Selective androgen receptor degrader (SARD) ligands and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11230531-B2
Application number	US-202016783161-A
Country	US
Kind code	B2
Filing date	Feb 5, 2020
Priority date	Jun 10, 2016
Publication date	Jan 25, 2022
Grant date	Jan 25, 2022

Abstract

This invention is directed to pyrrole, pyrazole, imidazole, triazole, and morpholine based selective androgen receptor degrader (SARD) compounds including heterocyclic anilide rings and their synthetic precursors, R-isomers, and non-hydroxylated and/or non-chiral propanamides, and pharmaceutical compositions and uses thereof in treating prostate cancer, advanced prostate cancer, castration resistant prostate cancer, triple negative breast cancer, other cancers expressing the androgen receptor, androgenic alopecia or other hyperandrogenic dermal diseases, Kennedy's disease, amyotrophic lateral sclerosis (ALS), abdominal aortic aneurysm (AAA), and uterine fibroids, and to methods for reducing the levels of androgen receptor-full length (AR-FL) including pathogenic or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.

First claim

What is claimed is:

1. A method of treating, suppressing, reducing the incidence of, reducing the severity of, or inhibiting the progression of an androgen-dependent disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by the structure of formula I:

wherein
T is OH;
R 1 is CH 3 ;
Y is H, CF 3 , F, I, Br, Cl, or CN;
Z is H, NO 2 , CN, halide, COOH, COR, NHCOR, or CONHR;
X is CH or N;
R is H, alkyl, alkenyl, or haloalkyl;
A is R 2 ;
R 2 is a 5-membered unsaturated ring having at least one nitrogen atom and 1, or 2 double bonds, optionally substituted with at least one of Q 1 , Q 2 , Q 3 or Q 4 , each independently selected from hydrogen, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, substituted or unsubstituted aryl, F, Cl, Br, I, CN, NO 2 , OR, benzyl, NCS, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR, or COR;
or its optical isomer, pharmaceutically acceptable salt, or any combination thereof.

2. The method of claim 1 , wherein the SARD compound is represented by the structure of formula IA:

or its optical isomer, pharmaceutically acceptable salt, or any combination thereof.

3. The method of claim 1 , wherein the SARD compound is represented by the structure of formula IB:

or its optical isomer, pharmaceutically acceptable salt, or any combination thereof.

4. The method of claim 1 , wherein the SARD compound is represented by the structure of formula II:

wherein
T is OH;
R 1 is CH 3 ;
Y is H, CF 3 , F, I, Br, Cl, or CN;
Z is H, NO 2 , CN, halide, COOH, COR, NHCOR, or CONHR;
X is CH or N;
R is H, alkyl, alkenyl, or haloalkyl;
A is R 2
R 2 is a pyrrole, pyrazole, triazole, or imidazole ring, said ring optionally substituted with at least one of Q 1 , Q 2 , Q 3 or Q 4 , each independently selected from hydrogen, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, substituted or unsubstituted aryl, F, Cl, Br, I, CN, NO 2 , OR, benzyl, NCS, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR, or COR;
or its optical isomer, pharmaceutically acceptable salt, or any combination thereof.

5. The method of claim 4 , wherein the SARD compound is represented by the structure of formula IIA:

or its optical isomer, pharmaceutically acceptable salt, or any combination thereof.

6. The SARD compound of claim 4 , represented by the structure of formula IIB:

or its optical isomer, pharmaceutically acceptable salt, or any combination thereof.

7. The method of claim 1 , wherein the SARD compound is represented by the structure of formula VII:

wherein
X is CH or N;
Y is H, CF 3 , F, I, Br, Cl, or CN;
Z is H, NO 2 , CN, halide, COOH, COR, NHCOR, or CONHR;
R 1 is CH 3 ;
T is OH;
R is H, alkyl, alkenyl, or haloalkyl; and
Q 2 , Q 3 or Q 4 are each independently selected from hydrogen, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, substituted or unsubstituted aryl, F, Cl, Br, I, CN, NO 2 , OR, arylalkyl, NCS, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR; or its optical isomer, pharmaceutically acceptable salt, or any combination thereof.

8. The method of claim 7 , wherein the SARD compound is represented by the structure of formula VIIA:

or its optical isomer, pharmaceutically acceptable salt, or any combination thereof.

9. The method of claim 7 , wherein the SARD compound is represented by the structure of formula VIIB:

or its optical isomer, pharmaceutically acceptable salt, or any combination thereof.

10. The method of claim 1 , wherein Q 1 , Q 2 , Q 3 or Q 4 is hydrogen, CN, NO 2 , CF 3 , F, Cl, Br, I, NHCOOR, N(R) 2 , NHCOR, COR, or substituted or unsubstituted phenyl.

11. The method of claim 1 , wherein the SARD compound is represented by the structure of any one of the following compounds:

12. The method of claim 1 , wherein the compound exhibits at least one of AR-splice variant (AR-SV) degradation activity, full length (AR-FL) degradation activity, AR-SV inhibitory, or AR-FL inhibitory activity.

13. The method of claim 1 , wherein the SARD compound is formulated for topical use.

14. The method of claim 13 , wherein the compound is formulated in the form of a solution, lotion, salve, cream, ointment, liposome, spray, gel, foam, roller stick, cleansing soap or bar, emulsion, mousse, aerosol, or shampoo.

15. The method of claim 1 , wherein said disease or condition is triple negative breast cancer, Kennedy's disease, acne, hirsutism, alopecia, a hormonal condition, sexual perversion, hypersexuality, paraphilias, androgen psychosis, virilization, androgen insensitivity syndrome, cancer, amyotrophic lateral sclerosis (ALS), uterine fibroids, or abdominal aortic aneurysm (AAA).

16. The method according to claim 15 , wherein the acne is acne vulgaris.

17. The method of claim 1 , further decreasing sebum production.

18. The method according to claim 17 , wherein the decreasing sebum production treats at least one of seborrhea, seborrheic dermatitis, or acne.

19. The method according to claim 15 , wherein the alopecia is at least one of androgenic alopecia, alopecia areata, alopecia secondary to chemotherapy, alopecia secondary to radiation therapy, alopecia induced by scarring, or alopecia induced by stress.

20. The method according to claim 15 , wherein the hormonal condition is at least one of precocious puberty, dysmenorrhea, amenorrhea, multilocular uterus syndrome, endometriosis, hysteromyoma, abnormal uterine bleeding, early menarche, fibrocystic breast disease, fibroids of the uterus, ovarian cysts, polycystic ovary syndrome, pre-eclampsia, eclamp

Assignees

• Univ Tennessee Res Found

Inventors

• Narayanan Ramesh
• Miller Duane D
• Ponnusamy Thamarai
• Hwang Dong-Jin
• He Yali

Classifications

• C07D231/16 Primary

  Halogen atoms or nitro radicals · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07C317/46

  the carbon skeleton being further substituted by singly-bound oxygen atoms · CPC title

• C07D249/08

  1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles · CPC title

• A61K31/4192

  1,2,3-Triazoles · CPC title