Ureido-containing benzoimidazole compounds and application thereof

A technology of benzimidazoles and compounds, which is applied in the field of benzimidazoles and their preparation, and achieves the effects of novel structure types and good development and application prospects

Active Publication Date: 2019-07-12
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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  • Ureido-containing benzoimidazole compounds and application thereof
  • Ureido-containing benzoimidazole compounds and application thereof
  • Ureido-containing benzoimidazole compounds and application thereof

Examples

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preparation example Construction

[0035] The schemes outline the preparative steps used to prepare the compounds of the invention.

[0036]

[0037] Among them, R, R 3 , R 5 as mentioned earlier.

[0038] 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

[0039] Example 1: 1-{3-{[2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methyl-pyridin-4-yl}oxy}propyl} -Preparation of 3-phenylurea (compound X01)

[0040] Step A: Preparation of 2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylthio}-1H-benzimidazole

[0041] 2-Chloromethyl-4-(3-methoxypropoxy)-3-picoline hydrochloride (0.50g, 1.88mmol) was placed in a 125ml eggplant-shaped bottle, and 11ml of ethanol was added to dissolve it, Then 1H-benzimidazole-2-thiol (0.28g, 1.88mmol) and 4ml NaOH (80g / L) were added, refluxed at 68°C for 4h, and the reaction was complete as monitored by TLC. The reaction liquid was poured into a 100ml beaker, cooled naturally to room temperature, a white solid was precipitated, and recrystallized from ethyl acetate and petroleum ether (2:1) to obtain 0.58 g of white needle-like crystals, with a yield of 89.3%. m.p.: 115-118°C (literature value: 116-118°C).

[0042] Step B: Preparation of 3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}ox...

Embodiment 2

[0048] Example 2: 1-{3-{[2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methyl-pyridin-4-yl}oxy}propyl} - Preparation of 3-(4-chlorophenyl)urea (compound X02)

[0049] Referring to the preparation method of Example 01, 0.32 g of white solid was obtained with a yield of 76.2%, m.p.: 165.8-167.3°C; ESI-MS: m / z 600.7, 602.0, [M+H] + ; 1 H NMR (400MHz, DMSO-d 6)δ8.23(d,J=5.6Hz,1H),7.59(dt,J=7.2,3.5Hz,1H),7.45(dd,J=6.1,3.1Hz,1H),7.39–7.32(m,2H ),7.23–7.12(m,3H),6.97(d,J=5.7Hz,1H),5.23(s,2H),4.70(s,2H),4.59(t,J=5.1Hz,1H),4.12 (t, J=6.2Hz, 2H), 3.77(d, J=5.0Hz, 2H), 3.62(t, J=4.9Hz, 2H), 3.57(q, J=5.9Hz, 2H), 3.11(d , J=4.9Hz, 2H), 2.98(t, J=5.0Hz, 2H), 2.20(s, 3H), 1.89(p, J=6.2Hz, 2H).

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Abstract

The invention belongs to the technical field of medicines, and relates to ureido-containing benzoimidazole compounds, a preparation method thereof, and an application of the ureido-containing benzoimidazole compounds in preparing medicines for anti-tumor diseases. The structural general formula of the ureido-containing benzimidazole compounds, and precursor drugs, pharmaceutical active metabolitesand pharmaceutically acceptable salts thereof is shown as the follows, wherein R can be selected from hydrogen, phenyl, 4-chlorophenyl, 4-methylphenyl and 3-(trifluoromethyl)phenyl, and R<3> and R<5>can be selected from hydrogen and methyl. The compounds disclosed by the invention are simple and convenient in synthesis method and are suitable for industrial production. A biological activity testshows that the compounds have anti-tumor activity and are novel antitumor medicines.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a benzimidazole compound containing a ureido group and a preparation method thereof, and also relates to its function as BRaf kinase, vascular endothelial growth factor receptor-2 (Vascular endothelial growth factor receptor-2, VEGFR-2), Application of platelet-derived growth factor receptors-β (Platelet-derived growth factor receptors-β, PDGFR-β) and T-LAK cell-originated protein kinase (TOPK) inhibitors. 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 therape...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61K31/4439A61P35/00
CPCA61P35/00C07D401/12
Inventor 胡春王旭康张传明谭孝雨曹小龙张春旺徐文李凤荣
Owner SHENYANG PHARMA UNIVERSITY
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