Salts of heterocyclic modulators of HIF activity for treatment of disease

Patent metadata

Field	Value
Publication number	US-10363248-B2
Application number	US-201715492751-A
Country	US
Kind code	B2
Filing date	Apr 20, 2017
Priority date	Feb 25, 2014
Publication date	Jul 30, 2019
Grant date	Jul 30, 2019

Abstract

The present disclosure relates to salts of heterocyclic compounds and methods that inhibit HIF pathway activity. The compounds are designed to treat or prevent cancer and other hypoxia-mediated diseases.

First claim

What is claimed is:

1. A method of treatment of cancer comprising administering to a patient with cancer a therapeutically effective amount of a compound of structural Formula III:

wherein:
M is selected from the group consisting of an inorganic acid, an organic acid, an amino acid;
with the proviso that M is not trifluoroacetic acid;
a is a fractional or whole number between about 0.5 and about 3.5 inclusive;
b is a fractional or whole number between about 0 and about 10 inclusive;
X 2 and X 4 are N and X 5 is O; X 4 and X 5 are N and X 2 is O; X 2 and X 5 are N and X 4 is O; X 2 is CH, X 4 is N, and X 5 is O; or X 2 is CH, X 4 is O, and X 5 is N;
Z 2 is selected from the group consisting of N and CR 14 ;
R 1 is selected from the group consisting of heterocycloalkyl, alkoxyalkoxy, alkylsulfonylalkoxy, heterocycloalkyloxy, heterocycloalkylcarbonyl, alkoxyalkylamido, heterocycloalkylsulfonyl, alkoxyalkylsulfonamido, wherein said heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylcarbonyl, and heterocycloalkylsulfonyl can be optionally substituted with one or more substituents selected from the group consisting hydrogen, alkyl, and oxo;
R 14 , R 39 , and R 40 are independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, haloalkyl, perhaloalkyl, cyano, hydroxy, alkoxy, haloalkoxy, perhaloalkoxy, alkylthio, amino, and saturated 3- to 7-membered cycloalkyl, any of which may be optionally substituted; and

R 18 is selected from the group consisting of alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkylthio, haloalkylthio, and perhaloalkylthio.

2. The method as recited in claim 1 wherein R 1 is selected from the group consisting of

3. The method as recited in claim 1 wherein R 18 is selected from the group consisting of isopropyl, tert-butyl, —CF 3 , —OCF 3 , —OCHF 2 , and —SCF 3 .

4. The method as recited in claim 1 wherein:
R 1 is selected from the group consisting of

R 13 , R 14 , R 16 , R 17 , and R 19 are hydrogen; and
R 18 is selected from the group consisting of isopropyl, tert-butyl, —CF 3 , —OCF 3 , —OCHF 2 , and —SCF 3 .

5. The method of claim 1 , wherein the compound is in a solid form.

6. The method of claim 1 , wherein the compound is in a crystalline form.

7. The method of claim 1 , wherein M is selected from the group consisting of (+)-camphor-10-sulfonic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, acetic acid, aspartic acid, benzenesulfonic acid, citric acid, cyclamic acid, di(tert-butyl) naphthalenesulfonic acid, dodecylsulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, glutamic acid, glycerophosphoric acid, glycine, hydroboric acid, hydrobromic acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, nitric acid, oxalic acid, phosphoric acid, p-toluenesulfonic acid, pyruvic acid, saccharine, succinic acid, sulfuric acid, tartaric acid, and thiocyanic acid.

8. The method of claim 1 , wherein M is selected from the group consisting of hydrochloric acid, benzenesulfonic acid, and methanesulfonic acid.

9. The method of claim 1 , wherein a equals 1 and M is hydrochloric acid.

10. The method of claim 1 , wherein a equals 1 and M is benzenesulfonic acid.

11. The method of claim 1 , wherein a equals 1 and M is methanesulfonic acid.

12. The method of claim 1 , wherein the compound has structural Formula V

wherein M is selected from the group consisting of hydrochloric acid, di(tert-butyl) naphthalenesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, cyclamic acid, p-toluenesulfonic acid, thiocyanic acid, nitric acid, methanesulfonic acid, dodecylsulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, oxalic acid, saccharine, 2,2-dichloroacetic acid, glycerophosphoric acid, phosphoric acid, (+)-camphor-10-sulfonic acid, sulfuric acid, maleic acid, and pyruvic acid;
a is a fractional or whole number between about 0.5 and about 3.5 inclusive; and
b is a fractional or whole number between about 0 and about 5 inclusive.

13. The method of claim 12 , wherein M is chosen from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, nitric acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, and maleic acid.

14. The method of claim 13 , wherein M is chosen from hydrochloric acid, methanesulfonic acid, and benzenesulfonic acid.

15. The method of claim 12 , wherein:
a is a number between 1 and 2 inclusive; and
b is a number between 0 and about 2 inclusive.

16. The method of claim 12 , wherein a equals 1, and M is hydrochloric acid.

17. The method of claim 12 , wherein a equals 1 and M is benzenesulfonic acid.

18. The method of claim 12 , wherein a equals 1 and M is methanesulfonic acid.

19. The method of claim 1 , wherein the compound has structural Formula VI

wherein X is chosen from chloride, di(tert-butyl) naphthalenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, cyclamate, tosylate, thiocyanate, nitrate, mesylate, dodecylsulfonate, naphthalene-2-sulfonate, besylate, oxalate, saccharate, 2,2-dichloroacetate, glycerophosphorate, phosphorate, (+)-camphor-10-sulfonate, maleate, sulfate, and pyruvate.

20. The method of claim 19 , wherein X is chosen from chloride, sulfate, tosylate, nitrate, mesylate, besylate, and maleate.

21. The method of claim 19 , wherein X is chosen from chloride, mesylate, and besylate.

22. A method of treatment of cancer comprising administering to a patient with cancer a therapeutically effective amount of a compound selected from the group consisting of:
5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole hydrochloride;
5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole methanesulfonate; and
5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole benzenesulfonate.

23. The method as recited in claim 22 , wherein the compound is 5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole hydrochloride.

24. The method as recited in claim 22 , wherein the compound is 5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole methanesulfonate.

25. The method as recited in claim 22 , wherein the compound is 5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole benzenesulfonate.

26. The method as recited in claim 1 wherein said cancer is selected from the group consisting of colon cancer, breast cancer,

Assignees

• Univ Texas

Inventors

• Jones Philip
• Di Francesco Maria Emilia
• Mcafoos Timothy

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/454 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title