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1-aryl-3-[4-(pyridine-2-ylmethoxy) phenyl urea compound and application

A technology of -3-{4-{, compounds, applied in the field of medicine, achieving good development and application prospects and novel structure types

Active Publication Date: 2019-07-19
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, TOPK has become a new target for tumor treatment, and there is no drug specifically targeting this target on the market. Therefore, inhibitors that can specifically bind to TOPK have become a research hotspot for new anti-tumor drugs.

Method used

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  • 1-aryl-3-[4-(pyridine-2-ylmethoxy) phenyl urea compound and application
  • 1-aryl-3-[4-(pyridine-2-ylmethoxy) phenyl urea compound and application
  • 1-aryl-3-[4-(pyridine-2-ylmethoxy) phenyl urea compound and application

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preparation example Construction

[0054] The following schemes outline the preparative steps for preparing compounds of the invention.

[0055]

[0056] Among them, R, R 3 , R 4 , R 5 as mentioned earlier.

[0057] The present invention is described in detail with the following examples. However, it should be understood that the present invention is not limited to the specific recited examples below.

Embodiment 1

[0058] Example 1: 1-(3,5-difluorophenyl)-3-{4-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methoxy }phenyl}urea (compound Z01)

[0059] Step A: Preparation of 4-(3-methoxypropoxy)-3-methyl-2-[(4-nitrophenoxy)methyl]pyridine

[0060] Add 4-nitrophenol (13.91g, 0.10mol), 2-chloromethyl-3-methyl-4-(3-methoxypropoxy)pyridine hydrochloride (26.62g , 0.10mol) and absolute ethanol (200mL). A 3 mol / L sodium hydroxide aqueous solution (100 mL) was added dropwise at room temperature. After the dropwise addition, react at room temperature for 6h. After the reaction, part of the ethanol was distilled off under reduced pressure, and 200 mL of water was added to the residue to precipitate a large amount of white solid. The filter cake was filtered with suction, washed with water, and dried in air to obtain 30.68 g of white solid, with a yield of 92.6%. The product was used directly in the next step without further purification.

[0061] Step B: Preparation of 4-{[4-(3-methoxypropoxy)-3-m...

Embodiment 2

[0065] Example 2: 1-{4-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methoxy}phenyl}-3-[3-(trifluoro Preparation of methyl) phenyl] urea (compound Z02)

[0066] Referring to the preparation method of Example 1, 0.16 g of white solid was obtained with a yield of 41%, m.p.: 126.2-127.3°C; 1 H NMR (400MHz, DMSO-d 6 )δ8.98(s,1H),8.61(s,1H),8.27(d,J=5.7Hz,1H),8.01(s,1H),7.56(d,J=8.5Hz,1H),7.51- 7.48(m,1H),7.36(d,J=2.2Hz,1H),7.34(d,J=2.3Hz,1H),7.29(d,J=7.5Hz,1H),7.00(d,J=5.8 Hz,1H),6.98(d,J=2.2Hz,1H),6.96(d,J=2.2Hz,1H),5.11(s,2H),4.11(t,J=6.2Hz,2H),3.49( t,J=6.2Hz,2H),3.25(s,3H),2.18(s,3H),2.02-1.96(m,3H).ESI-MS(m / z):490.3([M+H] + ); 512.1 ([M+Na] + ).

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Abstract

The invention belongs to the technical field of medicines and relates to a 1-aryl-3-[4-(pyridine-2-ylmethoxy) phenyl urea compound as well as a preparation method and the application thereof in preparing medicines for treating tumor diseases. The 1-aryl-3-[4-(pyridine-2-ylmethoxy) phenyl urea compound, a predrug, a medicine active metabolite and a pharmaceutically acceptable salt thereof have structural formulae as shown in the specification, in the formulae, R is one or more of hydrogen, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkoxy and halogen;and R1, R4 and R5 can be independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkoxy and C1-C4 C1-C4 alkoxy substituted C1-C4 C1-C4 alkoxy. The compound providedby the invention is simple and convenient in synthesis method and applicable to industrial production, and biological activity tests show that the compound has anti-tumor activity and is a type of novel anti-tumor medicines.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to 1-aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea compounds and a preparation method thereof, and also relates to its function as BRaf kinase, vascular Endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor-β (Platelet-derived growth factor receptors-β, PDGFR-β) and T-LAK cell-derived protein kinase (T-LAK cell-originated protein kinase, TOPK) inhibitor application. Background technique [0002] In recent years, with the continuous elucidation of tumor pathogenesis and the continuous discovery of anti-tumor targets, multi-target inhibition of tumor signal transduction has become an important direction for the development of tumor drugs. Compared with single-target drugs and multiple single-target drugs in combination, multi-target drugs have more advantages: drug interactions can be avoided, adverse reactions can be reduced, and the therapeutic ef...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/68C07D213/69A61P35/00A61K31/44
CPCC07D213/68C07D213/69A61P35/00
Inventor 胡春谢环黄二芳张传明谭孝雨朱安娜刘诗含王锋卢德峰
Owner SHENYANG PHARMA UNIVERSITY
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