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

Protein degradation targeting chimera compound, preparation method and medical application thereof

A compound and pharmaceutical technology, applied in the field of medicine, can solve problems such as long progression-free period

Active Publication Date: 2021-12-07
ANCUREALL PHARMA SHANGHAI CO LTD
View PDF3 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Salirasib phase I multiple-dose clinical trial study was found to be safe and well tolerated in Japanese patients with relapsed / refractory solid tumors. Although the number of participants with KRAS mutations was limited, preliminary results showed that the progression-free period was very long and warranted further study ( Furuse J et al., Cancer Chemother Pharmacol. 2018; 82(3):511-519)

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
  • Protein degradation targeting chimera compound, preparation method and medical application thereof
  • Protein degradation targeting chimera compound, preparation method and medical application thereof
  • Protein degradation targeting chimera compound, preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0218] Example 1N-(2-{2-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole -4-ylamino]-ethoxy}-ethyl)-2-(3,7,11-trimethyldodeca-2,6,10-trienylthio)-benzamide (1 ) preparation

[0219]

[0220] Step 1: Preparation of 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (1a)

[0221] At 140°C, 3-fluorophthalic anhydride (28g, 168mmol), 3-amino-2,6-piperidinedione hydrochloride (27.74g, 168mmol) and sodium acetate (16.5g, 201.6mml) were dissolved in 420ml of acetic acid Stirring for 14 hours. The reaction solution was cooled to room temperature, and a solid precipitated out, which was filtered, and the filter cake was washed with methyl tert-butyl ether. Blast drying (60° C.) for 8 hours gave 38 g of white solid, which was directly used in the next reaction without further purification.

[0222] Step 2: Preparation of 1-bromo-3,7,11-trimethyldodecane-2,6,10-triene (1b)

[0223] Dissolve 1-hydroxy-3,7,11-trimethyldodecane-2,6,10-triene (7.457g, 33.5mmol)...

Embodiment 2

[0236] Example 2N-(2-{2-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole -5-ylamino]-ethoxy}-ethyl)-2-(3,7,11-trimethyldodeca-2,6,10-trienylthio)-benzamide (2 ) preparation

[0237]

[0238] The preparation method is the same as in Example 1, except that 3-fluorophthalic anhydride in step 1 is replaced with 4-fluorophthalic anhydride to obtain N-(2-{2-[2-(2,6-dioxo-piperidine -3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylamino]-ethoxy}-ethyl)-2-(3,7,11 - Trimethyldodeca-2,6,10-trienylthio)-benzamide.

[0239] 1 H-NMR (400MHz, DMSO-d 6 )δ: 11.05(s, 1H), 8.29(d, J=4.8Hz, 1H), 8.19(d, J=8.0Hz, 1H), 7.55(d, J=8.4Hz, 1H), 7.48-7.32( m,5H),7.26(d,J=8.0Hz,1H),7.22(t,J=7.6Hz,1H),7.00(s,1H),6.89(d,J=8.4Hz,1H),5.05- 5.00(dd,J=5.2,12.8Hz,2H),4.66(t,J=5.2Hz,1H),3.62(t,J=4.4Hz,2H),3.55(t,J=4.4Hz,2H), 3.49-3.45(m,2H),3.39-3.33(m,4H),2.95-2.84(m,3H),2.59-2.50(m,3H),2.01-1.86(m,8H),1.70-1.54(m ,12H).

[0240] LC-MS(ESI):701.3(M+H) + .

Embodiment 3

[0241]Example 3 2-{2-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4 -ylamino]-ethoxy}-ethyl 2-(3,7,11-trimethyl-dodeca-2,6,10-trienylthio)-benzoate (3) preparation

[0242]

[0243] Step 1: 2-(2,6-Dioxo-piperidin-3-yl)-4-[2-(2-hydroxy-ethoxy)-ethylamino]-isoindole-1,3- Preparation of diketone (3a)

[0244] Compound 1a (2.0g, 7.2mmol), diglycolamine (1.14g, 10.9mmol) and diisopropylethylamine (1.86g, 14.4mmol) were dissolved in DMF (10mL), and the reaction system was heated to Stir overnight at 90°C. The reaction solution was lowered to room temperature, then poured into 60ml of water, extracted with ethyl acetate 150ml×2, the organic phase was washed with saturated brine 100ml×2, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / ammonia methanol=100:1-50:1) to obtain 880 mg of the product as a yellow solid.

[0245] Step ...

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 relates to a protein degradation targeting chimera compound, a preparation method and a medical application thereof. Specifically, the present invention relates to a compound represented by general formula (I) and its preparation method, as well as its use as a PPMTase protein degradation agent, especially in the prevention and / or treatment of human cancer. Wherein, the definition of each group in the general formula (I) is the same as that in the description.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a novel protein degradation targeting chimera (PROTAC) compound, its preparation method, a pharmaceutical composition containing it, and its use as a PPMTase protein degradation agent compound, especially in the prevention and / or or applications in the treatment of cancer. Background technique [0002] Ubiquitin, a small protein molecule, consists of 76 amino acid residues, has a molecular weight of about 8.5kDa, has a highly conserved sequence and is widely present in eukaryotic organisms. The genes encoding ubiquitin in eukaryotes are arranged in a tandem repeat (Tandem repeat), and its eight different amino acid residues can form complex polyubiquitin chains on target proteins. Ubiquitination refers to the process in which ubiquitin molecules classify intracellular proteins under the action of a series of special enzymes, select target protein molecules from them, and specifically modif...

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
Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04A61K31/4439A61P35/00
CPCA61P35/00C07D401/04
Inventor 司聚同
Owner ANCUREALL PHARMA SHANGHAI CO LTD
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