Pyridine compound containing adamantane substituent groups, and applications thereof in preparation of anti-tumor drugs

A technology of compounds and pyridines, applied in the field of chemical medicine, can solve problems such as the influence of normal cells

Inactive Publication Date: 2018-08-07
陈海鹏
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

MNK plays an important role in the occurrence and development of tumors, but its deletion has little effe

Method used

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  • Pyridine compound containing adamantane substituent groups, and applications thereof in preparation of anti-tumor drugs
  • Pyridine compound containing adamantane substituent groups, and applications thereof in preparation of anti-tumor drugs
  • Pyridine compound containing adamantane substituent groups, and applications thereof in preparation of anti-tumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1: 2-(1-cyclohexylvinyl)-5-(3-methyl-4-(((1R, 3R, 5R, 7R)-2-methyladamantan-2-yl)oxy ) Synthesis of phenyl) pyridine

[0025] 1.1 Synthesis of (1r, 3r, 5r, 7r)-2-(4-chloro-2-methylphenoxy)-2-methyladamantane

[0026]

[0027] To a solution of (1R,3R,5R,7R)-2-methyladamant-2-ol (Compound 1) (111.4mg, 0.67mmol) dissolved in DMF (6.7mL) at 0-5°C Add 60% NaH (34.8 mg, 0.87 mmol) by mass fraction, then stir the above solution at room temperature for 30 minutes, add 1,4-dichloro-2-methylbenzene (compound 2) (107.9 mg, 0.67 mmol) And the reaction was stirred for 1 hour. The obtained crude product was diluted with EtOAc. Transfer to a separatory funnel, separate the layers and separate the organic layer, wash the organic layer with water (30 mL), brine, wash over Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave (1r,3r,5r,7r)-2-(4-chloro-2-methylphenoxy)-2-methyladamantane (compound 3), 146.1 mg, yielding The rate is 75%. The crude pro...

Embodiment 2

[0034] Example 2: 2-(3-fluoro-naphthalen-2-yl)-5-(3-methyl-4-(((1R, 3R, 5R, 7R)-2-methyladamantan-2-yl )Synthesis of oxy)phenyl)pyridine

[0035]

[0036] 3-fluoro-naphthalene-2-boronic acid (0.375mmol), compound 4 (137.97mg, 0.375mmol), Na 2 CO 3 (119.8mg, 1.13mmol), DME (0.61mL) and H 2 O (0.15 mL) was added to a 5 mL microwave vial. vial with N 2 Degas for 11 minutes, then add PdCl 2 (dppf)CH 2 Cl 2 (33.1 mg, 0.045 mmol) adduct. The reaction mixture was heated at 120 °C for 50 minutes by microwave irradiation. The resulting mixture was diluted with ethyl acetate and filtered through celite, then concentrated in vacuo. Purification by flash chromatography using 0-100% ethyl acetate / heptane as eluent gave 2-(3-fluoro-naphthalen-2-yl)-5-(3-methyl-4) as a bright yellow powder -(((1R,3R,5R,7R)-2-methyladamantan-2-yl)oxy)phenyl)pyridine, 146.7 mg, 82% yield. LC-MS (ESI, pos, ion) m / z: 478[M+H].

Embodiment 3

[0037] Example 3: 2-(3-methyl-naphthalen-2-yl)-5-(3-methyl-4-(((1R, 3R, 5R, 7R)-2-methyladamantane-2- Synthesis of base)oxy)phenyl)pyridine

[0038]

[0039] 3-Methyl-naphthalene-2-boronic acid (0.375mmol), compound 4 (137.97mg, 0.375mmol), Na 2 CO 3 (119.8mg, 1.13mmol), DME (0.61mL) and H 2 O (0.15 mL) was added to a 5 mL microwave vial. vial with N 2 Degas for 11 minutes, then add PdCl 2 (dppf)CH 2 Cl 2 (33.1 mg, 0.045 mmol) adduct. The reaction mixture was heated at 120 °C for 50 minutes by microwave irradiation. The resulting mixture was diluted with ethyl acetate and filtered through celite, then concentrated in vacuo. Purification by flash chromatography using 0-100% ethyl acetate / heptane as eluent gave 2-(3-methyl-naphthalen-2-yl)-5-(3-methyl- 4-(((1R,3R,5R,7R)-2-methyladamantan-2-yl)oxy)phenyl)pyridine, 134.8 mg, 76% yield. LC-MS (ESI, pos, ion) m / z: 474[M+H].

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Abstract

The invention discloses a pyridine compound containing adamantane substituent groups, and applications thereof in preparation of anti-tumor drugs. The structure for the pyridine compound is represented by formula I, wherein R1, R2, R3, and R4 are independently selected from H, F, or CH3. It is shown by pharmacological results that the pyridine compound possesses MNK1 kinases inhibition effects, wherein the IC50 of JMNK-N002 to JMNK-N005 on MNK1 kinases inhibition activity is 100nM. The pyridine compound possesses relatively in vitro inhibition activity on human pancreatic cancer cell line MiaPaCa2. It is confirmed that the pyridine compound can be used in study on anti-cancer drugs.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and relates to a pyridine compound formula (I) containing an adamantane substituent and its use in the preparation of antitumor drugs. Background technique [0002] Cancer is a malignant disease with a very high mortality rate. It is difficult to treat and has a high mortality rate, which brings a heavy burden to patients and families. In recent years, the incidence of cancer in our country has increased significantly, making cancer prevention and treatment face a severe situation. In recent years, the incidence of cancer in my country has gradually increased, which has attracted widespread attention from people from all walks of life. According to relevant research reports, in the 1970s, cancer in my country increased from 10.13% to 22.32%, and the death rate increased by 82.11%. Cancer is the number one cause of death in cities and the second in rural areas. Especially in today's aging ...

Claims

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Application Information

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IPC IPC(8): C07D213/30A61P35/00
CPCA61P35/00C07D213/30
Inventor 陈海鹏
Owner 陈海鹏
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