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Lactam histone deacetylase inhibitors

A compound, selected technology, applied in the field of medicinal chemistry

Active Publication Date: 2016-04-27
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] HDACs targets are a class of anti-tumor targets with promising applications. The existing HDACs inhibitors still cannot fully meet the clinical needs. It is yet to be discovered that structurally novel and selective HDACs inhibitors can be used to prevent and / or treat diseases associated with histone depletion. Diseases associated with uncontrolled activity of acetylases, especially neoplastic diseases

Method used

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  • Lactam histone deacetylase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] (E)-N-(2-aminophenyl)-4-((2-oxo-3-(pyridin-2-ylmethylene)piperidin-1-yl)methyl)benzamide

[0089]

[0090] Step a: Preparation of tert-butyl-2-oxopiperidine-1-carboxylic acid

[0091] Add piperidin-2-one (5g, 50mmol), di-tert-butyl dicarbonate (13.1g, 60mmol) and acetonitrile 100mL in sequence in a 250mL eggplant-shaped flask, cool to 0°C in an ice bath, and slowly add 4-bis Aminopyridine (1.22g, 10mmol, after addition, reacted at room temperature for 24h, TLC detected that the reaction was complete, evaporated the solvent under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1) to obtain Color oily liquid (6.07g, 30.5mmol). 1 H-NMR (300MHz, CDCl 3 )δ3.65(m, 2H), 2.50(m, 2H), 1.82(m, 4H), 1.52(s, 9H).ESIMS: [M+H] + : 222.12.

[0092] Step b: (E)-tert-Butyl-2-oxo-3-(pyridin-2-ylmethylene)piperidine-1-carboxylic acid tert-butyl ester

[0093]Add tert-butyl-2-oxopiperidine-1-carboxylic acid (...

Embodiment 2

[0103] (E)-N-(2-amino-4-fluorophenyl)-4-[[2-oxo-3-(pyridin-2-ylmethylene)piperidin-1-yl]methyl]benzene Formamide

[0104]

[0105] Using piperidin-2-one, 4-fluoro-1,2-phenylenediamine as raw materials, pyridine-2-carbaldehyde, and methyl p-bromomethylbenzoate, the target compound white was obtained by a method similar to Example 1 Solid (E)-N-(2-amino-4-fluorophenyl)-4-[[2-oxo-3-(pyridin-2-ylmethylene)piperidin-1-yl]methyl] Benzamide, yield 41.1%; Mp: 217-219°C; 1 H-NMR (300MHz, DMSO-d6) δ9.60(s, 1H), 8.67(d, J=3.9Hz, 1H), 7.96(d, J=8Hz, 1H), 7.87-7.81(m, 1H) , 7.63(s, 1H), 7.55(d, J=7.9Hz, 1H), 7.40(d, J=8.1Hz, 2H), 7.34-7.30(m, 1H), 7.13-7.08(m, 1H), 6.53(dd, J=11.3, 3Hz, 1H), 6.39-6.32(m, 1H), 5.25(s, 2H), 4.73(s, 2H), 3.4(s, 2H), 3.18-3.15(m, 2H ), 1.82-1.80 (m, 2H).ESIMS: [M+Na] + : 453.2.

Embodiment 3

[0107] (E)-N-(2-Aminophenyl-4-[[3-(furan-2-ylmethylene)-2-oxopiperidin-1-yl]methyl]benzamide

[0108]

[0109] The preparation method was as in Example 1 to obtain a white solid with a yield of 62.3%. Mp: 212-214°C; 1 H-NMR (300MHz, DMSO-d 6 )δ9.66(s, 1H, -CONHAr-), 7.95(d, J=8Hz, 2H, H-Ar), 7.84(d, J=8Hz, 2H, H-Ar), 7.84-7.83(m, 1H, H-Ar), 7.62 (s, 1H, -CH=), 7.4 (d, J=1Hz, 2H, H-Ar), 7.12-7.08 (m, 1H, H-Ar), 6.80 (d, J=3.3Hz, 1H, H-Ar), 6.66-6.64(m, 1H, H-Ar), 6.53(dd, J 1 =11Hz,J 2 =3Hz, 1H, H-Ar), 6.39-6.32(s, 1H, H-Ar), 5.24(s, 2H, -NH 2 ), 4.65 (s, 2H, -CH 2 -), 2.88(s, 2H, -CH 2 -), 1.84(s, 2H, -CH 2 -), 1.24(m, 2H, -CH 2 -);IR(KBrcm -1 ): 3457, 3348, 3292, 3104, 2989, 2949, 2389, 1728; MSm / z: 424.2 [M+Na] + .

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Abstract

The invention relates to the field of medicinal chemistry, and specifically relates to lactam histone deacetylase inhibitors, preparation methods thereof, medicine compositions containing the histone deacetylase inhibitors, and applications of the inhibitors in preventing and / or treating diseases related to uncontrolled histone deacetylase activity.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of lactam histone deacetylase inhibitors, a preparation method, a drug combination containing the histone deacetylase inhibitor, and the use of such inhibitors in the prevention and / or Use in a medicament for the treatment of diseases associated with uncontrolled histone deacetylase activity. Background technique [0002] The orderly transcriptional regulation of genes is the prerequisite for the cells of the body to maintain normal functions. If the transcriptional regulation of genes is dysfunctional, the cells may become cancerous. The acetylation and deacetylation of core histones are closely related to gene regulation, and responsible for histone acetylation and deacetylation is a pair of proteases with mutually antagonistic functions—histone acetyltransferases (HATs) and histone deacetylation enzymes (HDACs). HDACs are a group of enzymes that regulate...

Claims

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Application Information

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IPC IPC(8): C07D401/06C07D405/06C07D211/86C07D207/38A61K31/4545A61K31/4525A61K31/445A61K31/4015A61P35/00A61P35/02A61P3/10A61P31/18
CPCC07D207/38C07D211/86C07D401/06C07D405/06
Inventor 陈亚东陈新汤啸天赵爽朱雍钮家琪陆涛
Owner CHINA PHARM UNIV
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