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Tacrine derivative as CDKs inhibitor and application thereof

A derivative, the technology of tacrine, applied in the field of organic compound synthesis and pharmaceutical applications, can solve the problems of neglecting anti-cancer activity and low anti-proliferation activity of tumor cells, and achieve the effect of novel structure and high anti-proliferation activity

Active Publication Date: 2022-08-05
GENERAL HOSPITAL OF THE NORTHERN WAR ZONE OF THE CHINESE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, tacrine's anticancer activity has been largely overlooked by researchers
[0006] However, tacrine and its derivatives studied so far have low antiproliferative activity on tumor cells, and there is no report of tacrine and its derivatives as CDK2 and CDK9 inhibitors. Therefore, tacrine derivatives are Further research is still needed in the preparation of prevention or treatment of tumors

Method used

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  • Tacrine derivative as CDKs inhibitor and application thereof
  • Tacrine derivative as CDKs inhibitor and application thereof
  • Tacrine derivative as CDKs inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 7-Bromo-1,2,3,4-tetrahydroacridine-9-amine (ZLWT-2)

[0034] like figure 1 As shown, to a solution of 2-amino-5-bromobenzonitrile (Compound 1) (1 equiv) in cyclohexanone (50 mL) was added anhydrous ZnCl 2 (3 equivalents). The mixture was stirred at 140°C for 3 hours. After cooling, after filtration, the filtrate was concentrated and purified by silica gel chromatography to obtain the target compound ZLWT-2. Yield 76%, off-white solid. 1 H NMR (400MHz, DMSO-d 6 )δ8.48(d,J=1.9Hz,1H),7.66-7.55(m,2H),6.71(s,2H),2.82(t,J=5.8Hz,2H),2.57-2.48(m,2H) ),1.81(dd,J=7.6,4.4Hz,4H).ESI-MS m / z 277.2[M+H] + .

Embodiment 2

[0035] Example 2 6-Bromo-1,2,3,4-tetrahydroacridin-9-amine (Compound 11)

[0036] like Figure 4 As shown, 2-amino-4-bromobenzonitrile (compound 10) was used as the raw material, and the synthesis method was as in Example 1 to obtain compound 11. Yield 66%, off-white solid compound 11. 1 H NMR (400MHz, DMSO-d 6 )δ8.31(d, J=2.1Hz, 1H), 7.53-7.26(m, 2H), 6.58(s, 2H), 2.76(m, 2H), 2.64-2.52(m, 2H), 1.78(m ,4H).ESI-MS m / z277.1[M+H] + .

Embodiment 3

[0037] Example 3N-(4-Bromopyridin-2-yl)acetamide (Compound 3a)

[0038]

[0039] like figure 2 As indicated, to a solution of 4-bromo-2-aminopyridine (compound 2) (5 g, 28.90 mmol) in acetic anhydride (50 mL) was added DMAP (0.035 g, 0.3 mmol). After the mixture was stirred at 140°C for 6 hours, it was poured into ice water, neutralized with 2M NaOH, and filtered to obtain compound 3a as a white solid with a yield of 78%. ESI-MS m / z 214.8[M+H] + .

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PUM

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Abstract

The invention relates to a tacrine derivative serving as a CDKs inhibitor and application of the tacrine derivative, the structural general formula of the derivative is shown in the formula I. The tacrine derivative has the advantages of novel structure, high anti-proliferative activity and CDK2 and CDK9 inhibitory activity. Therefore, the compound plays an important role in preparation of drugs for preventing or treating tumors;

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis and medical application, in particular to tacrine derivatives as CDKs inhibitors and applications thereof. Background technique [0002] The cell cycle is a fundamental process in life, a series of events that take place in a cell leading to the formation of two identical daughter cells. The cell cycle controls the transition from quiescence or cytokinesis to cell proliferation and ensures genomic stability through its checkpoints. Kinases are the major components of phosphotransferases in the human genome, catalyzing the reversible transfer of the γ-phosphate group of ATP to target substrates, mediating signal transduction, and regulating most aspects of cellular life. Currently, approximately 518 human protein kinases and 20 lipid kinases have been identified. Protein kinases are enzymes that play a key regulatory role in almost every aspect of cell biology and are classifie...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D219/10C07D405/04C07D401/04C07D401/14C07D405/14A61P35/00A61K31/473A61K31/5377A61K31/496
CPCC07D219/10C07D405/04C07D401/04C07D401/14C07D405/14A61P35/00Y02P20/55
Inventor 赵庆春刘文武陆鸿远许子华吴丽萌黄耀广刘文杰李德平
Owner GENERAL HOSPITAL OF THE NORTHERN WAR ZONE OF THE CHINESE PEOPLES LIBERATION ARMY
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