Amine-linked c3-glutarimide degronimers for target protein degradation

A CR6R7, compound technology, applied in the field of amine-linked C3-glutarimide degron for target protein degradation

Pending Publication Date: 2019-05-21
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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  • Amine-linked c3-glutarimide degronimers for target protein degradation
  • Amine-linked c3-glutarimide degronimers for target protein degradation
  • Amine-linked c3-glutarimide degronimers for target protein degradation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 3

[1414] Example 3: Exemplary preparation of 3-substituted-2,6-dioxopiperidine intermediates via LHMDS-mediated SN2 on 3-Br-glutarimide

[1415] Option 4:

[1416]

[1417] Preparation of 3-(3-methyl-6-oxopyridazin-1(6H)-yl)piperidine-2,6-dione (compound 148)

[1418]

[1419] Compound 148

[1420] To a stirred solution of 6-methylpyridazin-3(2H)-one 4-1 (300mg, 2.72mmol) in THF (10ml) was added LiHMDS (4.08ml, 4.08mmol) at -30°C and the reaction was stirred The mixture was 1 hour, then 3-bromopiperidine-2,6-dione 2-1 (522 mg, 2.72 mmol) was added, gradually warmed to room temperature, and finally heated under reflux overnight. After TLC showed complete consumption of 4-1, the reaction mass was quenched with ice water, volatiles were removed, the residue was partitioned between ethyl acetate and water, the combined organic extracts were dried over sodium sulfate, concentrated, and chromatographed by column Purification of the residual crude material (eluting with 2% MeO...

example

[1867] (Example procedure: PCT International Application 2008046758, April 24, 2008) To a solution of 4-(benzyloxy)benzaldehyde (1 equiv) in 50 mL of methanol was slowly added potassium cyanide (2 equiv) at room temperature and methylamine.HCl (1.5 equiv) in water (50 mL). The reaction mixture was heated at 40 °C for 2 hours, then at room temperature for 18 hours and monitored by TLC. After completion, the reaction mixture was extracted with 3 x 100 mL of dichloromethane. The organic layer was washed with Na 2 SO 4 Drying and concentration gave the desired 2-(4-(benzyloxy)phenyl)-2-(methylamino)acetonitrile which was used in the next step without further purification.

[1868] step 2

[1869]

[1870] 5-(4-(Benzyloxy)phenyl)-1-methylimidazolidin-2-one:

[1871] A solution of 2-(4-(benzyloxy)phenyl)-2-(methylamino)acetonitrile (1.0 equiv) in THF (0.4M) was added to LiAlH at 0 °C 4 (6.0 equivalents) in suspension in THF (0.4M). The reaction was heated at reflux overnig...

Embodiment 1

[2233] plan 1:

[2234]

[2235] General procedure:

[2236] A mixture of 1-1 (1 mmol) and 1-2 (1 mmol) in dimethylacetamide was heated in the presence of DIPEA (3 mmol) in a sealed tube at 90°C. After TLC showed complete consumption of 1-1, the reaction mixture was cooled, partitioned between ethyl acetate and water, the combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by reverse phase preparative HPLC to afford the desired product 1-3 as a solid.

[2237] General method for preparative HPLC purification:

[2238] method 1

[2239] Preparative HPLC was performed on a Waters automatic purification apparatus equipped with a YMC-Actus Triart C18 (100×30 mm, 5 μ) column, operated at ambient temperature, and the flow rate was 30.0 mL / min. Mobile phase: A = 20mM NH in water 4 HCO 3 , B = acetonitrile; gradient profile: the initial composition of the mobile phase is 80% A and...

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Abstract

This invention provides amine-linked C3-glutarimide Degronimers and Degrons for therapeutic applications as described further herein, and methods of use and compositions thereof as well as methods fortheir preparation.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application 62 / 334,338, filed May 10, 2016. The entire content of this application is hereby incorporated by reference for all purposes. technical field [0003] The present invention provides amine-linked C for use in therapeutic applications as further described herein. 3 - Glutarimide degronimers and degrons, methods and compositions for their use and methods for their preparation. 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 development, immune...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07K14/47C07K14/72
CPCC07D401/14C07D405/14C07D401/04C07D401/12C07D413/04C07D413/12C07D471/04C07D487/04C07D495/14C07D211/88A61K31/45A61K31/454A61K31/4545A61K31/4709A61K31/513Y02A50/30A61K47/545A61K47/554
Inventor A·J·菲利普斯C·G·纳斯沃斯舒克J·A·亨德森梁焱科陈启礼M·杜普莱西斯何敏生K·拉扎斯基
Owner C4 THERAPEUTICS INC
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