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Pyrimidinylpyrazinamide compound, and application thereof

A technology of pyrimidine piperazine amide and pyrimidine piperazine, which is applied in the field of medicinal chemistry, can solve problems such as the lack of effective treatment drugs, and achieve the effects of reducing the size of cerebral infarction, easily obtaining raw materials and having strong inhibitory effect.

Active Publication Date: 2017-11-21
GMU MEDICAL DRUG DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these drugs are widely used, most of them can only prevent stroke or early treatment of stroke patients, and there is no effective treatment for brain tissue damage caused by ischemia

Method used

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  • Pyrimidinylpyrazinamide compound, and application thereof
  • Pyrimidinylpyrazinamide compound, and application thereof
  • Pyrimidinylpyrazinamide compound, and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] The preparation of embodiment 1 (4-(2-pyrimidine piperazinyl)) (2-chloroquinazoline) ketone (compound 10)

[0067]

[0068] Add 100g of indolinone (isatin) and a stirrer into a 500ml eggplant-shaped bottle, prepare an aqueous solution of 1.5 equivalents of KOH according to 20% (w / w), add in batches, after the addition, heat to 40°C, the red indole The ketone solution gradually becomes shallow as the reaction progresses, and the reaction is completed after 8 hours. The water is evaporated under reduced pressure below 40°C, and a small amount of ethanol is added to the solid initial product. After uniform suspension, filter, wash twice with a small amount of ethanol, remove KOH, and Wash with acetone twice to remove ethanol and water. To avoid moisture absorption, the yellow filter cake was quickly sealed and dried in vacuum. Mass spectrometry identification (ESI-MS calcd.for C 8 h 6 KNO 3 : [M+H]+, 204.24; found, 204.00) The crude product is compound 6, a yellow p...

Embodiment 2

[0072] Preparation of Example 2 (4-(2-pyrimidine piperazinyl)) (2-cyanoquinazoline) ketone (10a)

[0073]

[0074] 250mg compound 10 was dissolved in DMSO:H with 1.2 equivalents of sodium cyanide and 1 equivalent of 1,4-diazabicyclo[2.2.2]octane (DABCO) 2 In the mixed solution of O=9:1, under the protection of nitrogen, seal and heat to 100°C, and keep stirring. After 5 hours, the reaction was completed, cooled to room temperature, added 300ml of water, extracted 4 times with 50ml of dichloromethane, washed the combined dichloromethane layer once with 100ml water, once with 100ml saturated saline, dried over anhydrous sodium sulfate, and evaporated to dryness Silica gel column chromatography gave the yellow target product 10a in a yield of 70%.

[0075] 1 H NMR (400M Hz, CDCl 3 ): δ8.35(d, J=4.4Hz, 2H), 8.21(d, J=8.0Hz, 1H), 8.13-8.09(m, 2H), 7.87(t, J=7.6Hz, 1H), 6.58 (t,J=4.8Hz,1H),4.08-4.06(m,2H),4.03-4.00(m,2H),3.89-3.86(m,2H),3.38-3.36(m,2H); 13 C NMR (100MHz, CDC...

Embodiment 3

[0076] Preparation of Example 3 (4-(2-pyrimidinepiperazinyl)) (2-N, N-dimethylaminoquinazoline) ketone (10b)

[0077]

[0078] Dissolve 350mg of compound 10, 2 equivalents of dimethylamine hydrochloride and 2 equivalents of 1,8-diazabicycloundec-7-ene (DBU) in 5ml of methanol, keep stirring under nitrogen protection, seal the tube and heat to 80°C After 12 hours, the reaction was completed, the heating was stopped, cooled to room temperature, the reaction liquid was directly evaporated to dryness, and silica gel column chromatography gave the yellow-green target product 10b with a yield of 48%.

[0079] 1 H NMR (400M Hz, CDCl 3 ): δ8.31(d, J=8.0Hz, 2H), 7.69(d, J=8.8Hz, 1H), 7.66-7.56(m, 2H), 7.15(t, J=7.6Hz, 1H), 6.53 (t,J=4.8Hz,1H),4.03-4.01(m,2H),3.98-3.96(m,2H),3.81-3.79(m,2H),3.37-3.35(m,2H),3.28(s ,6H); 13 C NMR (100MHz, CDCl 3 ): δ165.4, 163.4, 161.5, 158.8, 157.8(2C), 153.6, 134.4, 126.1, 125.5, 122.5, 115.4, 110.6, 46.5, 44.0, 43.6, 41.6, 37.2(2C); ESI-MS calc...

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Abstract

The invention discloses a pyrimidinylpyrazinamide compound having a structure represented by formula I, or a pharmaceutically acceptable salt or a stereoisomer or a prodrug thereof. The above new compound can highly-efficiently inhibit BV2 from secreting IL-1beta, the IC50 value can reach 1.0 [mu]M or less, and the inhibition effect of the new compound is higher than that of a positive drug Minozac. The compound has no inhibitory effect on the secretion of the IL-1beta by C6, so the compound is safe. Further in-vivo experiments prove that the compound can significantly reduce the area of cerebral ischemia induced cerebral infarction, and has the potential to be developed to treat cerebral apoplexy.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a pyrimidine piperazine amide compound and its application. Background technique [0002] Stroke is a central nervous system disease characterized by acute brain function damage caused by cerebral blood circulation disorder. This disease has a high incidence rate and seriously endangers human health. It is the second largest cause of death and the first cause of disability in the world today. Stroke not only brings great suffering to patients, but also brings huge economic burden to the country due to its high treatment costs. In the United States, the direct and indirect costs of stroke are estimated to exceed $50 billion. In the European Union, more than 1.5 million people died of cardiovascular disease, and more than 1 / 4 died of stroke. According to epidemiological surveys, about 1.5 million new cases of cerebral apoplexy occur in my country every year, and abou...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/78C07D239/72C07D239/84C07D403/14C07D401/14C07D409/14A61K31/517A61P29/00A61P25/00A61P25/28A61P25/16A61P37/02A61P9/10A61P25/08
CPCC07D239/72C07D239/78C07D239/84C07D401/14C07D403/14C07D409/14
Inventor 胡文辉余细勇孙平赵昕吴波
Owner GMU MEDICAL DRUG DEV CO LTD
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