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Amide-containing benzimidazole compounds and applications thereof

A technology of benzimidazole and compound, applied in the field of T-LAK cell-derived protein kinase inhibitor

Active Publication Date: 2021-12-21
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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  • Amide-containing benzimidazole compounds and applications thereof
  • Amide-containing benzimidazole compounds and applications thereof
  • Amide-containing benzimidazole compounds and applications thereof

Examples

Experimental program
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preparation example Construction

[0059] The schemes outline the preparative steps used to prepare the compounds of the invention.

[0060]

[0061] process

[0062] Among them, R 1 , R 2 , R 3 , R 5 as mentioned earlier.

[0063] 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

[0064] Example 1: 2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy} -Preparation of N-cyclohexylacetamide (compound X01)

[0065] Step A: Preparation of 2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylthio}-1H-benzimidazole

[0066] 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).

[0067] Step B: Preparation of 3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridi...

Embodiment 2

[0071] Example 2: 2-{3-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3-methylpyridin-4-yl}oxy}propoxy} -Preparation of N-isopropylacetamide (compound X02)

[0072] Referring to the preparation method of Example 1, 0.57 g of white solid was obtained with a yield of 87.2%. m.p.: 162.9-164.7℃; IR: (KBr,cm -1 )3278,3086,2924,1656,1584,1464,1442,1369,732; 1 H-NMR (400MHz, DMSO): δ8.36(d, 1H, J=7.4Hz, Pyridine-6-H), 8.22(d, 1H, J=5.6Hz, Ar-H), 7.63~7.45(m ,1H,Ar-H),7.44~7.37(m,1H,Ar-H),7.21~7.13(m,2H,Pyridine-5-H,N-H),6.96(d,1H,J=5.7Hz,Ar -H),4.78(s,2H,SCH 2 ),4.69(s,2H,OCH 2 ), 4.12(t, J=6.2Hz, 2H, CH 2 ),3.82(dq,J=13.5,6.7Hz,1H,NCH),3.57(dd,J=10.5,5.7Hz,2H,CH 2 ),2.20(s,3H),1.89(p,J=6.1Hz,2H),1.08(s,3H),1.08(s,3H),1.07(s,3H); ESI-MS(m / z) :429.3([M+H] + ).

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Abstract

The invention belongs to the technical field of medicine, and relates to 2-[(pyridin-2-ylmethyl)thio]-1H-benzimidazole compounds and their preparation methods and applications. The general formula of described 2-[(pyridin-2-ylmethyl)thio]-1H-benzimidazoles and pharmaceutically acceptable salts is as follows: R 1 , R 2 Same or different, selected from hydrogen, C1‑C8 alkyl, C3‑C6 cycloalkyl, phenyl, halogen substituted phenyl, C1‑C4 alkyl substituted phenyl, C1‑C4 alkoxy substituted phenyl , phenyl substituted with halogen and C1‑C4 alkoxy, phenyl substituted with halogen and C1‑C4 alkoxy, phenyl substituted with halogen substituted C1‑C4 alkyl, benzyl, 4‑benzyloxy Phenyl; or R 1 , R 2 Together with the nitrogen atoms connected to them, they form substituted or unsubstituted morpholinyl, phenylpiperazine or benzhydrylpiperazine; the substituents are C1-C4 alkoxy, C1-C4 alkyl, halogen; R 3 , R 5 Can be selected from H, C1-C4 alkyl. The synthesis method of the compound of the invention is simple and convenient, suitable for industrial production, and has obvious antitumor activity.

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 Patents(China)
IPC IPC(8): C07D401/12A61K31/4439A61K31/496A61K31/5377A61P35/00
CPCC07D401/12A61P35/00
Inventor 胡春孙胜男张传明李永鹏孙媛媛秦凤云王琳
Owner SHENYANG PHARMA UNIVERSITY
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