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Aminopyrimidino-five-membered-heterocyclic compound, and intermediate, preparation method, medicine composition and application thereof

A compound and drug technology, applied in the field of aminopyrimido five-membered heterocyclic compounds, can solve problems such as tumors

Active Publication Date: 2020-03-10
SHANGHAI MAXINOVEL PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, if the cancerous cells themselves or the functions of the above-mentioned immune cells are changed, they may escape the elimination of the body's immune system, and malignant hyperplasia forms tumors

Method used

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  • Aminopyrimidino-five-membered-heterocyclic compound, and intermediate, preparation method, medicine composition and application thereof
  • Aminopyrimidino-five-membered-heterocyclic compound, and intermediate, preparation method, medicine composition and application thereof
  • Aminopyrimidino-five-membered-heterocyclic compound, and intermediate, preparation method, medicine composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0165] Example 1: 2-amino-7-(2-fluorobenzyl)-4-(furan-2-yl)-5H,7H-furo[3,4-d]pyrimidin-5-one (compound 1)

[0166] synthetic route

[0167]

[0168] Synthesis of compound 1-c

[0169]Methyl 2,4-dichloro-6-methyl-pyrimidine-5-carboxylate (940mg, 4.25mmol), 2-furyltributylstannane (1.42g, 4.0mmol), tetrakis(triphenyl)phosphine palladium (260mg, 0.22mmol), and tetrahydrofuran (30mL) were stirred at 60°C under nitrogen for 16 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / dichloromethane=3 / 1) to obtain white solid 1-c (870 mg, yield: 81%).

[0170] LC-MS(ESI):m / z=253[M+H] + .

[0171] Synthesis of compound 1-b

[0172] A mixture of compound 1-c (800 mg, 3.2 mmol), selenium dioxide (880 mg, 8.0 mmol) and dioxane (20 mL) was heated under reflux for 8 hours. After cooling to room temperature, the reaction mixture was concentrated under re...

Embodiment 2

[0179] Example 2: 2-amino-7-(4-chloro-2-fluorobenzyl)-4-(furan-2-yl)-5H,7H-furo[3,4-d]pyrimidin-5-one (compound 2)

[0180] synthetic route

[0181]

[0182] Synthesis of compound 2-f

[0183] Dissolve furfural (9.6 g, 0.1 mol), O-methylisourea sulfate (20.64 g, 0.12 mol) and ethyl acetoacetate (14.3 g, 0.11 mol) in anhydrous N,N-dimethylformamide (200 mL), sodium bicarbonate (33.6 g, 0.4 mmol) was added to the solution. The reaction mixture was heated to 70°C under nitrogen protection, stirred for 3 hours and then cooled to room temperature. Add saturated brine (300mL), a large amount of yellow suspension appeared, extracted with ethyl acetate (500mL×2), combined the organic phases, washed with water (200mL) and saturated brine (100mL), dried over anhydrous sodium sulfate, and reduced pressure After concentration, the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=6-3:1) to obtain light yellow solid 2-f (15.0 g, yield: 57%). LC...

Embodiment 3

[0200] Example 3: 4-{[2-amino-4-(furan-2-yl)-5-oxo-5H,7H-furo[3,4-d]pyrimidin-7-yl]methyl-2 -Fluorobenzonitrile (Compound 3)

[0201]

[0202] Using 2-d and 2-fluoro-4-cyanobenzyl bromide as raw materials, the synthesis method is the same as in Example 2.

[0203] LC-MS(ESI):m / z=351[M+H] + .

[0204] 1 H NMR (500MHz, d 6 -DMSO) δ: 8.27(d, J=3.5Hz, 1H), 8.11(brs, 1H), 8.03(s, 1H), 7.92(brs, 1H), 7.89(t, J=7.5Hz, 1H), 7.50(d, J=10.0Hz, 1H), 7.34(d, J=8.0Hz, 1H), 6.78(dd, J=1.5Hz, 3.5Hz, 1H), 5.67(dd, J=3.5Hz, 8.5Hz , 1H), 3.45 (dd, J = 3.5Hz, 15.0Hz, 1H), 3.14 (dd, J = 8.5Hz, 15.0Hz, 1H) ppm.

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Abstract

The invention discloses an aminopyrimidino-five-membered-heterocyclic compound represented as the formula (I), and an intermediate, a preparation method, a medicine composition and an application thereof, wherein the aminopyrimidino-five-membered-heterocyclic compound has significant antagonistic effect on adenosine A2A receptor, so that the compound can be used as an adenosine A2A receptor antagonist and can effectively alleviate or treat related diseases such as immunologic tolerance, central nervous system disease, inflammatory disease, etc.

Description

technical field [0001] The invention relates to an aminopyrimido five-membered heterocyclic compound, its intermediate, preparation method, pharmaceutical composition and application. Background technique [0002] Immune regulation is an important means for the body to maintain a stable internal environment and resist external harmful stimuli. Adenosine, as an important transmitter and regulator of the body, will increase significantly in metabolic disorders and cell damage, activate adenosine receptors to exert biological effects, and participate in the body's immune regulation. Recent studies have shown that in many pathological processes such as ischemia and hypoxia, inflammation, trauma, and transplantation, the activation of adenosine A2A receptors can play an important role in immune regulation, which may be related to the role of A2A receptors in T cells, B cells, and single It is related to higher expression levels on various immune cells such as nuclear macrophages...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D491/048C07D473/32C07D473/36A61K31/519A61P25/00A61P29/00A61P37/06A61P35/00A61P19/02A61P11/06A61P9/10A61P1/16A61P11/00
CPCC07D487/04C07D491/048C07D473/32C07D473/36A61P25/00A61P29/00A61P37/06A61P35/00A61P19/02A61P11/06A61P9/10A61P1/16A61P11/00A61K31/519A61K31/52
Inventor 王玉光张农吴添智吴新亮
Owner SHANGHAI MAXINOVEL PHARMA CO LTD
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