Bisphenol ether derivatives and methods for using the same

Patent metadata

Field	Value
Publication number	US-11779550-B2
Application number	US-202017116070-A
Country	US
Kind code	B2
Filing date	Dec 9, 2020
Priority date	Mar 12, 2015
Publication date	Oct 10, 2023
Grant date	Oct 10, 2023

Abstract

Compounds having a structure of Formula I:

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 1 , R 2 , L 1 , L 2 , L 3 , X, a, b, c, n, and m are as defined herein, are provided. Uses of such compounds for modulating androgen receptor activity and uses as therapeutics as well as methods for treatment of subjects in need thereof, including prostate cancer are also provided.

First claim

What is claimed is:

1. A method for modulating androgen receptor activity, comprising:
administering to a patient in need thereof a compound having the following structure (I):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
wherein:
X is —C(R 3 R 4 )—;
R 1 and R 2 are each independently H, halogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, —OH, —OR 5 , —O(C 1 -C 6 )alkyl, —OC(═O)R 13 , C 1 -C 10 acyl, —S(O) 0-2 R 5 , —NO 2 , —CN, —NH 2 , —NHR 5 , —N(R 5 R 6 ), —CO 2 H, CO 2 R 14 , or CONR 5 R 6 ;
R 3 and R 4 are each independently H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 2 -C 10 alkynyl;
R 5 and R 6 is each independently H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 2 -C 10 alkynyl;
R 7 is each independently H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, aryl, aminocarbonyl, C 1 -C 10 alkylcarbonyl, C 2 -C 10 alkenylcarbonyl, C 2 -C 10 alkynylcarbonyl, alkylaminocarbonyl, C 2 -C 10 alkenylaminocarbonyl, or C 2 -C 10 alkynylaminocarbonyl;
R 13 is each independently C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 2 -C 10 alkynyl;
R 14 is each independently H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, or aryl;
L 1 is hydroxyl or —OC(═O)R 13 ;
L 2 and L 3 are each independently H, halogen, hydroxyl, —OC(═O)R 13 , —OC 1 -C 10 alkyl, —OC 2 -C 10 alkenyl, —OC 2 -C 10 alkynyl, —OR 15 ,—SR 5 , —NR 5 R 6 , —O(C 1 -C 10 acyl), —OC 1 -C 10 alkylene-(—O—C 1 -C 10 alkyl) p , —OC 1 -C 10 alkylene-(—O—C 2 -C 10 alkynyl) p , —OC 1 -C 10 alkylene-(—O—C 2 -C 10 alkenyl) p , —OC 2 -C 10 alkenylene-(—O—C 1 -C 10 alkyl) p , —OC 2 -C 10 alkenylene-(—O—C 2 -C 10 alkenyl) p , —OC 2 -C 10 alkenylene-(—O—C 2 -C 10 alkynyl) p , —OC 2 -C 10 alkynylene-(—O—C 1 -C 10 alkyl) p , —OC 2 -C 10 alkynylene-(—O—C 1 -C 10 alkenyl) p , —OC 2 -C 10 alkynylene-(—O—C 2 -C 10 alkynyl) p , carbocyclyl, aryl, heterocyclyl, or heteroaryl;
wherein at least one of L 2 and L 3 is a hydroxyl, —OC(═O)R 13 , substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl;
R 15 is each independently selected from the group consisting of

wherein aa is a naturally occurring amino acid side chain and n is an integer from 1 to 200; and
a, b and c, are each independently 0, 1, 2, 3, 4, 5, or 6;
m and n are each independently 0,1, 2, 3, or 4; and
p is 1, 2, 3, or 4.

2. The method of claim 1 , wherein the modulating androgen receptor activity is for treating a condition or disease selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration.

3. The method of claim 2 , wherein the condition or disease is prostate cancer.

4. The method of claim 3 , wherein the condition or disease is androgen-dependent prostate cancer.

5. The method of claim 1 , wherein R 1 and R 2 are each independently H, —CN, or halogen.

6. The method of claim 1 , wherein R 3 and R 4 are each methyl.

7. The compound of claim 1 , wherein at least one of L 2 and L 3 is substituted or unsubstituted group selected from a pyrrole, furan, thiophene, pyrazole, pyridine, pyridazine, pyrimidine, imidazole, thiazole, isoxazole, oxadiazole, thiadiazole, oxazole, triazole, isothiazole, triazine, tetrazine, oxazine, azepine, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, or piperazine.

8. The method of claim 1 , wherein:
a) a is 0 or 1;
b) b is 0 or 1; or
c) c is 0 or 1.

9. The method of claim 1 , wherein the compound has one of the following structures (Ia), (Ib), (Ic) or (Id):

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

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

Assignees

• Univ British Columbia
• British Columbia Cancer Agency Branch

Inventors

• Andersen Raymond John
• Jian Kunzhong
• Sadar Marianne Dorothy
• Mawji Nasrin R
• Banuelos Carmen Adriana

Classifications

• A61K31/09 Primary

  having two or more such linkages · CPC title

• A61K31/047

  having two or more hydroxy groups, e.g. sorbitol · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07C43/225

  containing halogen · CPC title

• C07C43/23

  containing hydroxy or O-metal groups · CPC title