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MDM2-HDAC double-target inhibitor, medicinal composition and preparation and application of MDM2-HDAC double-target inhibitor

An MDM2-HDAC, dual-target technology, applied in drug combinations, active ingredients of heterocyclic compounds, antipyretics, etc., can solve the problems of p53 activity inhibition and proportion imbalance, and achieve inhibition of ubiquitination and reduction of drug resistance. , the effect of increasing clinical benefit

Active Publication Date: 2018-11-23
SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

MDM2 is often highly expressed in p53 wild-type tumor cells, resulting in an imbalance in the ratio of MDM2-p53 and inhibition of p53 activity

Method used

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  • MDM2-HDAC double-target inhibitor, medicinal composition and preparation and application of MDM2-HDAC double-target inhibitor
  • MDM2-HDAC double-target inhibitor, medicinal composition and preparation and application of MDM2-HDAC double-target inhibitor
  • MDM2-HDAC double-target inhibitor, medicinal composition and preparation and application of MDM2-HDAC double-target inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127]

[0128] Dissolve compound 1 (62mmol) and compound 2 (60mmol) in 200ml methanol, add piperidine (12mmol) after fully dissolved, and reflux at 70°C. After 5 hours, cool to room temperature and stir overnight. After the reaction was complete, the suspension was filtered, and the resulting solid was washed three times with methanol and then dried to obtain a yellow solid 3. Data for Compound 3: 1 H NMR (500MHz, DMSO-d 6 )δ7.76–7.72(m,1H),7.67(td,J=2.8,5.5Hz,1H),7.64(s,1H),7.57–7.54(m,2H),7.39(d,J=8.2Hz ,1H),6.94(dd,J=2.0,8.2Hz,1H),6.90(d,J=1.9Hz,1H); 13 C NMR (125MHz, DMSO) δ168.76, 144.95, 136.89, 135.32, 134.97, 134.02, 131.21, 130.01, 129.39, 128.18, 128.10, 124.13, 121.54, 119.99, 110.71;

[0129]

[0130] Compound 4 (1eq) was dissolved in ultra-dry toluene and compound 5 (1.1eq) and 6 (1.2eq) were added sequentially, stirred at 70°C for 5h, cooled to room temperature after the reaction was complete, concentrated by filtration, silica gel column chromatograph...

Embodiment 2

[0208]

[0209] After compound 28 (30mmol) and compound 29 (29mmol) were fully dissolved in 150ml of methanol, a methanol solution of sodium methoxide (25wt%, 10mL, 44mmol) was slowly added dropwise. Heat and stir at 50°C for 3 hours. The mixture became cloudy, cooled to room temperature and filtered. After washing with water and ice methanol three times, the filter cake was vacuum-dried to obtain 6.4 g of compound 30 as a white solid. 1 H NMR (400MHz, Chloroform-d) δ7.88–7.79(m,2H), 7.66–7.59(m,2H), 7.49–7.42(m,5H).

[0210]

[0211] Compound 31 (2.71 g, 20.0 mmol) and compound 32 (21.0 mmol) were dissolved in 50 ml of dichloromethane solution and stirred overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under vacuum to obtain 4.4 g of compound 33, which was used in the next step without further purification. ESI-MS(m / z):427(2M+H) +

[0212]

[0213] Compound 30 (7.3mmol) and compound 33 (7.3mmol) were dissol...

Embodiment 3

[0234]

[0235] Dissolve compound 39 (100mg, 0.536mmol) and compound 40 (230mg, 1.072mmol) in 3mL of toluene, add palladium acetate (2.4mg, 0.01072mmol) and potassium tert-butoxide (138mg, 1.233mmol) successively, and reflux reaction overnight . After fully cooling, add 6mL of petroleum ether to the system, filter, wash with petroleum ether and toluene respectively, and concentrate. After rough column chromatography purification, add 1,4-dioxane hydrochloric acid solution and stir for 1 hour, and concentrate to obtain a white solid. Compound 42. ESI-MS m / z 265(M+H) + .

[0236]

[0237] Compound 35 (70mg, 0.16mmol) and 2mL DCM were added to a 25mL round-bottomed flask. After fully dissolving, HATU (93mg, 0.24mmol) and DIEA (0.48mmol) were added successively. After stirring for 10 minutes, compound 42 (0.19mmol) was added. React overnight at room temperature. After the reaction was completed, it was extracted, dried and concentrated, purified by column chromatography ...

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Abstract

The invention provides a MDM2-HDAC double-target inhibitor, a medicinal composition and preparation and application of the MDM2-HDAC double-target inhibitor. The MDM2-HDAC double-target inhibitor hasa structure as shown in formula I. The inhibitor with the structure as shown in formula I, which is provided by the invention, can simultaneously inhibit activities of MDM2 and HDAC, promotes cancerous cells apoptosis, cell growth inhibition and period stagnation, has a double-target inhibitive ability, can reduce an apoptotic threshold of cancer cells, can improve the p53 acetylation level, enables p53 to stably exist in cell nuclei and prolongs the half-life period of the p53. The MDM2-HDAC double-target inhibitor provided by the invention can protect normal cells from being acted by toxicity of certain chemical therapeutic agents and radiation so as to carry out more effective treatment on cancers.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to an MDM2-HDAC dual-target inhibitor, a pharmaceutical composition and its preparation and application. Background technique [0002] TP53 (p53 gene) is the most important tumor suppressor gene in the human body, and clinical data show that about 50% of tumors are related to TP53 mutations. The p53 protein is the encoded product of TP53, also known as the "guardian angel" of the genome. The p53 protein plays a central role in repairing cell genome damage, maintaining genome stability, inducing apoptosis after irreversible damage to cells under stress conditions, and preventing malignant transformation of cells due to genetic variation. [0003] In tumor cells, p53 protein can induce tumor cell cycle arrest and apoptosis. MDM2 is an oncoprotein and a major inhibitor of the p53 protein. MDM2 inhibits p53 activity mainly through three ways: 1) MDM2 occupies the transcriptio...

Claims

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Application Information

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IPC IPC(8): C07D487/10C07D207/16C07D401/14C07D403/12A61K31/407A61K31/40A61K31/506A61K31/4192A61P35/00A61P25/28A61P3/00A61P27/02A61P29/00A61P37/02A61P9/00A61P31/00A61P25/14A61P25/16A61P25/08A61P3/10A61P27/06A61P19/02A61P17/06A61P11/00A61P11/06A61P1/00A61P1/04A61P1/16A61P13/12A61P25/18A61P25/24A61P9/04A61P9/10A61P31/12A61P31/10A61P33/06A61P33/02A61P7/06
CPCA61P1/00A61P1/04A61P1/16A61P3/00A61P3/10A61P7/06A61P9/00A61P9/04A61P9/10A61P11/00A61P11/06A61P13/12A61P17/06A61P19/02A61P25/08A61P25/14A61P25/16A61P25/18A61P25/24A61P25/28A61P27/02A61P27/06A61P29/00A61P31/00A61P31/10A61P31/12A61P33/02A61P33/06A61P35/00A61P37/02C07D207/16C07D401/14C07D403/12C07D487/10
Inventor 徐晶宁澄清黄恒军
Owner SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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