Benzothiophene-based selective estrogen receptor downregulators

Patent metadata

Field	Value
Publication number	US-10807964-B2
Application number	US-201916537079-A
Country	US
Kind code	B2
Filing date	Aug 9, 2019
Priority date	Dec 9, 2015
Publication date	Oct 20, 2020
Grant date	Oct 20, 2020

Abstract

This invention is benzothiophene-based estrogen receptor downregulators and their compositions and uses to treat estrogen-related medical disorders.

First claim

We claim:

1. A method of treating an estrogen receptor positive breast cancer in a human comprising administering to the human a selective estrogen receptor downregulator (SERD) compound having the structure:

wherein:
n is 0, 1, 2, 3, or 4;
R 3 is independently selected at each occurrence from hydrogen, halogen, —CN, —NO 2 , C 1 -C 6 alkyl and C 1 -C 6 fluoroalkyl; and
R 4 is independently selected at each occurrence from hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, —CN, —O(C 1 -C 6 alkyl), and —O(C 1 -C 6 fluoroalkyl);

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the SERD compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 , wherein the SERD compound is

or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 , wherein the SERD compound is

or a pharmaceutically acceptable salt thereof.

5. The method of claim 1 , wherein the SERD compound is

or a pharmaceutically acceptable salt thereof.

6. The method of claim 1 , wherein the SERD compound is

or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein the SERD compound is

or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein the SERD compound is

or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 , wherein the SERD compound is

or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , wherein the estrogen receptor positive breast cancer is metastatic.

11. The method of claim 1 , wherein the human is post-menopausal.

12. The method of claim 1 , wherein the SERD compound is administered in combination with a PI3 kinase inhibitor.

13. The method of claim 1 , wherein the SERD compound is administered in combination with a mTOR inhibitor.

14. The method of claim 13 , wherein the mTOR inhibitor is selected from the group consisting of everolimus, temsirolimus, ridaforolimus, zotarolimus, and sirolimus.

15. The method of claim 1 , wherein the estrogen receptor positive breast cancer is resistant to anti-hormonal treatment.

16. The method of claim 15 , wherein the anti-hormonal treatment is selected from the group consisting of tamoxifen, fulvestrant, steroidal aromatase inhibitors, and non-steroidal aromatase inhibitors.

17. The method of claim 15 , wherein the anti-hormonal treatment is selected from the group consisting of anastrozole, letrozole, exemestane, formestane, aminoglutethimide, testolactone, and fadrozole.

18. The method of claim 12 , wherein the PI3 kinase inhibitor is selected from the group consisting of idelalisib, pictilisib, duvelisib, buparlisib, BYL719, perifosine, BAY80-6946, GDC-0941, GDC-0032, PF-04691502, GDC-0941, PF-05212384, SAR245409, and BEZ235.

19. The method of claim 2 , wherein the estrogen receptor positive breast cancer is metastatic.

20. The method of claim 2 , wherein the human is post-menopausal.

21. The method of claim 2 , wherein the SERD compound is administered in combination with a PI3 kinase inhibitor.

22. The method of claim 2 , wherein the SERD compound is administered in combination with a mTOR inhibitor.

23. The method of claim 22 , wherein the mTOR inhibitor is selected from the group consisting of everolimus, temsirolimus, ridaforolimus, zotarolimus, and sirolimus.

24. The method of claim 2 , wherein the estrogen receptor positive breast cancer is resistant to anti-hormonal treatment.

25. The method of claim 24 , wherein the anti-hormonal treatment is selected from the group consisting of tamoxifen, fulvestrant, steroidal aromatase inhibitors, and non-steroidal aromatase inhibitors.

26. The method of claim 24 wherein the anti-hormonal treatment is selected from the group consisting of anastrozole, letrozole, exemestane, formestane, aminoglutethimide, testolactone, and fadrozole.

27. The method of claim 21 , wherein the PI3 kinase inhibitor is selected from the group consisting of idelalisib, pictilisib, duvelisib, buparlisib, BYL719, perifosine, BAY80-6946, GDC-0941, GDC-0032, PF-04691502, GDC-0941, PF-05212384, SAR245409, and BEZ235.

Assignees

• Univ Illinois

Inventors

• Thatcher Gregory R
• Xiong Rui
• Zhao Jiong
• Tonetti Debra A

Classifications

• A61K31/381 Primary

  having five-membered rings · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D409/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D333/64 Primary

  Oxygen atoms · CPC title

• A61P35/00

  Antineoplastic agents · CPC title