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1-Aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea compound and application thereof

Technology of a compound, picoline, applied in the field of medicine

Active Publication Date: 2019-07-26
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-[(pyridin-2-ylmethyl)thio]phenyl}urea compound and application thereof
  • 1-Aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea compound and application thereof
  • 1-Aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Embodiment 1: 1-4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}thio}phenyl}-3-phenylurea ( Preparation of compound Z01)

[0076] Step A: Preparation of 4-(3-methoxypropoxy)-3-methyl-2-{[(4-nitrophenyl)thio]methyl}pyridine

[0077] Add 4-nitrothiophenol (15.52g, 0.10mol) and 2-chloromethyl-3-methyl-4-(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, which was filtered by suction, washed with water, and dried in air to obtain 31.81 g of white solid, with a yield of 91.3%. The product was used directly in the next step without further purification.

[0078] Step B: Preparation of 4-{{[4-(3-methoxypropo...

Embodiment 2

[0082] Example 2: 1-{4-chlorophenyl)-3-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}thio Preparation of}phenyl}urea (compound Z02)

[0083] Referring to the preparation method of Example 1, 0.16 g of white solid was obtained with a yield of 49%, m.p.: 191.7-192.5°C; 1 H NMR (400MHz, DMSO-d 6 )δ8.83(s,1H),8.77(s,1H),8.17(d,J=5.6Hz,1H),7.52-7.44(m,2H),7.44-7.37(m,2H),7.37-7.28 (m,4H),6.90(d,J=5.7Hz,1H),4.22(s,2H),4.08(t,J=6.2Hz,2H),3.48(t,J=6.2Hz,2H),3.25 (s,3H),2.12(s,3H),1.97(p,J=6.3Hz,2H).ESI-MS:m / z472.4,474.0,475.1,476.0[M+H] + .

Embodiment 3

[0084] Example 3: 1-(4-bromophenyl)-3-{4-{{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methyl}thio Preparation of}phenyl}urea (compound Z03)

[0085] Referring to the preparation method of Example 1, 0.07 g of white solid was obtained, with a yield of 20%, m.p.: 177.9-178.5°C; 1 H NMR (400MHz, DMSO-d 6 )δ8.83(s,1H),8.77(s,1H),8.17(d,J=5.6Hz,1H),7.49-7.36(m,6H),7.32(d,J=8.7Hz,2H), 6.90(d, J=5.7Hz, 1H), 4.22(s, 2H), 4.08(t, J=6.2Hz, 2H), 3.48(t, J=6.2Hz, 2H), 3.25(s, 3H), 2.12(s,3H),1.97(p,J=6.3Hz,3H).ESI-MS:m / z516.0,518.0[M+H] + .

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Abstract

The invention belongs to the technical field of medicine and relates to 1-aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea compound, a preparation method thereof and application of the compound in thepreparation of antitumor drugs. The 1-aryl-3-{4-[(pyridin-2-ylmethyl)thio]phenyl}urea compound and its prodrug, pharmaceutical active metabolite and pharmaceutically acceptable salt have a structuralgeneral formula shown in the description, wherein X is independently selected from CH and N, R may be hydrogen, C1-C4 alkyl group, halogen-substituted C1-C4 alkyl group, C1-C4 alkoxy group, halogen-substituted C1-C4 alkoxy group, and halogen, R may be single or multiple, R3, R4 and R5 are independently selected from hydrogen, C1-C4 alkyl group, C1-C4 alkoxy group, halogen-substituted C1-C4 alkoxygroup, and C1-C4 alkoxy-substituted C1-C4 alkoxy group. The synthetic method of the compound of the invention is simple and is suitable for industrial production; bioactivity test shows that the compound of the invention has antitumor activity and is a novel antitumor drug.

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): C07D213/68C07D213/75C07D213/69A61P35/00A61K31/444A61K31/44
CPCC07D213/68C07D213/75C07D213/69A61P35/00
Inventor 胡春张传明李泓岳谭孝雨李永鹏孙慧颖高彤欣张恒朱天宇
Owner SHENYANG PHARMA UNIVERSITY
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