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Trifluoromethyl ketone compound used as histone deacetylase inhibitor and application thereof

A compound and aryl technology, which is applied in the field of trifluoromethyl ketone histone deacetylase inhibitors, can solve the problems of high toxicity, insufficient curative effect, and few types of deacetylase inhibitors.

Inactive Publication Date: 2010-02-17
苏州东南药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] The purpose of the present invention is to provide a novel histone deacetylase inhibitor, which solves the problems of less types of histone deacetylase inhibitors, inaccurate curative effect and high toxicity in the prior art for the treatment of tumors and leukemia.

Method used

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  • Trifluoromethyl ketone compound used as histone deacetylase inhibitor and application thereof
  • Trifluoromethyl ketone compound used as histone deacetylase inhibitor and application thereof
  • Trifluoromethyl ketone compound used as histone deacetylase inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1 Preparation of 1,1,1-trifluoro-8-(3-phenyl-1,2,4-oxadiazol-5-yl)-2-octanone (compound 1)

[0058]

[0059] Dissolve aniline oxime (5g, 36-7mmol) in 15mL pyridine, add 8-chloro-8-oxo-octanoic acid methyl ester (9.11g, 44.1mmol) dropwise within 30min at room temperature, and reflux reaction after addition , until the aniline oxime reaction was complete, cooled to room temperature, added ethyl acetate and water for distribution, the organic layer was washed successively with 2M aqueous hydrochloric acid solution, saturated sodium bicarbonate solution and saturated brine, the organic layer was dried with magnesium sulfate, passed through a silica gel column Chromatography gave a colorless oily liquid. Yield 65%. Heptanoic acid methyl esters of other substituents were synthesized in the same way, and the yield was 52-70%.

[0060] 1 H-NMR (500Hz, CDCl 3)δ: 8.06-8.08(m, 2H), 7.28-7.49(m, 3H), 3.66(s, CO2CH3, 3H), 2.94(t, J=7.5Hz, het-CH 2 CH 2 , 2H), 2.31(t...

Embodiment 2

[0064] Example 2 Preparation of 1,1,1-trifluoro-8-(3-p-tolyl-1,2,4-oxadiazol-5-yl)-2-octanone (compound 2)

[0065]

[0066] Preparation method: replace the aniline oxime in Example 1 with p-toluidine oxime, and the other preparation methods are the same.

[0067] Mp: 50-51°C. 1 H-NMR (300Hz, CDCl 3 )δ: 7.95(d, J=8.17Hz, 2H), 7.27(d, J=7.84Hz, 2H), 2.94(t, J=7.53Hz, het-CH 2 CH 2 , 2H), 2.72(t, J=7.19Hz, CH 2 CH 2 CO 2 CF 3 , 2H), 2.41(s, 3H), 1.86-1.93(m, CH 2 , 2H), 1.68-1.74 (m, CH 2 , 2H), 1.41-1.49(m, 2CH 2 , 4H). 13 C-NMR (75Hz, DMSO-d6) δ: 191.03 (q, J=34.2Hz), 179.52 (C-5), 168.22 (C-3), 141.39, 129.49, 127.27, 124.01, 115.53 (d, J= 290.48Hz), 36.13, 28.51, 28.16, 26.40, 26.26, 22.07, 21.26. HRMS [Found: m / z 339.1326 (M-H) - , 363.1291 (M+Na) + ;Calcd for C 17 h 19 f 3 N 2 o 2 : M, 340.1399.

Embodiment 3

[0068] Example 3 Preparation of 1,1,1-trifluoro-8-(3-p-methoxyphenyl-1,2,4-oxadiazol-5-yl)-2-octanone (compound 3)

[0069]

[0070] Preparation method: replace the aniline oxime in Example 1 with 4-methoxyanilinoxime, and the other preparation methods are the same.

[0071] Mp: 39-41°C. 1 H-NMR (300Hz, CDCl 3 )δ: 8.00(m, 2H), 6.98(m, 2H), 3.86(s, 3H), 2.93(t, J=7.53Hz, het-CH 2 CH 2 , 2H), 2.73(t, J=7.19Hz, CH 2 CH 2 CO 2 CF 3 , 2H), 1.83-1.93 (m, CH2, 2H), 1.66-1.75 (m, CH2, 2H), 1.36-1.45 (m, 2CH 2 , 4H). 13 C-NMR (75Hz, DMSO-d6) δ: 179.40 (C-5), 167.94 (C-3), 161.85, 128.95, 119.33, 114.20, 55.32, 36.15, 28.53, 28.18, 26.42, 26.28, 22.09. HRMS [Found: m / z 355.1275 (M-H) - , 379.1240 (M+Na) + ; Calcd for C 17 h 19 f 3 N 2 o 3 : M, 356.1348.

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Abstract

The invention discloses a compound in the formula (I) or pharmaceutically acceptable salt thereof. Ar is aryl or heterocyclic group and is substituted by optional one or more of the following groups:C1-8 alkyl, C1-8 alkoxy, halogen, nitro , C1-8 aminoalkyl, C1-8 alkyl amino group, C1-8 thio-alkyl, C1-8 halogenated alkyl, C1-8 halogenated alkoxy, C1-8 ester group, phenyl or heterocyclic group. n is an integer from 0 to 8. The drugs prepared by the compound can be used for treating solid tumors or leukemia correlating with cell differentiation or proliferation.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a class of trifluoromethyl ketone histone deacetylase inhibitors and applications thereof. Background technique [0002] The formation of many diseases, including tumors, is a rather complex process, involving how various genes respond to changes in the internal and external environment, thereby achieving the regulation of expression in time and space. A frontier field emerging in genetics in recent years - epigenetics (Epigenetics) provides new ideas for answering these questions. The molecular basis of epigenetics mainly involves two aspects: one is the methylation modification of DNA, and the other is the acetylation modification of chromatin histones. In addition to the DNA sequence as the genetic code, epigenetic mechanisms are the most fundamental regulators of gene expression and subsequent protein synthesis. In eukaryotic cells, in the G0 phase, DNA is tig...

Claims

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Application Information

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IPC IPC(8): C07D271/06C07D413/04A61K31/4245A61P35/00A61P35/02
Inventor 吉民魏红涛吴晓晴
Owner 苏州东南药业股份有限公司
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