SET8 lysine methyltransferase inhibitor, intermediate, preparation method and applications thereof

A technology for lysine methyl and inhibitors, applied in the field of preparation of SET8 lysine methyltransferase inhibitors and intermediates thereof

Active Publication Date: 2020-01-14
HAINAN YILING MEDICAL INDUSTRY & DEVELOPMENT CO LTD +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are few reports on the compounds targeting SET8 lysine methyltransferase. Therefore, the researc...

Method used

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  • SET8 lysine methyltransferase inhibitor, intermediate, preparation method and applications thereof
  • SET8 lysine methyltransferase inhibitor, intermediate, preparation method and applications thereof
  • SET8 lysine methyltransferase inhibitor, intermediate, preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Embodiment 1: Preparation of tert-butyl 2-((2-(4-methoxyphenyl)thioacetyl)carbamoyl)morpholine-4-carboxylate (formula II)

[0046]

[0047] Starting materials 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1.0 mmol, 231 mg), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (HATU, 1.1mmol, 418mg) was dissolved in 4mL of dry dichloromethane, under nitrogen protection, after stirring at room temperature for 20 minutes, the raw material 2-(4-methoxyphenyl ) Thioacetamide (1.1mmol, 199mg), after continuing to stir for 1 hour, N,N-diisopropylethylamine (DIEA, 1.1mmol, 142mg) was added dropwise into the above reaction system, and continued under nitrogen protection at room temperature The reaction was stirred for 2 days. After the reaction solution was diluted with 50 mL of ethyl acetate, it was washed with 20 mL of water and saturated sodium chloride solution successively, dried over anhydrous sodium sulfate, and after concentrating the react...

Embodiment 2

[0048] Example 2 Preparation of 2-(1-cyclohexyl-3-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)morpholine-4-carboxylic acid tert-butyl ester ( Formula III)

[0049]

[0050] Formula II (0.16mmol, 63mg), cyclohexylhydrazine hydrochloride (0.2mmol, 30mg), sodium acetate (0.36mmol, 30mg) were successively dissolved in a mixed solvent of 1mL acetic acid and 1mL 1,4-dioxane Finally, seal it, and then react under heating at 80°C until the reaction of II is complete. After the reaction solution was diluted with 30mL ethyl acetate, washed successively with 20mL saturated sodium carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, after concentrating the reaction solution, column chromatography separated [V (petroleum ether): V( Ethyl acetate)=3:1-1:1], 40 mg of light yellow oily substance III was obtained, and the yield was 55%.

Embodiment 3

[0051] Example 3 Preparation of 2-(1-cyclohexyl-3-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)morpholine (Formula I)

[0052] Formula III (0.09mmol, 41mg), anisole (0.1mmol, 11mg), 0.5mL of hydrogen chloride in 1,4-dioxane solution (4M) were successively dissolved in 3mL of dichloromethane, and sealed for 3 days , to complete the reaction of III. The reaction solution was evaporated to dryness to obtain a yellow oil, which was diluted with 30 mL of ethyl acetate, washed with 20 mL of saturated sodium carbonate solution, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography [V(ammonia di Chloromethane solution): V (methanol) = 25:1-20:1] to obtain 26 mg of yellow oil I, with a yield of 81%.

[0053] 1 H NMR (400MHz, CDCl 3 ):δ7.25-7.23(m,2H),6.82-6.80(m,2H),4.67-4.64(m,2H),4.28-4.21(m,2H),3.98(s,2H),3.85-3.79 (m,1H),3.77(s,3H),3.73-3.67(m,1H),3.31-3.25(m,1H),3.19-3.15(m,1H),3.01-2.87(m,2H),1.98 -2.85(m,6H),1.73-1.70(m,1H),1.40-1.26(m,4H). 1...

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PUM

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Abstract

The invention provides an SET8 lysine methyltransferase inhibitor, an intermediate, a preparation method and applications thereof, wherein the structural general formula of the inhibitor is represented in the specification, and the inhibitor has remarkable inhibition activity on SET8 lysine methyltransferase, has remarkable in-vitro anti-tumor activity, and can be further developed into a targetedanti-tumor drug taking SET8 as a target.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a SET8 lysine methyltransferase inhibitor and its intermediate, preparation method and application. Background technique [0002] Epigenetics is the change in gene expression that does not depend on changes in gene sequence, but on DNA methylation and chemical modification of histones. Genetic mutations, epigenetic mutations, lifestyle and environmental factors collectively affect human health and disease. The mutations of genes encoding epigenetic regulation are mainly reflected in four aspects: histone modification changes, DNA promoter hypermethylation, DNA extensive hypomethylation and abnormal chromatin structure during the development of tumors. Abnormal DNA methylation is likely to cause the inhibition of transcription of tumor suppressor genes, genome instability and abnormal activation of oncogenes. Mutations in histone-modifying enzymes in tumors, includi...

Claims

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Application Information

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IPC IPC(8): C07D413/04A61P35/00A61K31/5377
CPCC07D413/04A61P35/00Y02P20/55
Inventor 苏学明李玮杨超
Owner HAINAN YILING MEDICAL INDUSTRY & DEVELOPMENT CO LTD
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