dihalo is F.
3. The compound, stereoisomer or pharmaceutically acceptable salt of claim 1 , wherein bond α is present and R 2 is a C1 alkyl.
4. The compound of claim 1 , having the following structure:
where X=H or F,
or a stereoisomer or pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , having the following structure:
or stereoisomer or pharmaceutically acceptable salt thereof.
6. A composition comprising the compound or stereoisomer or pharmaceutically acceptable salt thereof of claim 1 , and a pharmaceutically acceptable carrier.
7. The composition of claim 6 , which is a pharmaceutical composition.
8. A process for making the compound of claim 1 , comprising:
a) contacting 3-fluoro-4-hydroxybenzaldoxime with a chlorinating agent so as to produce a chloro oxime thereof; and
b) contacting the chloro oxime with 4-penten-2-one followed by addition of suitable base thereto,
so as to produce the compound.
9. A method of treating a tumor in a subject comprising administering to the subject the compound or stereoisomer or pharmaceutically acceptable salt of claim 1 in an amount effective to treat a tumor in a subject.
10. A method of inhibiting progression of a tumor in a subject comprising administering to the subject the compound or stereoisomer or pharmaceutically acceptable salt of claim 1 in an amount effective to inhibit progression of a tumor in a subject.
11. A method of stimulating expansion of an anti-tumor reactive effector cell in a subject comprising administering to the subject the compound or stereoisomer or pharmaceutically acceptable salt of claim 1 in an amount effective to stimulate expansion of an anti-tumor reactive effector cell.
12. The method of claim 9 , wherein the tumor is a melanoma.
13. The method of claim 9 , wherein the tumor is a colon cancer.
14. A method of reducing an inflammation in a subject comprising administering to the subject the compound or stereoisomer or pharmaceutically acceptable salt of claim 1 in an amount effective to reduce inflammation in a subject wherein the compound of claim 1 or stereoisomer or pharmaceutically acceptable salt thereof inhibits migration inhibitory factor (MIF).
15. The method of claim 9 , wherein a compound having the structure:
or a stereoisomer or pharmaceutically acceptable salt thereof is administered.
16. The method of claim 9 , wherein the subject is human.
17. A method of manufacturing a medicament comprising admixing the compound or stereoisomer or pharmaceutically acceptable salt thereof of claim 1 , and a pharmaceutically acceptable carrier.
18. A pharmaceutical composition comprising the compound or stereoisomer or pharmaceutically acceptable salt thereof of claim 1 , and a pharmaceutically acceptable carrier.
19. A method of treating a tumor in a subject comprising administering to the subject the compound or stereoisomer or pharmaceutically acceptable salt of claim 1 and an anti-tumor agent, in an amount effective to treat a tumor in a subject.
20. A method of treating an autoimmune disease in a subject comprising administering to the subject the compound or stereoisomer or pharmaceutically acceptable salt of claim 1 and an anti-autoimmune agent, in an amount effective to treat an autoimmune disease in a subject wherein the compound of claim 1 or stereoisomer or pharmaceutically acceptable salt thereof inhibits migration inhibitory factor (MIF).