Targeted protein degradation c-Met degradation agent as well as preparation method and application thereof

A targeting and solvate technology, applied in the field of medicine, can solve the problems of c-Met small molecule inhibitor acquired drug resistance, etc., achieve significant proliferation inhibitory activity, improve cell selectivity, and good cell selectivity

Active Publication Date: 2021-01-19
SUZHOU UNIV
View PDF4 Cites 8 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The main content of the present invention is aimed at the problem of acquired drug resistance of c-Met small molecule inhibitors, providing a c-Met degrader based on the strategy of targeting protein...

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
  • Targeted protein degradation c-Met degradation agent as well as preparation method and application thereof
  • Targeted protein degradation c-Met degradation agent as well as preparation method and application thereof
  • Targeted protein degradation c-Met degradation agent as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044]Example 1: Preparation of 2-(4-(4-(2-fluoro-4-(1-(((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamido)phenoxy)- 1,6-naphthyridin-7-yl)-1H-pyrazol-1-yl)acetic acid

[0045]

[0046] In the above reaction scheme, the reagents and conditions used are as follows: a) 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N, N-diisopropylethylamine, N,N-dimethylformamide; b) hydrogen, 10% wet palladium carbon, ethanol; c) cesium carbonate, N,N-dimethylformamide, 110 ° C; d ) Tetrakis(triphenylphosphine) palladium, cesium carbonate, 1,4-dioxane:water (5:1), 120°C; e) tert-butyl bromoacetate, potassium carbonate, N,N-dimethyl Formamide; f) trifluoroacetic acid, dichloromethane. The reaction steps are as follows:

[0047] Step 1: N-(4-(Benzyloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

[0048]

[0049] Dissolve 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (2.9g, 13mmol), 4-(benzyloxy)-3-fluoroaniline (2.82g, 1...

Embodiment 2

[0065] Example 2: Preparation of 2-((2-(2,6-dioxaperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetic acid

[0066]

[0067] Reagents and conditions: a) pyridine, 3-amino-2,6-piperidinedione hydrochloride, 110°C; b) tert-butyl bromoacetate, potassium carbonate, N,N-dimethylformamide; c) Trifluoroacetic acid, dichloromethane.

[0068] Step 1: 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione

[0069]

[0070] 4-Hydroxyisobenzofuran-1,3-dione (952mg, 5.84mmol) was dissolved in 10mL of pyridine, and 3-amino-2,6-piperidinedione hydrochloride (960mg, 5.84mmol) was added to react The solution was heated to 110°C and stirred overnight. After the reaction was completed, it was cooled to room temperature, pyridine was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol=100:1 to 100:3) to obtain a white solid (1.5 g, yield 93%). 1 H NMR (400MHz, DMSO-d 6 )δ11.20(s, 1H), 11.11(s, 1H), 7.66(t, J=7.8Hz, 1H), 7...

Embodiment 3

[0078]

[0079] Reagents and conditions: a) 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine, N,N-Dimethylformamide; b) trifluoroacetic acid, dichloromethane; c) 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea Hexafluorophosphate, N,N-Diisopropylethylamine, N,N-Dimethylformamide.

[0080] Step 1: tert-butyl(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolyl-4-yl)oxy) Acetylamino) ethyl) carbamate

[0081]

[0082] 2-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (1eq), (2-amino Ethyl) tert-butyl carbamate (1.2eq) was dissolved in 2mL N,N-dimethylformamide, and N,N-diisopropylethylamine (3eq) and 2-(7-aza Benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.1eq), continue to stir for 1 hour, after the reaction is completed, add 50mL ethyl acetate to dilute, ethyl acetate The phase was washed by adding saturated aqueous sodium bicarbonate solution (50mL*3), and washed by satura...

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 targeted protein degradation c-Met degradation agent as well as a preparation method and application thereof. The invention provides a c-Met degradation agent based on a targeted protein degradation PROTAC strategy, a preparation method thereof and application of the c-Met degradation agent in the treatment of non-small cell lung cancer, gastric cancer and other cancers.The compound has a remarkable c-Met degradation effect and a remarkable cell proliferation inhibition effect, has the potential of serving as an anti-tumor drug to treat tumors, shows remarkable proliferation inhibition activity in an EBC1 drug-resistant cell strain constructed by lentiviral transfection, is obviously superior to a small molecule inhibitor LXM262. and obviously improves the cell selectivity. The compound has significant advantages in overcoming tumor c-Met acquired drug resistance, especially the compound S27 only provides good activity for c-Met dependent EBC-1 lung cancer cells, it is indicated that the compound S27 has good cell selectivity while the original small molecule inhibitor is multi-target, and the compound also has an inhibition effect on a c-Met non-dependent cell line.

Description

technical field [0001] The invention relates to a targeted protein degradation c-Met degradation agent and its preparation method and application, belonging to the technical field of medicine. Background technique [0002] c-Met, also known as hepatocyte growth factor (HGF) receptor, belongs to the family of receptor tyrosine kinases (RTKs). The combination of HGF and c-Met can regulate a variety of downstream signaling pathways to participate in a variety of physiological processes, including cell proliferation and survival, apoptosis and angiogenesis; when the HGF / c-Met signaling pathway is abnormal, it will lead to tumors happened. Furthermore, overexpression of the c-Met signaling pathway is associated with clinically poorer outcomes and resistance to EGFR inhibitors. Crizotinib and Cabozantinib are two small-molecule inhibitors of c-Met that are currently on the market. They are effective in clinical tumor treatment, but both face the problem of reduced curative effec...

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): C07D471/04C07D401/04C07D401/12C07K5/062C07K5/097C07K5/103A61K45/06A61K31/4545A61K31/454A61K38/05A61K38/06A61K38/07A61P35/00A61P35/02
CPCC07D471/04C07D401/04C07D401/12A61P35/00A61P35/02C07K5/0821C07K5/1013C07K5/06034
Inventor 龙亚秋王旭封顺
Owner SUZHOU UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap