Triazolocyclic compound, and preparation method, intermediate and application thereof

A compound and solvate technology, applied in the field of triazolo ring compounds, can solve problems such as unreported

Active Publication Date: 2020-05-29
SHANGHAI TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, although dual-target small molecule drugs based on A2A receptor antagonists and HDAC inhibitors have been reported, such as dual-target compounds of A2A receptors and dopamine D2 receptors ( et al., J Med Chem, 2015, 58, 718-738), HDAC and cyclin-dependent kinase 4 / 9 (CDK4 / 9) dual-target compound (Li et al., J Med Chem, 2018, 61, 3166-3192 ), HDAC and nicotinamide phosphoribosyltransferase (NAMPT) dual-target compounds (Dong et al., JMed Chem, 2017, 60, 7965-7983), but dual-target small molecule compounds targeting both HDAC and A2A receptors have not see the report

Method used

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  • Triazolocyclic compound, and preparation method, intermediate and application thereof
  • Triazolocyclic compound, and preparation method, intermediate and application thereof
  • Triazolocyclic compound, and preparation method, intermediate and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0275] Example 1: 4-(((7-amino-2-(furan-2-yl-[1,2,4]triazol[1,5-a][1,3,5]triazine-5- Base) amino) methyl)-N-hydroxybenzamide (compound I-1) preparation

[0276] Step 1: 4-(((7-amino-2-(furan-2-yl-[1,2,4]triazol[1,5-a][1,3,5]triazin-5-yl )amino)methyl)-Preparation of methyl N-hydroxybenzoate (intermediate Int-1)

[0277]

[0278] 2-(furan-2-yl)-5-methylsulfonyl-[1,2,4]triazol[1,5-a][1,3,5]triazin-7-amine (0.10g, 0.36mmol) (see J Med Chem, 2015, 58, 718-738 for the preparation method) and methyl 4-aminomethylbenzoate (0.248g, 1.5mmol) were dissolved in acetonitrile (10mL), and stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to obtain a white solid intermediate Int-1 (0.124 g, yield 95%). 1 H NMR (500MHz, DMSO-d 6 )δ8.25(s,2H),8.11–8.02(m,1H),7.92(d,J=8.1Hz,2H),7.86(s,1H),7.46(d,J=7.9Hz,2H), 7.10–6.99 (m, 1H), 6.67 (s, 1H), 4.64–4.52 (m, 2H), 3....

Embodiment 2

[0282] Example 2: 4-(2-((7-amino-2-(furan-2-yl-[1,2,4]triazol[1,5-a][1,3,5]triazine- Preparation of 5-yl)amino)ethyl)-N-hydroxybenzamide (compound 1-2)

[0283]

[0284] Replace the "methyl 4-aminomethylbenzoate" in Step 1 of Example 1 with "methyl 4-(2-aminoethyl)benzoate" (see WO2017133521 for the preparation method), and the rest of the required raw materials, reagents and The preparation method is the same as in Example 1, and white solid compound (I-2) can be obtained. 1 H NMR (500MHz, DMSO-d 6 )δ11.15(s,1H),8.99(s,1H),8.21(s,2H),7.87(s,1H),7.69(d,J=7.8Hz,2H),7.62–7.49(m,1H ),7.37–7.29(m,2H),7.06(d,J=3.2Hz,1H),6.68(s,1H),3.55–3.44(m,2H),2.95–2.83(m,2H); HRMS( ESI) C 17 h 17 N 8 o 3 + [M+H] + Calculated: 381.1424; Found: 381.1428.

Embodiment 3

[0285] Example 3: 4-(3-((7-amino-2-(furan-2-yl-[1,2,4]triazol[1,5-a][1,3,5]triazine- Preparation of 5-yl)amino)propyl)-N-hydroxybenzamide (compound I-3)

[0286]

[0287] Replace "4-aminomethylbenzoic acid methyl ester" in Example 1 with "4-(3-aminopropyl) benzoic acid methyl ester" (see WO2012117421 for the preparation method), and the remaining required raw materials, reagents and preparation methods Same as Example 1, white solid compound (I-3) can be obtained. 1 H NMR (800MHz, DMSO-d 6 )δ11.13(s,1H),8.96(s,1H),8.50–7.91(m,2H),7.87(s,1H),7.68(d,J=8.0Hz,2H),7.61–7.49(m ,1H),7.31(d,J=7.9Hz,2H),7.07–7.03(m,1H),6.68(s,1H),3.32–3.25(m,2H),2.68(t,J=7.7Hz, 2H),1.89–1.81(m,2H); HRMS(ESI)C 18 h 19 N 8 o 3 + [M+H] + Calculated: 395.1580, Found: 395.1561.

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Abstract

The invention discloses a triazolocyclic compound, and a preparation method, an intermediate and an application thereof. The structure of the triazolocyclic compound is represented by formula I or I',and the triazolocyclic compound can be used as an adenosine A2A receptor antagonist or a histone deacetylase HDAC inhibitor. Furthermore, the triazolocyclic compound can have adenosine A2A receptor antagonistic activity and histone deacetylase HDAC inhibitory activity at the same time, so that the triazolocyclic compound can be used for treating tumors, central nervous system diseases and other related diseases.

Description

technical field [0001] The invention relates to a triazolo ring compound, its preparation method, intermediate and application. Background technique [0002] Adenosine is an endogenous purine nucleoside substance, which exerts its physiological regulation function mainly by binding to adenosine receptors (AR) on the cell membrane. Adenosine receptors belong to G protein-coupled receptors (GPCR, or seven transmembrane receptors, 7TMR), which are divided into four subtypes: A1, A2A, A2B and A3, of which A2A receptors are located in both the central nervous system and the periphery. There is a wide distribution. A2A receptors are distributed in high density in the central nervous system and are closely related to the pathogenesis of various degenerative central nervous system diseases such as Parkinson's disease, Alzheimer's disease and Huntington's disease (Gomes et al ., Biochimica et Biophysica Acta, 2011, 1808, 1380-1399). For example, in Parkinson's disease, A2A recepto...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/53A61P35/00A61P25/28A61P25/04A61P25/00
CPCC07D487/04A61P35/00A61P25/28A61P25/04A61P25/00A61K31/53C07D487/12A61K31/5365A61P25/16
Inventor 程建军闫文仲
Owner SHANGHAI TECH UNIV
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