Coumarin-modified androgens for the treatment of prostate cancer

Patent metadata

Field	Value
Publication number	US-12337004-B2
Application number	US-202017606998-A
Country	US
Kind code	B2
Filing date	Apr 27, 2020
Priority date	Apr 27, 2019
Publication date	Jun 24, 2025
Grant date	Jun 24, 2025

Abstract

Provided are androstane and dihydrotestosterone compounds functionalized with carbocyclic groups or heterocyclic groups that may be saturated or unsaturated. The compounds may be used in methods of inhibiting cell growth of malignant cells and/or hyperplastic cells and/or treating individuals having diseases associated with malignant cell growth (e.g., cancer, such as, for example, prostate cancer) and/or hyperplastic cell growth and/or molecular imaging of malignant cells and/or hyperplastic cells and/or inducing degradation of a target protein. Also provided are compositions.

First claim

The invention claimed is:

1. A compound having the following structure:

wherein
R 1 is hydrogen or an alkyl group;
L 1 is a linking group, L 2 is optional and is a linking group,
Z is an end group comprising (a) a substituted or unsubstituted coumarin group or
(b)

or a substituted variant thereof, and R 2 is an alkyl group or hydrogen.

2. The compound of claim 1 , wherein L 1 and/or L 2 independently are chosen from:

wherein n is 1, 2, 3, 4, 5, or 6 and m is 1, 2, 3, 4, 5, or 6.

3. The compound of claim 1 , wherein Z is chosen from:

and

or substituted variant thereof,
wherein X′ is independently at each occurrence chosen from hydrogen, alkyl groups, cycloalkyl groups, alkoxy groups, halogens, and combinations thereof.

4. The compound of claim 3 , wherein the compound has the following structure:

wherein n is 1, 2, or 3.

5. The compound of claim 4 , wherein the compound has the following structure:

6. The compound of claim 1 , wherein the compound has the following structure:

wherein n is 1, 2, or 3.

7. The compound of claim 6 , wherein the compound has the following structure:

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

9. The composition of claim 8 , further comprising one or more additional drugs.

10. The composition of claim 9 , wherein the one or more additional drugs are chosen from anti-androgen drugs, 5α-reductase drugs, androgen metabolism inhibitor drugs, and combinations thereof.

11. The composition of claim 10 , wherein the anti-androgen drugs are chosen from flutamide, bicalutamide, enzalutamide, apalutamide, darolutamide, dilutamide, and combinations thereof and/or the 5α-reductase drugs are chosen from finasteride, dutasteride, and combinations thereof and/or the androgen metabolism drugs are chosen from abiraterone acetate, abiraterone acetate fine particle, ketoconazole, and combinations thereof.

12. The composition of claim 8 , wherein the compound has the following structure:

or a combination thereof.

13. A method of treating a malignant cell growth disease and/or a hyperplastic cell growth disease in an individual, comprising administering to the individual a compound of claim 1 , wherein the individual's malignant cell growth disease or hyperplastic cell growth disease is treated.

14. The method of claim 13 , wherein the malignant cell growth disease is cancer.

15. The method of claim 14 , wherein the cancer is a hormonal cancer.

16. The method of claim 15 , wherein the hormonal cancer is chosen from breast cancers, ovarian cancers, uterine or endometrial cancers, prostate cancers, and combinations thereof.

17. The method of claim 16 , wherein the hormonal cancer is prostate cancer.

18. The method of claim 17 , wherein the prostate cancer is castration-resistant prostate cancer.

19. The method of claim 18 , wherein the cells of the castration-resistant prostate cancer express AR-V7.

20. The method of claim 13 , wherein the compound has the following structure:

or a combination thereof.

21. A method of impairing androgen receptor (AR) transactivation and/or androgen receptor dimerization in an individual in need of treatment comprising:
administering to the individual in need of treatment a compound of claim 1 or a composition comprising a compound of claim 1 , such that the compound contacts one or more cells, wherein androgen receptor transactivation and/or androgen receptor dimerization is impaired in the individual.

22. The method of claim 21 , further comprising contacting the cell with flutamide, bicalutamide, enzalutamide, apalutamide, darolutamide, dilutamide, finasteride, dutasteride, or a combination thereof.

23. The method of claim 21 , wherein the compound has the following structure:

or a combination thereof.

Assignees

• Health Research Inc
• Univ Kentucky Res Found

Inventors

• Mohler James L
• Fiandalo Michael V
• Watt David
• Sviripa Vitaliy

Classifications

• C07J43/006

  spiro-condensed · CPC title

• C07J43/003 Primary

  not condensed · CPC title

• A61K49/0002

  General or multifunctional contrast agents, e.g. chelated agents · CPC title

• A61K31/58

  containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048}) · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title