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Arctigenin amino acid ester derivatives, preparation method and use thereof

A technology of arctigenin and amino acids, which is applied in drug combinations, nervous system diseases, organic chemistry, etc., can solve problems such as low pass rate, high plasma protein binding rate, and low bioavailability of the blood-brain barrier, achieving reasonable design, Ease of synthesis, significant neuroprotective effects

Active Publication Date: 2017-12-12
LIAONING UNIV OF TRADITIONAL CHINESE MEDICINE
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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 amino acid ester derivatives, preparation method and use thereof
  • Arctigenin amino acid ester derivatives, preparation method and use thereof
  • Arctigenin amino acid ester derivatives, preparation method and use thereof

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Embodiment 1

[0037] Embodiment 1: synthetic compound 1-1, please refer to figure 1 and figure 2

[0038] .

[0039] Will N -Boc- L-Alanine (30.4 mg, 0.16 mmol) was dissolved in dry toluene, 2,4,6-trichlorobenzoyl chloride (30.5 μL, 0.20 mmol) and DIPEA (26.0 μL, 0.20 mmol) were added, and after stirring for 10 min Arctigenin (50 mg, 0.134 mmol) was added, and DMAP (32.7 mg, 0.27 mmol) was added at one time, and stirring was continued at room temperature for 3 h. TLC showed that the reaction was almost complete. After concentration under reduced pressure, silica gel thin-layer preparation plate was purified to obtain 63 mg of white powder with a yield of 86%. [α] D 25 = -25.6 (c 1.0, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) δ 6.96 (d, J = 7.3 Hz, 1H), 6.76(d, J = 9.7 Hz, 2H), 6.67 (d, J = 7.9 Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H), 6.50(s, 1H), 5.12 (m, 1H), 4.58 (m, 1H), 4.18 (t, J = 7.8 Hz, 1H), 3.93 – 3.88(m, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.74 (s, 3H), 2.97 (s, 2H), 2.6...

Embodiment 2

[0040] Embodiment 2: synthetic compound 1-2, please refer to image 3 and Figure 4

[0041] .

[0042] The CAS number is 57294-38-9 N -Boc-GAMMA-aminobutyric acid (32.5 mg, 0.16 mmol) was dissolved in dry toluene, 2,4,6-trichlorobenzoyl chloride (30.5 μL, 0.20 mmol) and DIPEA (26.0 μL, 0.20 mmol) were added, After stirring for 10 min, arctigenin (50 mg, 0.134 mmol) was added, and DMAP (32.7 mg, 0.27 mmol) was added at one time, and stirring was continued at room temperature for 3 h. TLC showed that the reaction was almost complete. After concentration under reduced pressure, it was purified by silica gel thin-layer preparative plate to obtain 65 mg of white powder with a yield of 87%. [α] D 20 =-9.5( c 1.0, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ) δ 6.94 (d, J =7.9 Hz, 1H), 6.83 – 6.72 (m, 2H), 6.67 (d, J = 7.1 Hz, 1H), 6.54 (d, J = 7.7Hz, 1H), 6.50 (s, 1H), 4.82 (s, 1H), 4.19 – 4.15 (m, 1H), 3.93 – 3.88 (m,1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.76 (s, 3H), 3.26 –...

Embodiment 3

[0043] Embodiment 3: synthetic compound 1-3, please refer to Figure 5 and Figure 6

[0044] .

[0045] Will N -Boc-glycine (28.0 mg, 0.16 mmol) was dissolved in dry toluene, 2,4,6-trichlorobenzoyl chloride (30.5 μL, 0.20 mmol) and DIPEA (26.0 μL, 0.20 mmol) were added and stirred for 10 min Arctigenin (50 mg, 0.134 mmol) was added, and DMAP (32.7 mg, 0.27 mmol) was added at one time, and stirring was continued at room temperature for 3 h. TLC showed that the reaction was almost complete. After concentration under reduced pressure, it was purified by silica gel thin layer preparative plate to obtain 59 mg of white powder with a yield of 83%. [α] D 20 =-16.3( c 1.0, CHCl 3 ), 1 H NMR (400 MHz, CDCl 3 , mixture of rotamers) δ 6.95 (d, J = 8.0Hz, 0.7H), 6.81 (d, J = 7.9 Hz, 0.3H), 6.76 – 6.72 (m, 1.7H), 6.67 – 6.62 (m,1H), 6.61 – 6.59(m, 0.3H), 6.54 – 6.51 (m, 1H), 6.49 – 6.45 ( m, 1H), 5.64(br, 0.3H), 5.10 (br, 0.7H), 4.21 – 4.15 (m, 2H), 4.15 – 4.07 (m, 1H), 3...

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Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to novel arctigenin amino-acid ester derivatives, and a preparation method and application thereof. The structure of the arctigenin amino-acid ester derivatives is disclosed as General Formula I. The preparation method comprises the following steps: dissolving amino acids and arctigenin in a solvent, adding a condensing agent in an ice bath, stirring at room temperature or in a heating state for 1-24 hours, and tracking the reaction by thin-layer chromatography; and after the reaction finishes, evaporating to remove the solvent, and purifying by silica gel column chromatography to obtain the arctigenin amino-acid ester derivatives. The preparation method is reasonable in design and easy for synthesis. The synthesized compounds have a novel chemical structure; the in-vitro cell activity experiment proves that the most synthesized amino-acid ester derivatives have an obvious neural protection action; and the compounds I-2, I-5 and I-6 have higher activity than arctigenin, and thus, provide new therapeutic drugs for preventing and treating parkinsonism and other neurodegenerative diseases.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a novel arctigenin amino acid ester derivative and a preparation method thereof, as well as its use as a drug 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 Gait disturbance, while patients may be accompanied by non-motor symptoms such as depression, constipation, and sleep disturbance. 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 sig...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/33A61K31/365A61P25/16A61P25/00
CPCC07D307/33
Inventor 窦德强吴平康廷国
Owner LIAONING UNIV OF TRADITIONAL CHINESE MEDICINE
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