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Five-membered heterocycle pyrimidine compounds, preparation method and application thereof

A technology for five-membered heterocycles and compounds is applied to a class of five-membered heterocyclic pyrimidine compounds and the fields of their preparation and use, and can solve problems such as limited structure

Inactive Publication Date: 2012-05-23
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 there are many inhibitors developed for this signaling pathway, the structure is still very limited.

Method used

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  • Five-membered heterocycle pyrimidine compounds, preparation method and application thereof
  • Five-membered heterocycle pyrimidine compounds, preparation method and application thereof
  • Five-membered heterocycle pyrimidine compounds, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0077] Preparation Example 1 Preparation of Compound IA-0

[0078]

[0079] 1.1 Preparation of 3-fluoro-4-(thien[2,3-d]pyrimidine-4-oxyl)aniline

[0080] Dissolve 4-amino-2-fluorophenol (80mg, 0.63mmol) in 6ml of anhydrous DMF, add NaH (25mg, 1.1mmol) under ice-cooling conditions, stir for 10 minutes, add dropwise 4-chlorothiophene[2,3 -d] Pyrimidine (65mg, 0.38mmol) in DMF (2ml), stirring in ice bath was continued for 1 hour. After the reaction was completed, add ice water dropwise to quench the reaction, extract with ether, wash the organic phase with water, wash with saturated brine, dry over anhydrous sodium sulfate, spin off the solvent, and perform column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 3-Fluoro-4-(thiophene[2,3-d]pyrimidin-4-oxyl)aniline (95 mg), yield: 95%.

[0081] 1 HNMR (300MHz, C5D5N) δ: 3.81(s, 2H), 6.52(m, 2H), 7.05(t, J=8.4Hz, 1H), 7.53(dd, J=6.0Hz, J=16.2Hz, 2H) , 8.62(s, 1H).MS-EI m / z 261(M + ).

[0082] 1.2 Preparation...

preparation Embodiment 2

[0086] Preparation Example 2 Preparation of Compound IA-1

[0087]

[0088] 2.1 Preparation of 3-fluoro-4-(5-phenylthiophene[2,3-d]pyrimidin-4-oxyl)aniline

[0089] Dissolve 4-amino-2-fluorophenol (27mg, 0.21mmol) in 3ml of anhydrous DMF, add NaH (8.2mg, 0.34mmol) under ice-cooling conditions, stir for 10 minutes, add 4-chloro-5-benzene dropwise Thiopheno[2,3-d]pyrimidine (purchased from Alfa Aesar Chemical Co., Ltd.) (30 mg, 0.12 mmol) in DMF (1 ml) was stirred in an ice bath for 1 hour. After the reaction was complete, add ice water dropwise to quench the reaction, extract with ether, wash the organic phase with water, wash with saturated brine, dry over anhydrous sodium sulfate, spin off the solvent, and separate by column chromatography (petroleum ether: ethyl acetate = 3:1) Purified to obtain 3-fluoro-4-(5-phenylthiopheno[2,3-d]pyrimidin-4-oxyl)aniline (30 mg), yield: 73%.

[0090] 1 HNMR (300MHz, CD 3 Cl) δ: 3.75(s, 2H), 6.48(m, 2H), 6.70(t, J=8.7Hz, 1H), 7.38(m, ...

preparation Embodiment 3

[0095] Preparation Example 3 Preparation of Compound IA-2

[0096] 3.1 Preparation of intermediate 4-chloro-5-(4-fluorophenyl)thiophene[2,3-d]pyrimidine

[0097]

[0098] Preparation of 2-(1-(4-fluorophenyl)ethylene)malononitrile:

[0099] Add 4-fluoroacetophenone (2.0g), malononitrile (1.9g), ammonium acetate (0.9g), and 2ml of glacial acetic acid into the reaction flask, add 20ml of m-xylene, heat to reflux to 180°C, and use a water separator The device will remove the generated water. After the reaction was completed, the solvent was evaporated to dryness, extracted with water-ethyl acetate, the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was spun off, and column chromatography (petroleum ether: ethyl acetate=10:1) gave 2-(1-(4-Fluorophenyl)ethylene)malononitrile (2.2 g, 81%).

[0100] 1 HNMR (300MHz, CDCl 3 )δ: 2.62(s, 3H), 7.21(m, 2H), 7.60(m, 2H).

[0101] Preparation of 2-amino-4-(4-fluoroph...

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Abstract

The invention relates to five-membered heterocycle pyrimidine compounds, their pharmaceutical acceptable salt or pharmaceutical acceptable solvate and a preparation method thereof. The five-membered heterocycle pyrimidine compounds possess a c-Met inhibitory activity and have a structure as shown in the general formula 1. The invention also relates to a drug combination which contains the compounds and applications of the compounds in preparation of drugs used for prevention and treatment of in vivo Hepatocyte Growth Factor Receptor (HGFR) related abnormal cell proliferation, morphologic change and hyperkinesis associated diseases, angiogenesis or cancer metastasis associated diseases, and especially for prevention and treatment of tumor growth and metastasis.

Description

technical field [0001] The present invention relates to a class of five-membered heterocyclic (thiophene, furan, pyrrole) pyrimidine compounds with c-Met inhibitory activity and their pharmaceutically acceptable salts or pharmaceutically acceptable solvates. The preparation method includes The pharmaceutical composition of the compound, and the preparation of these compounds are used to prevent or treat diseases related to abnormal cell proliferation, morphological changes and hyperkinetic function related to the hepatocyte growth factor receptor (HGFR) in the organism, as well as diseases related to vascular Use of medicines for neonatal or cancer metastasis-related diseases, especially medicines for treating or preventing tumor growth and metastasis. Background technique [0002] Hepatocyte growth factor (hepatocyte growth factor, HGF), also known as scatter factor (Scatterfactor, SF), is the endogenous ligand of c-Met, a family of tyrosine kinase receptors. Proto-oncogen...

Claims

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Application Information

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IPC IPC(8): C07D495/04C07D491/048C07D487/04A61K31/519A61P35/00A61P35/04
Inventor 张翱耿美玉赵爱铃艾菁刘振凯
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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