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1-aminobenzo [4, 5] imidazo [1, 2-a] pyrazine-3-formamide compound and preparation and application thereof

The technology of a compound, imidazolo, is applied in the field of medicinal chemistry to achieve the effect of simple preparation method, mild reaction conditions and good subtype selectivity

Active Publication Date: 2022-04-05
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the development of small-molecule adenosine receptor inhibitors is still in the initial stage, and there is still a lot of room for improvement. Therefore, there is an urgent need to develop more novel adenosine receptor inhibitors with anticancer activity

Method used

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  • 1-aminobenzo [4, 5] imidazo [1, 2-a] pyrazine-3-formamide compound and preparation and application thereof
  • 1-aminobenzo [4, 5] imidazo [1, 2-a] pyrazine-3-formamide compound and preparation and application thereof
  • 1-aminobenzo [4, 5] imidazo [1, 2-a] pyrazine-3-formamide compound and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Example 1 Preparation of 1-aminobenzo[4,5]imidazo[1,2-a]pyrazine-3-carboxamides (compound 14a)

[0081] Concrete preparation process is as follows:

[0082] (1) Preparation of compound shown in formula 3:

[0083] The chemical reaction formula of the preparation process is as follows:

[0084]

[0085] According to the above reaction formula, the compound shown in Formula 1 (1,2-phenylenediamine, 3.2 g, 30 mmol) and 50 mL of acetic acid were added to the reaction flask at room temperature, and the starting materials were slowly added after cooling in an ice bath, namely The compound shown in formula 1 (methyl 2,2,2-trichloroimidoacetate, 4mL, 30mmol) was stirred at room temperature for 2 hours after the addition was completed, and TLC showed that the reaction was completed and then the reactant was filtered, and the resulting filter cake was Washing with water (3 times, 25 mL each time), and finally vacuum drying to obtain the compound (2-trichloromethyl-benzopyrim...

Embodiment 2

[0130] Example 2 Preparation of 1-aminobenzo[4,5]imidazo[1,2-a]pyrazine-3-carboxamides (compound 14b)

[0131] The preparation process of compound 14b is the same as the preparation process of compound 14a in Example 1, except that in step S9, n-pentylamine is used instead of 2-aminomethylpyridine to prepare the compound shown in formula 13, and finally the compound can be prepared 14b (46 mg, 70%). Its chemical structural formula is as follows:

[0132]

[0133] The spectrum information of the product is as follows:

[0134] 1 H NMR (500MHz, Chloroform-d) δ8.75(s, 1H), 7.94(dd, J=17.1, 8.3Hz, 2H), 7.77(t, J=5.3Hz, 1H), 7.59–7.56(m, 1H),7.51–7.47(m,1H),5.88(s,2H),3.48(q,J=6.8Hz,2H),1.64(p,J=7.3Hz,2H),1.43–1.38(m,2H ),1.36–1.32(m,3H),0.91–0.89(m,3H). 13 CNMR (126MHz, Chloroform-d) δ163.7, 148.1, 143.7, 135.7, 130.1, 129.7, 126.6, 123.8, 121.0, 111.7, 39.5, 31.5, 29.7, 26.7, 22.6, 14.0.

Embodiment 3

[0135] Example 3 Preparation of 1-aminobenzo[4,5]imidazo[1,2-a]pyrazine-3-carboxamides (compound 14c)

[0136] The preparation process of compound 14c is the same as the preparation process of compound 14a in Example 1, except that in step S9, isobutylamine is used instead of 2-aminomethylpyridine to prepare the compound shown in formula 13, and finally the compound can be prepared 14c (43 mg, 70%). Its chemical structural formula is as follows:

[0137]

[0138] The spectrum information of the product is as follows:

[0139] 1 H NMR (500MHz, Chloroform-d) δ8.76(s,1H),7.96(dd,J=16.6,8.3Hz,2H),7.84(s,1H),7.59(t,J=7.7Hz,1H) ,7.51(t,J=7.7Hz,1H),5.77(s,2H),3.33(t,J=6.6Hz,2H),1.02(d,J=6.7Hz,6H). 13 C NMR (126MHz, DMSO-d 6 ) δ 163.9, 149.3, 143.6, 136.2, 130.6, 130.3, 126.4, 123.5, 120.6, 113.6, 111.2, 46.5, 28.8, 20.5.

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Abstract

The invention belongs to the technical field of medical chemistry, and particularly relates to a 1-aminobenzo [4, 5] imidazo [1, 2-a] pyrazine-3-formamide compound and preparation and application thereof.The structure of the compound is shown in the formula (I), and the compound is novel in structure, is an adenosine receptor inhibitor, and can be used for preparing a novel compound. The compound has good inhibitory activity on adenosine A2A receptors and good subtype selectivity, can be used as a targeted adenosine A2A receptor inhibitor for immunotherapy, and achieves the effect of treating tumors by inhibiting the activity of the adenosine A2A receptors and releasing the removal function of an immune system on tumor cells. Meanwhile, the preparation method of the compound is simple, the cheap and easily available compound is used as the raw material, the reaction condition is mild, the total yield and the purity are high, the production of dozens of grams can be realized, and the research of later clinical candidate adenosine A2A receptor inhibitors is supported.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to 1-aminobenzo[4,5]imidazo[1,2-a]pyrazine-3-carboxamide compounds and their preparation and application. Background technique [0002] The adenosine receptor is a G protein-coupled receptor consisting of seven transmembrane alpha helices, including the A 1 ,A 2A ,A 2B and A 3 There are 4 subtypes of receptors. There is a large amount of extracellular adenosine in the tumor microenvironment, and the high concentration of extracellular adenosine will interact with the G protein-coupled adenosine receptor on the surface of the immune cell membrane, and transmit the immunosuppressive signal to the immune cell, thereby inhibiting The proliferation and maturation of immune cells such as T cells, NK cells, macrophages, and dendritic DC cells inhibit the production of immune cytokines (IL-2, IFN-g), resulting in immune damage to the body and tumors. Cells exhibi...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/4985A61P35/00
CPCC07D487/04A61K31/4985A61P35/00
Inventor 胡文浩丁文刘书豪张芷菁吴琳娜黄炜枫张小雷史滔达雷金平
Owner SUN YAT SEN UNIV
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