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Oxygen-containing five-membered heterocyclic compound, synthesis method, pharmaceutical composition and application

A five-membered heterocycle and compound technology, applied in the field of medicine and its preparation and application, can solve problems that cannot meet the needs of clinical drug development

Active Publication Date: 2020-10-30
JIANGNAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, none of the existing SHP2 inhibitors are mutant SHP2 inhibitors, which cannot meet the needs of clinical drug development

Method used

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  • Oxygen-containing five-membered heterocyclic compound, synthesis method, pharmaceutical composition and application
  • Oxygen-containing five-membered heterocyclic compound, synthesis method, pharmaceutical composition and application
  • Oxygen-containing five-membered heterocyclic compound, synthesis method, pharmaceutical composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] Example 1 Synthesis of oxygen-containing five-membered heterocyclic compounds

[0126] Preparation of important intermediates:

[0127]

[0128] Reagents and conditions: a) acetonitrile, 120°C; b) iron powder, ammonium chloride, ethanol and water at 90°C; c) diethyl oxalate, 150°C.

[0129] Under ice bath conditions, 2-propylamine (3.54 g, 0.06 mol) was slowly added dropwise to a solution of 4-fluoro-3-nitrobenzonitrile (5 g, 0.03 mol) in acetonitrile (40 mL), stirred for 5 min, and then placed in the solution. The reaction was refluxed in an oil bath at 120 °C for 1.5 h. After monitoring the completion of the reaction, dichloromethane (200 mL) and hydrochloric acid (200 mL, 1 mol / L) were added for extraction. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to obtain compound I-1. (6.17 g, 100% yield). 1H NMR (400MHz, CDCl 3 )δ8.52(d,J=2.0Hz,1H),8.35(s,1H),7.59(dd,J=9.1,1.8Hz,1H),6.92(d,J=9.1Hz,1H),3.88( m,1H),1.37(d,J=6.4 H...

Embodiment 2

[0175] Example 2 Synthesis of oxygen-containing five-membered heterocyclic compounds

[0176]

[0177] Reagents and conditions: a) N,N'-carbonyldiimidazole, dichloromethane; b) hydrazine hydrate, methanol;

[0178] A solution of 2-furancarboxylic acid (2 g, 0.018 mol) in dichloromethane (20 mL) was activated with N,N'-carbonyldiimidazole (3.2 g, 0.02 mol), and after monitoring complete activation, methyl 3-aminobenzoate was added The ester (2.72g, 0.018mol) was placed at room temperature and reacted overnight. After monitoring the completion of the reaction, a large amount of dichloromethane was added, washed 3 times with saturated aqueous sodium bicarbonate solution, and then washed 3 times with hydrochloric acid (1mol / L), and vacuumed After drying, the product was recrystallized from ethyl acetate to obtain a white solid product II-1 (3.8 g, yield 81.5%). 1 H NMR (400MHz, DMSO-d 6 )δ10.41(s, 1H), 8.43(t, J=1.9Hz, 1H), 8.04(m, 1H), 7.96(m, 1H), 7.69(dt, J=7.9, 1.3Hz, 1H)...

Embodiment 3

[0210] Example 3 Synthesis of oxygen-containing five-membered heterocyclic compounds

[0211] Preparation of important intermediates:

[0212]

[0213] Under ice bath conditions, isopropylamine (2.69 g, 45.56 mol) was slowly added dropwise to a solution of 2-fluoro-5-bromonitrobenzene (5 g, 22.73 mol) in acetonitrile (40 mL), stirred for 5 min and then placed at 120 °C The reaction was refluxed in an oil bath for 1.5 h, and after monitoring the completion of the reaction, dichloromethane (200 mL) and hydrochloric acid (200 mL, 1 mol / L) were added for extraction, the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to obtain compound III-1 (5.26 g, 90% yield). 1 H NMR (400MHz, DMSO-d 6 )δ8.16(d,J=2.5Hz,1H),7.89(d,J=7.7Hz,1H),7.65(dd,J=9.3,2.5Hz,1H),7.09(d,J=9.3Hz, 1H),3.93(dq,J=13.1,6.5Hz,1H),1.26(d,J=6.3Hz,6H).MS(ESI):m / z calcd.For C 9 H 12 BrN 2 O 2 [M+H] +259.0, found 259.0

[0214] will contain compound III-1 (5 g, 0.02 mol) and...

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Abstract

The invention discloses an oxygen-containing five-membered heterocyclic compound, a synthesis method, a pharmaceutical composition and application thereof, and belongs to the technical field of medicines and preparation and application thereof. The oxygen-containing five-membered heterocycle has the biological activity of inhibiting the protein tyrosine phosphatase SHP2, can be used as a tool compound for researching the biological function relevance of the protein tyrosine phosphatase SHP2 in the cell signal transduction process, and provides a new means for preventing and treating cancers and metabolic and immune diseases.

Description

technical field [0001] The invention belongs to the technical field of medicine and its preparation and application, and specifically relates to a class of oxygen-containing five-membered heterocyclic compounds, a synthesis method, a pharmaceutical composition and uses. Background technique [0002] SHP2 is a non-receptor protein tyrosine phosphatase that exists widely in the body. It consists of two SH2 domains (N-SH2 and C-SH2), a catalytically active PTP domain and proline-rich acid groups and tyrosine phosphorylation tails. SHP2 acts as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), fibroblast factor (FGF), interleukin-3 (IL-3), leukemia inhibitory factor (LIF) and α-interferon (INF) -α) and other downstream signaling molecules of growth factors, involved in multiple signaling pathways (such as RAS / MARK pathway, PI3K / AKT pathway, JAK / STAT pathway, JNK pathway, NF-B pathway, RHO pathway, NFAT pathway, etc.), in Plays a key role in cellular informa...

Claims

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Application Information

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IPC IPC(8): C07D413/04C07D413/14C07D417/04A61K31/498A61P35/00
CPCC07D413/14A61P35/00C07D413/04C07D417/14C07D409/12C07D271/08A61P3/00A61P37/00A61P9/00A61P25/00
Inventor 王文龙李佳周宇波于丽杰孟祥东冯勃王智佳吴婧
Owner JIANGNAN UNIV
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