Oxazolo[5,4-d]pyrido[1,2-a]pyrimidone derivative and application thereof

A 4-d, 2-a technology, applied in drug combination, organic chemistry, antineoplastic drugs, etc.

Active Publication Date: 2021-05-28
XINJIANG TECHN INST OF PHYSICS & CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are few reports on finding anti-cancer active ingredients with low toxicity and high curative effect from natural animals and plants. Therefore, chemically synthesized anti-cancer drugs are still one of the hotspots of domestic and foreign scientists in recent years.

Method used

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  • Oxazolo[5,4-d]pyrido[1,2-a]pyrimidone derivative and application thereof
  • Oxazolo[5,4-d]pyrido[1,2-a]pyrimidone derivative and application thereof
  • Oxazolo[5,4-d]pyrido[1,2-a]pyrimidone derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] Preparation of Compound A:

[0106] At a temperature of -10°C, dissolve 57.3ml, 0.83mol of sodium nitrite and 100g, 0.83mol of ethyl cyanoacetate in 700ml of pure water, slowly add 36.6ml, 0.055mol of 85% concentrated phosphoric acid, and add the time Continued for 3 hours, then raised the temperature to 45°C and stirred for 1 hour, added 74ml of concentrated hydrochloric acid, 0.88mol, and continued to stir overnight at a temperature of 0°C, a large amount of white solid precipitated, and the white compound A was obtained by filtration as 2-cyano-2- Ethyl hydroxyiminoacetate does not need to be purified for the next step reaction;

[0107] Preparation of compound B:

[0108] At room temperature, the obtained white compound A was 43 g of ethyl 2-cyano-2-hydroxyiminoacetate, 0.3 mol was dissolved in 500 ml of pure water, and 350 ml of saturated sodium bicarbonate solution was slowly added dropwise under stirring , then add 156g of sodium dithionite, 0.9mol, heat up to ...

Embodiment 2

[0160] Preparation of compounds D1-D48:

[0161] Dissolve 10 mmol of the compounds C1-C48 obtained in Example 1 in anhydrous dichloromethane, then slowly add 10 mL of trifluoroacetic acid dropwise, react at room temperature until all the raw materials disappear, concentrate the reaction solution, and wash the mixture with a forward silica gel column chromatography gradient. Off, the eluent is sherwood oil with a volume ratio of 1:1: ethyl acetate, and compounds D1-D48 are obtained respectively;

[0162] Compound D1 is 2-methyl-5-amino-4-carboxylic acid ethyl oxazole, yield: 84%, light yellow solid;

[0163] 1 H NMR (400MHz, CDCl 3 )δ5.31(s, 2H), 4.33(q, J=7.2Hz, 2H), 2.34(s, 3H), 1.37(t, J=7.1Hz, 3H);

[0164] Compound D2 is 2-ethyl-5-amino-4-ethyl oxazole, yield: 80%, light yellow solid;

[0165] 1 H NMR (400MHz, CDCl 3 )δ5.58(s, 2H), 4.25(q, J=7.1Hz, 2H), 2.58(q, J=7.6Hz, 2H), 1.28(t, J=7.1Hz, 3H), 1.20(t, J=7.6Hz,3H);

[0166] Compound D3 is ethyl oxazole 2-propyl-5...

Embodiment 3

[0258] Preparation of compound E1:

[0259]Compound D1 obtained in Example 2 was 2-methyl-5-amino-4-formic acid ethyl oxazole 0.17g, 10mmol was dissolved in 20mL of anhydrous dioxane, and valerolactam 0.15g, 15mmol was added , then slowly drop phosphorus oxychloride 0.38g, 2.5mmol, reflux reaction until all raw materials disappear, use dichloromethane to extract, dry over anhydrous sodium sulfate, concentrate under reduced pressure, adopt forward silica gel column chromatography gradient elution, wash The deagent is petroleum ether at a volume ratio of 1:2: ethyl acetate, and compound E1 is obtained as 2-methyl-5,6,7,8-tetrahydro-10H-oxazolo[5,4-d]pyrido [1,2-a]pyrimidin-10-one, yield: 76%, light yellow solid, melting point: 89-91°C;

[0260] 1 H NMR (400MHz, CDCl 3 )δ4.09(t, J=6.1Hz, 2H), 3.00(t, J=6.7Hz, 2H), 2.57(s, 3H), 2.03–1.91(m, 6H).13C NMR(100MHz, CDCl 3 )δ162.62, 160.05, 158.34, 157.01, 118.81, 42.89, 32.11, 21.97, 19.10, 14.57. HRMS (ESI) calcd for C 10 h 11 N...

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Abstract

The invention relates to an oxazolo[5,4-d]pyrido[1,2-a]pyrimidone derivative and application thereof. Ethyl cyanoacetate is used as a raw material, a hydroxylamine compound (A) is generated under the action of sodium nitrite and phosphoric acid, 2-amino ethyl cyanoacetate (B) is obtained through reduction with sodium hydrosulfite, the 2-amino ethyl cyanoacetate (B) reacts with different substituted acyl chlorides under alkali conditions, and oxazole compounds (D1-D48) of different substituted 5-amino-4-formate are generated under the action of trifluoroacetic acid, and then react with valerolactam under the action of phosphorus oxychloride to obtain the oxazolo[5,4-d]pyrido[1,2-a]pyrimidone compounds (E1-E48). The inhibitory activity of the 48 compounds on Hela cervical cancer cells, MCF-7 breast cancer cells and A549 lung cancer cells is investigated, and the result shows that 11 compounds have the inhibitory activity on the Hela cervical cancer cells; eight compounds have inhibitory activity on MCF-7 breast cancer cells; and five compounds have inhibitory activity on A549 lung cancer cells. E32, E33, E45, E46 and E47 have inhibitory activity on three tumor cells; and E29 and E42 have inhibitory activity on Hela cervical cancer cells and MCF-7 breast cancer cells.

Description

technical field [0001] The invention relates to an oxazolo[5,4-d]pyrido[1,2-a]pyrimidinone derivative and its application. The result of cell activity screening of this kind of compound shows that: there are 11 compounds that are effective on Hela cervical Cancer cells have inhibitory activity; 8 compounds have inhibitory activity against MCF-7 breast cancer cells; 5 compounds have inhibitory activity against A549 lung cancer cells. Background technique [0002] According to the statistics of the World Health Organization, there are about 10 million cancers in the world every year, and about 7 million deaths. Cardiovascular disease is the second killer of humans. Although most of the chemically synthesized anticancer drugs also produce toxic and side effects on normal cells of the human body. However, there are few reports on finding anticancer active ingredients with low toxicity and high curative effect from natural animals and plants. Therefore, chemically synthesized a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/14A61P35/00
CPCC07D498/14A61P35/00
Inventor 阿吉艾克拜尔·艾萨曾艳聂礼飞胡尔西地·博扎罗夫赵江瑜
Owner XINJIANG TECHN INST OF PHYSICS & CHEM CHINESE ACAD OF SCI
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