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2-amino-5-heteroaryl substituted pyrazine derivative and application thereof

A technology of pyrazine derivatives and heteroaryl groups, applied in the field of pyrazine derivatives, can solve problems such as toxic side effects, expensive drugs and the like

Pending Publication Date: 2021-05-28
徐新杰
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] A variety of drugs, including combinations of drugs, are currently used to treat malaria, however, many of these drugs are expensive, and some exhibit significant toxicity and unwanted side effects in humans, and, drug-resistant malaria strains The emergence has become a significant problem in the current malaria treatment. WHO recommends artemisinin combined with other types of antimalarial drugs as the first-line treatment for malaria caused by P. Suspected emergence of artemisinin-resistant Plasmodium falciparum in parts of Vietnam highlights urgent need for new malaria drugs with novel chemical classes

Method used

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  • 2-amino-5-heteroaryl substituted pyrazine derivative and application thereof
  • 2-amino-5-heteroaryl substituted pyrazine derivative and application thereof
  • 2-amino-5-heteroaryl substituted pyrazine derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Embodiment 1: The synthetic route of compound 6 is as follows:

[0065]

[0066] Step 1): Make 6-bromopyrazole into Grignard reagent, add trimethyl borate dropwise to it, control the molar ratio of trimethyl borate to 6-bromopyrazole to be (1.1~1.2):1, during the reaction Cool and control the reaction temperature at 10-20°C. After the dropwise addition, continue to cool and react for 30 minutes to obtain a 6-substituted pyrazole boronic acid compound;

[0067] Step 2): dissolving the pyrazole boronic acid compound obtained in step 1) in tetrahydrofuran, adding 2-amino-3-bromopyrazine to it, and controlling the molar ratio of the pyrazole boronic acid compound to 2-amino-3-bromopyrazine The ratio is (1.05~1.10):1, the reaction temperature is 45~55°C, and after 1~2h of reaction, compound 6, the product of Suzuki coupling reaction, is obtained with a yield of 66%.

Embodiment 2

[0068] Embodiment 2: The synthetic route of compound 18 is as follows:

[0069]

[0070] Step 1): Make 2-bromooxazole into Grignard reagent, add trimethyl borate dropwise to it, control the molar ratio of trimethyl borate to 2-bromooxazole to be (1.1~1.2):1, react Cool during the process, control the reaction temperature at 10-20°C, continue to cool and react for 30 minutes after the dropwise addition, and obtain the 2-substituted oxazole boronic acid compound;

[0071] Step 2): Dissolving the oxazole boronic acid compound obtained in step 1) in toluene, adding 2-amino-3-ethylpyrazine to it to control the interaction between the oxazole boronic acid compound and 2-amino-3-ethylpyrazine The molar ratio was (1.05-1.10):1, the reaction temperature was 45-55°C, and after 1-2 hours of reaction, compound 18, the product of Suzuki coupling reaction, was obtained with a yield of 73%.

Embodiment 3

[0072] Embodiment 3: The synthetic route of compound 38 is as follows:

[0073]

[0074] Step 1): Use 2-amino-5-(5-pyrazolyl)-pyrazine as a raw material, dissolve it in tetrahydrofuran to prepare a solution, add liquid bromine dropwise to it under ventilated conditions, and control the liquid bromine and 2-amino- The molar ratio of 5-(5-pyrazolyl)-pyrazine is (0.9~0.95):1, add catalyst iron filings to it, and react at room temperature to obtain 2-amino-3-bromo-5-(5-pyridine Azolyl)-pyrazine, the yield is 85%;

[0075] Step 2): Add trimethyl borate dropwise to propionamide, control the molar ratio of trimethyl borate to propionamide to be (1.1-1.2):1, cool during the reaction, control the reaction temperature at 10-20°C, drop After the addition was completed, the cooling reaction was continued for 30 minutes to obtain the propionamide boric acid compound;

[0076] Step 3): Dissolve the 2-amino-3-bromo-5-(5-pyrazolyl)-pyrazine obtained in step 1) in tetrahydrofuran, and add...

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Abstract

The invention provides a 2-amino-5-heteroaryl substituted pyrazine derivative with a chemical structure as shown in a formula 1, a pharmaceutical preparation containing the 2-amino-5-heteroaryl substituted pyrazine derivative, and application of the 2-amino-5-heteroaryl substituted pyrazine derivative in drugs for treating or preventing malaria. Compared with the prior art, the compound has the effects of resisting plasmodium falciparum proliferation and resisting plasmodium falciparum of different strains, and has the advantages of longer half-life period, lower plasma clearance rate, higher distribution volume and better oral bioavailability.

Description

technical field [0001] The invention relates to a pyrazine derivative, in particular to a 2-amino-5-heteroaryl substituted pyrazine derivative and its application in medicines for preventing or treating malaria. Background technique [0002] Malaria is a disease endemic in many developing countries. About 40% of the world's population lives in countries where the disease is endemic; approximately 247 million people suffer from the disease each year. [0003] A variety of drugs, including combinations of drugs, are currently used to treat malaria, however, many of these drugs are expensive, and some exhibit significant toxicity and unwanted side effects in humans, and, drug-resistant malaria strains The emergence has become a significant problem in the current malaria treatment. WHO recommends artemisinin combined with other types of antimalarial drugs as the first-line treatment for malaria caused by P. The suspected emergence of artemisinin-resistant Plasmodium falciparum...

Claims

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Application Information

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IPC IPC(8): C07D403/04C07D413/04C07D405/04C07D409/04C07D417/04A61K31/501A61P33/06
CPCC07D403/04C07D413/04C07D405/04C07D409/04C07D417/04A61P33/06Y02A50/30
Inventor 徐新杰
Owner 徐新杰
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