EGFR proteolysis targeting chimeric molecules and associated methods of use

A technology for linking moieties and bifunctional compounds, applied in EGFR proteolysis targeting chimeric molecules and related fields of use, can solve problems such as uncertain accessibility, and achieve the effect of broad-spectrum pharmacological activity

Inactive Publication Date: 2020-02-04
ARVINAS OPERATIONS INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] However, given the restricted cellular localization of transmembrane proteins and the uncertain accessibility of membrane-bound receptors for ubiquitination via cytosolic mechanisms, an outstanding question is whether the PROTAC approach can induce degradation of transmembrane proteins

Method used

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  • EGFR proteolysis targeting chimeric molecules and associated methods of use
  • EGFR proteolysis targeting chimeric molecules and associated methods of use
  • EGFR proteolysis targeting chimeric molecules and associated methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1894] Synthesis of Example 1

[1895] (2S,4R)-1-((S)-2-(tert-butyl)-14-(4-(4-(4-((2-chlorobenzyl)amino)-7H-pyrrolo[2, 3-d]pyrimidin-6-yl)benzyl)piperazin-1-yl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxyl- N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[1896]

[1897] Synthesis scheme:

[1898]

[1899] 1. Step – Synthesis of tert-butyl 2-(2-(2-(2-((methylsulfonyl)oxy)ethoxy)ethoxy)ethoxy)acetate

[1900]

[1901] To tert-butyl 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)acetate (300.0mg, 1.13mmol) and TEA (344.5mg, 3.40mmol) at 0°C To a solution of DCM (5 mL) was added MsCl (195.8 mg, 1.70 mmol). The solution was stirred at room temperature for 1 hour. The mixture was quenched with water, then extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (15 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude title compound 2-(2-(2-(2-((meth...

Embodiment 8

[1917] Synthesis of Example 8

[1918] 4-((17-(4-(4-(4-((2-chlorobenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)piperazine-1 -yl)-3,6,9,12,15-pentaoxahetadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 - dione

[1919]

[1920] Synthesis scheme:

[1921]

[1922] 1. Step – 2-(2,6-Dioxopiperidin-3-yl)-4-((17-Hydroxy-3,6,9,12,15-pentaoxahetadecyl)amino) Synthesis of Isoindoline-1,3-dione

[1923]

[1924] To 17-amino-3,6,9,12,15-pentoxahetadecan-1-ol hydrochloride (2.00g, 7.1mmol) and 2-(2,6-dioxopiperidine-3 To a solution of -yl)-4-fluoroisoindoline-1,3-dione (2.94 g, 10.65 mmol) in NMP (10 mL) was added DIEA (3.67 g, 28.4 mmol). The solution was stirred at 90°C for 2.5 hours. It was then cooled to room temperature and quenched with water (20 mL). The mixture was extracted with DCM (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column ch...

Embodiment 10

[1932] Synthesis of Example 10

[1933]

[1934]4-((2-(2-(2-(2-(4-(4-((2-chlorobenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzene Oxy)ethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1935] Synthesis scheme:

[1936]

[1937] 1. Step – 6-(4-(2-(2-(2-(2-(N,N-di-tert-butoxycarbonyl-amino)ethoxy)ethoxy)ethoxy)ethoxy )Phenyl)-N-(2-chlorobenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine synthesis

[1938]

[1939] At 25°C, to 2-(2-(2-(2-(N,N-di-tert-butoxycarbonyl-amino)aminoethoxy)ethoxy)ethoxy)ethyl methanesulfonate (490mg, 1.04mmol) in DMF (10mL) and 4-(4-((2-chlorobenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenol (364mg, 1.04mmol) added K 2 CO 3 (430 mg, 3.12 mmol). The resulting solution was stirred at 70 °C for 16 hours. The resulting solution was cooled to 20 °C. with H 2 O (40 mL) diluted the mixture. The mixture was extracted with EtOAc (40 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate ...

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Abstract

The present disclosure relates to bifunctional compounds, which find utility as modulators of receptor tyrosine kinase (RTK) proteins. In particular, the present disclosure is directed to bifunctionalcompounds, which contain on one end a ligand which binds to an E3 ubiquitin ligase and on the other end a moiety which binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effectuate ubiquitination, and therefore, degradation (and inhibition) of the target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation / inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions ofthe present disclosure.

Description

[0001] Citations to related applications [0002] This application requires U.S. Provisional Patent Application Serial No. 62 / 438,901, filed December 23, 2016, and titled EGFR Proteolysis Targeting Chimeric Molecules and Associated Methods of Use, and the September 2017 Priority to U.S. Provisional Patent Application Serial No. 62 / 563,494, entitled EGFR Proteolysis Targeting Chimeric Molecules and Associated Methods of Use, filed on March 26, which is incorporated in its entirety by Incorporated into this article by way of reference. [0003] Federal Statement of Support [0004] This invention was made with government support under Grant No. R35CA197589 of the National Institutes of Health. The government has certain rights in this invention. technical field [0005] This specification provides a bifunctional compound comprising a target protein binding part and an E3 ubiquitin ligase binding part, as well as related methods of use. Bifunctional compounds can be used as m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D417/04C07D403/14A61K31/519A61P35/00A61P29/00
CPCA61K47/545A61K31/519A61K31/427A61K31/454A61K31/517A61K31/55A61K31/496A61K31/551A61K45/06A61K38/07A61K31/52A61K31/506A61P1/04A61P11/00A61P17/00A61P17/06A61P25/00A61P29/00A61P35/00A61P43/00A61P9/10C07D487/04C07D417/04C07D403/14A61K47/55C07D471/04
Inventor 安德鲁·P·克鲁库尔特·齐默尔曼J·王迈克尔·贝尔林H·董亚力克西·伊先科Y·钱克雷格·M·克鲁斯绍尔·海梅-菲格罗阿乔治·布斯莱姆
Owner ARVINAS OPERATIONS INC
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