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

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

Inactive Publication Date: 2020-12-29
LUNAN PHARMA GROUP CORPORATION
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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-heterocyclyl-substituted pyrazine derivative and application thereof
  • 2-amino-5-heterocyclyl-substituted pyrazine derivative and application thereof
  • 2-amino-5-heterocyclyl-substituted pyrazine derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Embodiment 1: The synthetic route of compound 2 is as follows:

[0109]

[0110] Step 1): Take the sodium salt of diaminopyrazine as raw material, mix and heat 192g of phosphorus oxychloride and 1.8g of sulfuric acid to 60-70°C, then slowly add 120g of sodium salt of diaminopyrazine to it, and then dissolve the The mixture was heated to 100-150°C for 2h, then cooled to 30-40°C, neutralized with 30% sodium hydroxide solution, extracted and rectified to obtain 100g of 2-amino-3-chloropyrazine, yield 87%;

[0111] Step 2): Make m-bromopyridine into Grignard reagent, add trimethyl borate dropwise thereto, control the molar ratio of trimethyl borate to m-bromopyridine to be (1.1-1.2):1, cool during the reaction, Control the reaction temperature at 10-20°C, and continue the cooling reaction for 30 minutes after the dropwise addition to obtain meta-substituted pyridine boronic acid compounds;

[0112] Step 3): Dissolve the 2-amino-3-chloropyrazine in step 1) in tetrahydro...

Embodiment 2

[0113] Embodiment 2: The synthetic route of compound 20 is as follows:

[0114]

[0115] Step 1): using diaminopyrazine as a raw material, dissolve it in tetrahydrofuran to obtain a solution, add aluminum trichloride catalyst and n-propane chloride to it under nitrogen protection, and control the amount of aluminum trichloride to be that of diaminopyrazine. 1.5%, the molar ratio of n-chlorinated propane to diaminopyrazine is (1.2~1.5):1, react under the condition of 80~90°C to get 2-amino-3-n-propylpyrazine, the yield is 88 %;

[0116]Step 2): Make m-bromopyridine into Grignard reagent, add trimethyl borate dropwise thereto, control the molar ratio of trimethyl borate to m-bromopyridine to be (1.1-1.2):1, cool during the reaction, Control the reaction temperature at 10-20°C, and continue the cooling reaction for 30 minutes after the dropwise addition to obtain meta-substituted pyridine boronic acid compounds;

[0117] Step 3): Dissolve the 2-amino-3-n-propylpyrazine in st...

Embodiment 3

[0118] Embodiment 3: The synthetic route of compound 82 is as follows:

[0119]

[0120] Step 1): using diaminopyrazine as a raw material, dissolve it in tetrahydrofuran to obtain a solution, add aluminum trichloride catalyst and cyclohexane bromide to it under nitrogen protection, and control the amount of aluminum trichloride to be diaminopyrazine The molar ratio of bromocyclohexane to diaminopyrazine is (1.2~1.5):1, react under the condition of 80~90℃ to get 2-amino-3-cyclohexylpyrazine, the yield is 79%;

[0121] Step 2): Make m-bromopyridine into Grignard reagent, add trimethyl borate dropwise thereto, control the molar ratio of trimethyl borate to m-bromopyridine to be (1.1-1.2):1, cool during the reaction, Control the reaction temperature at 10-20°C, and continue the cooling reaction for 30 minutes after the dropwise addition to obtain meta-substituted pyridine boronic acid compounds;

[0122] Step 3): Dissolve the 2-amino-3-cyclohexylpyrazine in step 1) in tetrahy...

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Abstract

The invention provides a 2-amino-5-heterocyclyl-substituted pyrazine derivative with a chemical structure shown in a formula 1, a pharmaceutical preparation containing the 2-amino-5-heterocyclyl-substituted pyrazine derivative, and application of the 2-amino-5-heterocyclyl-substituted pyrazine derivative in medicines for treating or preventing malaria. The compound provided by the invention has effects significantly superior to those of the prior art against plasmodium falciparum proliferation and against plasmodium falciparum of different strains, and has a longer half-life period, a lower plasma clearance rate, a 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-heterocyclic substituted pyrazine derivative and its application in medicines for preventing or treating malaria. Background technique [0002] Malaria is caused by protozoan parasites of the genus Plasmodium and is endemic in many developing countries. About 40% of the world's population lives in countries where the disease is endemic; about 247 million people suffer from the disease each year, which infects and destroys red blood cells, causing fever, severe anemia, cerebral malaria and, if left untreated, die. Plasmodium falciparum, the dominant species in sub-Saharan Africa, kills an estimated 600,000 people each year. Children under 5 years of age and pregnant women have the highest burden of disease in Africa. Plasmodium vivax causes 25-40% of the global malaria burden, especially in South and Southeast Asia and Central and South America. The other three main species...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D413/04C07D417/04C07D417/14C07D413/14C07D409/14A61K31/497A61P33/06
CPCC07D401/04C07D413/04C07D417/04C07D417/14C07D413/14C07D409/14A61P33/06Y02A50/30
Inventor 孙颖李铁健石铁生周利田洪武
Owner LUNAN PHARMA GROUP CORPORATION
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