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Pyrimidine antitumor compound with 1,3,4-oxadiazole structure and its preparation method and application

An oxadiazole pyrimidine and anti-tumor drug technology, applied in the field of medicine, can solve unseen problems, and achieve the effects of simplifying synthesis steps, improving anti-tumor effect, and excellent anti-proliferation ability

Inactive Publication Date: 2020-04-21
中国医科大学
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This invention combines the structural characteristics of pyrimidine acyl hydrazine anti-tumor compounds designed by our team in the past, and introduces a new group - 1,3,4-oxadiazole structure to replace the bis-acyl hydrazine structure, in order to obtain better anti-tumor activity Brand new compound, no related structure report

Method used

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  • Pyrimidine antitumor compound with 1,3,4-oxadiazole structure and its preparation method and application
  • Pyrimidine antitumor compound with 1,3,4-oxadiazole structure and its preparation method and application
  • Pyrimidine antitumor compound with 1,3,4-oxadiazole structure and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] N-(3-(5-phenyl-1,3,4-oxadiazole)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-sulfonamide ( A1) Preparation

[0039] a. Preparation of uracil-5-sulfonyl chloride

[0040]Add uracil (5g, 44.61mmoL) and thionyl chloride (13.27g, 111.52mmoL) into a 100mL reaction flask, react at room temperature for 1h, then add chlorosulfonic acid (17.73g, 133.82mmoL) and react at 60°C for 1h, 70 ° C to continue the reaction for 8h. After the reaction was completed, the reaction solution was added to the mixture of glacial acetic acid and ice water to precipitate a precipitate, which was filtered by suction, washed with water several times, and dried to obtain 7.25 g of white solid, yield: 77.21%.

[0041] b. Preparation of m-nitrobenzohydrazide

[0042] Add m-nitrobenzoic acid (5g, 29.92mmol), acetonitrile 50ml, potassium carbonate (10.34g, 74.80mmol), dimethyl sulfate (5.66g, 44.88mmol) in a 100ml reaction flask, react at 50°C, thin-layer chromatography Monitor the progress of th...

Embodiment 2

[0054] N-(3-(5-(o-tolyl)-1,3,4-oxadiazole)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5- Preparation of sulfonamide (A2)

[0055] Using o-toluic acid as a raw material, 3-(5-(o-tolyl)-1,3,4-oxadiazole)aniline was prepared according to the steps of Example 1c, 1d, and 1e, and prepared according to the steps of Example 1f N-(3-(5-(o-tolyl)-1,3,4-oxadiazol-2-yl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydro Pyrimidine-5-sulfonamide (A2), off-white solid, yield: 42.56%.

[0056] 1 H NMR (600MHz, DMSO-d 6 )δ11.92(s,1H),11.65(s,1H),10.58(s,1H),8.17(s,1H),8.01(d,J=7.3Hz,1H),7.88(s,1H), 7.76(d, J=7.3Hz, 1H), 7.52(d, J=4.4Hz, 2H), 7.48–7.43(m, 2H), 7.39(d, J=7.4Hz, 1H), 2.67(s, 3H ).MS(ESI,m / z):424.08[M-H] - .

Embodiment 3

[0058] N-(3-(5-(m-tolyl)-1,3,4-oxadiazole)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5- Preparation of sulfonamide (A3)

[0059] Using m-toluic acid as a raw material, 3-(5-(m-tolyl)-1,3,4-oxadiazole)aniline was prepared according to the steps of Example 1c, 1d, and 1e, and prepared according to the steps of Example 1f N-(3-(5-(m-tolyl)-1,3,4-oxadiazole)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5- Sulfonamide (A3), off-white solid, yield: 37.58%.

[0060] 1 H NMR (600MHz, DMSO-d 6 )δ11.91(s,1H),11.65(s,1H),10.56(s,1H),8.18(s,1H),7.89–7.85(m,3H),7.77(d,J=7.4Hz,1H ),7.53–7.48(m,2H),7.43(d,J=7.2Hz,1H),7.39(d,J=7.7Hz,1H),2.40(s,3H).MS(ESI,m / z) :424.08[M-H] - .

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Abstract

The invention belongs to the technical field of medicines, relates to compounds having antitumor activity and having specific chemical structures, and particularly relates to pyrimidine type antitumorcompounds having a 1,3,4-oxadiazole structure and a preparation method and application thereof. The general structure formula of the pyrimidine type antitumor compounds is shown as follows in the description. The novel compounds greatly improve antitumor effects, and have more excellent anti-proliferation capability for human lung cancer A549 cells when compared with pyrimidine acylhydrazine compounds. Synthetic steps are simplified in a synthesis process, thus making future industrial production possible.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a class of compounds with specific chemical structures having anti-tumor activity, specifically pyrimidine anti-tumor compounds with 1,3,4-oxadiazole structure and its preparation method and application. Background technique [0002] Cancer is an important disease that threatens human health, and has surpassed cardiovascular disease to become the number one killer of human death. According to the World Health Organization, it is estimated that 12 million people will die of malignant tumors in 2030. Although the current anti-tumor drugs have certain curative effects, they have disadvantages such as poor selectivity and high toxicity and side effects. New breakthroughs in drug therapy are expected. Pyrimidine compounds have good anti-tumor activity. They mainly function in the process of DNA synthesis and replication, and when DNA is damaged, they are synthesized through the pyrimi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/12A61K31/506A61P35/00
CPCA61P35/00C07D413/12
Inventor 孟繁浩卢国庆李馨阳李帅何鑫刘凯利
Owner 中国医科大学
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