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Protein degradation targeting chimeric 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: 2021-03-30
ANCUREALL PHARMA SHANGHAI CO LTD
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  • 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

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

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Abstract

The invention relates to a protein degradation targeting chimeric compound, a preparation method and medical application thereof, specifically to a compound as shown in a general formula (I), a preparation method of the compound, and application of the compound as a PPMTase protein degradation agent, particularly to application of the compound in prevention and / or treatment of human cancers, wherein the definition of each group in the general formula (I) is the same as the definition in the specification.

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

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Application Information

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