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Anti-tumor 2-amino nicotinonitrile, application and preparation method thereof

A technology for anti-tumor drugs and compounds, applied in the field of medicine, can solve problems such as poor selectivity, toxic and side effects, and achieve the effects of rapid response, high selectivity, and growth inhibition in vitro

Inactive Publication Date: 2013-01-16
CHINA PHARM UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the existing tumor drugs have problems such as poor selectivity, toxic side effects, and drug resistance.

Method used

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  • Anti-tumor 2-amino nicotinonitrile, application and preparation method thereof
  • Anti-tumor 2-amino nicotinonitrile, application and preparation method thereof
  • Anti-tumor 2-amino nicotinonitrile, application and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027]

[0028] 4-(4-Hydroxy-3,5-dimethoxyphenyl)-6-phenyl-2-aminonicotinonitrile (a) (W11)

[0029] Dissolve syringaldehyde (2 mmol), acetophenone (2 mmol) and malononitrile (2 mmol) in 1,4-dioxane, then add ammonium acetate (4 mmol), microwave (300 W) Auxiliary heating at 120°C for 20 min. Ice water was added to the reaction mixture to precipitate the product, and then recrystallized to obtain the product with a yield of 84%. IR (KBr) v / cm -1 : 3471, 3395, 3358, 3065, 2953, 2111, 1630, 1573, 1588, 1514, 1464, 1379, 1250, 1211, 1109, 770, 699; 1 H NMR (300 MHz, DMSO-d 6 ) δ / ppm: 8.88 (s, 1H, OH), 8.12-8.15 (m, 2H, ArH), 7.45-7.56 (m, 3H, ArH), 7.32 (s, 1H, H5), 7.00 (s, 2H , ArH), 6.91 (s, 2H, NH 2 ), 3.86 (s, 6H, 2×OCH 3 ); 13 C NMR (75.5 MHz, DMSO-d 6 ) δ / ppm: 160.9, 158.3, 155.0, 147.9, 137.7, 137.3, 130.0, 128.5, 127.2, 126.6, 117.5, 109.1, 106.3, 86.5, 56.2; MS (ESI) m / z: 348.3 + , 370.3 [M+Na] + ; Anal. Calcd for C 20 h 17 N 3 o 3 : C, 69.15; H, 4.93; N...

Embodiment 2

[0031]

[0032] 4-(4-Hydroxy-3-methoxyphenyl)-6-phenyl-2-aminonicotinonitrile (b) (W12)

[0033] Dissolve vanillin (2 mmol), acetophenone (2 mmol), and malononitrile (2 mmol) in 1,4-dioxane, then add ammonium acetate (4 mmol), microwave (300 W) Auxiliary heating at 120°C for 20 min. Ice water was added to the reaction mixture to precipitate the product, and then recrystallized to obtain the product with a yield of 82%. IR (KBr) v / cm -1 : 3486, 3401, 3308, 3196, 2209, 1632, 1577, 1551, 1519, 1469, 1278, 1220, 1126, 764; 1 H NMR (300 MHz, DMSO-d 6 ) δ / ppm: 9.53 (s, 1H, OH), 8.11-8.14 (m, 2H, ArH), 7.42-7.56 (m, 3H, ArH), 7.24-7.29 (m, 2H, H5, ArH), 7.15 (dd, 1H, ArH, J = 2.1, 8.1 Hz), 6.85-6.96 (m, 3H, ArH, NH 2 ), 3.87 (s, 3H, OCH 3 );13 C NMR (75.5 MHz, DMSO-d 6 ) δ / ppm: 161.0, 158.3, 154.9, 148.2, 147.5, 137.7, 129.9, 128.6, 127.7, 121.4, 117.5, 115.5, 112.6, 109.0, 86.4, 55.8 [MS (ESI 3H.8) m / z ] + , 340.3 [M+Na] + , 356.0 [M+K] + ; Anal. Calcd for C 19 h 15 ...

Embodiment 3

[0034] Embodiment 3 Pharmacological experiments related to (W11) and (W12)

[0035] 1. Screening for anti-tumor activity in vitro

[0036] 1.1 Test substance

[0037] The test substances are the compounds prepared in Example 1 and Example 2 of the present invention.

[0038] a(W11) is the compound prepared in Example 1 of the present invention, the Chinese name is 4-(4-hydroxy-3,5-dimethoxyphenyl)-6-phenyl-2-aminonicotinonitrile; b(W12 ) is the compound prepared in Example 2 of the present invention, and its Chinese name is 4-(4-hydroxy-3,5-dimethoxyphenyl)-6-phenyl-2-aminonicotinonitrile. The positive drug is doxorubicin, purchased from Sigma.

[0039] 1.2 Tested cell lines

[0040] Human gastric cancer SGC7901, human liver cancer HepG2, human leukemia cell line HKB, human pancreatic cancer cell line KP4, and human lung cancer cell lines NCI-H292 and NCI-H727 were selected.

[0041] 1.3 Experimental method

[0042] Take a bottle of cells in a good state in the expon...

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Abstract

The invention provides a novel anti-tumor drug which is represented by the molecular formula (I) and specifically relates to anti-tumor 2-amino nicotinonitrile. The invention further provides a synthetic method of the anti-tumor drug. The method includes dissolving 2mmol of vanillic aldehyde or 2mmol of syringaldehyde, 2mmol of acetophenone and 2mmol of malononitrile in 1, 4-dioxane, then adding 4mmol of ammonium acetate, heating a mixture at the temperature of 120 DEG C for reaction for 20 minutes by using a microwave with the length of 300W as an assistant, adding ice water to the reaction mixture to separate out a product, and finally subjecting the mixture to recrystallization to obtain the 2-amino nicotinonitrile. The synthetic method of the anti-tumor drug is simple, and the anti-tumor drug can be rapidly and efficiently synthesized by means of a one-pot four-component reaction assisted by the microwave. The anti-tumor drug which is represented by the molecular formula (I) is capable of obviously inhibiting activities of proliferation of liver cancer cells, gastric cancer cells, breast cancer cells, pancreatic cancer cells, brain cancer cells, lung cancer cells and ovarian cancer cells.

Description

1. Technical field [0001] The invention provides a novel 2-aminonicotinonitrile antitumor drug, a pharmaceutical composition containing the compound and its use as an antitumor agent, belonging to the technical field of medicine. 2. Background technology [0002] Malignant tumors seriously threaten human life and health. About 7 million people die from cancer every year in the world, accounting for about a quarter of the total death toll. Gastric cancer is the most common malignant tumor in my country, and its death rate accounts for the first place among all kinds of malignant tumors. Liver cancer is the second cancer "killer" in my country, and it has jumped to the first place in some high-incidence areas of liver cancer, accounting for 45% of liver cancer deaths worldwide. At present, the mortality rate of existing cancer patients exceeds 30%, which has become the second largest factor in the death of Chinese residents. Pancreatic cancer is one of the cancers with the h...

Claims

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Application Information

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IPC IPC(8): C07D213/85A61K31/4418A61P35/00A61P35/02
Inventor 张评浒杨晓慧张陆勇周永红王治民
Owner CHINA PHARM UNIV
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