Aminopyrazine compound or salt, isomer, preparation method and use thereof

A technology of aminopyrazines and compounds, applied in the field of medicinal chemistry, can solve the problems of reducing anti-platelet aggregation activity and achieve the effects of improving anti-platelet aggregation activity, reducing mean pulmonary hypertension, and improving stability

Active Publication Date: 2021-12-24
CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The inventors have found through long-term and large-scale screening that the change of the long chain of carboxylic acid of aminopyrazine compounds has a great influence on the activity, and changing the length of the chain length will reduce the anti-platelet aggregation activity

Method used

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  • Aminopyrazine compound or salt, isomer, preparation method and use thereof
  • Aminopyrazine compound or salt, isomer, preparation method and use thereof
  • Aminopyrazine compound or salt, isomer, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0183] Example 1 Preparation of 2-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy}acetic acid

[0184]

[0185] Step 1: Preparation of 5,6-diphenyl-2-hydroxypyrazine

[0186]

[0187] Under nitrogen protection, bibenzoyl (31.0g, 0.10mol), aminoacetamide (13.0g, 0.12mol) and NaOH (7.00g, 0.24mol) were sequentially added to 1L methanol solvent, heated to reflux for 3-4h , the reaction was monitored by LC-MS, and the starting material was completely reacted. Cool the reaction solution to 0-5°C, then add 12.5mL 12N HCl solution dropwise, and stir the reaction solution at room temperature for 30min, then add 10g sodium bicarbonate and 130mL water, filter the reaction solution, wash the solid with a small amount of water and methanol respectively , dried in vacuo to obtain 22.0 g of white solid 5,6-diphenyl-2-hydroxypyrazine, yield: 88.7%, ESI-MS: m / z=249.2 (M+H) + .

[0188] Step 2: Preparation of 5-chloro-2,3-diphenylpyrazine

[0189]

[0190] Under the prote...

Embodiment 2

[0200] Example 2 Preparation of 2-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]ethoxy}acetic acid

[0201]

[0202] The synthesis method is the same as in Example 1, the only difference being that 2-(N-isopropylamino)ethanol in step 3 of Example 1 is replaced by N-methylaminoethanol to obtain yellow oily 2-{2- [N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]ethoxy}acetic acid; ESI-MS: m / z=364.2(M+H) + ; 1 H NMR (400MHz, d 6 -DMSO)δ12.64(s,1H),8.19(s,1H),7.37-7.20(m,10H),4.07(s,2H),3.71-3.62(m,4H),3.13(s,3H) .

Embodiment 3

[0203] Example 3 Preparation of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid

[0204]

[0205] Step 1: Preparation of 5,6-diphenyl-2-hydroxypyrazine

[0206]

[0207] Under the protection of nitrogen, add bibenzoyl (63.0g, 0.30mol), aminoacetamide (39.0g, 0.36mol) and NaOH (29.0g, 0.72mol) to 1L methanol solvent in sequence, and heat to reflux for 3-4h , the reaction was monitored by LC-MS, and the starting material was completely reacted. Cool the reaction solution to 0-5°C, then add 37.5mL 12N HCl solution dropwise, and stir the reaction solution at room temperature for 30min, then add 30g sodium bicarbonate and 380mL water, filter the reaction solution, wash the solid with a small amount of water and methanol respectively , dried in vacuo to obtain 68.0 g of white solid 5,6-diphenyl-2-hydroxypyrazine, yield: 91.4%, ESI-MS: m / z=249.2 (M+H) + .

[0208] Step 2: Preparation of 5-chloro-2,3-diphenylpyrazine

[0209]

[0210] Under ...

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Abstract

A kind of aminopyrazine compound shown as general formula (I) or its pharmaceutically acceptable salt, isomer is disclosed, and it has prostaglandin I 2 (PGI 2 ) receptor agonist activity, used as IP receptor agonist to treat related diseases.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to 2 (PGI 2 ) receptor agonistic aminopyrazine compound or its salt, isomer, its preparation method and its use in the preparation of medicines for treating pulmonary hypertension, platelet aggregation or arteriosclerosis obliterans. Background technique [0002] Prostaglandin I 2 (PGI 2 ) is a member of the eicosanoid family of lipids and is an antagonist of thromboxane, and its reduced synthesis can promote thrombosis. excited PGI 2 The receptor (IP receptor) not only inhibits the platelet-mediated aggregation process but also has a strong vasodilation effect. The diseases that IP receptor agonists can treat mainly include pulmonary arterial hypertension (PAH), PAH related to various diseases, arteriosclerosis obliterans, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, ischemia Reperfusion injury, restenosis, atrial fibrillation, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D241/20A61K31/4965A61P7/02
CPCA61K31/4965C07D241/20A61P7/02
Inventor 王颖蔡显荣鄢胜勇张涛刘强强马云龙乔惠付海霞
Owner CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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