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Compounds and methods for the targeted degradation of androgen receptor

A technology of androgen receptors, compounds, applied in and optional fields, can solve problems such as disease development, patient tolerance, etc.

Inactive Publication Date: 2020-05-29
ARVINAS OPERATIONS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

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

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

Embodiment 1

[0802] Example 1: (2S,4R)-1-((S)-2-(2-(3-(5-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl) )-5,5-Dimethyl-4-oxo-2-thioimidazolidin-1-yl)phenoxy)pentyloxy)propoxy)acetamido)-3,3-dimethyl Butyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide:

[0803]

[0804] Step 1: tert-butyl 2-(3-{[5-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo Synthesis of -2-sulfinyl imidazolidin-1-yl}phenoxy)pentyl]oxy}propoxy)acetate (BG)

[0805] To tert-butyl 2-[3-[(5-[[(4-methylbenzene)sulfonyl]oxy]pentyl)oxy]propoxy]acetate (AB, 150mg, 0.35mmol) in acetonitrile ( 10 mL) was added 4-[3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-sulfinylimidazolidin-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 in an oil bath at 80 °C. LC-MS indicated formation of the desired product. Then, the reaction mixture was extracted with ethyl acetate (20 mL×2). The organic laye...

Embodiment 2

[0810] Example 2: (2S,4R)-1-((S)-2-(2-(3-(5-(4-(3-(6-cyano-5-(trifluoromethyl)pyridine 3 -yl)-5,5-dimethyl-4-oxo-2-thioimidazolidin-1-yl)phenoxy)pentyloxy)propoxy)acetamido)-3,3-di Methylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide:

[0811]

[0812] Step 1: Synthesis of 2-[3-({5-[(4-methylbenzenesulfonyl)oxy]pentyl}oxy)propoxy]acetic acid (L-1)

[0813] To tert-butyl 2-[3-({5-[(4-methylbenzenesulfonyl)oxy]pentyl}oxy)propoxy]acetate (AB, 1.3g, 3.02mmol) at room temperature To a stirred solution in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL). The resulting solution was stirred at room temperature for 3 hours. Then, the reaction mixture was concentrated in vacuo to afford 1.5 g (crude product) of L-1 which was used in the next step without any further purification. LC-MS (ES + ):m / z 375.34[MH + ],t R = 1.39 min (2.6 minutes run time).

[0814] Step 2: (2S,4R)-1-[(2S)-3,3-Dimethyl-2-{2-[3-({5-[(4-methylbenzenesulfony...

Embodiment 54

[0845] Example 54: (2S,4R)-1-((S)-2-(2-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5 ,5-Dimethyl-4-oxo-2-thioimidazolidin-1-yl)phenoxy)hexa-2,4-diynyloxy)acetamido)-3,3-dimethyl Butyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide:

[0846]

[0847] Step 1: tert-butyl 2-{[6-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2- Synthesis of Sulfurylimidazolidin-1-yl}phenoxy)hexa-2,4-diyn-1-yl]oxy}acetate (BJ)

[0848] This material was synthesized according to a similar procedure as described in reaction stage 1 in the synthesis of Example 1. LC-MS (ES + ):m / z 634.05[MNa + ],t R = 1.26 min (2.0 minutes run time).

[0849] Step 2: 2-{[6-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfinyl Synthesis of imidazolidin-1-yl}phenoxy)hexa-2,4-diyn-1-yl]oxy}acetic acid (BK)

[0850] This material was synthesized according to a similar procedure as described in reaction stage 2 in the synthesis of Example 1 . LC-MS (ES ...

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Abstract

The present disclosure relates to bifunctional compounds, which find utility to degrade (and inhibit) Androgen Receptor. In particular, the present invention is directed to compounds, which contain onone 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

[0001] References to related applications [0002] This disclosure is an International Patent Application claiming priority to U.S. Patent Application Serial No. 15 / 663,273, a continuation-in-part of U.S. Nonprovisional Patent Application Serial No. 15 / 002,303, filed January 20, 2016, U.S. Nonprovisional Patent Application Serial No. 15 / 002,303 claimed to be filed January 20, 2015 and titled: Compounds and Methods for Targeted Degradation of the Androgen Receptor U.S. Provisional Patent Application Serial No. 62 / 105,210 All of the above patents are hereby incorporated by reference in their entirety. Background technique [0003] 1. Discovery of technology areas. The present invention describes bifunctional compounds that are useful for modifying the ubiquitination and subsequent degradation of target polypeptides and proteins, in particular the androgen receptor. In certain aspects, the compound comprises: a VonHippel-Lindau (VHL) binding moiety that binds to a VHL E3 ubiqui...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07D417/14C07D207/16A61P35/00C07D401/14C07C255/47C07D213/82C07D231/14C07D401/12C07D237/24C07D239/42C07D411/12C07D411/14C07D417/12
CPCA61K47/555A61K47/64A61P35/00C07C255/54C07C271/24C07D207/16C07D213/82C07D231/14C07D237/24C07D239/42C07D401/12C07D401/14C07D403/12C07D411/12C07D411/14C07D417/12C07D417/14C07K5/06034C07C2601/04A61K31/422A61K31/427A61K45/06A61K47/55C07D413/12C07D413/14
Inventor 安德鲁·P·克鲁迈克尔·贝尔林陈昕克雷格·M·克鲁斯H·董Y·钱劳伦斯·斯奈德J·王库尔特·齐默尔曼
Owner ARVINAS OPERATIONS INC
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