Compositions and methods for treating estrogen-related medical disorders

Patent metadata

Field	Value
Publication number	US-10464930-B2
Application number	US-201816177112-A
Country	US
Kind code	B2
Filing date	Oct 31, 2018
Priority date	Oct 24, 2012
Publication date	Nov 5, 2019
Grant date	Nov 5, 2019

Abstract

Disclosed is a compound of formula (I). or a pharmaceutically acceptable salt thereof. Also disclosed are pharmaceutical compositions including the compound of formula (I) and methods of using the compound of formula (I).

First claim

The invention claimed is:

1. A method for treatment of an estrogen-related medical disorder, the method comprising administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of at least one compound of formula (II-i)

or a pharmaceutically acceptable salt thereof,
wherein
A 1 is selected from the group consisting of halogen, trifluoromethyl, and —OR 1 ;
A 2 is selected from the group consisting of halogen and trifluoromethyl;
A 3 is selected from the group consisting of alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocycle, and heteroaryl;
A 4 is selected from the group consisting of hydrogen, halogen, cyano, trifluoromethyl, aryl-heteroaryl wherein the aryl is substituted or unsubstituted, and —OR 3 ;
R 1 is selected from the group consisting of —SO 3 R x1 and —PO 3 R y1 R z1 ;
R 3 is selected from the group consisting of hydrogen, alkyl, —SO 3 R x1 , —PO 3 R y1 R z1 , and —C(═O)R a ;
R x1 , R y1 and R z1 , at each occurrence, are independently selected from the group consisting of hydrogen and a pharmaceutically acceptable cation; and
R a is alkyl or —OH,

wherein the estrogen-related medical disorder is breast cancer or osteoporosis.

2. The method of claim 1 , wherein the estrogen-related medical disorder is breast cancer.

3. The method of claim 2 , wherein the breast cancer is a tamoxifen resistant breast cancer.

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

5. A method for treatment of an estrogen-related medical disorder, the method comprising administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of at least one compound selected from the group consisting of:
(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)(4-(trifluoromethyl)phenyl)methanone;
(3-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-2-yl)(4-(trifluoromethyl)phenyl)methanone;
cyclopropyl(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)methanone;
cyclopropyl(3-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-2-yl)methanone;
(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)(pyridin-4-yl)methanone;
(3-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-2-yl)(pyridin-4-yl)methanone;
1-(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)-2-methylpropan-1-one;
1-(3-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-2-yl)-2-methylpropan-1-one;
(4-ethynylphenyl)(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)methanone;
(4-ethynylphenyl)(3-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-2-yl)methanone;
(3-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-2-yl)(p-tolyl)methanone;
(4-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)phenyl)(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)methanone;
(4-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)phenyl)(3-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-2-yl)methanone;
(3r,5r,7r)-adamantan-1-yl(2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-y1)methanone; and
(3r, 5r,7r)-adamantan-1-yl (3-(4-fluorophenyl)-6-hydroxybenzo [b]thiophen-2-yl)methanone,
or a pharmaceutically acceptable salt thereof,

wherein the estrogen-related medical disorder is breast cancer or osteoporosis.

6. The method of claim 5 , wherein the estrogen-related medical disorder is breast cancer.

7. The method of claim 6 , wherein the breast cancer is a tamoxifen resistant breast cancer.

8. The method of claim 6 , wherein the breast cancer is a triple negative breast cancer.

9. A method for treatment of an estrogen-related medical disorder, the method comprising administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of at least one compound of formula (II-ii)

or a pharmaceutically acceptable salt thereof,
wherein
A 1 is selected from the group consisting of halogen, trifluoromethyl, and —OR 1 ;
A 2 is selected from the group consisting of halogen and trifluoromethyl;
A 3 is selected from the group consisting of alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocycle, and heteroaryl;
A 4 is selected from the group consisting of hydrogen, halogen, alkyl, cyano, trifluoromethyl, aryl-heteroaryl wherein the aryl is substituted or unsubstituted, and —OR 3 ;
R 1 and R 3 are each independently selected from the group consisting of hydrogen, alkyl, —SO 3 R x1 , —PO 3 R y1 R z1 , and —C(═O)R a ;
R x1 , R y1 and Rz 1 , at each occurrence, are independently selected from the group consisting of hydrogen and a pharmaceutically acceptable cation; and
R a is alkyl or —OH,

wherein the estrogen-related medical disorder is breast cancer or osteoporosis.

10. The method of claim 9 , wherein the estrogen-related medical disorder is breast cancer.

11. The method of claim 10 , wherein the breast cancer is a tamoxifen resistant breast cancer.

12. The method of claim 10 , wherein the breast cancer is a triple negative breast cancer.

Assignees

• Univ Illinois

Inventors

• Thatcher Gregory R
• Siklos Marton
• Xiong Rui

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• G01N33/5758

  involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites · CPC title