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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
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  • 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 degradation PROTAC and its preparation method and application, as well as the c-Met degrader Application of Met degradation agent in the treatment of cancers such as non-small cell lung cancer and gastric cancer

Method used

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  • 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...

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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

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Application Information

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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
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