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Arctigenin ether derivative and preparing method and application thereof

A technology of arctigenin ether and derivatives, which is applied in the field of drug synthesis, can solve the problems of low pass rate, high plasma protein binding rate, low bioavailability, blood-brain barrier, etc., and achieve the effect of reasonable design and easy synthesis

Active Publication Date: 2016-07-06
LIAONING UNIV OF TRADITIONAL CHINESE MEDICINE
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

However, it has strong activity (50μM level) and high plasma protein binding rate (Han Xueying; Wang Wei; Tan Riqiu; Dou Deqiang, Determination of plasma protein binding rate of arctiin and arctigenin by ultrafiltration. Chinese Journal of Traditional Chinese Medicine 2013, 38, (3 ),432-434.), low bioavailability and low blood-brain barrier passage rate limit the direct administration of arctigenin

Method used

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  • Arctigenin ether derivative and preparing method and application thereof
  • Arctigenin ether derivative and preparing method and application thereof
  • Arctigenin ether derivative and preparing method and application thereof

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Embodiment 1

[0035] Embodiment 1: synthetic compound 1-1, please refer to figure 1 and figure 2

[0036] .

[0037] Dissolve arctigenin (50mg, 0.134mmol) in 2ml of dry N,N-dimethylformamide (DMF), add potassium carbonate (37mg, 0.268mmol), stir at room temperature for 10min, then add 4-iodo-2 -Methoxypyridine-3-carbaldehyde (42mg, 0.161mmol), stirred at 120°C for 8h. After cooling to room temperature, 10 mL of ice water was added, the solid precipitated out, filtered with suction, the filter cake was washed with 5% potassium bisulfate solution, dried in vacuo and recrystallized from methanol to obtain 60 mg of white solid with a yield of 88%. [α] D 25 =+3.9(c1.0,CHCl 3 ); 1 H-NMR (400MHz, CDCl 3)δ10.58(s,1H),8.03(d,J=5.9Hz,1H),7.05(d,J=8.0Hz,1H),6.85–6.70(m,3H),6.62–6.52(m,2H ),6.13(d,J=5.9Hz,1H),4.20(t,J=8.2Hz,1H),4.06(s,3H),3.92(t,J=8.5Hz,1H),3.86(s,3H ),3.84(s,3H),3.71(s,3H),3.01(d,J=5.6Hz,2H),2.73–2.58(m,3H),2.56–2.46(m,1H); ESI-MS( m / z):[M+Na] + =530.3(Calcd:507.2).

Embodiment 2

[0038] Embodiment 2: synthetic compound 1-2, please refer to image 3 and Figure 4

[0039] .

[0040] Dissolve arctigenin (50mg, 0.134mmol) in 2ml of dry N,N-dimethylformamide (DMF), add potassium carbonate (37mg, 0.268mmol), stir at room temperature for 10min, then add 2-bromo-3 - Trifluoromethylpyrimidine (37mg, 0.161mmol), stirred at 120°C for 8h. After cooling to room temperature, 10 mL of ice water was added, and the solid precipitated out. Suction filtration, the filter cake was washed with 5% potassium bisulfate solution, dried in vacuo, and methanol was recrystallized to obtain 64 mg of a white solid, with a yield of 92%. The white solid, [α] D 20 =-1.5(c1.0, CHCl 3 ); 1 HNMR (400MHz, CDCl 3 )δ8.71(d,J=4.8Hz,1H),7.33(d,J=4.8Hz,1H),7.11(d,J=8.0Hz,1H),6.81(s,1H),6.78–6.74( m,2H),6.59–6.54(m,1H),6.53(s,1H),4.23–4.15(m,1H),3.95–3.88(m,1H),3.86(s,3H),3.83(s, 3H), 3.68(s,3H), 3.09–2.96(m,2H), 2.72–2.50(m,4H); ESI-MS(m / z):[M+Na] + =540.8(Calcd:518.1).

Embodiment 3

[0041] Embodiment 3: synthetic compound 1-3, please refer to Figure 5 and Figure 6

[0042] .

[0043] Arctigenin (50mg, 0.134mmol) was dissolved in 2ml of acetone, potassium carbonate (37mg, 0.268mmol) and 3-nitrobromobenzene (33mg, 0.161mmol) were added successively, and refluxed for 4h. Remove the solvent under reduced pressure, add 20 mL of water, filter with suction, wash the filter cake several times with 5% potassium bisulfate solution, and recrystallize methanol after vacuum drying to obtain 42 mg of light yellow solid with a yield of 63%. [α] D 20 =-2.1(c1.0,CHCl 3 ); 1 HNMR (400MHz, CDCl 3 )δ7.85(d,J=7.0Hz,1H),7.62(s,1H),7.41(t,J=8.2Hz,1H),7.21(dd,J=8.2,1.4Hz,1H),6.97( d,J=8.0Hz,1H),6.82(s,1H),6.76(d,J=8.1Hz,1H),6.71(d,J=8.0Hz,1H),6.57(d,J=8.0Hz, 1H),6.53(s,1H),4.19(dd,J=8.7,7.6Hz,1H),3.91(t,J=8.4Hz,1H),3.83(s,3H),3.81(s,3H), 3.72(s,3H),2.99(d,J=5.6Hz,2H),2.71–2.47(m,4H);ESI-MS(m / z):[M+Na] + =516.8(Calcd:493.2).

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Abstract

The invention relates to the technical field of medicine synthesis, in particular to a novel arctigenin ether derivative and a preparing method and application thereof.The arctigenin ether derivative has the structure in the following general formula I shown in the description.The preparing method of the arctigenin ether derivative comprises the steps that arctigenin or a derivative thereof, alkaline and halide are dissolved into an organic solvent for a heating reaction for 1-8 h, and a thin-layer chromatography tracking reaction is adopted; after the reaction is finished, decompression is carried out to steam the solvent away or ethyl acetate ordichloromethane is used for extraction after water is added for diluting; then chromatographic purification is carried out with a silica gel column or suction filtration is carried out after water is added for diluting, and the novel arctigenin ether derivative is obtained.The adopted preparing method is reasonable in design, synthesis is easy, synthesized compounds has a novel chemical structure, it is verified through in vitro cell activity experiments that the synthesized compounds I-1 and I-7 have a remarkable nerve protection function which is higher than that of arctigenin, and new treatment medicine for preventing and treating neurodegenerative diseases such as the parkinsoncs disease is provided.

Description

technical field [0001] The present invention relates to the technical field of drug synthesis, in particular to novel arctigenin ether derivatives and their preparation methods, and their use as drugs for the preparation of neurodegenerative diseases such as Parkinson's disease (PD). Background technique [0002] Parkinson's disease (PD) is a common neurodegenerative disease. The prevalence of PD in people over 65 years old in my country is about 1.7%. Its clinical manifestations mainly include resting tremor, bradykinesia, muscle rigidity and Posture and gait disorders, while patients may be accompanied by non-motor symptoms such as depression, constipation, and sleep disturbances. Most patients with Parkinson's disease are sporadic cases, and less than 10% of patients have a family history. [0003] The main pathological change of Parkinson's disease is the degeneration and death of dopamine (DA) neurons in the substantia nigra of the midbrain, which causes a significant d...

Claims

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Application Information

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IPC IPC(8): C07D405/12C07D307/33A61K31/443A61K31/506A61K31/341A61P25/16
CPCC07D307/33C07D405/12
Inventor 窦德强吴平康廷国
Owner LIAONING UNIV OF TRADITIONAL CHINESE MEDICINE
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