Novel pyrazine derivatives, preparation method therefor and medical application thereof

一种衍生物、吡嗪类的技术，应用在医药领域，能够解决氧化变质、需反复给药、半衰期短等问题

Active Publication Date: 2015-11-04
GUANGZHOU MAGPIE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although caffeic acid has good pharmacological effects, it is also very prone to oxidative deterioration, which is inconvenient for storage and storage
Its structure contains phenolic hydroxyl and carboxyl groups, which can be excreted with urine as glucuronic acid and sulfuric acid conjugates (Gumbinger H G, et al. Planta Med, 1993, 59(6):491-493), and the half-life in the body It is also very short and requires repeated administration, which limits clinical application

Method used

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  • Novel pyrazine derivatives, preparation method therefor and medical application thereof
  • Novel pyrazine derivatives, preparation method therefor and medical application thereof
  • Novel pyrazine derivatives, preparation method therefor and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Embodiment 1, the synthesis of compound IND-003 ( figure 2 )

[0091] TMP (13.6g, 100.0mmol) was dissolved in 300mL of water, and KMnO was added in batches 4 (31.6g, 200.0mmol), heated to 50°C, reacted for 10h. After the reaction is complete, cool, extract with ethyl acetate, discard the organic phase, adjust the pH value of the aqueous phase to 3 with 10% hydrochloric acid, then extract with ethyl acetate, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure. 3,5,6-Trimethylpyrazine-2-carboxylic acid (Compound 1) (9.6 g, 57.8%) was obtained as a yellow solid. ESI-MS:[M+H] + m / z167.0.

[0092] TMP (15g, 110.3mmol) was dissolved in 250mL of carbon tetrachloride, NBS (20g, 112.4mmol) and catalytic amount of benzoyl peroxide were added respectively, heated to 80°C, and reacted overnight. After the reaction was complete, an appropriate amount of water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evapo...

Embodiment 2

[0094] Embodiment 2, the synthesis of compound IND-004 ( figure 2 )

[0095] Dissolve caffeic acid (0.36g, 2mmol) in 10mL of N,N-dimethylformamide, add K 2 CO 3 (0.31g, 2.4mmol), TMP-Br (0.43g, 2mmol), stirred at room temperature for 2h. After the reaction was complete, an appropriate amount of water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Column chromatography separation (ethyl acetate:petroleum ether=1:1) gave white solid compound IND-004 (0.36g, 57%). ESI-MS:[M+H] + m / z 315.23. 1 H-NMR: (300MHz, DMSO-d6) δ: 9.62(s, 1H), 9.16(s, 1H), 7.50(d, J=15.9Hz, 1H), 7.05(d, J=1.8Hz, 1H) ,7.01(dd,J=8.1,1.8Hz,1H),6.76(d,J=8.1Hz,1H),6.32(d,J=15.9Hz,1H),5.24(s,2H),2.48(s, 3H), 2.44(s,3H), 2.42(s,3H). 13 C-NMR: 166.72, 151.27, 149.06, 149.00, 148.90, 146.20, 146.03, 145.34, 125.90, 122.00, 116.18, 115.39, 113.83, 64.86, 21.69, 21.47, 20.58. Anal. (C 17 h 18 N 2 o 4 ) C, H, C; found C 64.92...

Embodiment 3

[0096] Embodiment 3, the synthesis of compound IND-006 ( figure 2 )

[0097] Dissolve (E)-3-(3,4-diacetoxyphenyl)acrylic acid (0.53g, 2mmol) in 10mL of N,N-dimethylformamide, add K 2 CO 3 (0.31g, 2.4mmol), TMP-Br (0.43g, 2mmol), stirred at room temperature for 2h. After the reaction was complete, an appropriate amount of water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Separation by column chromatography (ethyl acetate:petroleum ether=1:1) gave white solid compound IND-006 (0.60 g, 75%). ESI-MS:[M+H] + m / z 399.28. 1 H-NMR: (300MHz, CDCl 3 )δ: 7.65(d, J=15.9Hz, 1H), 7.40(dd, J=8.4, 2.1Hz, 1H), 7.35(d, J=2.1Hz, 1H), 7.21(d, J=8.4Hz, 1H), 6.43(d, J=15.9Hz, 1H), 5.53(s, 2H), 2.57(s, 3H), 2.52(s, 6H), 2.30(s, 6H). 13 C-NMR: 168.06, 167.98, 166.17, 151.43, 149.14, 144.72, 143.60, 143.57, 142.43, 133.12, 126.44, 123.96, 122.82, 118.58, 65.29, 21.70, 21.46, 20.66, 21 h 22 N 2 o 6 ) C, H, ...

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Abstract

The invention relates to pyrazine derivatives, a preparation method therefor and medical application thereof. The pyrazine derivatives can be used for scavenging free radicals and inhibiting calcium ions from being overloaded, play a role in protecting cells and can be used for preventing or treating related diseases such as cardiovascular and cerebrovascular diseases, neurodegenerative diseases and the like.

Description

technical field [0001] The invention belongs to the technical field of medicine, relates to a pyrazine derivative or a pharmaceutically acceptable salt thereof, also relates to a preparation method of the pyrazine derivative, and also relates to the use of the pyrazine derivative or a composition thereof in pharmacy or medical applications. Background technique [0002] Tetramethylpyrazine (tetramethylpyrazine, TMP) is an alkaloid isolated from the traditional Chinese medicine Ligusticum chuanxiong. It is clinically used to treat coronary heart disease, angina pectoris and ischemic cerebrovascular disease (including cerebral thrombosis and cerebral embolism). TMP has many pharmacological activities. First, the anticoagulant effect of TMP is obvious. TMP can significantly inhibit the expression of LPS-induced plasminogen activator inhibitor 1 (PAI-1) protein and its mRNA in endothelial cells (Song, et al.Chinese Medical J.2000,113:136), at low doses It can inhibit the deco...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/12A61K31/497A61P9/00A61P9/10A61P7/02A61P11/00A61P25/28A61P25/16A61P25/14A61P21/00A61P21/04A61P27/06A61P5/14A61P9/12A61P11/06A61P11/08A61P13/12A61P25/08A61P3/10A61P27/12A61P1/16A61P17/00A61P29/00A61P3/04A61P27/00A61P39/06A61P25/00A61P3/00
CPCA61K31/497C07D241/12C07D241/24C07D403/12C07D403/06A61K31/4965A61P9/00A61P27/06A61P3/10A61P25/08A61P25/16A61P25/28
Inventor 王玉强于沛孙业伟单璐琛张高小张在军易鹏
Owner GUANGZHOU MAGPIE PHARMA
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