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Lactam histone deacetylase inhibitors

A technology of benzamide and compound, applied in the field of medicinal chemistry

Active Publication Date: 2018-08-14
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
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  • Lactam histone deacetylase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] (E)-N-(2-Aminophenyl)-4-((2-oxo-3-(pyridin-2-ylmethylene)piperidin-1-yl)methyl)benzamide

[0091]

[0092] Step a: Preparation of tert-butyl-2-oxopiperidine-1-carboxylic acid

[0093] Add piperidin-2-one (5g, 50mmol), di-tert-butyl dicarbonate (13.1g, 60mmol), and acetonitrile 100mL in a 250mL eggplant-shaped flask. Cool to 0℃ in an ice bath, and slowly add 4-dicarbonate in batches. Methylaminopyridine (1.22g, 10mmol, after addition, react at room temperature for 24h, TLC detects that the reaction is complete, the solvent is evaporated under reduced pressure, the residue is separated by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) 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.

[0094] Step b: (E)-tert-Butyl-2-oxo-3-(pyridin-2-ylmethylene)piperidine-1-carboxylic acid tert-butyl ester

[0095] Add tert-butyl-2-oxopiperidine-1-carboxylic acid (4g, 20mmol) in a ...

Embodiment 2

[0105] (E)-N-(2-Amino-4-fluorophenyl)-4-[[2-oxo-3-(pyridin-2-ylmethylene)piperidin-1-yl]methyl]benzene Formamide

[0106]

[0107] Using piperidin-2-one, 4-fluoro-1,2-phenylenediamine as raw materials, pyridine-2-carboxaldehyde, and methyl p-bromomethyl benzoate, the target compound white was prepared 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, the yield is 41.1%; Mp: 217-219°C; 1 H-NMR (300MHz, DMSO-d6) δ 9.60 (s, 1H), 8.67 (d, J = 3.9 Hz, 1H), 7.96 (d, J = 8 Hz, 1H), 7.87-7.81 (m, 1H) , 7.63 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 8.1 Hz, 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

[0109] (E)-N-(2-Aminophenyl-4-[[3-(furan-2-ylmethylene)-2-oxopiperidin-1-yl]methyl]benzamide

[0110]

[0111] The preparation method is as in Example 1, and a white solid is obtained 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=1 Hz, 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(KBr cm -1 ): 3457, 3348, 3292, 3104, 2989, 2949, 2389, 1728; MS m / 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 prevention and / or Use in medicine for treating diseases related to uncontrolled histone deacetylase activity. Background technique [0002] Orderly gene transcription regulation is a prerequisite for the normal function of cells in the body. If the gene transcription regulation function is disordered, cells may become cancerous. The acetylation and deacetylation of core histones are closely related to gene regulation, and the acetylation and deacetylation of histones are a pair of protease-histone acetyltransferases (HATs) and histone deacetylation that are antagonistic to each other. Enzymes (HDACs). HDACs are a group of enzymes that regulate a series of biological effects including chromatin reorgani...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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