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Compounds and methods for the targeted degradation of androgen receptor

Inactive Publication Date: 2018-12-06
ARVINAS OPERATIONS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0068]Where applicable or not specifically disclaimed, any one of the embodiments described herein are contemplated to be able to combine with any other one or more embodiments, even though the embodiments are described under different aspects of the invention. As such, the preceding general areas of utility are given by way of example only and are not intended to be limiting on the scope of the present disclosure and appended claims. Additional objects and advantages associated with the compositions, methods, and processes of the present invention will be appreciated by one of ordinary skill in the art in light of the instant claims, description, and examples. For example, the various aspects and embodiments of the invention may be utilized in numerous combinations, all of which are expressly contemplated by the present description. These additional advantages objects and embodiments are expressly included within the scope of the present invention. The publications and other materials used herein to illuminate the background of the invention, and in particular cases, to provide additional details respecting the practice, are incorporated by reference.

Problems solved by technology

Despite the development of effective targeted therapies, most patients develop resistance and the disease progresses.

Method used

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  • Compounds and methods for the targeted degradation of androgen receptor
  • Compounds and methods for the targeted degradation of androgen receptor
  • Compounds and methods for the targeted degradation of androgen receptor

Examples

Experimental program
Comparison scheme
Effect test

example 1

-((S)-2-(2-(3-(5-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)pentyloxy)propoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0513]

Step 1: Synthesis of tert-butyl 2-(3-{[5-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}phenoxy)pentyl]oxy}propoxy)acetate (BG)

[0514]To a stirred solution of tert-butyl 2-[3-[(5-[[(4-methylbenzene)sulfonyl]oxy]pentyl)oxy]propoxy]acetate (AB, 150 mg, 0.35 mmol) in acetonitrile (10 mL) was added 4-[3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (ABM-3, 141 mg, 0.35 mmol) and potassium carbonate (144 mg, 1.04 mmol). The resulting mixture was stirred overnight at 80° C. in an oil bath. LC-MS indicated formation of the desired product. The reaction mixture was then extracted with ethyl acetate (20 mL×2). The organic layers were combined, washed with s...

example 2

-((S)-2-(2-(3-(5-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)pentyloxy)propoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0517]

Step 1: Synthesis of 2-[3-({5-[(4-methylbenzenesulfonyl)oxy]pentyl}oxy)propoxy]acetic Acid (L-1)

[0518]To a stirred solution of tert-butyl 2-[3-({5-[(4-methylbenzenesulfonyl)oxy]pentyl}oxy)propoxy]acetate (AB, 1.3 g, 3.02 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) at rt. The resulting solution was stirred at rt for 3 h. The reaction mixture was then concentrated under vacuum to give 1.5 g (crude) of L-1, which was used for next step without any further purification. LC-MS (ES+): m / z 375.34 [MH+], tR=1.39 min (2.6 minute run).

Step 2: Synthesis of (2S,4R)-1-[(2S)-3,3-dimethyl-2-{2-[3-({5-[(4-methylbenzenesulfonyl)oxy]pentyl}oxy)propoxy]acetamido}butanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrol...

example 54

((S)-2-(2-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)hexa-2,4-diynyloxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0523]

Step 1: Synthesis of tert-butyl 2-{[6-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}phenoxy)hexa-2,4-diyn-1-yl]oxy}acetate (BJ)

[0524]This material was synthesized according to a similar procedure described in reaction step 1 for the synthesis of Example 1. LC-MS (ES+): m / z 634.05 [MNa+], tR=1.26 min (2.0 minute run).

Step 2: Synthesis of 2-{[6-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}phenoxy)hexa-2,4-diyn-1-yl]oxy}acetic Acid (BK)

[0525]This material was synthesized according to a similar procedure described in reaction step 2 for the synthesis of example 1. LC-MS (ES+): m / z 556.10 [MH+], tR=1.54 min (2.6 minute run).

Step 3: Synthesis of (2S,4R)-1-[(2S)-2...

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Abstract

The present invention relates to bifunctional compounds, which find utility to degrade and (inhibit) Androgen Receptor. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds Androgen Receptor such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation / inhibition of Androgen Receptor.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a divisional application of U.S. Non-provisional patent application Ser. No. 15 / 002,303, filed 20 Jan. 2016, which claims the benefit of U.S. Provisional Patent Application Ser. No. 62 / 105,210, filed 20 Jan. 2015, both of which are entitled Compounds and Methods for the Targeted Degradation of the Androgen Receptor, and incorporated herein by reference in their entirety.BACKGROUND[0002]1. Field of the Discovery[0003]The present description relates to bifunctional compounds, which are useful for the modifying the ubiquitination and subsequent degradation of target polypeptides and proteins, in particular, androgen receptor. In certain aspects, the compounds comprise a Von Hippel-Lindau (VHL) binding moiety, which binds to the VHL E3 ubiquitin ligase, a target protein binding moiety, which binds to the target protein (e.g., androgen receptor), and optionally a linker moiety which links the VHL binding moiety and target p...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D417/14A61P25/28A61P35/00C07K5/078C07D413/14C07D417/12C07D471/10C07D491/107C07D401/04C07D233/86C07D413/12A61K45/06
CPCC07D417/14A61P25/28A61P35/00C07K5/06165C07D413/14A61K45/06C07D471/10C07D491/107C07D401/04C07D233/86C07D413/12C07D417/12A61K31/427A61K31/4439A61K31/422A61K47/55A61K31/4166
Inventor CREW, ANDREW P.DONG, HANQINGWANG, JINGCHEN, XINQIAN, YIMINZIMMERMANN, KURTCREWS, CRAIG M.BERLIN, MICHAELSNYDER, LAWRENCE
Owner ARVINAS OPERATIONS INC
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