Pyrazine compound and preparation method thereof

A compound, pyrazine technology

Active Publication Date: 2020-10-20
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 compound and preparation method thereof
  • Pyrazine compound and preparation method thereof
  • Pyrazine compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] The synthesis of embodiment 1 compound OLB-1

[0061]

[0062] Step (1): Compound 1-0 (15.0g, 110.3mmol) was dissolved in glacial acetic acid (150ml), hydrogen peroxide (30%, 12.5ml, 110.2mmol) was added dropwise at 70°C, and the reaction was continued overnight. After the reaction, cool, dilute with aqueous sodium hydroxide solution (50%), extract with dichloromethane, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude compound directly dissolved in acetic anhydride (30ml), react at 107°C for 3 hours, and the reaction ends Afterwards, cooling, concentrating, pouring into ice water to dilute, adjusting the pH to greater than 10 with sodium hydroxide solution, stirring overnight, extracting with dichloromethane, drying over anhydrous sodium sulfate, filtering, concentrating, and silica gel column chromatography to obtain the product 1-1 (6.8 g, 41%). 1 H NMR (400MHz, DMSO-d 6 )δ5.39(s,1H), 3.81(s,2H), 2.42(s,3H), 2.42(s,3H), 2.41(s,3H). ...

Embodiment 2

[0069] The synthesis of embodiment 2 compound OLB-2

[0070]

[0071] Step (1): Compound 1-0 (20g, 147mmol), N-bromosuccinimide (26.7g, 150mmol) and benzoyl peroxide (50mg, 0.2mmol) were dissolved in carbon tetrachloride ( 70ml), under the irradiation of an incandescent lamp, reflux reaction for 10 hours, after the reaction, filter and concentrate to obtain the crude product 1-2, which is directly put into the next reaction. 1 H NMR (400MHz, CDCl 3 )δ4.54(s,2H), 2.57(s,1H), 2.50(s,1H), 2.49(s,1H).

[0072]

[0073] Step (2): Compound 1-2 (17.5g, 82mmol), potassium phthalimide (21.0g, 110mmol) and sodium iodide (0.5g, 3.3mmol) were dissolved in N,N-dimethyl methyl formamide (100ml), stirred at 95°C for 2 hours. After the reaction, filter, pour the filtrate into ice water to obtain a white precipitate, filter with suction, and recrystallize the filter cake with ethanol to obtain product 1-3 (18.7g, 81%). 1 H NMR (400MHz, DMSO-d 6 )δ8.01–7.79 (m, 4H), 4.90 (s, 2H), 2.5...

Embodiment 3

[0081] Example 3: OLB-1 and OLB-2 significantly reduce SH-SY5Y cell death caused by OGD

[0082] MTT method was used to detect and evaluate the neuroprotective effect of TMP (tetramethylmethylpyrazine) and its derivatives. Cultivate cells, collect logarithmic phase cells, adjust the concentration of cell suspension, add drugs and incubate with OGD for 4 hours, add MTT-containing culture medium, incubate for 4 hours, carefully suck out the culture medium in the wells, and add 150 μl dimethyl sulfoxide to each well (DMSO), shake at a low speed on a shaker for 10 minutes to fully dissolve the crystals, measure the absorbance of each well at the OD (absorbance) value of 490nm in the enzyme-linked immunosorbent assay instrument (set zero adjustment wells at the same time (medium, MTT, dimethylformazol) base sulfoxide), control wells (cells, drug dissolution medium at the same concentration, culture medium, MTT, dimethyl sulfoxide)). Data are expressed as mean ± SEM; n = 8 for each ...

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Abstract

The invention relates to a pyrazine compound, a stereoisomer, a tautomer and a pharmaceutically acceptable salt thereof, wherein the pyrazine compound, the stereoisomer, the tautomer and the pharmaceutically acceptable salt thereof can treat 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, inflammations, oxidative damage and mitochondria-related diseases.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a pyrazine compound and its preparation method and application. Background technique [0002] Neurodegenerative diseases (ND) include Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia (FTD), amyotrophic lateral sclerosis, Friedreich Chronic diseases such as ataxia, which lead to the gradual death of neurons, often bring great pain and burden to patients and families. 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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/12A61K31/4965A61P25/28A61P25/16A61P25/04A61P25/02A61P25/00A61P29/00A61P9/10A61P3/10A61P9/00
CPCC07D241/12A61P25/28A61P25/16A61P25/04A61P25/02A61P25/00A61P29/00A61P9/10A61P3/10A61P9/00
Inventor 谢永美杨细飞李书鹏
Owner SHENZHEN OLIVE BIOPHARMACEUTICALS CO LTD
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