Second generation GRP94-selective inhibitors

Patent metadata

Field	Value
Publication number	US-11028041-B2
Application number	US-201816640897-A
Country	US
Kind code	B2
Filing date	Aug 23, 2018
Priority date	Aug 25, 2017
Publication date	Jun 8, 2021
Grant date	Jun 8, 2021

Abstract

The present technology provides compounds selective for the Grp94 isoform, as well as compositions including such compounds, that are useful for treatment of multiple myeloma, melanoma, lung cancer, hepatocellular carcinoma, breast cancer, prostate cancer, and/or glaucoma. Methods using the compounds are also provided.

First claim

What is claimed:

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein
X 1 is Cl or F;
X 2 is CH 2 , O, S, or NH;
R 1 , R 2 , R 4 , R 5 , and R 6 are each independently H, alkoxy, hydroxyl, thiol, or halo; and
R 3 is H, alkoxy, amino, hydroxyl, thiol, or halo.

2. The compound of claim 1 , wherein when X 2 is 0 and R 4 , R 5 , and R 6 are each independently H, then R 1 and R 2 are each independently H, alkoxy, or halo and R 3 is H, alkoxy, amino, or halo.

3. The compound of claim 1 , wherein at least two of R 1 , R 2 , and R 3 are each independently H.

4. The compound of claim 1 , wherein at least two of R 4 , R 5 , and R 6 are each independently H.

5. The compound of claim 1 , wherein when at least one of R 1 , R 2 , and R 3 is hydroxyl, then at least one of R 4 , R 5 , and R 6 is not H.

6. The compound of claim 1 , wherein when one of R 1 , R 2 , and R 3 is hydroxyl and the remaining R 1 , R 2 , and R 3 each independently H, then at least one of R 4 , R 5 , and R 6 is not H.

7. The compound of claim 1 , wherein R 1 , R 2 , and R 3 are each independently H.

8. The compound of claim 1 , wherein the compound is of Formula II:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 , wherein when X 2 is O and R 4 , R 5 , and R 6 are each independently H, then R 1 and R 2 are each independently H, alkoxy, or halo and R 3 is H, alkoxy, amino, or halo.

10. The compound of claim 8 , wherein when at least one of R 1 , R 2 , and R 3 is hydroxyl, then at least one of R 4 , R 5 , and R 6 is not H.

11. The compound of claim 8 , wherein when one of R 1 , R 2 , and R 3 is hydroxyl and the remaining R 1 , R 2 , and R 3 each independently H, then at least one of R 4 , R 5 , and R 6 is not H.

12. A compound of Formula III

or a pharmaceutically acceptable salt thereof, wherein
X 3 is Cl or F;
X 4 is CH 2 , O, S, or NH; and
R 7 is alkoxy, hydroxyl, thiol, or halo.

13. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition for treating metastatic cancer, the composition comprising an effective amount of the compound claim 1 and a pharmaceutically acceptable excipient.

15. A method for inhibiting cell motility of a cancer cell, the method comprising contacting the cancer cell with a compound of claim 1 .

16. A method of treating a patient or animal suffering from metastatic cancer, the method comprising administration of an effective amount of a compound of claim 1 to the patient or animal suffering from the metastatic cancer, wherein the metastatic cancer is selected from multiple myeloma, melanoma, lung cancer, hepatocellular carcinoma, breast cancer, or prostate cancer.

17. A pharmaceutical composition for treating glaucoma, the composition comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable excipient.

18. A method of inhibiting death of a cell exhibiting mutant myocilin, the method comprising contacting the cell with a compound of claim 1 .

19. A method of treating a patient or animal suffering from glaucoma, the method comprising administration of an effective amount of a compound of claim 1 to the patient or animal suffering from the glaucoma.

20. The method of claim 19 , wherein the glaucoma is myocilin glaucoma.

Assignees

• Univ Kansas

Inventors

• Blagg Brian S J
• Crowley Vincent Matthew

Classifications

• C07C219/34

  having amino groups and esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton · CPC title

• C07C69/78

  Benzoic acid esters · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• C07C69/76

  Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07D213/55

  Acids; Esters · CPC title