Indole derivatives as estrogen receptor degraders

a technology of estrogen receptor and indole derivatives, which is applied in the field of compounds, compositions, and medicaments, can solve problems such as incomplete blockade of estrogen-mediated activity

Inactive Publication Date: 2018-03-15
ARVINAS OPERATIONS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010]The present disclosure describes bifunctional compounds which function to recruit endogenous proteins to an E3 Ubiquitin Ligase for degradation, and methods of using the same. In particular, the present disclosure provides bifunctional or proteolysis targeting chimeric (PROTAC) compounds, which find utility as modulators of targeted ubiquitination of a variety of polypeptides and other proteins, which are then degraded and / or otherwise inhibited by the bifunctional compounds as described herein. An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with the degradation / inhibition of targeted polypeptides from virtually any protein class or family. In addition, the description provides methods of using an effective amount of the compounds as described herein for the treatment or amelioration of a disease condition, such as cancer.

Problems solved by technology

Conventional nonsteroidal antiestrogens, such as tamoxifen, compete efficiently for ER binding but their effectiveness is often limited by the partial agonism they display, which results in an incomplete blockade of estrogen-mediated activity.

Method used

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  • Indole derivatives as estrogen receptor degraders
  • Indole derivatives as estrogen receptor degraders
  • Indole derivatives as estrogen receptor degraders

Examples

Experimental program
Comparison scheme
Effect test

example # 1

Example #1: (2S,4R)-1-[(2S)-2-[1-(4-[[2-(4-fluorophenyl)-5-hydroxy-3-methyl-1H-indol-1-yl]methyl]phenyl)-1,4,7,10-tetraoxadodecan-12-amido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

[0409]

Step 1: Preparation of 2-bromo-1-(4-fluorophenyl) propan-1-one

[0410]In a 250 mL round bottom flask, 1-(4-fluorophenyl) propan-1-one (5.0 g, 32.86 mmol, 1.00 equiv) and PyBr3.HBr (11.5 g, 35.96 mmol, 1.10 equiv) were dissolved in dichloromethane (50 mL) at room temperature. The resulting solution was stirred for 1 hour at room temperature. The reaction was then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate (100 mL×2) and the organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure. This resulted in 5.0 g (66%) of 2-bromo-1-(4-fluorophenyl)propan-1-one as light yellow oil.

Step 2: Preparation of 5-(benzyloxy)-2-...

example # 2

Example #2: (2S,4R)-1-[(2S)-2-[1-(4-[[2-(4-fluorophenyl)-5-hydroxy-3-methyl-1H-indol-1-yl]methyl]phenyl)-1,4,7,10-tetraoxadodecan-12-amido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0420]

[0421]In a 50 mL round-bottom flask, 1-(4-[[2-(4-fluorophenyl)-5-hydroxy-3-methyl-1H-indol-1-yl]methyl]phenyl)-1,4,7,10-tetraoxadodecan-12-oic acid (80.0 mg, 0.15 mmol, 1.00 equiv), (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (66.0 mg, 0.15 mmol, 1.00 equiv), (benzotriazole-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (79.0 mg, 1.20 equiv) and N,N-diisopropylethylamine (58.0 mg, 0.45 mmol, 3.00 equiv) were dissolved in N,N-dimethylformamide (2 mL) at 0° C. The resulting solution was stirred for 1 hour at 0° C. The reaction was then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate (20 mL...

example # 3

Example #3: (2S,4R)-1-[(2S)-2-[2-[2-([1-[2-(4-[[2-(4-fluorophenyl)-5-hydroxy-3-methyl-1H-indol-1-yl]methyl]phenoxy)ethyl]piperidin-4-yl]oxy)ethoxy]acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

[0422]

Step 1: Preparation of 1-benzyl-4-[2-(oxan-2-yloxy)ethoxy]piperidine

[0423]In 250 mL round bottom flask, sodium hydride (5.0 g, 208.33 mmol, 4.00 equiv) was added to a solution of 1-benzylpiperidin-4-ol (9.0 g, 47.05 mmol, 1.50 equiv) in N, N-dimethylformamide (150 mL) at room temperature. The resulting mixture was stirred for 20 minutes at room temperature. Then 2-(2-bromoethoxy)oxane (6.5 g, 31.09 mmol, 1.00 equiv) was added and the reaction mixture was heated to 50° C. and stirred overnight. The reaction was then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate (100 mL×2) and the organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The organi...

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Abstract

The present disclosure relates to compounds and a pharmaceutically acceptable salt thereof, compositions, combinations and medicaments containing the compounds, and processes for their preparation. The disclosure also relates to the use of the compounds, combinations, compositions and medicaments, for example as inhibitors of the activity of the estrogen receptor, including degrading the estrogen receptor, the treatment of diseases and conditions mediated by the estrogen receptor.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Patent Application 62 / 395,228; filed: 15 Sep. 2016 and titled: Indole Derivatives as Estrogen Receptor Degraders, which is incorporated herein by reference in its entirety.BACKGROUND1. Field of the Discovery[0002]Embodiments of the present disclosure relate to compounds, compositions, and medicaments including the compounds and processes for the preparation thereof. The present disclosure also relates to the use of the compounds, compositions and medicaments, for example, as inhibitors of the activity of the estrogen receptor, including degrading the estrogen receptor, the treatment of diseases and conditions mediated by the estrogen receptor, e.g. the treatment of breast cancer.2. Background Information[0003]The estrogen receptor (ER) is a member of the nuclear hormone receptor family and functions as a ligand-activated transcription factor involved with the up and down regulation o...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D417/14C07D413/14C07D403/14C07D403/12
CPCC07D417/14C07D403/12C07D403/14C07D413/14C07K5/06034C07K5/06052
Inventor CREW, ANDREW P.QIAN, YIMINDONG, HANQINGWANG, JINGCREWS, CRAIG M.
Owner ARVINAS OPERATIONS INC
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