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3-amino-benzo five-membered heterocyclic compounds and preparation method and applications thereof

A five-membered heterocycle and compound technology, applied in the field of 3-amino-benzo five-membered heterocycle compounds, can solve the problems of weakening the direct relationship and the like

Inactive Publication Date: 2015-12-23
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although, many of the reported small molecule inhibitors exhibit high c-Met activity, and have shown good anti-tumor activity in vivo and in vitro; however, most of the small molecule inhibitors of c-Met in clinical research Also has significant inhibitory activity against other tyrosine kinases, this multiple pharmacological profile weakens the direct relationship between the evaluation of the antitumor effect of these inhibitors and c-Met activity

Method used

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  • 3-amino-benzo five-membered heterocyclic compounds and preparation method and applications thereof
  • 3-amino-benzo five-membered heterocyclic compounds and preparation method and applications thereof
  • 3-amino-benzo five-membered heterocyclic compounds and preparation method and applications thereof

Examples

Experimental program
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preparation example Construction

[0055] General formula for the preparation of compounds IA-1 to IA-19

[0056]

[0057] Compound 1 (its synthetic reference JiZQetal, JMedChem2008, 51:1231-1241) (1equiv) was mixed with various acids 2 (its synthetic reference WO:2005 / 030140A2) (1equiv), and an appropriate amount of dichloromethane (DCM ) or dimethyl sulfoxide (DMF), stirred at 0°C, added HATU (1.8 equiv), stirred for 5 min, then added triethylamine (TEA) (1 equiv), stirred for 5 min, raised to room temperature and stirred overnight. After the reaction was monitored by TLC, dichloromethane or ethyl acetate was added to dilute the reaction solution, the organic layer was washed 3 times with water, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (0-10% Methanol: dichloromethane) to give the target product IA. Table 1. Corresponding structural formulas of starting materials 2a–2s for the synthesis of compound IA

[0058...

preparation Embodiment 1

[0059] Preparation Example 1: Preparation of Compound IA-1

[0060]

[0061] Compound 1 (40 mg, 0.178 mmol) was mixed with acid 2a (40 mg, 0.178 mmol), dissolved in 3 mL of dichloromethane, stirred at 0 ° C, added HATU (122 mg, 0.32 mmol), stirred for 5 min, and then added triethylamine ( 25μL, 0.178mmol), after stirring for 5min, rise to room temperature and stir overnight. After the reaction was monitored by TLC, 40 mL of dichloromethane was added to dilute the reaction solution, the organic layer was washed with water (3 × 20 mL), the organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography ( 0-30% methanol:dichloromethane) afforded the target product IA-1 as a white solid (55 mg, 72%).

[0062] 1 HNMR (300MHz, CDC1 3 )δ9.63(s,1H),8.77(s,1H),7.69(d,J=8.5Hz,2H),7.58–7.44(m,5H),7.40(d,J=8.4Hz,1H), 7.16–6.98(m,3H),4.18(s,2H),1.77–1.62(m,4H).

preparation Embodiment 2

[0063] Preparation Example 2: Preparation of Compound IA-2

[0064] IA-2 was synthesized as a white solid (74%) in the same manner as IA-1 except that the corresponding acid 2b was used.

[0065] 1 H-NMR (300MHz, CDC1 3 )δ10.11(s,1H),8.08(s,1H),7.71(d,J=8.7Hz,2H),7.55–7.34(m,6H),7.11(d,J=7.2Hz,1H), 6.89(d,J=8.9Hz,2H),4.15(s,2H),3.80(s,3H),1.79(dd,J=7.6,4.8Hz,2H),1.62–1.58(dd,J=7.6, 4.8Hz, 2H).

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Abstract

The invention provides 3-amino-benzo five-membered heterocyclic compounds having the structure represented by the general formula (I) and pharmaceutical acceptable salts or pharmaceutical acceptable solvates thereof, and a preparation method and an application thereof in preparation of drugs for inhibiting the activity of tyrosine kinase c-Met, an application thereof in preparation of drugs for prevention or treatment of diseases related to cell abnormal proliferation, morphologic changes and hyperkinesia which are related to hepatocyte growth factor receptor (c-Met) in biological bodies and diseases related to angiogenesis or cancerometastasis, and particularly an application thereof in preparation of drugs for treatment or prevention of tumor growth and metastasis. Active separation of c-Met and VEGFR2 by the target compounds is achieved, and moreover, the better c-Met inhibitory activity is retained.

Description

technical field [0001] The invention relates to a class of 3-amino-benzo five-membered heterocyclic compounds, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, pharmaceutical compositions containing the compounds, and preparation methods thereof. The present invention also relates to the preparation of such compounds for inhibiting the activity of tyrosine kinase c-Met, preventing or treating abnormal cell proliferation, morphological changes and motor functions related to the hepatocyte growth factor receptor (c-Met) in organisms Hypertension-related diseases, and the use of drugs for diseases related to angiogenesis or cancer metastasis, especially the use in the preparation of drugs for treating or preventing tumor growth and metastasis. Background technique [0002] Receptor tyrosine kinase c-Met belongs to a unique subfamily of receptor tyrosine kinase family, which is the exclusive receptor of hepatocyte growth factor (hepatocyte growt...

Claims

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Application Information

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IPC IPC(8): C07D261/20C07D413/12C07D413/14C07D231/56C07D401/12A61K31/423A61K31/454A61K31/496A61K31/416A61K31/4439A61P35/00A61P35/04
Inventor 张翱耿美玉蒋晓龙艾菁彭霞
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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