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2-hydroxymethyl-3,5,6-trimethylpyrazine derivatives, preparation methods and application thereof

A technology of trimethylpyrazine and hydroxymethyl, applied in the field of 2-hydroxymethyl-3,5,6-trimethylpyrazine derivatives, its preparation and application, can solve unsatisfactory curative effect, Low bioavailability, short half-life, etc.

Inactive Publication Date: 2010-07-28
TIANJIN HANKANG PHARMA BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the application, it was found that ligustrazine has the disadvantages of fast metabolism, short half-life, low bioavailability, etc., and the curative effect is not satisfactory. Long-term use may cause chronic toxic effects such as decreased serum globulin, increased serum muscle, and increased blood sugar. possible

Method used

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  • 2-hydroxymethyl-3,5,6-trimethylpyrazine derivatives, preparation methods and application thereof
  • 2-hydroxymethyl-3,5,6-trimethylpyrazine derivatives, preparation methods and application thereof
  • 2-hydroxymethyl-3,5,6-trimethylpyrazine derivatives, preparation methods and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0134] Example 1: (3,5,6-trimethylpyrazin-2-yl)methanol nitrate (HK-001)

[0135]

[0136] In the reaction bottle, add 2-hydroxymethyl-3,5,6-trimethylpyrazine (A) 15.2g, 60ml acetic acid, 10ml acetic anhydride, under stirring at room temperature, dropwise add 7.5g fuming nitric acid, in 20 The dropwise addition was completed within 1 minute, and then the reaction was incubated for 16 hours. TLC detected that the reaction was complete, and the reaction was stopped. The reaction solution was added to 200 g of crushed ice with stirring, and 120 ml of ethyl acetate was added, and the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate, 9:1) to obtain (3,5,6-trimethylpyrazin-2-yl)methanol nitrate 9.6g. HPLC: 99.1%, elemental analysis: (theoretical value / measured value), C (48.73 / 48.62), H (5.62 / 5.55), N (...

Embodiment 2

[0137] Example 2: (3,5,6-trimethylpyrazin-2-yl)methanol 4-((nitroxyl)methyl)benzoate (HK-002)

[0138]

[0139] a. In the reaction flask, add 7.6g of 2-hydroxymethyl-3,5,6-trimethylpyrazine (A), 80ml of dichloromethane, 8.0g of triethylamine, and stir at 15°C-20°C Add 9.5g of p-chloromethylbenzoyl chloride (B), and then react at 30° C. for 3 hours. TLC monitoring, the reaction is over, stop the reaction. Add 50ml of water, stir and let stand, separate the dichloromethane layer, and dry over anhydrous magnesium sulfate. Dichloromethane was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate, 9:2) to obtain 9.8 g of p-chloromethylbenzoic acid (2-hydroxymethyl-3,5,6- trimethylpyrazine) ester (C). HPLC: 98.11%, ESI-MS: 303.1 (M-H).

[0140] b. In the reaction flask, add 6.0 g of p-chloromethylbenzoic acid (2-hydroxymethyl-3,5,6-trimethylpyrazine) ester (C), 120 ml of acetonitrile, and heat to 65° C. und...

Embodiment 3

[0141] Example 3: 3-methyl-1,2,5-oxadiazole-2-oxide-4-carboxylic acid (3,5,6-trimethylpyrazin-2-yl)methanol ester (HK-003 )

[0142]

[0143] In the reaction flask, add 7.6g of 2-hydroxymethyl-3,5,6-trimethylpyrazine (A), 160ml of dichloromethane, 6.5g of pyridine, and add 8.9g of 3-methyl- 1,2,5-oxadiazole-2-oxide-4-formyl chloride (D), and then reacted at room temperature for 4.5 hours. TLC monitoring, the reaction is over, stop the reaction. Add 80ml of water, stir and let it stand, separate the dichloromethane layer, evaporate the dichloromethane under reduced pressure, and purify the residue by silica gel column chromatography (n-hexane / ethyl acetate, 7:2) to obtain 7.7 g of solid, namely 3-Methyl-1,2,5-oxadiazole-2-oxide-4-carboxylic acid (3,5,6-trimethylpyrazin-2-yl)methanol ester (HK-003). HPLC: 99.16%, ESI-MS: 277.1 (M-H).

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Abstract

The invention provides 2-hydroxymethyl-3,5,6-trimethylpyrazine derivatives with the structure of a formula (I) or pharmaceutically acceptable salts thereof, relating to the field of related antithrombotic medicines, wherein the definition of R is shown in the specification of the invention. The invention also provides preparation methods of the derivatives or pharmaceutically acceptable salts thereof, medicine compositions and application of the derivatives used as effective components in preparing medicines for treating cerebral thrombosis, cerebral infarction, angina, myocardial infarction and arrhythmia related with thrombus.

Description

technical field [0001] The present invention belongs to the technical field of medicine, more specifically, relates to a class of chemically synthesized 2-hydroxymethyl-3,5,6-trimethylpyrazine derivatives or pharmaceutically acceptable salts thereof. The preparation method of the derivative or its pharmaceutically acceptable salt, the pharmaceutical composition and its use as an active ingredient in the preparation of drugs for the treatment of cerebral thrombosis, cerebral infarction, angina pectoris, myocardial infarction, coronary heart disease, arrhythmia related to thrombus, etc. Background technique [0002] With the increasingly serious problem of population aging, cardiovascular and cerebrovascular diseases have become the number one enemy that seriously affects people's health and life. Diseases related to thrombosis, such as cerebral thrombosis, cerebral infarction, angina pectoris, and myocardial infarction, take the lives of tens of millions of people every year ...

Claims

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Application Information

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IPC IPC(8): C07D241/12C07D413/12C07D493/04C07D401/12A61K31/4965A61K31/497A61P7/02A61P9/10A61P9/06
Inventor 严洁
Owner TIANJIN HANKANG PHARMA BIOTECH
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