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C3-carbon linked glutarimide degronimers for target protein degradation

A determinant, ligand-targeting technology applied in the field of C3-carbon-linked glutarimide degronomers for target protein degradation

Pending Publication Date: 2019-04-16
C4 THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This study suggests that thalidomide-cereblon binding in vivo may be responsible for the teratogenicity of thalidomide

Method used

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  • C3-carbon linked glutarimide degronimers for target protein degradation
  • C3-carbon linked glutarimide degronimers for target protein degradation
  • C3-carbon linked glutarimide degronimers for target protein degradation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0961] Example 1: 1,3-(4-bromophenyl)piperidine-2,6-dione

[0962]

[0963] Dimethyl 2-(4-bromophenyl)glutarate

[0964]

[0965] Sodium hydride (1.1 equiv) was suspended in THF and cooled to 0 °C. Methyl 2-(4-bromophenyl)acetate (1 equiv) was added dropwise and the reaction was mixed for 1 hour. Methyl 3-bromopropionate (1 eq.) was added dropwise. When the reaction was judged complete, it was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated and purified by silica gel chromatography to provide dimethyl 2-(4-bromophenyl)glutarate. (Eur JOC, 2015, (3), 556)

[0966] 3-(4-Bromophenyl)piperidine-2,6-dione

[0967]

[0968] To a stirred solution of sodium amide prepared in situ in liquid ammonia from metallic sodium and ammonia in the presence of a catalytic amount of iron(III) chloride was added 2-(4-bromophenyl)glutaric acid at -33 °C A solution of dimethyl ester in te...

Embodiment 2

[0969] Example 2: 3-(4-bromophenyl)piperidine-2,6-dione-3-d

[0970]

[0971] tert-butyl 3-(4-bromophenyl)-2,6-dioxopiperidine-1-carboxylate

[0972]

[0973] Catalytic amounts of DMAP and di-tert-butyl dicarbonate (1.05 equiv) were added to a solution of 3-(4-bromophenyl)piperidine-2,6-dione in acetonitrile at ambient temperature. Once the reaction was complete, the volatiles were removed by rotary evaporation and the residue was purified by silica gel chromatography to afford tert-butyl 3-(4-bromophenyl)-2,6-dioxopiperidine-1-carboxylate.

[0974] 3-(4-Bromophenyl)-2,6-dioxopiperidine-1-carboxylic acid tert-butyl ester-3-d

[0975]

[0976]A solution of tert-butyl 3-(4-bromophenyl)-2,6-dioxopiperidine-1-carboxylate in anhydrous THF was treated with bis(trimethylsilyl)amino Lithium (1.1 equivalents) was treated for 1 hour. The reaction was quenched with deuterated acetic acid (Bioorg. Med. Chem. Lett. 2003, 13, 3415) and warmed to ambient temperature. The crude r...

Embodiment 3

[0980] Example 3: 3-(4-bromophenyl)-3-fluoropiperidine-2,6-dione

[0981]

[0982] tert-butyl 3-(4-bromophenyl)-3-fluoro-2,6-dioxopiperidine-1-carboxylate

[0983]

[0984] A solution of tert-butyl 3-(4-bromophenyl)-2,6-dioxopiperidine-1-carboxylate in anhydrous THF was treated with bis(trimethylsilyl)amino Lithium (1.1 equivalents) was treated for 1 hour. A minimal amount of N-fluorobenzenesulfonimide (Bioorg. Med. Chem. Lett. 2003, 13, 3415) in anhydrous THF was added and the reaction was warmed to ambient temperature then quenched. The crude reaction was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, concentrated and purified by silica gel chromatography to provide 3-(4-bromophenyl)-3-fluoro-2,6-dioxopiper tert-Butyl pyridine-1-carboxylate.

[0985] 3-(4-Bromophenyl)-3-fluoropiperidine-2,6-dione

[0986]

[0987] A solution of tert-butyl 3-(4-bromophenyl)-3-fluoro-2,6-dioxopiperidine-1-carboxylate in DCM was treated...

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Abstract

This invention provides Degronimers that have carbon-linked E3 Ubiquitin Ligase targeting moieties (Degrons), which can be linked to a targeting ligand for a protein that has been selected for in vivodegradation, and methods of use and compositions thereof as well as methods for their preparation.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to US Application No. 62 / 334,362, filed May 10, 2016, which is hereby incorporated by reference for all purposes. technical field [0003] The present invention provides degronimers having carbon-linked E3 ubiquitin ligase targeting moieties (Degrons) that can be linked to Targeting ligand for protein degraded in vivo, the invention also provides its use method and composition as well as its preparation method. Background technique [0004] Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. Selective identification and removal of damaged, misfolded, or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). The UPP is central to the regulation of nearly all cellular processes, including antigen processing, apoptosis, organelle biogenesis, cell cycle, DNA transcription and repair, differentiation and...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07K14/47C07K14/72
CPCC07D401/14C07K14/72C07K14/47C07D405/14C07D413/14C07D221/22C07D401/04C07D401/06C07D401/12C07D413/04C07D417/04C07D417/14C07D471/04C07D471/08C07D487/04C07D495/04C07D495/14C07D519/00C07D211/86C07D211/88C07D211/90A61K31/45A61K31/451A61K31/454A61K31/4545Y02A50/30A61K47/545
Inventor A·J·菲利普斯C·G·纳斯沃斯舒克J·A·亨德森梁焱科何敏生K·拉扎斯基G·K·维茨H·U·沃拉
Owner C4 THERAPEUTICS INC
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