Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Bisphenol derivatives and their use as androgen receptor activity modulators

a technology of androgen receptors and derivatives, applied in the field of bisphenol related compounds, can solve problems such as hammering virtual docking drug discovery approaches

Inactive Publication Date: 2017-10-19
THE UNIV OF BRITISH COLUMBIA +1
View PDF4 Cites 16 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present disclosure describes compounds that can be used to modulate the activity of androgen receptors (AR) for research and therapeutic purposes. These compounds can be used to image prostate cancer and other diseases using various imaging techniques. The compounds can also be used to treat prostate cancer and other cancers. The compounds described in this disclosure have the ability to target specific forms of AR and can be used to treat castration-resistant prostate cancer. The compounds described in this disclosure have the advantage of being able to target both the nucleus and the cytoplasm of cells, making them useful for both research and therapeutic purposes.

Problems solved by technology

While the crystal structure has been resolved for the AR C-terminus LBD, this has not been the case for the NTD due to its high flexibility and intrinsic disorder in solution (Reid et al 2002 J. Biol. Chem. 277, 20079-20086) thereby hampering virtual docking drug discovery approaches.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Bisphenol derivatives and their use as androgen receptor activity modulators
  • Bisphenol derivatives and their use as androgen receptor activity modulators
  • Bisphenol derivatives and their use as androgen receptor activity modulators

Examples

Experimental program
Comparison scheme
Effect test

example 1

of (R)-3-(4-(2-(3,5-dichloro-4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol (Compound 1a)

[0271]

Steps a and b: Synthesis of (S)-4-(2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenol

[0272]The titled compound was synthesized as previously reported. See, WO 2014 / 179867.

Step c: (S)-2,6-dichloro-4-(2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenol

[0273]To a solution of (S)-4-(2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenol (500 mg, 1.46 mmol, 1.0 equiv) in MeOH (12 mL) was added NaCl (256 mg, 4.38 mmol, 3.0 equiv) and NaOH (87.6 mg, 2.19 mmol, 1.5 equiv). Aqueous sodium hypochlorite (6035 mg, 5.4% in H2O, 4.38 mmol, 3.0 equiv) was then added dropwise over 2 min at 0° C. After 2 hours, the mixture was extracted with ethyl acetate (2×30 mL). The organic layer was washed with deionized water (2×30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The ...

example 2

of (R)-3-(4-(2-(3,5-dibromo-4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol (Compound 3a)

[0276]

[0277]Compound 3a was synthesized according to Example 1 by suing NaBr instead of NaCl in step c. 1H NMR (400 MHz, DMSO-D6) δ (ppm)=7.39 (s, 1H), 7.30 (dd, J=2.0 Hz, 34.4 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 5.57-5.54 (m, 1H), 4.91 (d, J=4.8 Hz, 1H), 4.64 (t, J=5.6 Hz, 1H), 4.10-4.08 (m, 1H), 3.98-3.92 (m, 3H), 3.86-3.81 (m, 2H), 3.79-3.76 (m, 1H), 3.71 (dd, J=5.6 Hz, 11.2 Hz, 1H), 3.45-3.42 (m, 2H), 1.60 (s, 6H). 13C NMR spectrum of Compound 3a as synthesized is shown in FIG. 1.

example 3

of (S)-1-chloro-3-(2,6-dichloro-4-(2-(4-((R)-2-hydroxy-3-methoxypropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (Compound 5a)

[0278]

Step a: Synthesis of (S)-3-(4-(2-(3,5-dichloro-4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-2-hydroxypropyl 4-methylbenzenesulfonate

[0279]The titled compound was synthesized by tosylation of Compound 1a under basic conditions according to commonly known protocol, such as the protocol referenced for step a in Example 1.

Step b: Synthesis of (S)-1-chloro-3-(2,6-dichloro-4-(2-(4-(((R)-oxiran-2-yl)methoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol

[0280]The titled compound was synthesized via epoxidation reaction commonly known in the art under basic conditions. 1H NMR (400 MHz, CDCl3) δ (ppm)=7.13-7.10 (m, 4H), 6.86 (d, J=6.8 Hz, 2H), 4.24-4.12 (m, 4H), 3.99-3.94 (m, 1H), 3.85 (dd, J=5.2 Hz, 11.2 Hz, 1H), 3.77 (dd, J=5.6 Hz, 11.2 Hz, 1H), 3.38-3.33 (m, 1H), 2.93-2.89 (m, 1H), 2.76 (dd, J=2.4 Hz, 4.8 Hz, 1H), 1.62 (s, 6H).

Step c: Synthesis of (S)-1-...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

Compounds having a structure of Formula I:or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1, R2, R3, R11a, R11b, R11c, R11d, and X, are as defined herein, are provided. Uses of such compounds for modulating androgen receptor activity, imaging diagnostics in cancer and therapeutics, and methods for treatment of subjects in need thereof, including prostate cancer are also provided.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of priority to U.S. Provisional Application No. 62 / 323,196, filed on Apr. 15, 2016 and entitled “BISPHENOL DERIVATIVES AND THEIR USE AS ANDROGEN RECEPTOR ACTIVITY MODULATORS,” the disclosure of which is hereby incorporated by reference in its entirety for all purposes.STATEMENT OF GOVERNMENT INTEREST[0002]This invention was made in part with government support under Grant No. 2R01 CA105304 awarded by the National Cancer Institute. The United States Government has certain rights in this invention.TECHNICAL FIELD[0003]This invention generally relates to bisphenol-related compounds and their use for treatment of various indications. In particular the invention relates to bisphenol ether compounds having halogenated phenyl groups and / or sulfone linking groups and their use for treatment of various cancers, for example prostate cancer, including but not limited to, primary / localized prostate cancer (newly dia...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(United States)
IPC IPC(8): C07D295/088C07C317/28C07C317/22C07C317/18A61K45/06A61K31/09A61K31/5375A61K31/4164A61K31/145A61K31/10C07D233/60C07C43/23
CPCC07D295/088C07D233/60C07C317/28C07C317/22C07C317/18C07C43/23A61K31/09A61K31/5375A61K31/4164A61K31/145A61K31/10A61K45/06C07C69/28C07C311/04C07C311/51C07C233/18A61P13/08A61P15/00A61P17/00A61P17/02A61P17/14A61P21/00A61P27/02A61P35/00A61P35/04A61P43/00C07C317/16A61K31/165A61K31/222C07C69/02
Inventor ANDERSEN, RAYMONDSADAR, MARIANNE DOROTHYJIAN, KUNZHONGMAWJI, NASRIN R.WANG, JUNBANUELOS, CARMEN ADRIANAYANG, YU-CHI
Owner THE UNIV OF BRITISH COLUMBIA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com