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Androgen receptor modulators and methods for their use

a technology of androgen receptors and modulators, applied in the field of tricyclic compounds, can solve problems such as virtual docking drug discovery approaches

Inactive Publication Date: 2020-04-23
ESSA PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present disclosure provides compounds that can be used to treat various diseases and conditions by acting as androgen receptor modulators. These compounds have a specific structure and can be used alone or in combination with other compounds to achieve desired effects. The technical effects of these compounds include the ability to treat diseases such as prostate cancer, breast cancer, and osteoporosis. The compounds can be used as pharmaceutical agents or in the development of other therapeutic agents.

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

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  • Androgen receptor modulators and methods for their use
  • Androgen receptor modulators and methods for their use
  • Androgen receptor modulators and methods for their use

Examples

Experimental program
Comparison scheme
Effect test

example 1

of 5-[[4-[1-[3,5-dichloro-4-(3-chloropropoxy)phenyl]-1-methyl-ethyl]phenoxy]methyl]-4-methylsulfonyl-oxazole (A3)

[0962]

(4-Methylsulfonyloxazol-5-yl) 4-methylbenzenesulfonate (2)

[0963]To a solution of 4-methylsulfonyloxazol-5-ol (1) (0.10 g, 0.56 mmol), TEA (0.11 g, 1.1 mmol) and DMAP (14 mg, 0.11 mol) in DCM (3 mL) was added Tosyl chloride (0.10 g, 0.52 mmol) dropwise at 0° C. Then the solution was stirred at the same temperature for 1 hour. TLC showed the reaction was completed. The mixture was poured into H2O (5 mL), extracted with DCM (3 mL×3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (4-methylsulfonyloxazol-5-yl) 4-methylbenzenesulfonate (2) (0.11 g, yield: 56.6%) as yellow oil. 1H NMR (400 MHz, CHCl3-d) δ 7.98 (s, 1H), 7.93 (d, J=8.40 Hz, 2H), 7.42 (d, J=8.80 Hz, 2H), 4.95 (s, 2H), 3.22 (s, 3H).

Methyl 3,5-dichloro-4-(3-chloropropoxy)benzoate (5)

[0964]To a mixture of methyl 3, 5-dichlo...

example 2

of 4-((4-(2-(3,5-dichloro-4-(3-chloropropoxy)phenyl)propan-2-yl)phenoxy) methyl)-1-(methylsulfonyl)-1H-imidazole (A5)

[0968]

(1-Trityl-1H-imidazol-4-yl)methanol (2)

[0969]To a solution of (1H-imidazol-4-yl)methanol (0.5 g, 5.3 mmol) and Et3N (1.1 g, 10.2 mmol) in DCM (20 mL) was added TrCl (1.5 g, 5.3 mmol) and the mixture was stirred at 50° C. for 4 hours. TLC showed the reaction was completed. The reaction was cooled down, quenched with water (40 mL), extracted with DCM (5 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to give (1-trityl-1H-imidazol-4-yl)methanol (2) (1.0 g, yield: 76.8%) as colorless oil. 1H NMR (400 MHz, CHCl3-d) δ=7.37-7.44 (m, 9H), 7.29 (d, J=1.34 Hz, 2H), 7.10 (dd, J=8.01, 1.41 Hz, 6H), 4.87 (t, J=5.56 Hz, 1H), 4.33 (d, J=5.50 Hz, 2H).

4-(Chloromethyl)-1-trityl-1H-imidazole (3)

[0970]To a solution of (1-tritylimidazol...

example 3

of 2-((4-(2-(3,5-dichloro-4-(3-chloropropoxy)phenyl)propan-2-yl)phenoxy)methyl)-5-(methylsulfonyl)-1, 3, 4-oxadiazole (A7)

[0974]

Methyl 2-(4-(2-(3,5-dichloro-4-(3-chloropropoxy)phenyl)propan-2-yl)phenoxy)acetate (3)

[0975]To a solution of 4-(2-(3,5-dichloro-4-(3-chloropropoxy)phenyl)propan-2-yl)phenol (1) (1.00 g, 2.6 mmol) and methyl 2-bromoacetate (2) (0.49 g, 3.2 mmol) in DMF (10 mL) was added Cs2CO3 (1.30 g, 4.0 mmol) at 25° C. The mixture was stirred at 50° C. for 4 hours. LCMS showed the reaction was completed. The mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL×5), dried over Na2SO4, filtered and concentrated under reduced pressure to give the methyl 2-(4-(2-(3,5-dichloro-4-(3-chloropropoxy)phenyl)propan-2-yl)phenoxy)acetate (3) (1.00 g, yield: 70%) as colorless oil. LCMS (M+23) m z: calcd 444.07. found 467.1.

2-(4-(2-(3,5-Dichloro-4-(3-chloropropoxy)phenyl)propan-2-yl)phenoxy) acetohydrazide (...

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Abstract

The present invention relates to compounds of formula (I)-(VI) and / or (A)-(H-I), or any subgenera thereof, or a pharmaceutically acceptable salt, tautomer or stereoisomer. The compounds of the present disclosure are useful in modulating androgen receptor activity and for treating cancer including prostate cancer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application No. 62 / 747,209, filed Oct. 18, 2018, U.S. Provisional Application No. 62 / 803,516, filed Feb. 10, 2019, and U.S. Provisional Application No. 62 / 857,516, filed Jun. 5, 2019, the disclosures of which are herein incorporated by reference in their entirety for all purposes.FIELD OF THE INVENTION[0002]The present disclosure generally relates to tricyclic compounds and their use for treatment of various indications. In particular the disclosure relates to tricyclic compounds and their use for treatment of various cancers, for example prostate cancer, including but not limited to, primary / localized prostate cancer (newly diagnosed), locally advanced prostate cancer, recurrent prostate cancer, non-metastatic castration-resistant prostate cancer, metastatic prostate cancer, metastatic castration-resistant prostate cancer (CRPC), and hormone-sensitive prostate cancer. This invention al...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D263/46C07D233/84C07D271/113C07D261/08C07D263/48C07D231/38C07D239/42C07D233/74C07D277/36C07D277/42C07D277/56C07D307/64C07D241/20C07D263/38A61P35/00
CPCC07D263/46A61P35/00C07D271/113C07D261/08C07D263/48C07D231/38C07D239/42C07D233/74C07D277/36C07D277/42C07D277/56C07D307/64C07D241/20C07D263/38C07D233/84A61K31/42A61K31/421A61K31/4164A61K31/4245C07D233/88C07D233/80C07D233/76C07D413/12
Inventor ZHOU, HAN-JIEVIRSIK, PETER
Owner ESSA PHARMA INC
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