Compounds and compositions for stabilizing hypoxia inducible factor-2 alpha as a method for treating cancer

1. A composition for stabilizing hypoxia inducible factor-2 alpha (HIF-2α) comprising:

A) an effective amount of a compound having the formula:

wherein R is chosen from:

i) —OR 1 ;

ii) —NR 2 R 3 ; or

iii) —OM 1 ;

R 1 is:

i) hydrogen; or

ii) C 1 -C 6 linear, C 3 -C 6 branched or C 3 -C 6 cyclic alkyl;

R 2 and R 3 are independently:

i) hydrogen;

ii) C 1 -C 6 linear, C 3 -C 6 branched or C 3 -C 6 cyclic alkyl; or

iii) R 2 and R 3 can be taken together to form a ring having from 2 to 7 carbon atoms and from 1 to 3 heteroatoms chosen from nitrogen, oxygen and sulfur including the nitrogen atom to which R 2 and R 3 are bonded; and

M 1 is a cation; and

R 4 is:

i) —OH; or

ii) —OM 2 ; and

M 2 is a cation; and

B) one or more pharmaceutically acceptable ingredients; and

C) Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF).

2. The composition according to claim 1 , wherein R is —OR 1 .

3. The composition according to claim 1 , wherein R 1 is hydrogen.

4. The composition according to claim 1 , wherein R 1 is methyl.

5. The composition according to claim 1 , wherein R 4 is —OH.

6. The composition according to claim 1 , wherein R is M 1 .

7. The composition according to claim 1 , having the formula:

8. The composition according to claim 7 , wherein M 1 is chosen from sodium, lithium, potassium, ammonium, and silver and M 2 is hydrogen or a cation chosen from sodium, lithium, potassium, ammonium, and silver.

9. The composition according to claim 7 , having the formula:

wherein M 1 is sodium or ammonium.

10. The composition according to claim 1 , wherein M 1 is a cation having the formula:

wherein R a , R b and R c are each independently:

i) hydrogen;

ii) substituted or unsubstituted C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 cyclic alkyl;

iii) substituted or unsubstituted benzyl;

wherein one or more of R a , R b and R c can be independently substituted by one or more units chosen from:

i) C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 alkoxy;

ii) C 1 -C 12 linear, C 3 -C 12 branched, or C 3 -C 12 haloalkoxy;

iii) halogen;

iv) hydroxyl;

v) thio; or

vi) one or more of R a , R b and R c can contain one or more units capable of forming a cation, anion, or zwitterions.

11. The composition according to claim 10 , wherein the cation M 1 is chosen from:

i) 2-hydroxyethyl ammonium [HN + H 2 (CH 2 CH 2 OH)];

ii) methyl-2-hydroxyethyl ammonium [H 2 N + (CH 3 )(CH 2 CH 2 OH)];

iii) di-(2-hydroxyethyl) ammonium [H 2 N + (CH 2 CH 2 OH) 2 ];

iv) tri-(2-hydroxyethyl) ammonium [HN + (CH 2 CH 2 OH) 3 ]; and

v) tris-(hydroxymethyl)methyl ammonium [H 3 N + C[(CH 2 OH)] 3 ].

12. The composition according to claim 1 , wherein the composition is a salt of an amino acid chosen from lysine, ornithine, arginine, and glutamine.

13. The composition according to claim 1 , having the formula:

14. The composition according to claim 1 , wherein the compound is chosen from:

sodium {[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetate; disodium {[5-(3-fluorophenyl)-3-oxidopyridine-2-carbonyl]-amino}acetate; potassium {[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetate; dipotassium {[5-(3-fluorophenyl)-3-oxidopyridine-2-carbonyl]-amino}acetate; ammonium {[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetate; diammonium {[5-(3-fluorophenyl)-3-oxidopyridine-2-carbonyl]-amino}acetate; sodium potassium {[5-(3-fluorophenyl)-3-oxidopyridine-2-carbonyl]-amino}acetate; sodium ammonium {[5-(3-fluorophenyl)-3-oxidopyridine-2-carbonyl]-amino}acetate; potassium ammonium {[5-(3-fluorophenyl)-3-oxidopyridine-2-carbonyl]-amino}acetate; calcium bis{[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetate; magnesium bis{[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetate; barium bis{[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetate; methyl ammonium {[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetate; calcium {[5-(3-fluorophenyl)-3-oxidopyridine-2-carbonyl]-amino}acetate; magnesium {[5-(3-fluorophenyl)-3-oxidopyridine-2-carbonyl]-amino}acetate; barium {[5-(3-fluorophenyl)-3-oxidopyridine-2-carbonyl]-amino}acetate; dimethyl ammonium {[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetate; diethyl ammonium {[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetate; triethyl ammonium {[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetate; dimethylethyl ammonium {[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetate; methyldiethyl ammonium {[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetate; 2-hydroxyethyl ammonium {[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetate; methyl-2-hydroxyethyl ammonium {[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetate; di(2-hydroxyethyl) ammonium {[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetate; tri(2-hydroxyethyl) ammonium {[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetate; tris(hydroxymethyl)methyl ammonium {[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetate; and N-benzyl-2-(benzylamino)ethanaminium {[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetate.

15. The composition according to claim 1 , wherein R is —NR 2 R 3 .

16. The composition according to claim 1 , wherein R 2 and R 3 are each independently hydrogen or methyl.

17. The composition according to claim 1 , wherein R is —NH 2 .

18. The composition according to claim 1 , comprising a compound chosen from:

{[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid;

methyl {[5-(3-fluoropheny1)-3-hydroxypyridine-2-carbony1]amino}acetate;

ethy1 {[5-(3-fluoropheny1)-3-hydroxypyridine-2-carbony1]amino}acetate;

5-(3-fluoropheny1)-N-(2-amino-2-oxoethy1)-3-hydroxypyridin-2-y1 amide;

5-(3-fluorophenyl)-N-(2-methylamino-2-oxoethyl)-3-hydroxypyridin-2-yl amide; and

5-(3-fluorophenyl)-N-(2-dimethylamino-2-oxoethyl)-3-hydroxypyridin-2-yl amide.