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2-[(pyridin-2-ylmethyl)sulfanyl]-1h-benzimidazole compounds and their application

A technology of benzimidazole and 2-{{2-{ is applied in the field of T-LAK cell-derived protein kinase inhibitors, and achieves the effects of good development and application prospects and novel structure types.

Active Publication Date: 2021-03-19
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • 2-[(pyridin-2-ylmethyl)sulfanyl]-1h-benzimidazole compounds and their application
  • 2-[(pyridin-2-ylmethyl)sulfanyl]-1h-benzimidazole compounds and their application
  • 2-[(pyridin-2-ylmethyl)sulfanyl]-1h-benzimidazole compounds and their application

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Experimental program
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preparation example Construction

[0047] The schemes outline the preparative steps used to prepare the compounds of the invention.

[0048]

[0049] process

[0050] Among them, R 1 , R 2 , R 3 , R 5 as mentioned earlier.

[0051] 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

[0052] Example 1: 2-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3,5-dimethylpyridin-4-yl}oxy}-N-ring Preparation of hexylacetamide (compound X01)

[0053] Step A: Preparation of 2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]thio}-1H-benzimidazole

[0054] Put 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride (0.42g, 1.88mmol) in a 125mL eggplant-shaped bottle, add 20ml of ethanol to dissolve it, and then add 1H- Benzimidazole-2-thiol (0.28g, 1.88mmol) and 4mL NaOH (80g / L) were refluxed at 68°C for 4h, and the reaction was complete as monitored by TLC. Naturally cooled to room temperature, a white solid was precipitated, and recrystallized from ethyl acetate and petroleum ether (2:1) to obtain 0.50 g of white needle-like crystals, with a yield of 89.5%.

[0055] Step B: Preparation of 2-{[(1H-benzimidazol-2-yl)thio]methyl}-3,5-dimethylpyridin-4-ol

[0056] 2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfanyl}-1H-benzimidazole (0.50g, 1.67mmol) was placed in a 100m...

Embodiment 2

[0059] Example 2: 2-{{2-{[(1H-benzimidazol-2-yl)thio]methyl}-3,5-dimethylpyridin-4-yl}oxy}-N-( Preparation of 5-bromo-2-methoxyphenyl)acetamide (compound X02)

[0060] Referring to the preparation method of Example 1, 0.16 g of white solid was obtained, with a yield of 49%, m.p.: 137.7-139.1°C; 1 H NMR (400MHz, DMSO-d 6 )δ11.40(s,1H),9.94(s,1H),8.18(d,J=2.5Hz,1H),7.66-7.61(m,1H),7.53(d,J=3.0Hz,1H), 7.51(d, J=2.3Hz, 1H), 7.26(dd, J=8.7, 2.5Hz, 1H), 7.22(d, J=3.7Hz, 1H), 7.22-7.18(m, 1H), 7.05(d ,J=8.9Hz,1H),5.22(s,2H),4.51(s,2H),3.88(s,3H),1.92(s,3H),1.82(s,3H).ESI-MS:m / z 527.2,529.2([M+H] + ).

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Abstract

The invention belongs to the technical field of medicine, and relates to 2-[(pyridyl-2-yl methyl)thio]-1H-benzimidazole compounds, a preparation method thereof and application of the compounds in preparation of drugs for antitumor diseases. The structural general formula of the 2-[(pyridyl-2-yl methyl)thio]-1H-benzimidazole compounds and prodrugs, pharmaceutically active metabolites and pharmaceutically acceptable salts of the 2-[(pyridyl-2-yl methyl)thio]-1H-benzimidazole compounds are shown in the description, wherein R1 and R2 are the same or different, and are selected from hydrogen, C3-C6cycloalkyl groups, phenyl groups, halogen-substituted phenyl groups, C1-C4 alkoxy-substituted phenyl groups, phenyl groups with simultaneous substitution of halogen and C1-C4 alkoxy groups and benzylgroups, or substituted or unsubstituted phenylpiperazinyl, benzylpiperazinyl or diphenylmethylpiperazinyl groups are formed by R1, R2 and nitrogen atoms attached to R1 and R2; and the substituent groups comprise C1-C4 alkyl groups, C1-C4 alkoxy groups and halogen, and R3 and R5 can be selected from H and C1-C4 alkyl groups. The synthesis method of the compounds is simple and convenient, and is suitable for industrial production, and it is shown by biological activity tests that the compounds have antitumor activity, and are novel antitumor drugs.

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): C07D401/12A61P35/00A61K31/4439A61K31/496
CPCA61P35/00C07D401/12
Inventor 胡春孙灏张传明张帅阴爽罗丹妮金辄孙胜男
Owner SHENYANG PHARMA UNIVERSITY
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