Pyrazine compounds with multiple effects and preparation method thereof

A compound, pyrazine technology, applied in the field of pyrazine compounds and their preparation, can solve problems such as lack of treatment methods, complex and diverse pathogenesis, hidden disease process, etc.

Active Publication Date: 2020-10-23
SHENZHEN OLIVE BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The pathogenesis of DN is very hidden, the pathogenesis is complex and diverse, and there is still a lack of effective treatment methods in clinical practice.

Method used

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  • Pyrazine compounds with multiple effects and preparation method thereof
  • Pyrazine compounds with multiple effects and preparation method thereof
  • Pyrazine compounds with multiple effects and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Synthesis of Compound OLB-3

[0058]

[0059] Ligustrazine (13.6g, 100.0mmol) was dissolved in water (300mL), potassium permanganate (31.6g, 200.0mmol) was added in batches, and stirred at 50°C for 10 hours. After the reaction, cool, adjust the pH to 3 with hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the product TMA (10.3 g, 62%). 1 H NMR (400MHz, CDCl 3 )δ2.90(s,3H), 2.61(s,3H), 2.56(s,3H). MS (ESI) m / z: 167.0 [M+H]+.

[0060]

[0061] Compound imidazole (6.2g, 90.5mmol) and tert-butyldimethylsilyl chloride (13.6g, 90.5mmol) were dissolved in N,N-dimethylformamide (200mL), and compound 1a (5.0g, 36.2 mmol), stirred overnight at room temperature. After the reaction, dilute with water, extract with n-hexane, dry over anhydrous sodium sulfate, filter, and concentrate. A part (3.7 g) of the obtained crude product is dissolved in methanol (40 mL), and iodine (0.4 g) is added and stirred for 2 ...

Embodiment 2

[0068] Example 2: OLB-3 significantly reduces SH-SY5Y cell death caused by OGD

[0069] MTT method was used to detect and evaluate the neuroprotective effect of TMP (tetramethylpyrazine) and its derivatives. Cultivate cells, collect logarithmic phase cells, adjust the concentration of cell suspension, add drug treatment and OGD4h incubation, add MTT-containing culture medium, and incubate After 4 hours, carefully suck out the culture medium in the wells, add 150ulDMSO (dimethyl sulfoxide) to each well, shake at a low speed on a shaker for 10min, so that the crystals are fully dissolved, and measure each well at the OD (absorbance) value of 490nm in an enzyme-linked immunosorbent detector. The absorbance value of the well (set the zeroing well (medium, MTT, dimethyl sulfoxide) at the same time, the control well (cells, the same concentration of drug dissolution medium, culture medium, MTT, dimethyl sulfoxide)). Data representation Mean ± SEM; each group n = 8. One-way analysis ...

Embodiment 3

[0071] Example 3: OLB-3 significantly reduces the increase of inflammatory factors and oxidative stress caused by LPS

[0072] The SH-SY5Y cells were revived and cultured, and the cells in the logarithmic growth phase were taken. After 24 hours of culture, the SH-SY5Y neuroblastoma cells were treated with 1 μM all-trans retinoic acid to induce differentiation, and then inoculated into 6-well culture dishes for 24 hours. . Add 0.2uM (L) or 1uM (H) and 1μg / mL LPS to the culture solution for 24 hours, absorb the supernatant culture solution, and measure the changes of inflammatory factors and oxidative stress-related proteins with ELISA kits. The data are expressed as average Value ± SEM; each group n = 8. One-way analysis of variance and multiple comparisons showed that there were differences between the two groups. a, p<0.05vs. LPS group; b, p<0.01vs LPS group; c, p<0.001vs .LPS group.

[0073] Table 1

[0074] (pg / ml) WT LPS LPS+TMP(L) LPS+TMP(H) LPS+OLB...

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Abstract

The invention relates to pyrazine compounds, stereoisomers, tautomers and pharmaceutically acceptable salts of the pyrazine compounds. The pyrazine compounds can be used for treating Alzheimer's disease, Parkinson's disease, Huntington's disease, frontal temporal dementia (FTD), vascular dementia, HIV-related dementia, multiple sclerosis, progressive spinal cord lateral sclerosis, Friedel-Crafts ataxia, neuropathic pain or glaucoma and other neurodegenerative diseases, diabetes mellitus and related diabetic complications, inflammation, oxidative damage and mitochondria-related diseases.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a pyrazine compound with multiple functions and a preparation method thereof. Background technique [0002] Neurodegenerative diseases (Neurodegenerative diseases, ND) are chronic diseases that lead to the gradual death of neurons, including Alzheimer's disease, Parkinson's disease and Huntington's disease, which often bring great pain and suffering to patients and families. burden. With the aging of the population, it is expected that by 2040, ND will replace cancer and become the second largest type of disease that causes human death. However, there is currently no drug in the world that can effectively treat neurodegenerative diseases. [0003] Pathology of ND with oxidative stress, mitochondrial dysfunction, Ca 2+ Influx, immune inflammation, autophagy, and metal ions are closely related. It is a complex disease with multiple etiologies. The traditional single-target high-selectivi...

Claims

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Application Information

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IPC IPC(8): C07D241/24C07F7/18A61K31/4965A61K31/695A61P25/00A61P29/00A61P39/06A61P3/10A61P25/28A61P25/16A61P25/14A61P25/04A61P27/06A61P31/18A61P9/10
CPCC07D241/24C07F7/1804A61P25/00A61P29/00A61P39/06A61P3/10A61P25/28A61P25/16A61P25/14A61P25/04A61P27/06A61P31/18A61P9/10Y02P20/55
Inventor 谢永美李书鹏杨细飞
Owner SHENZHEN OLIVE BIOPHARMACEUTICALS CO LTD
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