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4-((4-substituted aryl-2-pyrimidinyl) amino) benzoyl hydrazide derivative as well as preparation method and application thereof

A technology for benzoyl hydrazide and derivatives, which is applied in the field of 4-amino) benzoyl hydrazide derivatives and their preparation, can solve the problems of large toxic and side effects, few tumor drugs, low bioavailability and the like, and achieves a simple reaction process. Easy to control, low cost of synthetic reaction, inhibition of inducing tumor cell apoptosis

Inactive Publication Date: 2017-08-18
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are many kinds of anticancer drugs, but there are few ideal tumor drugs, and the existing anticancer drugs more or less have the disadvantages of low bioavailability, large toxic and side effects, etc.

Method used

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  • 4-((4-substituted aryl-2-pyrimidinyl) amino) benzoyl hydrazide derivative as well as preparation method and application thereof
  • 4-((4-substituted aryl-2-pyrimidinyl) amino) benzoyl hydrazide derivative as well as preparation method and application thereof
  • 4-((4-substituted aryl-2-pyrimidinyl) amino) benzoyl hydrazide derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1: the synthesis of ethyl p-guanidine benzoate nitrate

[0027] In a 200mL dry single-neck bottle, first add ethyl p-aminobenzoate (5.0g, 0.030mol), cyanamide (50%w / w, 7.6g, 0.091mol), absolute ethanol (20mL); Concentrated hydrochloric acid (3.8 mL, 0.045 mol) was added dropwise under stirring, and the temperature was raised to reflux after the dropwise addition. After 24 hours of reaction, TLC detected that the reaction was complete, and the reaction was stopped. The reaction solution was concentrated under reduced pressure to remove the solvent, then 50 mL of water was added, and then an aqueous solution of ammonium nitrate (4.8 g, 0.061 mol) was added dropwise at 0°C. After the addition was completed, the reaction was incubated for 1 hour, filtered, the filter cake was collected, and dried to obtain a white solid The product was 6.3 g of ethyl guanidine benzoate nitrate, and the yield was 78%.

Embodiment 2

[0028] Example 2: Synthesis of 1-(2-pyridyl)-3-(dimethylamino)-2-propene-1-one

[0029] Add 2-acetylpyridine (5.0g, 0.041mol) and N,N-dimethylformamide dimethyl acetal (5.4g, 0.045mol) sequentially into a dry 100mL single-necked bottle, heat to 110°C, and reflux After 18 hours of reaction, TLC detected that the reaction was complete, and the reaction was stopped. After the reaction solution was concentrated under reduced pressure, 5 mL of ethyl acetate was added, stirred at room temperature for 1 h, filtered with suction, the filter cake was collected, and dried to obtain 4.2 g of a yellow-green solid with a yield of 58%. Spectral data: 1 H NMR (600MHz, DMSO-d 6 ):8.55~8.69(m,1H),7.98(d,J=7.7Hz,1H),7.91(dt,J=1.7,7.66Hz,1H),7.80(d,J=12.6Hz,1H),7.50 (ddd,J=1.2,4.77,7.52Hz,1H),6.38(d,J=10.6Hz,1H),3.18(s,3H),2.92(s,3H).

Embodiment 3

[0030] Embodiment 3: Synthesis of ethyl 4-((4-(2-pyridyl)-2-pyrimidinyl) amino)benzoate

[0031]Add 1-(2-pyridyl)-3-(dimethylamino)-2-propen-1-one (1.00 g, 0.0056 mol) and ethyl p-guanidinobenzoate nitric acid to a 50 mL dry single-necked bottle successively Salt (1.53g, 0.0056mol), sodium hydroxide solid (0.273g, 0.0068mol), absolute ethanol (10mL), heated to reflux, reacted for 18h, TLC detected that the reaction was complete, stop the reaction. After cooling to room temperature, it was filtered with suction, and the filter cake was collected and dried to obtain 1.52 g of off-white solid with a yield of 84%. Spectral data: 1 HNMR (600MHz, CDCl 3 ):8.73(d,J=4.4Hz,1H),8.62(d,J=4.9Hz,1H),8.42(d,J=7.7Hz,1H),8.07(d,J=8.2Hz,2H), 7.89-7.91(m,1H),7.87(d,J=5.6Hz,1H),7.81(d,J=8.0Hz,2H),7.56(br.s.,1H), 7.40~7.45(m,1H ), 4.38(q, J=7.0Hz, 2H), 1.41(t, J=6.9Hz, 3H).

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Abstract

The invention provides a 4-((4-substituted aryl-2-pyrimidinyl) amino) benzoyl hydrazide derivative as well as a preparation method and application thereof and relates to a tumor drug. The preparation method comprises the following steps: preparing intermediate p-guanidine benzoate nitrate; preparing intermediate 1-(substituted aryl)-3-(dimethylamino)-2-propylene-1-ketone; preparing intermediate 4-((4-substituted aryl-2-pyrimidinyl) amino) ethyl benzoate; preparing intermediate 4-((4-substituted aryl-2-pyrimidinyl) amino) benzohydrazide; preparing the 4-((4-substituted aryl-2-pyrimidinyl) amino) benzoyl hydrazide derivative. The 4-((4-substituted aryl-2-pyrimidinyl) amino) benzoyl hydrazide derivative can be applied to the preparation of a drug for treating or preventing a tumor-related disease. The 4-((4-substituted aryl-2-pyrimidinyl) amino) benzoyl hydrazide derivative has significant effects of inhibiting tumor cell growth and inducing tumor cell apoptosis and can be used for preparing the drug for treating or preventing the tumor-related disease.

Description

technical field [0001] The invention relates to tumor drugs, in particular to 4-((4-substituted aryl-2-pyrimidinyl)amino)benzoylhydrazine derivatives and their preparation methods and applications. Background technique [0002] Tumor drug therapy began in the 1940s. After 70 years of development, there are currently about 100 anti-tumor drugs in clinical use worldwide. In the 21st century, with the development of modern medicine, the in-depth study of the molecular mechanism of tumors, and the maturity of modern biomedical technology, the research and development of anti-tumor drugs worldwide has achieved fruitful results. According to incomplete statistics, there are more than 450 new anti-tumor drug candidates currently in the clinical research stage in the world, involving more than 2,850 clinical studies, including 223 phase III clinical studies, involving more than 80 new drugs. There are many kinds of anticancer drugs, but there are few ideal tumor drugs, and the exis...

Claims

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Application Information

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IPC IPC(8): C07D239/42C07D401/04A61K31/505A61K31/506A61P35/00
CPCC07D239/42C07D401/04
Inventor 吴振方美娟徐剑文赵俊明唐博文胡鸿雨周彤彤
Owner XIAMEN UNIV
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