Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Compound for simultaneously inducing EGFR and PARP protein degradation as well as preparation method and application thereof

A protein degradation and compound technology, used in medical preparations containing active ingredients, drug combinations, organic chemistry, etc. The effect of a low onset dose

Active Publication Date: 2021-06-11
SHENYANG PHARMA UNIVERSITY
View PDF5 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, there are some problems or shortcomings in the combined use of drugs. For example, due to unreasonable preparations, direct physical or chemical reactions occur during combined drug use, resulting in changes in drug action; Too many varieties will increase the incidence of drug interactions, affect the efficacy of drugs or increase toxicity, which will not only weaken the efficacy, but may even cause serious adverse reactions; the combination of drugs with the same pharmacological effect or toxicity, such as the use of each drug without reducing the dosage , there is a possibility of drug poisoning; it is difficult to determine the optimal dose of drugs for combination therapy; there is also a problem of combination timing in combination therapy, and proper combination of drugs and rational sequential drug use can improve the curative effect

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Compound for simultaneously inducing EGFR and PARP protein degradation as well as preparation method and application thereof
  • Compound for simultaneously inducing EGFR and PARP protein degradation as well as preparation method and application thereof
  • Compound for simultaneously inducing EGFR and PARP protein degradation as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] A preparation method for compound DP-1 that simultaneously induces EGFR and PARP protein degradation, comprising the following steps:

[0087] Step 1: Preparation of Intermediate A: Dissolve N-Boc tyrosine methyl ester (19) (5.90 g, 20 mmol) and 2 equivalents of propargyl bromide (20) in 20 mL of anhydrous DMF, and add 2 equivalents of Potassium carbonate, stirred at room temperature for 6 hours, carried out hydroxyl etherification protection, after the reaction was complete, added 200mL ethyl acetate and 200mL saturated aqueous sodium chloride solution, extracted and separated, the organic layer was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography , 6.50 g of yellow oily product (21) was obtained with a yield of 98%. Dissolve 2 mmol of compound (21) in 30 mL of a mixed solvent of methanol and tetrahydrofuran at a volume ratio of 1:1, add 5 equivalents of saturated aqueous sodium hydroxide solution under stirring, stir o...

Embodiment 2

[0107] A preparation method for compound DP-2 that simultaneously induces EGFR and PARP protein degradation, comprising the following steps:

[0108] Step 1: Preparation of intermediate A: N-Boc serine methyl ester (23) (4.10g, 20mmol) and 2 equivalents of propargyl bromide (20) were dissolved in 20mL of anhydrous DMF, and the reaction was added under stirring at 0°C 2 equivalents of sodium hydride, the reaction was naturally raised to room temperature and stirred overnight, and the hydroxyl etherification protection was carried out. After the reaction was complete, a saturated aqueous sodium chloride solution was added dropwise to quench the reaction, and 200 mL of ether was added, and the layers were extracted. After concentration, it was purified by silica gel column chromatography to obtain 3.61 g of yellow oily intermediate A (24), with a yield of 74%.

[0109] Step 2: intermediate A undergoes amide condensation with olaparib and gefitinib in sequence to prepare intermedi...

Embodiment 3

[0126] A preparation method for compounds DP-3 and DP-4 that simultaneously induce EGFR and PARP protein degradation, comprising the following steps:

[0127] Step 1: Preparation of Intermediate A: The method of Example 2 was used to prepare Intermediate A (24).

[0128] Step 2: intermediate A undergoes amide condensation with olaparib and gefitinib in sequence to prepare intermediate B;

[0129] (1) Combination with Olaparib: Dissolve Olaparib (7) (0.73g, 2mmol) and 1 equivalent of compounds (8b) and (8c) in 50mL of anhydrous dichloromethane, and stir at 0°C 1.1 equivalents of EDCI, HOBt and 2 equivalents of DIPEA were added in turn, and the reaction was stirred overnight at room temperature. After the reaction was complete, 50 mL of dichloromethane and 50 mL of saturated aqueous sodium bicarbonate solution were added, and the layers were extracted. The organic layer was dried with anhydrous sodium sulfate and concentrated. After purification by silica gel column chromatogra...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a compound capable of simultaneously inducing EGFR and PARP protein degradation as well as a preparation method and an application thereof, and belongs to the field of medicinal chemistry. The invention provides an application of a series of novel dual-targeting degradation compounds with two independent inhibitor units and an E3 ligase ligand or pharmaceutically acceptable salts, hydrates, stereoisomers or prodrugs thereof in preparation of drugs for treating or preventing tumors. The compound provided by the invention can effectively induce E3 ligase dependent degradation of EGFR and PARP in pancreatic cancer cell lines and 1299 cells at the same time, and can effectively inhibit the growth of cancer cells. The target diversity of advanced cancers with tumor heterogeneity and reverse chemotherapy drug resistance can be solved. The method provided by the invention provides a new treatment mode for treatment of EGFR and PARP mediated tumors and / or other diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a bifunctional compound capable of simultaneously inducing degradation of EGFR and PARP proteins based on PROTAC technology, a preparation method and application thereof. Background technique [0002] Chemotherapy resistance in advanced cancer is mediated by multiple factors including overexpression of cellular epidermal growth factor receptor (EGFR) and DNA repair enzymes (PARP). Overexpression of the cellular epidermal growth factor receptor tyrosine kinase is associated with increased DNA repair activity and activation of anti-apoptotic signaling. [0003] EGFR is a transmembrane protein tyrosine kinase that acts as a receptor for EGF family members to trigger the epidermal growth factor receptor signaling pathway in human epithelial cells, thereby regulating cell proliferation, invasion, metastasis, and apoptosis. Excessive, mutated, or amplified EGFR gene resul...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D417/14C07D403/14C07D401/14A61K31/517A61P35/00
CPCC07D417/14C07D403/14C07D401/14A61P35/00
Inventor 李华陈丽霞周宜荣霍峻锋刘洋顾小霞张文波
Owner SHENYANG PHARMA UNIVERSITY
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com