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SET8 lysine methyltransferase inhibitor as well as preparation method and application thereof

A lysine methyl, inhibitor technology, applied in organic chemical methods, pharmaceutical formulations, medical preparations containing active ingredients, etc.

Active Publication Date: 2020-02-07
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 research of a new class of compounds targeting SET8 lysine methyltransferase is the difficulty and focus of current research.

Method used

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  • SET8 lysine methyltransferase inhibitor as well as preparation method and application thereof
  • SET8 lysine methyltransferase inhibitor as well as preparation method and application thereof
  • SET8 lysine methyltransferase inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1 Preparation of 2-(3-(4-methoxybenzyl)-1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazole-5-yl)? Phenyl (compound 1) hydrochloride

[0061]

[0062] Step 1: Preparation of tert-butyl 2-((2-(4-methoxyphenyl)thioacetyl)carbamoyl)morpholine-4-carboxylate (compound 1-3)

[0063] The reaction equation is as follows:

[0064]

[0065] 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1.0mmol, 231mg), 2-(7-oxybenzotriazole)-N,N,N' shown in formula 1-1 , N'-tetramethyluronium hexafluorophosphate (HATU, 1.1mmol, 418mg) was dissolved in 4mL of dry dichloromethane (DCM), under nitrogen protection, stirred at room temperature for 20 minutes, and then added formula 1 to the above system 2-(4-Methoxyphenyl)thioacetamide (1.1mmol, 199mg) shown in -2, after stirring for 1 hour, N,N-diisopropylethylamine (DIEA, 1.1mmol, 142 mg) was dropped into the above reaction system, and continued to stir and react under nitrogen protection at room temperature for 2 days; the reaction...

Embodiment 2

[0075] Example 2 Preparation of 2-(1,3-bis(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)morpholine (compound 2)

[0076]

[0077] Step 1: Preparation of tert-butyl 2-(1,3-bis(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)morpholine-4-carboxylate (Compound 2 -1)

[0078]

[0079] Compound 1-3 (0.15mmol, 59mg), (4-methoxybenzyl)hydrazine hydrochloride (0.18mmol, 34mg), sodium acetate (0.36mmol, 30mg) were successively dissolved in 1mL acetic acid and 1mL 1,4 - After being placed in a mixed solvent of dioxane, seal the sealant, and then react under heating at 80° C. until the compound 1-3 is completely reacted. 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, concentrated, and separated by column chromatography [V (petroleum ether): V (ethyl acetate )=3:1-1:1], 50 mg of light yellow oil 2-1 was obtained, and the yield was 68%. ...

Embodiment 3

[0084] Example 3 Preparation of 2-(1-cyclohexyl-3-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)morpholine (compound 3)

[0085]

[0086] Step 1: Preparation of tert-butyl 2-(1-cyclohexyl-3-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)morpholine-4-carboxylate ( Compound 3-1)

[0087]

[0088] Compound 1-3 (0.16mmol, 63mg), cyclohexylhydrazine hydrochloride (0.2mmol, 30mg), sodium acetate (0.36mmol, 30mg) were successively dissolved in a mixture of 1mL acetic acid and 1mL 1,4-dioxane After being placed in the solvent, the sealant was sealed, and then the reaction compound 1-3 was completely reacted under heating at 80°C. 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], 40mg of light yellow oily substan...

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PUM

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Abstract

The invention provides an SET8 lysine methyltransferase inhibitor as well as a preparation method and application thereof. The inhibitor has a structural formula shown in the description. The inhibitor provided by the invention has a remarkable inhibition function on SET8 lysine methyltransferase, and in addition, has a remarkable inhibition effect on proliferation of tumor cells.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a SET8 lysine methyltransferase inhibitor, a preparation method and application thereof. 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, including histone...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14C07D413/04C07D401/04C07D249/08C07D405/14A61K31/5355A61K31/4439A61K31/4196A61P35/00
CPCC07D413/14C07D413/04C07D401/04C07D249/08C07D405/14A61P35/00A61K31/5377A61K31/454A61K31/4196C07B2200/07
Inventor 苏学明李玮杨超
Owner HAINAN YILING MEDICAL INDUSTRY & DEVELOPMENT CO LTD
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