Bromodomain inhibitors for androgen receptor-driven cancers

Patent metadata

Field	Value
Publication number	US-11801243-B2
Application number	US-202117482720-A
Country	US
Kind code	B2
Filing date	Sep 23, 2021
Priority date	Sep 23, 2020
Publication date	Oct 31, 2023
Grant date	Oct 31, 2023

Abstract

Methods for treating certain androgen receptor-positive forms of cancer using inhibitors of the CREB binding protein bromodomain are disclosed. In some methods, the AR-positive forms of cancer may be breast cancer, including triple negative forms, hormone receptor positive forms, and HER2-positive forms. In other methods, the AR-positive forms of cancer may be prostate cancer, including metastatic castration resistant prostate cancer. In some embodiments, methods of treating prostate cancer comprise the step of administering to a patient in need thereof the compound (1R,3R)-3-[(7S)-2-[(R)-(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

First claim

The invention claimed is:

1. A method of treating breast cancer in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H or —OH;
each R 2 is independently selected from C 1 -C 6 alkyl, halogen, —CN, and —OR 3 , wherein the alkyl is optionally substituted with one or more halogen;
each R 3 is independently C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with one or more halogen; and
n is 0, 1, 2, or 3.

2. The method of claim 1 , wherein the breast cancer is triple negative breast cancer.

3. The method of claim 1 , wherein the breast cancer is AR+.

4. The method of claim 1 , wherein the compound is selected from:

optionally wherein:
the breast cancer is triple negative breast cancer; and/or
the breast cancer is AR+.

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

optionally wherein:
the breast cancer is triple negative breast cancer; and/or
the breast cancer is AR+.

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

optionally wherein:
the breast cancer is triple negative breast cancer; and/or
the breast cancer is AR+.

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

optionally wherein:
the breast cancer is triple negative breast cancer; and/or
the breast cancer is AR+.

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

optionally wherein:
the breast cancer is triple negative breast cancer; and/or
the breast cancer is AR+.

9. A method of treating prostate cancer in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H or —OH;
each R 2 is independently selected from C 1 -C 6 alkyl, halogen, —CN, and —OR 3 , wherein the alkyl is optionally substituted with one or more halogen;
each R 3 is independently C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with one or more halogen; and
n is 0, 1, 2, or 3.

10. The method of claim 9 , wherein the prostate cancer is AR+.

11. The method of claim 9 , wherein the prostate cancer is AR-v7+.

12. The method of claim 9 , wherein the patient is diagnosed with castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer.

13. The method of claim 9 , wherein the compound is selected from:

optionally wherein:
the prostate cancer is AR+; and/or
the prostate cancer is AR-v7+.

14. The method of claim 13 , wherein the patient is diagnosed with disease progression following treatment with enzalutamide.

15. The method of claim 13 , wherein the patient is diagnosed with castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer.

16. A method of treating an Androgen Receptor-expressing cancer in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising (1R,3R)-3-[(7S)-2-[(R)-(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

17. The method of claim 16 , wherein the Androgen Receptor-expressing cancer is AR+breast cancer,
optionally wherein:
the AR+breast cancer is triple negative breast cancer; or
the AR+breast cancer is Her2− breast cancer; or
the AR+breast cancer is selected from ER− breast cancer, PR− breast cancer, and ER−/PR− breast cancer.

18. The method of claim 16 , wherein the Androgen Receptor-expressing cancer is AR+prostate cancer, optionally wherein the AR+prostate cancer is AR-v7+.

19. The method of claim 16 , wherein the Androgen Receptor-expressing cancer is castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer.

20. The method of claim 19 , wherein the patient is diagnosed with disease progression following treatment with enzalutamide.

21. A method of treating an Androgen Receptor-expressing cancer in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising:

or a pharmaceutically acceptable salt thereof.

22. The method of claim 21 , wherein the Androgen Receptor-expressing cancer is AR+breast cancer, optionally wherein the AR+breast cancer is triple negative breast cancer.

23. The method of claim 21 , wherein the Androgen Receptor-expressing cancer is AR+prostate cancer, optionally wherein the AR+prostate cancer is AR-v7+.

Assignees

• Forma Therapeutics Inc

Inventors

• Guichard Sylvie
• Caligiuri Maureen
• Ericsson Anna
• Xu Qunli
• Mohamed Hesham

Classifications

• A61K31/4745 Primary

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title