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N,N'-aryl substituted urea compound and application thereof

A compound, a technology of substituted urea, applied in the field of medicinal chemistry and pharmacotherapeutics, can solve the problems of inability to obtain the effect of anti-tumor angiogenesis, long treatment period, and high price

Inactive Publication Date: 2013-09-11
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But there are 3 obvious disadvantages: (1) the price is expensive, and the monthly treatment cost is about 50,000 yuan; (2) the treatment course is long; (3) tolerance has been found so far
From these research results, it can be seen that single inhibition of VEGF / VEGFR signaling pathway may not achieve ideal anti-angiogenesis effect

Method used

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  • N,N'-aryl substituted urea compound and application thereof
  • N,N'-aryl substituted urea compound and application thereof
  • N,N'-aryl substituted urea compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] 3-Methyl-4-(4-nitrophenyl)-4,5-dihydro-2H-pyrazol[3,4-b]pyridin-6(7H)-one (Intermediate IV-1) to prepare

[0039]

[0040] 0.97 g of 3-methyl-5-amino-1H-pyrazole, 1.51 g of p-nitrobenzaldehyde and 1.44 g of 2,2-dimethyl-1,3-dioxane-4,6-dione Put it into a 50 ml round bottom flask, dissolve it with 5 ml of N,N-dimethylformamide, heat to reflux until there is no CO 2 until released. A solid precipitated out of the solution, and after cooling to room temperature, 20 ml of isopropanol was added for dilution. Suction filtration, the solid was washed with a mixed solution of N,N-dimethylformamide and isopropanol (N,N-dimethylformamide:isopropanol=1:2), and dried to obtain the title compound, 1.72 g White solid, yield 63%.

[0041] 1 H-NMR (400MHz, DMSO-d 6 )δ: 1.86(s, 3H), 2.58(dd, J 1 =16Hz,J 2 =5.6Hz), 2.88(dd, J 1 =16Hz,J 2 =7.2Hz, 1H), 4.36(t, J=6.4Hz, 1H), 7.51(d, J=8.8Hz, 2H), 8.19(d, J=8.8Hz, 2H), 10.39(s, 1H), 11.90 (s, 1H).

Embodiment 2

[0043] Preparation of 4-(4-nitrophenyl)-4,5-dihydro-2H-pyrazol[3,4-b]pyridin-6(7H)-one (intermediate IV-2)

[0044]

[0045] Put 0.83 g of 5-amino-1H-pyrazole, 1.51 g of p-nitrobenzaldehyde and 1.44 g of 2,2-dimethyl-1,3-dioxane-4,6-dione into a 50 ml round bottom flask , after dissolving with 5 ml of N,N-dimethylformamide, heat the reaction under reflux until there is no CO 2 until released. A solid precipitated out of the solution, and after cooling to room temperature, 20 ml of isopropanol was added for dilution. Suction filtration, the solid was washed with a mixed solution of N,N-dimethylformamide and isopropanol (N,N-dimethylformamide:isopropanol=1:2), and dried to obtain the title compound, 1.53 g White solid, yield 59%.

[0046] 1 H-NMR (400MHz, DMSO-d 6 )δ: 2.63 (dd, J 1 =15.6Hz,J 2 =7.2Hz, 1H), 2.83(dd, J 1 =16Hz,J 2 =6.8Hz, 1H), 4.43(t, J=7.2Hz, 1H), 7.34(s, 1H), 7.51(d, J=8.4Hz, 2H), 8.20(d, J=8.4Hz, 2H), 10.49(s, 1H), 12.20(s, 1H).

Embodiment 3

[0048] Preparation of 3-methyl-4-(4-aminophenyl)-4,5-dihydro-2H-pyrazol[3,4-b]pyridin-6(7H)-one (intermediate V-1)

[0049]

[0050] 1.36 g of intermediate IV-1 was dissolved in 20 ml of methanol, and 136 mg of 10% Pd / C was added for catalytic hydrogenation. React at room temperature for 5 hours. After the reaction, the reaction solution was adjusted to pH=4 with dilute hydrochloric acid, and then the Pd / C was removed by suction filtration. NaHCO 3 After the filtrate was adjusted to pH > 7, a solid precipitated out, filtered with suction, washed with water, and dried to obtain 0.91 g of a white solid (intermediate V-1), with a yield of 66%.

[0051] 1 H-NMR (400MHz, DMSO-d 6 )δ: 1.82(s, 3H), 2.48(dd, J 1 =16Hz,J 2 =6.4Hz, 1H), 2.68(dd, J 1 =16Hz,J 2 =6.8Hz, 1H), 3.93(t, J=6.4Hz, 1H), 4.93(s, 2H), 6.48(d, J=8.4Hz, 2H), 6.81(d, J=8.4Hz, 2H), 10.21(s, 1H), 11.73(s, 1H).

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Abstract

The invention mainly relates to an N,N'-aryl substituted urea compound and an application thereof. The N,N'-aryl substituted urea compound is a compound shown in the formula I or a salt formed by the compound and a medicinal acid or alkali. The provided compound has the strong inhibitory activity for receptor protein kinases which comprise VEGFR2 (Endothelial Growth Factor Receptor 2), RGFR1 (Fibroblast Growth Factor Receptor 1) and PDGFR Alpha (Platelet Derived Growth Factor Receptor Alpha) and associated with the neogenesis of three kinds of tumor tissue blood vessels. Thus, the N,N'-aryl substituted urea compound can be used as a multi-target kinase inhibitor which is developed into a targeted anti-tumor medicine for treating solid tumors.

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics, and more specifically relates to N, N'-aryl substituted urea compounds and a preparation method thereof, which can be used as multi-target receptor tyrosine kinase inhibitor antitumor drugs . Background technique [0002] According to relevant data provided by the Cancer Prevention and Control Office of the Ministry of Health, malignant tumors have become the second leading cause of death in my country (the leading cause of death among urban residents). According to the data, the new incidence rates of male and female malignant tumors in my country are 130.3-305.4 / 100,000 people and 39.5-248.7 / 100,000 people respectively. first place. It is predicted that by 2020, there will be 5.5 million new cancer cases in China, of which the death toll will reach 4 million. [0003] At present, tumor surgery, tumor radiotherapy, and tumor chemotherapy constitute the three...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61P35/00
Inventor 李剑丁鹏陈玉龙朱进黄皇吴德燕刘璐琳刘云霞
Owner EAST CHINA UNIV OF SCI & TECH
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